WO2010082601A1 - Novel 2,5-disubstituted pyrrole derivative - Google Patents
Novel 2,5-disubstituted pyrrole derivative Download PDFInfo
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- WO2010082601A1 WO2010082601A1 PCT/JP2010/050339 JP2010050339W WO2010082601A1 WO 2010082601 A1 WO2010082601 A1 WO 2010082601A1 JP 2010050339 W JP2010050339 W JP 2010050339W WO 2010082601 A1 WO2010082601 A1 WO 2010082601A1
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- 0 *Oc1cc(C(*=C)=O)cc(OS(C(F)(F)F)(=O)=O)c1 Chemical compound *Oc1cc(C(*=C)=O)cc(OS(C(F)(F)F)(=O)=O)c1 0.000 description 5
- WLRYDASUBQGZTK-UHFFFAOYSA-N CC(C)Oc1cc(-c2ccc(C3=NCCO3)[nH]2)cc(Oc(cc2)ccc2/S(/C)=[O]/C)c1 Chemical compound CC(C)Oc1cc(-c2ccc(C3=NCCO3)[nH]2)cc(Oc(cc2)ccc2/S(/C)=[O]/C)c1 WLRYDASUBQGZTK-UHFFFAOYSA-N 0.000 description 1
- FRSWTKGVRPGQPF-UHFFFAOYSA-N CC1(C)OB(c2ccc(C(OC)=O)[nH]2)OC1(C)C Chemical compound CC1(C)OB(c2ccc(C(OC)=O)[nH]2)OC1(C)C FRSWTKGVRPGQPF-UHFFFAOYSA-N 0.000 description 1
- PQIHDMFKVXYHTB-UHFFFAOYSA-N CCN(CCC1Oc2cc(-c3ccc(C4=NCC5(CC5)O4)[nH]3)cc(Oc(cn3)ccc3SC)c2)C1=O Chemical compound CCN(CCC1Oc2cc(-c3ccc(C4=NCC5(CC5)O4)[nH]3)cc(Oc(cn3)ccc3SC)c2)C1=O PQIHDMFKVXYHTB-UHFFFAOYSA-N 0.000 description 1
- PFAOFSRMVVJNDS-UHFFFAOYSA-N CSc(nc1)ccc1Oc1cc(OC2CCOCC2)cc(-c2ccc(C3=NC(CO)CO3)[nH]2)c1 Chemical compound CSc(nc1)ccc1Oc1cc(OC2CCOCC2)cc(-c2ccc(C3=NC(CO)CO3)[nH]2)c1 PFAOFSRMVVJNDS-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to a 2,5-disubstituted pyrrole derivative or a pharmacologically acceptable salt thereof that has an excellent glucokinase activating action and is useful as a therapeutic agent for diabetes and the like.
- Gluconase (glucokinase, which may be abbreviated as GK in the present specification; EC2.7.1.1) is one of four types of hexokinase (hexokinase IV) found in mammals.
- Hexokinase is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate at the initial stage of glycolysis in the cell.
- GK is expressed mainly in the liver and pancreatic beta cells. ing. In pancreatic beta cells, it functions as a sensing mechanism of extracellular glucose concentration that regulates glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes the rate-limiting step, and the following reactions such as glycolysis and glycogen synthesis are regulated.
- GK of liver and pancreatic beta cells differ in the sequence of 15 amino acids on the N-terminal side due to differences in splicing, but have the same enzymatic properties.
- Three hexokinases (I, II, III) other than GK saturate the enzyme activity at a glucose concentration of 1 mM or less, whereas GK has a low affinity for glucose, and its Km value is 8-15 mM, which is a physiological blood glucose level. Close to value. Therefore, the increase in intracellular glucose metabolism via GK occurs in response to changes in blood glucose from normal blood glucose level (around 5 mM) to postprandial hyperglycemia (10-15 mM).
- Non-Patent Documents 1 to 3 Since ancient times, the hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has been proposed (Non-Patent Documents 1 to 3). Recent research results have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, demonstrating the hypothesis. For example, a mouse with a disrupted glucokinase gene died of severe hyperglycemia soon after birth, and a GK hetero-deficient mouse had poor glucose tolerance and impaired insulin secretion due to sugar stimulation (Non-Patent Document) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose level and an increase in glycogen content in the liver were observed, and the same phenomenon was observed in mice that artificially developed diabetes (Non-patent Document 5). ).
- GK functions as a glucose sensor and plays an important role in maintaining glucose homeostasis.
- a GK gene abnormality was found in a family with early-onset adult type diabetes called MODY2 (Maturity Onset Diabetes of the Young), and the relationship between this case and GK activity was clarified (Non-patent Document 6).
- families with mutations that increase GK activity have also been found, and in these families, fasting hypoglycemia symptoms accompanied by an increase in plasma insulin concentration are observed (Non-patent Document 7). From the above reports, GK functions as a glucose sensor in mammals including humans and plays an important role in blood glucose regulation.
- GK activator can be expected to have the effect of promoting glucose uptake and release of glucose to the liver and insulin secretion of pancreatic beta cells at the same time. is expected.
- pancreatic beta cell type GK is expressed exclusively in the feeding center (Ventromedial hypothalamus, VMH) of rat brain. It has been known that VMH has neurons that respond to glucose concentration. When glucose is administered into the rat ventricle, the amount of food intake decreases, whereas when glucose analog glucosamine is administered to inhibit glucose metabolism, food intake increases (Non-patent Document 8). From electrophysiological experiments, it is known that glucose-responsive neurons are activated in response to physiological glucose concentration changes (5-20 mM). At this time, glucokinase acts as a glucose sensor as in peripheral tissues. It was clarified that it was functioning (Non-Patent Document 9). Therefore, not only the liver and pancreatic beta cells but also substances that bring about activation of VMH glucokinase can be expected not only to lower blood glucose but also to correct obesity, which is a problem associated with many patients with type II diabetes.
- a substance having a GK activation action is used as a therapeutic and prophylactic agent for diabetes or for the treatment of chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like. It is useful as a preventive drug.
- Patent Document 1 describes a compound that requires an amide structure, but the compound of the present invention requires pyrrole instead of amide.
- Patent Document 2 describes a compound having a condensed pyrrole, but the compound of the present invention requires a pyrrole that is not condensed.
- Patent Document 3 describes a compound having 3,5-disubstituted pyrazole or 1,2,4-triazole, which is different from the 2,5-disubstituted pyrrole structure of the present invention.
- Patent Documents 4 to 15, Non-Patent Documents 10 and 11 are examples of structures different from the compounds of the present invention.
- An object of the present invention is to provide a 2,5-disubstituted pyrrole derivative and a GK activator using the derivative, and particularly to provide a therapeutic and prophylactic agent for diabetes and impaired glucose tolerance.
- a 2,5-disubstituted pyrrole compound having a specific chemical structure has an excellent GK activation action.
- the compound of the present invention has excellent GK selectivity, low toxicity, and few side effects.
- this 2,5-disubstituted pyrrole compound is diabetic, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic major It was found to be useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of (including angiopathy) and metabolic syndrome.
- the present invention has been completed based on the above findings.
- the present invention comprises (1) general formula (I)
- R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group
- R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A
- R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with
- R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group.
- the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
- U represents an oxygen atom or a carbonyl group; (However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
- n represents an integer of 0 to 3
- Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1
- R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, or a pharmacological thereof Top acceptable salt.
- R 2 is a phenyl group substituted at the 4- or 3-position with a group selected from Substituent Group C, and 1 at the 2-position with a group selected from Substituent Group C 5-
- Substituent group C includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, R 6 , R 7 is the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl group.
- R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A compound which is a methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group or a pharmacologically acceptable salt thereof.
- R 3 is independently one or two in the group consisting of a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted with 1 to 5 halogen atoms.
- a compound or a pharmacologically acceptable salt thereof which is a 3- to 6-membered saturated ring which may be substituted and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom.
- R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group).
- a compound in which U is a carbonyl group or a pharmacologically acceptable salt thereof.
- the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, or a 1,3-difluoro-2-propoxy group.
- R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, (C 1- C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group , R 2 is independently substituted with 1 to 5 groups independently selected from the substituent group A and independently substituted with 1 to 3 phenyl groups or groups selected from the substituent group A; A C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group, wherein R 3 may be independently substituted with 1 to 5 groups independently selected from Substituent Group B group, C 1 -C 6 A group consisting of an alkyl group and an hydroxy groups, (C
- the 3- to 6-membered saturated ring may be bonded to U (carbon atom). Or a group represented by the formula —NR 4 R 5 , wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, Together with the nitrogen atom to which 4 and R 5 are attached, forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group To do.
- the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
- U represents an oxygen atom or a carbonyl group (provided that a 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula —UR 3 ), n represents an integer of 0 to 3,
- Group A is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 halogenated alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group, (C 1- C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulf
- the substituent group B is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a carbamoyl group, a mono- C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 alkyl) aminocarbonyl group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, hydroxy group and 3-6 membered ring ether Kara Indicating the group. Or a pharmacologically acceptable salt thereof.
- R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group
- R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a
- R 3 is a halogen atom and is independently 1 to 5
- R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group
- R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a
- R 3 is a C 1 -C 6 alkyl group or a formula A group represented by —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group), U is a carbonyl group, and n is 0 A compound which is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.
- the general formula (I) is the general formula (Ia), R 1 is a carbamoyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl.
- the group represented by R 3 is a methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone -2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, Propyl carbonyl group or compound or pharmacologically acceptable salt thereof is a dimethylamino group.
- the general formula (I) is the general formula (Ib), R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl- 5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2
- a pyrazinyl group, the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3- Difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran
- the general formula (I) is the general formula (Ic), R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group; R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group, and the group represented by the formula —UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, (1S) -2- Fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-
- a glucokinase activator comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
- a pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
- the pharmaceutical composition activates glucokinase to achieve maintenance of glucose homeostasis or regulation of blood glucose, thereby treating and / or treating diseases that are treated, ameliorated, reduced and / or prevented. Or the pharmaceutical composition as described in (22) for prevention.
- the pharmaceutical composition is diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome
- diabetes impaired glucose tolerance
- gestational diabetes chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome
- the pharmaceutical composition according to (22) for treatment and / or prevention is provided.
- a method for activating glucokinase comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
- the disease is diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (33 ) Method.
- the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
- the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
- the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”.
- the same or different 1 to 5 “halogen atoms” are groups (C 1 -C 2 halogenated alkyl groups) bonded to the “C 1 -C 2 alkyl group”, Is more preferably a trifluoromethyl group or a fluoromethyl group, and particularly preferably a fluoromethyl group.
- the “C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups” is a group in which 1 or 2 hydroxy groups are bonded to the “C 1 -C 6 alkyl group”. is there.
- the “C 1 -C 6 alkylthio group” is a group in which one “C 1 -C 6 alkyl group” is bonded to a sulfur atom, and is a straight chain or branched chain having 1 to 6 carbon atoms. It is a chain alkylthio group.
- methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, 1-ethylpropylthio or hexylthio group preferably a linear or branched alkylthio group having 1 to 4 carbon atoms (C 1 -C 4 alkylthio group), more preferably methylthio or ethylthio group (C 1 -C 2 alkylthio group), and still more preferably methylthio group.
- (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group means that one “C 1 -C 6 alkylthio group” is the above “C 1 -C 6 alkyl group”.
- C 1 -C 4 alkylthio groups is the “C 1 1- C 4 alkyl group ”((C 1 -C 4 alkylthio)-(C 1 -C 4 alkyl) group), more preferably one of the above-mentioned“ C 1 -C 2 alkylthio groups ”.
- Group is a group ((C 1 -C 2 alkylthio)-(C 1 -C 2 alkyl) group) bonded to the“ C 1 -C 2 alkyl group ”, and more preferably 2-methylthioethyl It is a group.
- "mono--C 1 -C 6 alkylaminocarbonyl group” is an amino group in which one of the “C 1 -C 6 alkyl group” is bonded is a group attached to a carbonyl group.
- a methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl or butylaminocarbonyl group preferably an amino group to which one of the above “C 1 -C 4 alkyl groups” is bonded is a carbonyl group A group bonded to (mono-C 1 -C 4 alkylaminocarbonyl group), more preferably a methylaminocarbonyl group or an ethylaminocarbonyl group (mono-C 1 -C 2 alkylaminocarbonyl group), Even more preferred is a methylaminocarbonyl group.
- the “di- (C 1 -C 6 alkyl) aminocarbonyl group” is a group in which two identical or different “C 1 -C 6 alkyl groups” are bonded to a carbonyl group. is there.
- dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylaminocarbonyl group preferably
- An amino group to which two identical or different “C 1 -C 4 alkyl groups” are bonded is a group bonded to a carbonyl group (di- (C 1 -C 4 alkyl) aminocarbonyl group), more preferably Is a dimethylaminocarbonyl group, a diethylaminocarbonyl group or an N-ethyl-N-methylaminocarbonyl group (di
- the “C 2 -C 6 alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C 1 -C 6 alkyl group”.
- the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is.
- a methoxy group preferably a methoxy group.
- a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group.
- acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group and preferably a group (C 2 -C 5 alkyl) in which one said “C 1 -C 4 alkyl group” is bonded to a carbonyl group A carbonyl group), more preferably an acetyl group or a propionyl group (C 2 -C 3 alkylcarbonyl group), and even more preferably an acetyl group.
- the “C 2 -C 7 halogenated alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a carbonyl group.
- the aforementioned “C 1 -C 2 halogenated alkyl group” is a group (C 2 -C 3 halogenated alkylcarbony
- a “C 2 -C 7 alkoxycarbonyl group” is a group in which one of the above “C 1 -C 6 alkoxy groups” is bonded to a carbonyl group.
- methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group, preferably one of the above-mentioned “C 1 -C 4 alkoxy” Group ” is a group bonded to a carbonyl group (C 2 -C 5 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C 2 -C 3 alkoxycarbonyl group), and even more preferably Is a methoxycarbonyl group.
- the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”.
- trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or A pentafluoroethoxy group preferably a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group) More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 2 alkoxy group” (C 1 -C 2 halogenated alkoxy group)
- a “C 1 -C 6 alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a sulfonyl group, and is a straight chain or branched group having 1 to 6 carbon atoms. It is a branched alkylsulfonyl group.
- a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl or pentylsulfonyl group preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms A group (C 1 -C 4 alkylsulfonyl group), more preferably a methylsulfonyl group or an ethylsulfonyl group (C 1 -C 2 alkylsulfonyl group), and even more preferably a methylsulfonyl group.
- the “C 1 -C 6 halogenated alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a sulfonyl group, and has 1 to 6 carbon atoms.
- a straight-chain or branched alkylsulfonyl halide group For example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl or 2-fluoroethylsulfonyl group, preferably having 1 carbon atom Or a straight chain or branched chain alkylsulfonyl group having 4 to 4 straight chain or branched chain (C 1 -C 4 halogenated alkylsulfonyl group), more preferably a straight chain or branched chain halogenated group having 1 or 2 carbon atoms.
- An alkylsulfonyl group (C 1 -C 2 halogenated alkylsulfonyl group), and even more preferably a trifluoromethylsulfon
- the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.
- the “C 3 -C 6 cycloalkylsulfonyl group” is a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group or a cyclohexylsulfonyl group.
- Preferred is a cyclopropylsulfonyl group.
- (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkylsulfonyl”. A group bonded to “group”.
- the “1- C 2 alkoxy group” is a group ((C 1 -C 2 alkoxy)-(C 1 -C 2 alkylsulfonyl) group) bonded to the “C 1 -C 2 alkylsulfonyl group”, and more preferably Is a methoxymethyls
- (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group means that one “C 1 -C 6 halogenated alkoxy group” is the above “C 1- A group bonded to a “C 6 alkylsulfonyl group”.
- it is a trifluoromethoxymethylsulfonyl, trichloromethoxymethylsulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethylsulfonyl or fluoromethoxymethylsulfonyl group, preferably one of the aforementioned “C 1 -C 4 halogenated alkoxy groups” Is a group ((C 1 -C 4 halogenated alkoxy)-(C 1 -C 4 alkylsulfonyl) group) bonded to the “C 1 -C 4 alkylsulfonyl group”, more preferably one A group ((C 1 -C 2 halogenated alkoxy)-(C 1 -C 2 alkylsulfonyl) group in which the “C 1 -C 2 halogenated alkoxy group” is bonded to the “C 1 -C 2 alkylsulfonyl group”; And more preferably a trifluo
- the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted.
- a phenyl group substituted by one at 4-position or 3-position with a group selected from substituent group C is preferable.
- a pyridyl group or a pyrazinyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A is independently a group selected from the pyridyl group and the substituent group A. 1 to 3 substituted pyridyl groups, pyrazinyl groups, or a pyrazinyl group independently substituted with 1 to 3 groups selected from substituent group A.
- a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group B refers to a C 1 -C 6 alkyl group or the substituent group B C 1 -C 6 alkyl group independently substituted with 1 to 5 selected groups.
- it is a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 halogen atoms, more preferably a methyl group, an ethyl group, an isopropyl group, (1S) -2-fluoro.
- the “3- to 6-membered cyclic ether” is oxirane, oxetane, tetrahydrofuran or tetrahydropyran. Tetrahydrofuran is preferred.
- the “3- to 6-membered saturated ring optionally containing one oxygen atom or nitrogen atom” is a C 3 -C 6 cycloalkyl group, a 3- to 6-membered ring ether, or a 3- to 6-membered ring amine, Cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine or piperidine. Preference is given to cyclopentane, tetrahydrofuran or pyrrolidine.
- one to three independently substituted oxygen groups or one nitrogen atom may be substituted with a group consisting of “(C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group and oxo group)”.
- the “3- to 6-membered saturated ring which may be contained” means a 3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom, or a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group and an oxo group.
- “1 to 3 which may be independently substituted with a group consisting of a C 1 -C 6 alkyl group and an oxo group together with the nitrogen atom to which R 4 and R 5 are bonded may be used.
- a 4 to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom ”is independently selected from the group consisting of a C 1 -C 6 alkyl group and an oxo group.
- 4 to 6-membered hetero-saturated ring which may be substituted by 3 to 4 (a 4- to 6-membered fully-reduced saturated heterocyclic ring which contains one nitrogen atom and further contains one oxygen atom or nitrogen atom) Group), for example, azetidine, pyrrolidine, piperidine, morpholine, piperazine, 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, dimethylmorpholine, methylpiperazine or dimethylpiperazine, and preferably Zechijin, pyrrolidine or morpholine.
- the “group represented by the formula —V—NR 6 R 7 ” is the “group represented by the formula —C ( ⁇ O) —NR 6 R 7 ” or “the formula —SO 2 —NR 6 R 7” .
- a 6 to 6-membered heterosaturated ring which may be independently substituted with one or two C 1 -C 6 alkyl groups together with the nitrogen atom to which R 6 and R 7 are bonded.
- the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.) ” May be independently substituted with one or two C 1 -C 6 alkyl groups.
- To 6-membered heterosaturated ring (a 4- to 6-membered fully reduced saturated heterocyclic group containing one nitrogen atom and further containing one oxygen atom or nitrogen atom), such as azetidine, pyrrolidine , Piperidine, morpholine, piperazine, dimethylmorpholine, methylpiperazine or dimethylpiperazine, preferably azetidine or 4-methylpiperazine.
- R 1 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group.
- R 1 is more preferably a carbamoyl group.
- R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.
- R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, or a (1S) -1,2-dihydroxyethyl group. is there.
- R 2 is preferably a phenyl group substituted by one of the 4-position or 3-position with a group selected from Substituent Group C, and one 2-position of a group selected from Substituent Group C.
- a substituted 5-pyridyl group or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C (Substituent Group C is a C 1 -C 6 alkoxy group, C 1- A C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and each represents a hydrogen atom or C 1 -C 6; More preferably R 2 represents a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, a 2-methyl
- preferred R 3 is a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group) which may be independently substituted with 1 to 5 halogen atoms.
- a 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom.
- preferred R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 may be the same or different and each represents a hydrogen atom or C 1 — A C 6 alkyl group).
- the preferred group represented by the formula —NR 4 R 5 is a dimethylamino group.
- preferable groups represented by the formula -UR 3 are methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3- A difluoro-2-propoxy group, a cyclopentanone-2-yloxy group, a tetrahydrofuran-3-yloxy group, a 1-cyclopropylpyrrolidin-2-one-3-yloxy group, an isopropylcarbonyl group or a dimethylaminocarbonyl group.
- the preferred group represented by the formula —NR 6 R 7 is a methylamino group.
- n is preferably 1.
- the preferred substituent group A includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group, and a group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) R 6 and R 7 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group.), And more preferred substituent group A includes a methoxy group, a methylaminocarbonyl group, a methyl group A sulfonyl group or a methylaminosulfonyl group.
- a preferred substituent group B is a halogen atom, and a more preferred substituent group B is a fluorine atom.
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present in the molecule.
- these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
- an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
- the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
- the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
- the pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
- the compound having the general formula (I) of the present invention has a basic group, it is reacted with an acid, and when it has an acidic group, it is reacted with a base to form a salt. Can do.
- Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
- Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
- examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt.
- Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salt
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also included in the salts of the present invention.
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also the present invention. Included in the salt.
- the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably a compound having the general formula (I) of the present invention.
- metabolic syndrome is based on insulin resistance, and a state in which the risk of coronary artery disease is significantly increased by accumulation of a plurality of coronary risk factors (lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc. (Diabetes, Obesity and Metabolism, 9, 2007, 246-258, Journal of the American Medical Association, oci285: 2486-2497 (2001), Diabet. Med., 15: 539-553 ( 1998)).
- lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc.
- the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammal, including humans).
- the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammalian animal).
- Preferred diseases are diabetes or impaired glucose tolerance.
- it can be used as a medicament for the treatment of the above-mentioned diseases.
- the compound having the general formula (I) of the present invention can be produced according to Method A to Method U described below.
- solvent used in the reaction in each step of the following methods A to U is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example.
- Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol,
- the base used in the reaction of each step of the following methods A to U is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxy Sodium-t-butoxide, potassium methoxide, Alkali metal alkoxides such as lithium ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal trialkylsiloxides such as sodium trimethylsil
- the condensing agent used in the reaction in each step of the following methods A to U is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI ⁇ HCl), 1-ethyl -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC), 4- (4,6-dimethoxy-1,3,5- Triazin-2-yl) -4-methylmorpholinium chloride n-hydrate (DMT-MM), isobutyl chloroformat
- Examples of the demethylating agent used in the reaction of each step of the following methods A to U include sodium thiomethoxide, sodium thioethoxide, sodium thiophenoxide, iodotrimethylsilane, aluminum chloride, aluminum bromide, and three odors. Boron iodide, boron triiodide, methylmagnesium iodide, and hydrogen bromide.
- the palladium catalyst used in the reaction in each step of the following methods A to U is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II) , Palladium black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (Acetonitrile) palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium (II) sulfide, [1,1 ' -
- the oxidizing agent used in the reaction of each step of the following methods A to U is an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide solution, oxone or manganese dioxide.
- reaction temperature varies depending on the solvent, starting material, reagent, etc.
- reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
- each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent.
- an immiscible organic solvent such as ethyl acetate
- the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.
- a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
- the target compound in each step can be directly used in the next reaction without purification.
- Me represents a methyl group
- iPr represents an isopropyl group
- Ac represents an acetyl group
- Bn represents a benzyl group
- Boc represents a t-butoxycarbonyl group.
- Method A is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
- R 2 and R 3 are as defined above, R 8 represents a C 1 -C 6 alkyl group (preferably a methyl group or an ethyl group), R 9 , R 10 , R 11 and R 12 represent a hydrogen atom or one group of R 1 , and X is a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom Y represents a halogen atom, a C 1 -C 6 alkylsulfonyloxy group, a C 1 -C 6 alkoxysulfonyloxy group or a C 6 -C 10 arylsulfonyloxy group (preferably a halogen atom)
- R 2a , R 3a , R 9a , R 10a , R 11a, and R 12a are R, and more preferably a fluorine atom or a chlorine atom, and even more preferably a fluor
- the group similar to the group in the definition of group of R ⁇ 2 >, R ⁇ 3 >, R ⁇ 9 >, R ⁇ 10 >, R ⁇ 11 > and R ⁇ 12 > is shown.
- Step A1 This step is a step of producing a compound having the general formula (III).
- This step is performed by reacting a compound having the general formula (II) with a demethylating agent in a solvent.
- the compound having the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an amide, more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidinone.
- the demethylating agent used in this step is preferably sodium thiomethoxide.
- the reaction temperature in this step is usually 50 ° C. to 140 ° C., preferably 80 ° C. to 120 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
- Step A2 This step is a step of producing a compound having the general formula (V).
- This step is performed by reacting a compound having the general formula (III) with a compound having the general formula (IV) in a solvent in the presence of a base.
- the compound having the general formula (IV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an amide or a nitrile, and more preferably N, N-dimethylformamide or acetonitrile.
- the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate or cesium carbonate.
- the reaction temperature in this step is usually ⁇ 10 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.
- the reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 48 hours.
- Step A3 This step is a step of producing a compound having the general formula (VI).
- This step is performed by reacting a compound having the general formula (V) with a demethylating agent in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the demethylating agent used in this step is preferably boron tribromide.
- the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
- the reaction time in this step is usually 1 hour to 72 hours, preferably 12 hours to 36 hours.
- Step A4 This step is a step of producing a compound having the general formula (VII).
- This step is performed by reacting a compound having the general formula (VI) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
- the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
- the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
- the inorganic base used in this step is preferably an alkali metal acetate, and more preferably potassium acetate.
- the reaction temperature in this step is usually 50 ° C to 130 ° C, preferably 70 ° C to 110 ° C.
- the reaction time in this step is usually 1 to 24 hours, preferably 2 to 10 hours.
- Step A5 This step is a step of producing a compound having the general formula (IX).
- This step is performed by reacting a compound having the general formula (VII) with a compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent.
- the compound having the general formula (VIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an ether, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably tetrahydrofuran, toluene, or a mixed solvent of tetrahydrofuran and toluene.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 36 hours.
- Step A6 This step is a step of producing a compound having the general formula (XI).
- This step is performed by reacting a compound having the general formula (IX) with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base.
- the solvent used in this step is preferably an ether, alcohol, aromatic hydrocarbon or a mixed solvent thereof, more preferably dioxane, ethanol, toluene or a mixed solvent thereof. Even more preferred is dioxane or a mixed solvent of ethanol and toluene.
- the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
- the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
- the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
- Step A7 This step is a step of producing a compound having the general formula (XII).
- This step is performed by reacting a compound having the general formula (XI) with an acid in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; methanesulfonic acid and p-toluenesulfonic acid , Organic sulfonic acids such as pyridinium p-toluenesulfonate (PPTS), camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid and trifluoroacetic acid; aluminum chloride, zinc chloride, zinc iodide, tetra Lewis acids such as tin chloride, titanium trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins, preferably carboxylic acids, and more preferably trifluoroacetic acid.
- hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas
- mineral acids such as sulfuric acid, hydrobro
- the reaction temperature in this step is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.
- the reaction time in this step is usually 0.1 to 5 hours, preferably 0.5 to 3 hours.
- Step A8 This step is a step of producing a compound having the general formula (XIII).
- This step is performed by reacting a compound having the general formula (XII) with a base in a solvent.
- the solvent used in this step is preferably an alcohol, and more preferably ethanol.
- the base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide, and even more preferably an aqueous sodium hydroxide solution.
- the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 50 ° C to 80 ° C.
- the reaction time in this step is usually 0.1 to 24 hours, preferably 0.5 to 6 hours.
- Step A9 This step is a step of producing a compound having the general formula (XV).
- This step is performed by reacting a compound having the general formula (XIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base.
- the compound having the general formula (XIV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an alcohol, a halogenated hydrocarbon, an amide or a mixed solvent thereof, more preferably methanol, dichloromethane, N, N-dimethylformamide or dichloromethane. It is a mixed solvent of N, N-dimethylformamide.
- the condensing agent used in this step is preferably DMT-MM, HATU or WSCI ⁇ HCl.
- WSCI ⁇ HCl is used, HOBt or HOBT ⁇ H 2 O can coexist if necessary.
- the base used in this step is preferably an organic base, and more preferably N-methylmorpholine, N, N-diisopropylethylamine or 4-dimethylaminopyridine.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
- the reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
- Step A10 This step is a step of producing a compound having the general formula (Id).
- a compound having the general formula (XV) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran or dimethoxyethane.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the base used in this step is preferably an organic base, and more preferably triethylamine.
- the base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate.
- the reaction temperature in this step is usually ⁇ 100 ° C. to 85 ° C., and when methanesulfonic anhydride is used, it is preferably 10 ° C. to 60 ° C. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably ⁇ 78 ° C. to 30 ° C.
- the reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
- Method B is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
- R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are as described above. It shows the same meaning as the thing.
- Step B1 This step is a step of producing a compound having the general formula (XVI).
- This step comprises reacting the compound having the general formula (V) obtained in Step A2 Step A2 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
- Step B2 This step is a step of producing a compound having the general formula (XVII).
- step (XVI) the compound having the general formula (XVI) is reacted with the compound having the general formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in step A6 of the method A. Done.
- Step B3 This step is a step of producing a compound having the general formula (XVIII).
- This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XVII) with a base in a solvent.
- Step B4 This step is a step of producing a compound having the general formula (XIX).
- This step is performed by reacting a compound having the general formula (XVIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and Performed in the same manner as in step A9.
- Step B5 This step is a step of producing a compound having the general formula (XX).
- the compound having the general formula (XIX) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to form the step A10 of the above method A. The same is done.
- Step B6 This step is a step of producing a compound having the general formula (XXI).
- This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (XX) with a demethylating agent in a solvent.
- Step B7 This step is a step of producing a compound having the general formula (Id).
- the compound having the general formula (XXI) is reacted with the compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5
- it is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a as desired.
- Step B8 This step is a step of producing a compound having the general formula (Id).
- This step is carried out by reacting a compound having the general formula (XXI) with a compound having the general formula (XXII) in a solvent in the presence of a base, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
- the compound having the general formula (XXII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an amide or a ketone, and more preferably N, N-dimethylformamide or 2-butanone.
- the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
- the reaction temperature in this step is usually 25 ° C to 120 ° C, preferably 40 ° C to 80 ° C.
- the reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 48 hours.
- Method C is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
- R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
- Step C1 This step is a step of producing a compound having the general formula (XXIII).
- This step comprises reacting the compound having the general formula (III) obtained in the above-mentioned Method A, Step A1 with a compound having the general formula (XXII) in a solvent in the presence of a base, thereby Performed in the same manner as in step B8.
- Step C2 This step is a step of producing a compound having the general formula (XXIV).
- This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XXIII) with a demethylating agent in a solvent.
- Step C3 This step is a step of producing a compound having the general formula (XXV).
- This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XXIV) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
- Step C4 This step is a step of producing a compound having the general formula (XXVII).
- the compound having the general formula (XXV) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
- the compound having the general formula (XXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
- Step C5 This step is a step of producing a compound having the general formula (XXVIII).
- This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXVII) with an acid in a solvent.
- Step C6 This step is a step of producing a compound having the general formula (XXIX).
- This step is performed by reacting a compound having the general formula (XXVIII) with triisopropylsilyl chloride in a solvent in the presence of a base.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the base used in this step is preferably an organic base, and more preferably triethylamine or a mixed base of triethylamine and 4-dimethylaminopyridine.
- the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
- the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
- Step C7 This step is a step of producing a compound having the general formula (XXX).
- This step is performed by reacting a compound having the general formula (XXIX) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
- the solvent used in this step is preferably an ether, alcohol, ester or a mixed solvent thereof, more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. It is.
- the palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably palladium-activated carbon.
- the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
- the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
- Step C8 This step is a step of producing a compound having the general formula (XXXI).
- This step is performed by reacting a compound having the general formula (XXX) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base. Performed in the same manner as in step A9.
- Step C9 This step is a step of producing a compound having the general formula (XXXII).
- This step comprises reacting the compound having the general formula (XXXI) with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, The same is done.
- Step C10 This step is a step of producing a compound having the general formula (XXXIII).
- This step is performed by reacting a compound having the general formula (XXXII) with tetrabutylammonium fluoride in a solvent.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
- the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
- Step C11 This step is a step of producing a compound having the general formula (Id).
- This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXIII) with a compound having the general formula (IV) in the presence of a base in a solvent. If necessary, the amino group, hydroxy group and / or carboxyl group-protecting group in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is removed.
- Method D is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
- R 2a , R 3a , X and Y have the same meaning as described above.
- Step D1 This step is a step of producing a compound having the general formula (XXXIV).
- This step is performed in (i) or (ii).
- Step A3 is converted to the compound having the general formula (VIII). Is carried out in the same manner as in step A5 of the method A.
- Step B8 of Method B above This step is carried out in the same manner as in Step B8 of Method B above by reacting a compound having the general formula (VI) with a compound having the general formula (XXII) in the presence of a base in a solvent. Is called.
- Step D2 This step is a step of producing a compound having the general formula (XXXV).
- a compound having the general formula (XXXIV) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) -1H-pyrrole-2-carboxylate.
- the solvent used in this step is preferably an ether, and more preferably dioxane.
- the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
- the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
- the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
- Step D3 This step is a step of producing a compound having the general formula (XIII).
- This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
- Method E is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
- R 8 , R 2a , R 3a , X and Y have the same meaning as described above.
- Step E1 This step is a step of producing a compound having the general formula (XXXVI).
- This step comprises reacting a compound having the general formula (XXV) obtained in the above-mentioned Method C, Step C3 with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A6 of method A.
- Step E2 This step is a step of producing a compound having the general formula (XXXVII).
- This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXXVI) with an acid in a solvent.
- Step E3 This step is a step of producing a compound having the general formula (XXXVIII).
- This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXVII) with a compound having the general formula (IV) in the presence of a base in a solvent.
- Step E4 This step is a step of producing a compound having the general formula (XIII).
- This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XXXVIII) with a base in a solvent.
- Method F is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
- R 2a , R 3a and Y have the same meaning as described above.
- Step F1 This step is a step of producing a compound having the general formula (XXXV).
- Step C5 the compound having the general formula (XXVIII) obtained in the above-mentioned Method C, Step C5 is reacted with the compound having the general formula (IV) in a solvent in the presence of a base, thereby This is performed in the same manner as in step A2.
- Step F2 This step is a step of producing a compound having the general formula (XIII).
- This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
- Method G is a method for producing a compound having the general formula (XVIII) used in Method B, Step B4.
- R 2a , X and Y are as defined above.
- Step G1 This step is the step of producing compound (XXXIX).
- This step comprises reacting the compound having the general formula (III) obtained in Step A1 Step A1 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
- Step G2 This step is a step of producing compound (XL).
- This step is carried out in the same manner as in Step A6 of Method A above by reacting compound (XXXIX) with a compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent.
- Step G3 This step is a step of producing a compound having the general formula (XLI).
- This step is performed in the same manner as in Step A2 of Method A above by reacting compound (XL) with a compound having the general formula (IV) in a solvent in the presence of a base.
- Step G4 This step is a step of producing a compound having the general formula (XLII).
- This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XLI) with an acid in a solvent.
- Step G5 This step is a step of producing a compound having the general formula (XVIII).
- This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XLII) in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere.
- Method H is a method for producing a compound having the general formula (XXVIII) used in Step C6 of Method C.
- R 3a and X are as defined above.
- Step H1 This step is a step of producing a compound having the general formula (XXVIII).
- Step C2 in the presence of a palladium catalyst and an inorganic base in a solvent, the compound having the general formula (XXIV) obtained in the above-mentioned Method C, Step C2 is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
- Method I is a method for producing a compound having the general formula (XXIV) used in the above-mentioned Method C, Step C3.
- R 3a and X are as defined above.
- Step I1 This step is a step of producing a compound having the general formula (XLIV).
- the compound having the general formula (XLIII) is reacted with the compound having the general formula (IV) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 of the above method A It is performed in the same manner as the process.
- the compound having the general formula (XLIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- Step I2 This step is a step of producing a compound having the general formula (XXIV).
- This step is performed by reacting a compound having the general formula (XLIV) with trimethyl borate in a solvent in the presence of a base, and further with acetic acid and an oxidizing agent.
- the solvent used in this step is preferably an ether, and more preferably diethyl ether.
- the base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
- the oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably 30% hydrogen peroxide solution.
- the reaction temperature in this step is usually ⁇ 120 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
- the reaction time in this step is usually 1 hour to 48 hours, preferably 6 hours to 24 hours.
- Method J is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
- R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
- Step J1 This step is a step of producing a compound having the general formula (XLVI).
- This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XLV) with a compound having the general formula (IV) in a solvent in the presence of a base.
- the compound having the general formula (XLV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- Step J2 This step is a step of producing a compound having the general formula (XLVIII).
- This step is performed by reacting a compound having the general formula (XLVI) with a compound having trifluoromethanesulfonic anhydride (XLVII) in a solvent in the presence of a base.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the base used in this step is preferably an organic base, and more preferably pyridine.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
- Step J3 This step is a step of producing a compound having the general formula (XLIX).
- This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XLVIII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
- Step J4 This step is a step of producing a compound having the general formula (L).
- the compound having the general formula (XLIX) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
- Step J5 This step is a step of producing a compound having the general formula (LI).
- This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (L) with an acid in a solvent.
- Step J6 This step is a step of producing a compound having the general formula (LII).
- This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LI) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
- Step J7 This step is a step of producing a compound having the general formula (LIII).
- This step is performed by reacting a compound having the general formula (LII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent or in the presence or absence of a base. Performed in the same manner as in step A9.
- Step J8 This step is a step of producing a compound having the general formula (LIV).
- the compound having the general formula (LIII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
- Step J9 This step is a step of producing a compound having the general formula (Ie).
- R 8 O of the compound having the general formula (LIV) is converted to R 3a (R 3a is as defined above), and then R 2a , R 3a , R 9a as desired. , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
- the L method described below is an example of the J9th step.
- Method K is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
- R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
- Step K1 This step is a step of producing a compound having the general formula (LVII).
- This step is performed by reacting 3,5-dimethoxybenzaldehyde (LV) with a compound having the general formula (LVI) in a solvent.
- the compound having the general formula (LVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
- the reaction temperature in this step is usually ⁇ 110 ° C. to 40 ° C., preferably ⁇ 80 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
- Step K2 This step is a step of producing a compound having the general formula (LVIII).
- This step is performed by reacting a compound having the general formula (LVII) with an oxidizing agent in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably manganese dioxide.
- the reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 25 ° C. to 40 ° C.
- the reaction time in this step is usually 6 hours to 72 hours, preferably 12 hours to 36 hours.
- Step K3 This step is a step of producing a compound having the general formula (LIX).
- This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (LVIII) with a demethylating agent in a solvent.
- Step K4 This step is a step of producing a compound having the general formula (LX).
- This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LIX) with a compound having the general formula (IV) in a solvent in the presence of a base.
- Step K5 This step is a step of producing a compound having the general formula (LXI).
- This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (LX) with a demethylating agent in a solvent.
- Step K6 This step is a step of producing a compound having the general formula (LXII).
- Step K7 This step is a step of producing a compound having the general formula (LXIII).
- This step is performed in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (LXII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
- Step K8 This step is a step of producing a compound having the general formula (LXIV).
- Step K9 This step is a step of producing a compound having the general formula (LXV).
- This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (LXIV) with an acid in a solvent.
- Step K10 This step is a step of producing a compound having the general formula (LXVI).
- This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
- Step K11 This step is a step of producing a compound having the general formula (LXVII).
- This step comprises reacting a compound having the general formula (LXVI) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, Performed in the same manner as in step A9.
- Step K12 This step is a step of producing a compound having the general formula (Ie).
- the compound having the general formula (LXVII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
- Method L is a method for producing a compound having the general formula (If) wherein U is a carbonyl group and R 3 is a group represented by the formula —NR 4 R 5 among the compounds having the general formula (I). It is.
- R 2 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a and R 12a are as defined above.
- R 4a and R 5a each represents an amino group contained as a substituent in the groups of R 4 and R 5 which may be protected, and groups in the definition of the groups of R 4 and R 5. Similar groups are shown.
- Step L1 This step is a step of producing a compound having the general formula (LXVIII).
- This step is performed by reacting a compound having the general formula (LIV) obtained in the above-mentioned J method, step J8, with a base in a solvent.
- the solvent used in this step is preferably ethers or alcohols, and more preferably tetrahydrofuran or ethanol.
- the base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide or lithium hydroxide, and still more preferably an aqueous sodium hydroxide solution or hydroxide. Lithium aqueous solution.
- the reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
- the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
- Step L2 This step is a step of producing a compound having the general formula (If).
- a compound having the general formula (LXVIII) is reacted with a compound having the general formula (LXIX) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and then optionally R 2a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
- the compound having the general formula (LXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
- the solvent used in this step is preferably amides, alcohols or halogenated hydrocarbons, and more preferably N, N-dimethylformamide, methanol or dichloromethane.
- the condensing agent used in this step is preferably WSCI ⁇ HCl, DMT-MM or HATU.
- the base used in this step is preferably an organic base, and more preferably triethylamine, diisopropylethylamine or a combination of triethylamine and 4-dimethylaminopyridine.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 36 hours.
- Method M is a method for producing a compound having the general formula (LI) used in the J method, J6 step.
- R 8 and R 2a have the same meaning as described above.
- Step M1 This step is a step of producing a compound having the general formula (LI).
- Method N is a method for producing a compound having the general formula (X) used in Method A, Step A6, Method B, Step B2, and Method E, Step E1.
- R 8 and X are as defined above.
- Step N1 This step is a step of producing a compound having the general formula (LXXI).
- This step is performed by reacting a compound having the general formula (LXX) with a halogenating agent in a solvent.
- the compound having the general formula (LXX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
- the halogenating agent used in this step is, for example, an inorganic acid such as hydrochloric acid, hydrogen bromide or hydrogen iodide; a halogen molecule such as chlorine, bromine or iodine, or N-chlorosuccinimide, N-bromo.
- Succinimides such as succinimide and N-iodosuccinimide, preferably succinimide, and more preferably N-bromosuccinimide.
- the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
- Step N2 This step is a step of producing a compound having the general formula (X).
- This step is performed by reacting a compound having the general formula (LXXI) with di-t-butyl dicarbonate in the presence of a base in a solvent.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the base used in this step is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl.
- a mixed base of aminopyridine is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
- Method O is a method for producing a compound having the general formula (XXVI) used in Step C, Step C4, Method G, Step G2, Step J, Step J4 and Method K, Step K8.
- X has the same meaning as described above.
- Step O1 This step is a step of producing a compound having the general formula (LXXIII).
- This step is carried out in the same manner as the Nth step of the N method by reacting pyrrole-1-carboxylate t-butyl (LXXII) with a halogenating agent in a solvent.
- the pyrrole-1-carboxylic acid t-butyl (LXXII) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
- Step O2 This step is a step of producing a compound having the general formula (XXVI).
- This step is performed by reacting a compound having the general formula (LXXIII) with a compound having the general formula (LXXIV) in a solvent in the presence of a base.
- the compound having the general formula (LXXIV) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an ether, and more preferably diethyl ether.
- the base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
- the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
- Method P is benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl used in Method D, Step D2, Method H, Step H1 and Method M, Step M1. ) -1H-pyrrole-2-carboxylate (LXXVIII).
- Y has the same meaning as described above.
- Step P1 This step is a step for producing benzyl 1H-pyrrole-2-carboxylate (LXXVII).
- This step is performed by reacting pyrrole-2-carboxylic acid (LXXV) with a compound having the general formula (LXXVI) in a solvent in the presence of a base.
- the pyrrole-2-carboxylic acid (LXXV) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
- the compound having the general formula (LXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
- the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
- the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
- Step P2 This step is a step for producing benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (LXXVIII). .
- benzyl 1H-pyrrole-2-carboxylate (LXXVII) is converted to bis (pinacolato) diboron in the presence of an iridium catalyst and 4,4′-di-t-butyl-2,2′-dipyridyl in a solvent. By reacting with.
- the solvent used in this step is preferably a hydrocarbon, and more preferably hexane.
- the iridium catalyst used in this step is preferably methoxy (cyclooctadiene) iridium (I) dimer.
- the reaction temperature in this step is usually 0 ° C. to 70 ° C., preferably 25 ° C. to 60 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
- Method Q is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
- R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a and Y are as described above. Shows the same significance.
- Step Q1 This step is a step of producing a compound having the general formula (LXXX).
- Step A8 in the presence of a condensing agent and a base in a solvent, the compound having the general formula (XIII) obtained in the above-mentioned Method A, Step A8 is reacted with a compound having the general formula (LXXIX), thereby This is carried out in the same manner as in step A9 of the law.
- the compound having the general formula (LXXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- Step Q2 This step is a step of producing a compound having the general formula (Id).
- a compound having the general formula (LXXX) is reacted with a base in a solvent, and then optionally, an amino group, a hydroxy group, and R 2a , R 3a , R 9a , R 10a , R 11a and R 12a It is carried out by removing the protecting group of the carboxyl group.
- the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
- the base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
- Method R is a method for producing a compound having the general formula (LI) used in Method J, Step J6.
- R 8 , R 2a and X are as defined above.
- Step R1 This step is a step of producing a compound having the general formula (LXXXII).
- a compound having the general formula (LXXXI) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is performed in the same manner as in Step D2 of Method D above.
- the compound having the general formula (LXXXI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- Step R2 This step is a step of producing a compound having the general formula (LI).
- This step is performed by reacting a compound having the general formula (LXXXII) with a compound having the general formula (LXXXIII) in the presence of a copper catalyst, a base and molecular sieves 4A in a solvent.
- the compound having the general formula (LXXXIII) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the copper catalyst used in this step is preferably copper (II) acetate.
- the base used in this step is preferably an organic base, and more preferably triethylamine.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 12 hours to 360 hours, preferably 24 hours to 240 hours.
- Method S is a method for producing a compound having the general formula (LXVI) used in Method K, Step K11.
- R 2a and R 3a have the same meaning as described above.
- Step S1 This step is a step of producing a compound having the general formula (LXXXIV).
- Step K6 a compound having the general formula (LXII) obtained in Step K6, Step K6 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to methyl 5- (4,4,5,5-tetramethyl-1, Performed by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
- the solvent used in this step is preferably an ether, and more preferably dioxane.
- the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
- the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
- the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
- the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
- Step S2 This step is a step of producing a compound having the general formula (LXVI).
- This step is performed by reacting a compound having the general formula (LXXXIV) with a base in a solvent.
- the solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
- the base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide, and even more preferably an aqueous lithium hydroxide solution.
- the reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
- the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
- Method T is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
- R 2a , R 3a and X are as defined above.
- Step T1 This step is a step of producing a compound having the general formula (LXXXVII).
- This step is performed by reacting a compound having the general formula (LXXXV) with a compound having the general formula (LXXXVI) in the presence of a base in a solvent.
- the compound having the general formula (LXXXV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the compound having the general formula (LXXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
- the base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
- the reaction temperature in this step is usually 60 ° C to 180 ° C, preferably 100 ° C to 150 ° C.
- the reaction time in this step is usually 1 hour to 48 hours, preferably 12 hours to 36 hours.
- Step T2 This step is a step of producing a compound having the general formula (LXXXIV).
- Method U is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
- R 2a , R 3a , X and Y have the same meaning as described above.
- Step U1 This step is a step of producing a compound having the general formula (LXXXIX).
- This step is performed by reacting a compound having the general formula (LXXXVIII) with acetic anhydride in the presence of an acid.
- the compound having the general formula (LXXXVIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; acetic acid, formic acid and trifluoroacetic acid.
- Carboxylic acids preferably mineral acids, and more preferably sulfuric acid.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
- Step U2 This step is a step of producing a compound having the general formula (LXL).
- This step is performed by reacting a compound having the general formula (LXXXIX) with a chlorinating agent.
- the chlorinating agent used in this step is, for example, an inorganic acid such as hydrochloric acid; a halogen molecule such as chlorine; a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride; Oxalic acid chlorides; sulfinic acid reagents such as thionyl chloride; or sulfonic acid reagents such as sulfonyl chloride and toluenesulfonic acid chloride, preferably sulfinic acid reagents or oxalate chlorides More preferred is thionyl chloride or oxalyl chloride, and even more preferred is thionyl chloride.
- an inorganic acid such as hydrochloric acid
- a halogen molecule such as chlorine
- a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxy
- the reaction temperature in this step is usually ⁇ 20 ° C. to 100 ° C., preferably 25 ° C. to 80 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
- Step U3 This step is a step of producing a compound having the general formula (LXLII).
- This step is performed by reacting a compound having the general formula (LXL) with a compound having the general formula (LXLI) in a solvent.
- the compound having the general formula (LXLI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
- the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
- the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
- the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
- Step U4 This step is a step of producing a compound having the general formula (LXLIII).
- a compound having the general formula (LXLII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.
- Step U5 This step is a step of producing a compound having the general formula (LXXXIV).
- This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LXLIII) with a compound having the general formula (IV) in a solvent in the presence of a base.
- R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a in the definition of “amino group which may be protected”, “hydroxy group which may be protected” and “
- the protecting group of “optionally protected carboxyl group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).
- “protective group” of “optionally protected hydroxy group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a hydroxy group used in the field of synthetic organic chemistry
- the protecting group is not particularly limited, and examples thereof include a formyl group, the “C 2 -C 7 alkylcarbonyl group”, the “C 2 -C 7 halogenated alkylcarbonyl group”, and an alkoxyalkyl such as methoxyacetyl.
- Alkylcarbonyl groups such as carbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, ⁇ -naphthoyl, ⁇ -naphthoyl Arylcarbonyl groups such as 2-bromobenzoyl, 4-chloro Halogenated arylcarbonyl groups such as Nzoiru, 2,4,6-trimethylbenzoyl, 4-C 1 -C 6 alkylated ants such as toluoyl - ylcarbonyl group, C 1 -C 6 alkoxy such as 4-anisoyl Arylcarbonyl groups, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C 2 -C 7 alkoxycarbonylated arylcarbon
- “protective group” of “optionally protected carboxyl group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a carboxyl group used in the field of synthetic organic chemistry
- the protecting group is not particularly limited, but for example, the “C 1 -C 6 alkyl group”; the “C 2 -C 6 alkenyl group”; ethynyl, 1-propynyl, 2-propynyl, 1-methyl- A C 2 -C 6 alkynyl group such as 2-propynyl and 1-butynyl; the aforementioned “C 1 -C 6 halogenated alkyl group”; a C 1 -C 6 hydroxyalkyl group such as hydroxymethyl and 2-hydroxyethyl; (C 2 -C 7 alkylcarbonyl)-(C 1 -C 6 alkyl group) such as acetylmethyl; said “aralkyl group”; or
- protecting group of “amino group which may be protected” in the definition of R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a is a field of synthetic organic chemistry.
- alkylcarbonyl group preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group .
- the compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
- the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration).
- these various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It can be formulated with the resulting adjuvant.
- excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrating agents such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as
- the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
- excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
- a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
- solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
- the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
- water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
- a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
- the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
- the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
- the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
- Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography).
- TLC Thin Layer Chromatography
- the TLC plate silica gel 60F 254 manufactured by Merck or the NH-TLC plate manufactured by Fuji Silysia Chemical Co. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the detection method.
- a UV detector was adopted.
- silica gel for the column silica gel SK-85 (230-400 mesh) manufactured by Merck or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used.
- HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
- WSCI.HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
- HOBT.H 2 O 1-hydroxybenzotriazole monohydrate
- DMT-MM 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate.
- 1 H-NMR nuclear magnetic resonance
- MS Mass spectrometry
- diethyl azodicarboxylate 50% toluene solution, 16.2 mL, 37.2 mmol
- diethyl azodicarboxylate 50% toluene solution, 16.2 mL, 37.2 mmol
- Water 300 mL
- ethyl acetate 300 mL
- the organic layer was washed with saturated brine and dried over sodium sulfate.
- the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (4.06 g, yield 99%) as a white solid.
- WSCI ⁇ HCl (71 mg, 0.37 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours.
- the reaction mixture was diluted with methylene chloride (150 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
- Example 2a The compound synthesized in Example (2a) (56 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL), sodium thiomethoxide (25 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
- Example 3 The compound synthesized in Example 3 (150 mg, 0.31 mmol) was dissolved in methylene chloride (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (15 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
- Example (6a) Using the compound (220 mg, 0.552 mmol) synthesized in Example (6a), ⁇ -bromo- ⁇ -butyrolactone (110 ⁇ L, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol), and Example (6b) The target product (175 mg, 66% yield) was obtained in the same manner as a white solid.
- Tetrahydro-3-furanol 130 ⁇ L, 1.61 mmol
- triphenylphosphine 410 mg, 1.56 mmol
- diethyl azodicarboxylate 40% toluene solution, 720 ⁇ L, 1).
- 58 mmol was added dropwise.
- the compound synthesized in Example (6a) 250 mg, 0.627 mmol was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, followed by stirring at room temperature for 14 hours under a nitrogen atmosphere.
- Example 14 The compound synthesized in Example 14 (72.5 mg, 0.154 mmol) was dissolved in methylene chloride (5 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (70 ⁇ L, 0.534 mmol) at 0 ° C. Was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
- reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
- reaction mixture was diluted with methylene chloride (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
- Example (1a) 1-Bromo-3-ethoxy-5-methoxybenzene
- the compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and iodoethane ( 2.43 mL, 30.4 mmol) and potassium carbonate (7.00 g, 50.6 mmol) were added, and the mixture was stirred at 60 ° C. for 25 hours under a nitrogen atmosphere.
- the reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL).
- Example (17b) 3-Bromo-5-ethoxyphenol Using the compound synthesized in Example (17a) (4.75 g, 20.6 mmol) and sodium thiomethoxide (1.56 g, 22.3 mmol), Example (1a ) To give the target compound (4.19 g, 94% yield) as a white solid.
- reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with diethyl ether (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was dissolved in methylene chloride (30 mL), and trifluoroacetic acid (30 mL) was added dropwise. After stirring at room temperature for 1 hour in a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The mixture was diluted with methylene chloride (50 mL), and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
- Example (18c) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5- (2,2,2-trifluoroethoxy) phenol
- Example (18b) Synthesized compound (3.57 g, 13.2 mmol), bis (pinacolato) diboron (5.02 g, 19.8 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( 540 mg, 0.661 mmol) and potassium acetate (6.48 g, 66.0 mmol) were used to obtain the target compound (4.11 g, yield 98%) as a white solid in the same manner as in Example (1d).
- the reaction mixture was cooled to 0 ° C., and acetic acid (3.63 mL, 63.4 mmol) and 30% aqueous hydrogen peroxide (7.40 mL, 65.3 mmol) were added dropwise in this order. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate.
- the reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
- the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
- the reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
- the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate.
- methylmagnesium iodide (3.0 mol / L tetrahydrofuran solution, 0.58 mL, 1.74 mmol) was added, and the mixture was returned to room temperature and stirred for 2 hours.
- the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate.
- the organic layer was extracted with a separatory funnel previously cooled with ice, cooled to ⁇ 78 ° C., and a commercially available 40% methylamine / methanol solution (1.33 mL, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised to ° C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
- the organic layer was extracted with a separatory funnel previously cooled with ice, cooled to ⁇ 78 ° C., and a commercial maze of azetidine hydrochloride (2.24 mg, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised and the mixture was stirred for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
- the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
- Example (30b) The compound synthesized in Example (30b) (620 mg, 1.24 mmol) was dissolved in ethanol (12 mL), 2N aqueous sodium hydroxide solution (6.21 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was distilled off under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (600 mg, yield 100%) as a white solid.
- Example 31 Compound synthesized in Example 31 (156 mg, 0.32 mmol), dimethylamine hydrochloride (78 mg, 0.96 mmol), WSCI ⁇ HCl (123 mg, 0.64 mmol), 4-dimethylaminopyridine (118 mg, 0. 96 mmol) was used to obtain the target compound (111 mg, yield 67%) as a white solid in the same manner as in Example (1k).
- the mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
- reaction mixture was diluted with methylene chloride (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
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Abstract
Disclosed is a compound having an excellent glucokinase activating effect, or a pharmacologically acceptable salt thereof.
Specifically disclosed is a compound represented by general formula (I) or a pharmacologically acceptable salt thereof.
(In the formula, R1s may be the same or different and each represents a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkyl group substituted by one or two hydroxy groups, or the like; R2 represents a phenyl group which may be mono- to penta-substituted independently by a group selected from substituent group A, or a pyridyl group or pyrazinyl group which may be mono- to tri-substituted independently by a group selected from substituent group A; R3 represents an alkyl group which may be mono- to penta-substituted independently by a group selected from substituent group B, or the like; U represents an oxygen atom or a carbonyl group; n represents an integer of 0-3; substituent group A includes halogen atoms, C1-C6 alkoxy groups, C2-C7 alkylcarbonyl groups, C2-C7 halogenated alkylcarbonyl groups, C2-C7 alkoxycarbonyl groups and the like; and substituent group B includes halogen atoms, C2-C7 alkylcarbonyl groups, C2-C7 alkoxycarbonyl groups, a carbamoyl group and the like.)
Description
本発明は、優れたグルコキナーゼ活性化作用を有し、糖尿病等の治療薬として有用な2,5-二置換ピロール誘導体又はその薬理上許容される塩に関する。
The present invention relates to a 2,5-disubstituted pyrrole derivative or a pharmacologically acceptable salt thereof that has an excellent glucokinase activating action and is useful as a therapeutic agent for diabetes and the like.
グルコキナーゼ(glucokinase、本明細書中ではGKと略すことがある;EC2.7.1.1)は、哺乳類において見出される4種類のヘキソキナーゼのうちのひとつ(ヘキソキナーゼIV)である。ヘキソキナーゼは、細胞内における解糖系の最初の段階にてグルコースからグルコース‐6‐リン酸への変換を触媒する酵素であるが、うちGKはその発現が主に肝臓と膵臓ベータ細胞に限局している。膵臓ベータ細胞ではグルコース刺激インスリン分泌を規定する細胞外グルコース濃度の感知機構として機能し、肝臓ではGKの酵素反応が律速段階となり、以下の解糖、グリコーゲン合成等の反応が調節される。肝臓と膵臓ベータ細胞のGKはスプライシングの相違によってN末端側15アミノ酸の配列が異なるが、酵素学的性質は同一である。GK以外の3つのヘキソキナーゼ(I、II、III)は1mM以下のグルコース濃度で酵素活性が飽和するのに対し、GKのグルコースに対する親和性は低く、そのKm値は8-15mMと生理的な血糖値に近い。従って、正常血糖値(5mM前後)から食後高血糖(10-15mM)の血糖変化に呼応した形で、GKを介した細胞内グルコース代謝の亢進が起こる。
Gluconase (glucokinase, which may be abbreviated as GK in the present specification; EC2.7.1.1) is one of four types of hexokinase (hexokinase IV) found in mammals. Hexokinase is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate at the initial stage of glycolysis in the cell. Among them, GK is expressed mainly in the liver and pancreatic beta cells. ing. In pancreatic beta cells, it functions as a sensing mechanism of extracellular glucose concentration that regulates glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes the rate-limiting step, and the following reactions such as glycolysis and glycogen synthesis are regulated. GK of liver and pancreatic beta cells differ in the sequence of 15 amino acids on the N-terminal side due to differences in splicing, but have the same enzymatic properties. Three hexokinases (I, II, III) other than GK saturate the enzyme activity at a glucose concentration of 1 mM or less, whereas GK has a low affinity for glucose, and its Km value is 8-15 mM, which is a physiological blood glucose level. Close to value. Therefore, the increase in intracellular glucose metabolism via GK occurs in response to changes in blood glucose from normal blood glucose level (around 5 mM) to postprandial hyperglycemia (10-15 mM).
古くから、GKが肝臓および膵臓ベータ細胞内でグルコースセンサーとして機能しているという仮説が提唱されてきた(非特許文献1乃至3)。
最近の研究結果から、GKが実際に全身のグルコース恒常性の維持に重要な役割を担うことが証明され、仮説は実証された。例えば、グルコキナーゼ遺伝子を破壊したマウスは生後間もなく著明な高血糖症状を示し死亡し、またGKへテロ欠損マウスは耐糖能不良であり、糖刺激によるインスリン分泌が障害されていた(非特許文献4)。一方、GKを過剰発現させた正常マウスでは血糖値の低下、肝中グリコーゲン含量の増大などが見られ、その現象は人為的に糖尿病を発症させたマウスにおいても同様であった(非特許文献5)。 Since ancient times, the hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has been proposed (Non-Patent Documents 1 to 3).
Recent research results have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, demonstrating the hypothesis. For example, a mouse with a disrupted glucokinase gene died of severe hyperglycemia soon after birth, and a GK hetero-deficient mouse had poor glucose tolerance and impaired insulin secretion due to sugar stimulation (Non-Patent Document) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose level and an increase in glycogen content in the liver were observed, and the same phenomenon was observed in mice that artificially developed diabetes (Non-patent Document 5). ).
最近の研究結果から、GKが実際に全身のグルコース恒常性の維持に重要な役割を担うことが証明され、仮説は実証された。例えば、グルコキナーゼ遺伝子を破壊したマウスは生後間もなく著明な高血糖症状を示し死亡し、またGKへテロ欠損マウスは耐糖能不良であり、糖刺激によるインスリン分泌が障害されていた(非特許文献4)。一方、GKを過剰発現させた正常マウスでは血糖値の低下、肝中グリコーゲン含量の増大などが見られ、その現象は人為的に糖尿病を発症させたマウスにおいても同様であった(非特許文献5)。 Since ancient times, the hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has been proposed (Non-Patent Documents 1 to 3).
Recent research results have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, demonstrating the hypothesis. For example, a mouse with a disrupted glucokinase gene died of severe hyperglycemia soon after birth, and a GK hetero-deficient mouse had poor glucose tolerance and impaired insulin secretion due to sugar stimulation (Non-Patent Document) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose level and an increase in glycogen content in the liver were observed, and the same phenomenon was observed in mice that artificially developed diabetes (Non-patent Document 5). ).
また、ヒトにおいてもGKはグルコースセンサーとして機能し、グルコース恒常性の維持に重要な役割を果たしていることが近年の研究から明らかにされた。MODY2(Maturity Onset Diabetes of the Young)と呼ばれる若年発症成人型糖尿病の家系よりGK遺伝子の異常が発見され、この症例とGK活性との関連が明らかにされた(非特許文献6)。一方、GK活性を上昇させる突然変異を有する家系も見つかっており、このような家系では血漿中インスリン濃度の上昇を伴う空腹時低血糖症状が見られる(非特許文献7)。以上の報告から、GKはヒトを含む哺乳類でグルコースセンサーとして機能し、血糖調節に重要な役割を果たしている。従って、II型糖尿病をはじめとする糖代謝疾患において、GK活性化作用を有する物質は薬剤として有用であると考えられる。特にGK活性化物質には肝臓に対する糖取り込み促進作用及び糖放出抑制作用、膵臓ベータ細胞に対するインスリン分泌促進作用が同時に期待できるため、既存の薬剤では達することの出来ない強力な治療効果をもたらしうると予想される。
In recent human studies, it has been clarified that GK functions as a glucose sensor and plays an important role in maintaining glucose homeostasis. A GK gene abnormality was found in a family with early-onset adult type diabetes called MODY2 (Maturity Onset Diabetes of the Young), and the relationship between this case and GK activity was clarified (Non-patent Document 6). On the other hand, families with mutations that increase GK activity have also been found, and in these families, fasting hypoglycemia symptoms accompanied by an increase in plasma insulin concentration are observed (Non-patent Document 7). From the above reports, GK functions as a glucose sensor in mammals including humans and plays an important role in blood glucose regulation. Therefore, it is considered that a substance having a GK activation action is useful as a drug in sugar metabolism diseases such as type II diabetes. In particular, GK activator can be expected to have the effect of promoting glucose uptake and release of glucose to the liver and insulin secretion of pancreatic beta cells at the same time. is expected.
近年、膵臓ベータ細胞型GKがラット脳の摂食中枢(Ventromedial hypothalamus、VMH)に限局して発現していることが明らかとなった。VMHにはグルコース濃度に応答するニューロンが存在することが従来から知られている。ラット脳室内にグルコースを投与すると摂食量が低下するのに対し、グルコース類縁体のグルコサミンを投与しグルコース代謝を阻害すると摂食が亢進する(非特許文献8)。電気生理学的実験からグルコース応答性ニューロンは生理的なグルコース濃度変化(5-20mM)に応答して活性化されることが知られており、この際にグルコキナーゼが末梢組織と同様にグルコースセンサーとして機能していることが明らかにされた(非特許文献9)。従って肝臓、膵臓ベータ細胞のみならずVMHのグルコキナーゼ活性化をもたらす物質は血糖低下作用のみならず、多くのII型糖尿病患者に付随した問題となっている肥満をも是正する作用が期待できる。
Recently, it has become clear that pancreatic beta cell type GK is expressed exclusively in the feeding center (Ventromedial hypothalamus, VMH) of rat brain. It has been known that VMH has neurons that respond to glucose concentration. When glucose is administered into the rat ventricle, the amount of food intake decreases, whereas when glucose analog glucosamine is administered to inhibit glucose metabolism, food intake increases (Non-patent Document 8). From electrophysiological experiments, it is known that glucose-responsive neurons are activated in response to physiological glucose concentration changes (5-20 mM). At this time, glucokinase acts as a glucose sensor as in peripheral tissues. It was clarified that it was functioning (Non-Patent Document 9). Therefore, not only the liver and pancreatic beta cells but also substances that bring about activation of VMH glucokinase can be expected not only to lower blood glucose but also to correct obesity, which is a problem associated with many patients with type II diabetes.
上記の記載から、GK活性化作用を有する物質は、糖尿病の治療及び予防薬として、あるいは、網膜症、腎症、神経症、虚血性心疾患、動脈硬化等の糖尿病の慢性合併症の治療及び予防薬として有用である。
From the above description, a substance having a GK activation action is used as a therapeutic and prophylactic agent for diabetes or for the treatment of chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like. It is useful as a preventive drug.
なお、これまでにGK活性化能を有する化合物が複数報告されているが、いずれも本発明の化合物とは構造が異なる。例えば、特許文献1には、アミド構造を必須とする化合物が記載されているが、本発明の化合物は、アミドではなくピロールを必須とする。また、特許文献2には、縮環したピロールを有する化合物が記載されているが、本発明の化合物は縮環していないピロールを必須とする。さらに特許文献3には、3,5-二置換のピラゾール又は1,2,4-トリアゾールを有する化合物が記載されているが、本発明の2,5-二置換ピロール構造とは異なる。これらの他にもGK活性化作用を有する化合物が複数報告されているが、いずれも本発明の化合物とは構造が異なるものである。(例えば、特許文献4乃至15、非特許文献10及び11)。
In addition, although several compounds which have GK activation ability have been reported so far, all have a structure different from the compound of this invention. For example, Patent Document 1 describes a compound that requires an amide structure, but the compound of the present invention requires pyrrole instead of amide. Further, Patent Document 2 describes a compound having a condensed pyrrole, but the compound of the present invention requires a pyrrole that is not condensed. Further, Patent Document 3 describes a compound having 3,5-disubstituted pyrazole or 1,2,4-triazole, which is different from the 2,5-disubstituted pyrrole structure of the present invention. In addition to these, a plurality of compounds having a GK activating action have been reported, but all have structures different from the compounds of the present invention. (For example, Patent Documents 4 to 15, Non-Patent Documents 10 and 11).
本発明の課題は、2,5-二置換ピロール誘導体や、これを用いたGK活性化薬を提供し、特に糖尿病、耐糖能異常の治療および予防薬を提供することにある。発明者らは、GK活性化作用を有する化合物について鋭意研究を行った結果、特定の化学構造を有する2,5-二置換ピロール化合物が、優れたGK活性化作用を有することを見出した。また、本発明化合物は優れたGK選択性を有しており、毒性が低く、副作用も少ない。本発明者らは、この2,5-二置換ピロール化合物が、糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)及びメタボリックシンドロームからなる群から選ばれる疾患の治療及び/又は予防のための医薬の有効成分として有用であることを見出した。本発明は上記の知見を基にして完成された。
An object of the present invention is to provide a 2,5-disubstituted pyrrole derivative and a GK activator using the derivative, and particularly to provide a therapeutic and prophylactic agent for diabetes and impaired glucose tolerance. As a result of intensive studies on a compound having a GK activation action, the inventors have found that a 2,5-disubstituted pyrrole compound having a specific chemical structure has an excellent GK activation action. In addition, the compound of the present invention has excellent GK selectivity, low toxicity, and few side effects. The present inventors have found that this 2,5-disubstituted pyrrole compound is diabetic, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic major It was found to be useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of (including angiopathy) and metabolic syndrome. The present invention has been completed based on the above findings.
本発明は、(1)一般式(I)
The present invention comprises (1) general formula (I)
[式中、
R1は、同一又は異なって、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基、(C1-C6アルキルチオ)-(C1-C6アルキル)基、カルボキシル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基又はジ-(C1-C6アルキル)アミノカルボニル基を示し、
R2は、置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基又は置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基を示し、
R3は、置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基、C2-C6アルケニル基、(C1-C6アルキル基、C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環(但し、Uとは炭素原子で結合する。)又は式-NR4R5で表わされる基を示し、
R4、R5は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6アルコキシ基を示すか、R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。 [Where:
R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group,
R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good pyridyl or pyrazinyl group,
R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with 1 to 5 groups independently selected from the substituent group B , A C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom; And a group represented by the formula —NR 4 R 5 .
R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
R1は、同一又は異なって、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基、(C1-C6アルキルチオ)-(C1-C6アルキル)基、カルボキシル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基又はジ-(C1-C6アルキル)アミノカルボニル基を示し、
R2は、置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基又は置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基を示し、
R3は、置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基、C2-C6アルケニル基、(C1-C6アルキル基、C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環(但し、Uとは炭素原子で結合する。)又は式-NR4R5で表わされる基を示し、
R4、R5は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6アルコキシ基を示すか、R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。 [Where:
R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group,
R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good pyridyl or pyrazinyl group,
R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with 1 to 5 groups independently selected from the substituent group B , A C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom; And a group represented by the formula —NR 4 R 5 .
R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
Uは、酸素原子又はカルボニル基を示し、
(但し、式-U-R3で表わされる基から2-ヒドロキシ-1-メチルエトキシ基を除く。)
nは、0乃至3の整数を示し、
置換基群Aは、ハロゲン原子、C1-C6アルコキシ基、C2-C7アルキルカルボニル基、C2-C7ハロゲン化アルキルカルボニル基、C2-C7アルコキシカルボニル基、C2-C7ハロゲン化アルコキシカルボニル基、C1-C6アルキルスルホニル基、C1-C6ハロゲン化アルキルスルホニル基、C3-C6シクロアルキルスルホニル基、(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基、(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6ハロゲン化アルキル基を示すか、R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)からなる群を示し、
置換基群Bは、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7アルコキシカルボニル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基、ジ-(C1-C6アルキル)アミノカルボニル基、C1-C6アルキルチオ基、C1-C6アルキルスルホニル基、ヒドロキシ基及び3乃至6員環エーテルからなる群を示す。]を有する化合物又はその薬理上許容される塩に関する。 U represents an oxygen atom or a carbonyl group;
(However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
n represents an integer of 0 to 3,
Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) are shown, R 6, R 7 are the same or different, a hydrogen atom, or a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, 6 and a together with the nitrogen atom to which R 7 is bonded, C 1 -C 6 alkyl independently one or two substituted or .4 to form a 4 to 6-membered heterocyclic saturated ring or may have 6 membered group The heterosaturated ring may further comprise one oxygen or nitrogen atom)),
Substituent group B includes halogen atom, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 An alkyl) aminocarbonyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfonyl group, a hydroxy group, and a 3- to 6-membered ring ether. Or a pharmacologically acceptable salt thereof.
(但し、式-U-R3で表わされる基から2-ヒドロキシ-1-メチルエトキシ基を除く。)
nは、0乃至3の整数を示し、
置換基群Aは、ハロゲン原子、C1-C6アルコキシ基、C2-C7アルキルカルボニル基、C2-C7ハロゲン化アルキルカルボニル基、C2-C7アルコキシカルボニル基、C2-C7ハロゲン化アルコキシカルボニル基、C1-C6アルキルスルホニル基、C1-C6ハロゲン化アルキルスルホニル基、C3-C6シクロアルキルスルホニル基、(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基、(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6ハロゲン化アルキル基を示すか、R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)からなる群を示し、
置換基群Bは、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7アルコキシカルボニル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基、ジ-(C1-C6アルキル)アミノカルボニル基、C1-C6アルキルチオ基、C1-C6アルキルスルホニル基、ヒドロキシ基及び3乃至6員環エーテルからなる群を示す。]を有する化合物又はその薬理上許容される塩に関する。 U represents an oxygen atom or a carbonyl group;
(However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
n represents an integer of 0 to 3,
Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) are shown, R 6, R 7 are the same or different, a hydrogen atom, or a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, 6 and a together with the nitrogen atom to which R 7 is bonded, C 1 -C 6 alkyl independently one or two substituted or .4 to form a 4 to 6-membered heterocyclic saturated ring or may have 6 membered group The heterosaturated ring may further comprise one oxygen or nitrogen atom)),
Substituent group B includes halogen atom, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 An alkyl) aminocarbonyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfonyl group, a hydroxy group, and a 3- to 6-membered ring ether. Or a pharmacologically acceptable salt thereof.
本発明において、好適には、
(2) (1)において、
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基である化合物又はその薬理上許容される塩。 In the present invention, preferably,
(2) In (1),
A compound wherein R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, or a pharmacological thereof Top acceptable salt.
(2) (1)において、
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基である化合物又はその薬理上許容される塩。 In the present invention, preferably,
(2) In (1),
A compound wherein R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, or a pharmacological thereof Top acceptable salt.
(3) (1)又は(2)において、
一般式(I)が、一般式(Ia)であり、R1が、カルバモイル基である化合物又はその薬理上許容される塩。 (3) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ia) and R 1 is a carbamoyl group.
一般式(I)が、一般式(Ia)であり、R1が、カルバモイル基である化合物又はその薬理上許容される塩。 (3) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ia) and R 1 is a carbamoyl group.
(4) (1)又は(2)において、
一般式(I)が、一般式(Ib)であり、R1が、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基である化合物又はその薬理上許容される塩。 (4) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ib) and R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.
一般式(I)が、一般式(Ib)であり、R1が、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基である化合物又はその薬理上許容される塩。 (4) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein the general formula (I) is the general formula (Ib) and R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.
(5) (1)又は(2)において、
一般式(I)が、一般式(Ic)であり、R1が、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基である化合物又はその薬理上許容される塩。 (5) In (1) or (2),
A compound in which the general formula (I) is the general formula (Ic) and R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group Or a pharmacologically acceptable salt thereof.
一般式(I)が、一般式(Ic)であり、R1が、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基である化合物又はその薬理上許容される塩。 (5) In (1) or (2),
A compound in which the general formula (I) is the general formula (Ic) and R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group Or a pharmacologically acceptable salt thereof.
(6) (1)乃至(5)から選択されるいずれか一項において、
R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基である化合物又はその薬理上許容される塩。 (6) In any one item selected from (1) to (5),
R 2 is a phenyl group substituted at the 4- or 3-position with a group selected from Substituent Group C, and 1 at the 2-position with a group selected from Substituent Group C 5- A compound or a pharmacologically acceptable salt thereof, which is a 2-pyrazinyl group substituted at the 5-position with a pyridyl group or a group selected from substituent group C.
R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基である化合物又はその薬理上許容される塩。 (6) In any one item selected from (1) to (5),
R 2 is a phenyl group substituted at the 4- or 3-position with a group selected from Substituent Group C, and 1 at the 2-position with a group selected from Substituent Group C 5- A compound or a pharmacologically acceptable salt thereof, which is a 2-pyrazinyl group substituted at the 5-position with a pyridyl group or a group selected from substituent group C.
置換基群Cは、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群を示す。
Substituent group C includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, R 6 , R 7 is the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl group.
(7) (1)乃至(5)から選択されるいずれか一項において、
R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基である化合物又はその薬理上許容される塩。 (7) In any one item selected from (1) to (5),
R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A compound which is a methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group or a pharmacologically acceptable salt thereof.
R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基である化合物又はその薬理上許容される塩。 (7) In any one item selected from (1) to (5),
R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A compound which is a methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group or a pharmacologically acceptable salt thereof.
(8) (1)乃至(7)から選択されるいずれか一項において、
R3が、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環であり、Uが、酸素原子である化合物又はその薬理上許容される塩。 (8) In any one item selected from (1) to (7),
R 3 is independently one or two in the group consisting of a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted with 1 to 5 halogen atoms. A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may be substituted and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom.
R3が、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環であり、Uが、酸素原子である化合物又はその薬理上許容される塩。 (8) In any one item selected from (1) to (7),
R 3 is independently one or two in the group consisting of a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted with 1 to 5 halogen atoms. A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may be substituted and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom.
(9) (1)乃至(7)から選択されるいずれか一項において、
R3が、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、Uが、カルボニル基である化合物又はその薬理上許容される塩。 (9) In any one item selected from (1) to (7),
R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group). A compound in which U is a carbonyl group or a pharmacologically acceptable salt thereof.
R3が、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、Uが、カルボニル基である化合物又はその薬理上許容される塩。 (9) In any one item selected from (1) to (7),
R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group). A compound in which U is a carbonyl group or a pharmacologically acceptable salt thereof.
(10) (1)乃至(7)から選択されるいずれか一項において、
式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (10) In any one item selected from (1) to (7),
The group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, or a 1,3-difluoro-2-propoxy group. , A compound which is a cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, isopropylcarbonyl group or dimethylaminocarbonyl group, or a pharmacologically acceptable salt thereof salt.
式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (10) In any one item selected from (1) to (7),
The group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, or a 1,3-difluoro-2-propoxy group. , A compound which is a cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, isopropylcarbonyl group or dimethylaminocarbonyl group, or a pharmacologically acceptable salt thereof salt.
(11) (1)において、
[R1が、同一又は異なって、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基、(C1-C6アルキルチオ)-(C1-C6アルキル)基、カルボキシル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基又はジ-(C1-C6アルキル)アミノカルボニル基を示し、R2が、置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基又は置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基を示し、R3が、置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基、C2-C6アルケニル基、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環(但し、Uとは炭素原子で結合する。)又は式-NR4R5で表わされる基を示し、R4、R5が、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6アルコキシ基を示すか、R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。Uが、酸素原子又はカルボニル基を示し、(但し、式-U-R3で表わされる基から2-ヒドロキシ-1-メチルエトキシ基を除く。)nが、0乃至3の整数を示し、置換基群Aが、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7ハロゲン化アルキルカルボニル基、C2-C7アルコキシカルボニル基、C2-C7ハロゲン化アルコキシカルボニル基、C1-C6アルキルスルホニル基、C1-C6ハロゲン化アルキルスルホニル基、C3-C6シクロアルキルスルホニル基、(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基、(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6ハロゲン化アルキル基を示すか、R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)からなる群を示し、置換基群Bが、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7アルコキシカルボニル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基、ジ-(C1-C6アルキル)アミノカルボニル基、C1-C6アルキルチオ基、C1-C6アルキルスルホニル基、ヒドロキシ基及び3乃至6員環エーテルからなる群を示す。]を有する化合物又はその薬理上許容される塩。 (11) In (1),
[R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, (C 1- C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group , R 2 is independently substituted with 1 to 5 groups independently selected from the substituent group A and independently substituted with 1 to 3 phenyl groups or groups selected from the substituent group A; A C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group, wherein R 3 may be independently substituted with 1 to 5 groups independently selected from Substituent Group B group, C 1 -C 6 A group consisting of an alkyl group and an oxo group may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom. The 3- to 6-membered saturated ring may be bonded to U (carbon atom). Or a group represented by the formula —NR 4 R 5 , wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, Together with the nitrogen atom to which 4 and R 5 are attached, forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group To do. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom. U represents an oxygen atom or a carbonyl group (provided that a 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula —UR 3 ), n represents an integer of 0 to 3, Group A is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 halogenated alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group, (C 1- C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and a group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or sulfonyl group) R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, or a nitrogen to which R 6 and R 7 are bonded. Together with the atoms, it forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 or 2 C 1 -C 6 alkyl groups. The substituent group B is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a carbamoyl group, a mono- C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 alkyl) aminocarbonyl group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, hydroxy group and 3-6 membered ring ether Kara Indicating the group. Or a pharmacologically acceptable salt thereof.
[R1が、同一又は異なって、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基、(C1-C6アルキルチオ)-(C1-C6アルキル)基、カルボキシル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基又はジ-(C1-C6アルキル)アミノカルボニル基を示し、R2が、置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基又は置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基を示し、R3が、置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基、C2-C6アルケニル基、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環(但し、Uとは炭素原子で結合する。)又は式-NR4R5で表わされる基を示し、R4、R5が、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6アルコキシ基を示すか、R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。Uが、酸素原子又はカルボニル基を示し、(但し、式-U-R3で表わされる基から2-ヒドロキシ-1-メチルエトキシ基を除く。)nが、0乃至3の整数を示し、置換基群Aが、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7ハロゲン化アルキルカルボニル基、C2-C7アルコキシカルボニル基、C2-C7ハロゲン化アルコキシカルボニル基、C1-C6アルキルスルホニル基、C1-C6ハロゲン化アルキルスルホニル基、C3-C6シクロアルキルスルホニル基、(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基、(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6ハロゲン化アルキル基を示すか、R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)からなる群を示し、置換基群Bが、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7アルコキシカルボニル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基、ジ-(C1-C6アルキル)アミノカルボニル基、C1-C6アルキルチオ基、C1-C6アルキルスルホニル基、ヒドロキシ基及び3乃至6員環エーテルからなる群を示す。]を有する化合物又はその薬理上許容される塩。 (11) In (1),
[R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, (C 1- C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group , R 2 is independently substituted with 1 to 5 groups independently selected from the substituent group A and independently substituted with 1 to 3 phenyl groups or groups selected from the substituent group A; A C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group, wherein R 3 may be independently substituted with 1 to 5 groups independently selected from Substituent Group B group, C 1 -C 6 A group consisting of an alkyl group and an oxo group may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom. The 3- to 6-membered saturated ring may be bonded to U (carbon atom). Or a group represented by the formula —NR 4 R 5 , wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, Together with the nitrogen atom to which 4 and R 5 are attached, forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group To do. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom. U represents an oxygen atom or a carbonyl group (provided that a 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula —UR 3 ), n represents an integer of 0 to 3, Group A is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 halogenated alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group, (C 1- C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and a group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or sulfonyl group) R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, or a nitrogen to which R 6 and R 7 are bonded. Together with the atoms, it forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 or 2 C 1 -C 6 alkyl groups. The substituent group B is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a carbamoyl group, a mono- C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 alkyl) aminocarbonyl group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, hydroxy group and 3-6 membered ring ether Kara Indicating the group. Or a pharmacologically acceptable salt thereof.
(12) (1)において、
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基であり、R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基であり、置換基群Cが、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群であり、R3が、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環であり、Uが酸素原子であり、nが、0乃至3の整数である化合物又はその薬理上許容される塩。 (12) In (1),
R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a C 1 -C 6 alkyl group). R 3 is a halogen atom and is independently 1 to 5 An optionally substituted C 1 -C 6 alkyl group or a group consisting of (C 3 -C 6 cycloalkyl group and oxo group) independently 1 or 2 optionally substituted oxygen atom or nitrogen atom A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may contain one, U is an oxygen atom, and n is an integer of 0 to 3.
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基であり、R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基であり、置換基群Cが、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群であり、R3が、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環であり、Uが酸素原子であり、nが、0乃至3の整数である化合物又はその薬理上許容される塩。 (12) In (1),
R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a C 1 -C 6 alkyl group). R 3 is a halogen atom and is independently 1 to 5 An optionally substituted C 1 -C 6 alkyl group or a group consisting of (C 3 -C 6 cycloalkyl group and oxo group) independently 1 or 2 optionally substituted oxygen atom or nitrogen atom A compound or a pharmacologically acceptable salt thereof, which is a 3- to 6-membered saturated ring which may contain one, U is an oxygen atom, and n is an integer of 0 to 3.
(13) (1)において、
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基であり、R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基であり、置換基群Cが、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群であり、R3が、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、Uがカルボニル基であり、nが、0乃至3の整数である化合物又はその薬理上許容される塩。 (13) In (1),
R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a C 1 -C 6 alkyl group). Wherein R 3 is a C 1 -C 6 alkyl group or a formula A group represented by —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group), U is a carbonyl group, and n is 0 A compound which is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.
R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基であり、R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基であり、置換基群Cが、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群であり、R3が、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、Uがカルボニル基であり、nが、0乃至3の整数である化合物又はその薬理上許容される塩。 (13) In (1),
R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, and R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a C 1 -C 6 alkyl group). Wherein R 3 is a C 1 -C 6 alkyl group or a formula A group represented by —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group), U is a carbonyl group, and n is 0 A compound which is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.
(14) (1)において、
一般式(I)が、一般式(Ia)であり、R1が、カルバモイル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (14) In (1),
The general formula (I) is the general formula (Ia), R 1 is a carbamoyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl. A 2-methylsulfonyl-5-pyridyl group, a 2-methylaminosulfonyl-5-pyridyl group, a 5-methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group having the formula —U— The group represented by R 3 is a methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone -2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, Propyl carbonyl group or compound or pharmacologically acceptable salt thereof is a dimethylamino group.
一般式(I)が、一般式(Ia)であり、R1が、カルバモイル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (14) In (1),
The general formula (I) is the general formula (Ia), R 1 is a carbamoyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl. A 2-methylsulfonyl-5-pyridyl group, a 2-methylaminosulfonyl-5-pyridyl group, a 5-methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group having the formula —U— The group represented by R 3 is a methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone -2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, Propyl carbonyl group or compound or pharmacologically acceptable salt thereof is a dimethylamino group.
(15) (1)において、
一般式(I)が、一般式(Ib)であり、R1が、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (15) In (1),
The general formula (I) is the general formula (Ib), R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl- 5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2 A pyrazinyl group, the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3- Difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpi 2-one-3-yloxy group, an isopropyl group or a compound or pharmacologically acceptable salt thereof is a dimethylamino group.
一般式(I)が、一般式(Ib)であり、R1が、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (15) In (1),
The general formula (I) is the general formula (Ib), R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl- 5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2 A pyrazinyl group, the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3- Difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpi 2-one-3-yloxy group, an isopropyl group or a compound or pharmacologically acceptable salt thereof is a dimethylamino group.
(16) (1)において、
一般式(I)が、一般式(Ic)であり、R1が、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (16) In (1),
The general formula (I) is the general formula (Ic), R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group; R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group, and the group represented by the formula —UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, (1S) -2- Fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone-2-yloxy group, Tetrahydrofuran-3-yloxy group, 1-cyclopropyl-2-one-3-yloxy group, an isopropyl group or a compound or a pharmacologically acceptable salt thereof is a dimethylamino group.
一般式(I)が、一般式(Ic)であり、R1が、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基であり、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基であり、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 (16) In (1),
The general formula (I) is the general formula (Ic), R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group; R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group, and the group represented by the formula —UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, (1S) -2- Fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone-2-yloxy group, Tetrahydrofuran-3-yloxy group, 1-cyclopropyl-2-one-3-yloxy group, an isopropyl group or a compound or a pharmacologically acceptable salt thereof is a dimethylamino group.
(17) 一般式(I)を有する化合物が、
{(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール、
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール、
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド、
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
{(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン、
2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン、
1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン、又は、
3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
である化合物又はその薬理上許容される塩。 (17) A compound having the general formula (I)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-dihydro-1,3-oxazol-5-yl] methanol,
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one,
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone,
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one, or
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-yl} benzamide or a pharmacologically acceptable salt thereof.
{(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール、
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール、
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド、
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、
{(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン、
2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン、
1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン、又は、
3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
である化合物又はその薬理上許容される塩。 (17) A compound having the general formula (I)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol,
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-dihydro-1,3-oxazol-5-yl] methanol,
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide,
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one,
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone,
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one, or
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-yl} benzamide or a pharmacologically acceptable salt thereof.
(18) 上記(17)に記載してある化合物又はその薬理上許容される塩のうちの化合物。
(18) A compound among the compounds described in (17) above or a pharmacologically acceptable salt thereof.
(19) 一般式(I)を有する化合物が、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール、
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド、
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、又は、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
である化合物又はその薬理上許容される塩。 (19) A compound having the general formula (I)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide, or
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ A compound which is 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide or a pharmacologically acceptable salt thereof.
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール、
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド、
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、又は、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
である化合物又はその薬理上許容される塩。 (19) A compound having the general formula (I)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide, or
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ A compound which is 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide or a pharmacologically acceptable salt thereof.
(20) 上記(19)に記載してある化合物又はその薬理上許容される塩のうちの化合物。
(20) A compound described in the above (19) or a pharmacologically acceptable salt thereof.
(21) (1)乃至(20)から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有するグルコキナーゼ活性化剤。
(21) A glucokinase activator comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
(22) (1)乃至(20)から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
(22) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
(23) 医薬組成物が、グルコキナーゼ活性化作用を有する(22)に記載の医薬組成物。
(23) The pharmaceutical composition according to (22), wherein the pharmaceutical composition has a glucokinase activating action.
(24) 医薬組成物が、グルコキナーゼ活性化作用により、治療及び/又は予防される疾病の治療及び/又は予防のための(22)に記載の医薬組成物。
(24) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is for the treatment and / or prevention of a disease which is treated and / or prevented by glucokinase activating action.
(25) 医薬組成物が、グルコキナーゼを活性化させ、グルコースの恒常性の維持又は血糖調節が達成されることにより、症状の治療、改善、軽減及び/又は予防がなされる疾病の治療及び/又は予防のための(22)に記載の医薬組成物。
(25) The pharmaceutical composition activates glucokinase to achieve maintenance of glucose homeostasis or regulation of blood glucose, thereby treating and / or treating diseases that are treated, ameliorated, reduced and / or prevented. Or the pharmaceutical composition as described in (22) for prevention.
(26) 医薬組成物が、糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームの治療及び/又は予防のための(22)に記載の医薬組成物。
(26) The pharmaceutical composition is diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome The pharmaceutical composition according to (22) for treatment and / or prevention.
(27) 医薬組成物が、糖尿病又は耐糖能異常の治療及び/又は予防のための(22)に記載の医薬組成物。
(27) The pharmaceutical composition according to (22), wherein the pharmaceutical composition is for the treatment and / or prevention of diabetes or impaired glucose tolerance.
(28)医薬組成物を製造するための、(1)乃至(20)から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。
(28) Use of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
(29)医薬組成物がグルコキナーゼを活性化するための組成物である(28)に記載の使用。
(29) The use according to (28), wherein the pharmaceutical composition is a composition for activating glucokinase.
(30) 医薬組成物が糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームの治療及び/又は予防のための組成物である(28)に記載の使用。
(30) Treatment for diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome And / or the use according to (28), which is a composition for prevention.
(31) 医薬組成物が糖尿病又は耐糖能異常の治療及び/又は予防のための組成物である(28)に記載の使用。
(31) The use according to (28), wherein the pharmaceutical composition is a composition for the treatment and / or prevention of diabetes or impaired glucose tolerance.
(32) (1)乃至(20)から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与するグルコキナーゼ活性化方法。
(32) A method for activating glucokinase, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
(33) (1)乃至(20)から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び/又は予防方法。
(33) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal Prevention method.
(34) 疾病が糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームである(33)に記載の方法。
(34) The disease is diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (33 ) Method.
(35) 疾病が糖尿病又は耐糖能異常である(33)に記載の方法。
(35) The method according to (33), wherein the disease is diabetes or impaired glucose tolerance.
(36) 温血動物がヒトである(32)乃至(35)から選択されるいずれか一項に記載の方法
を挙げることができる。 (36) The method according to any one of (32) to (35), wherein the warm-blooded animal is a human.
を挙げることができる。 (36) The method according to any one of (32) to (35), wherein the warm-blooded animal is a human.
本発明において、「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又は沃素原子である。好適には、フッ素原子又は塩素原子であり、より好適には、フッ素原子である。
In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
本発明において、「C1-C6アルキル基」は、炭素数1乃至6個の直鎖又は分枝鎖アルキル基である。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、s-ブチル、t-ブチル、ペンチル、イソペンチル、2-メチルブチル、ネオペンチル、1-エチルプロピル、ヘキシル、イソヘキシル、4-メチルペンチル、3-メチルペンチル、2-メチルペンチル、1-メチルペンチル、3,3-ジメチルブチル、2,2-ジメチルブチル、1,1-ジメチルブチル又は1,2-ジメチルブチル基であり、好適には、炭素数1乃至4個の直鎖又は分枝鎖アルキル基(C1-C4アルキル基)であり、より好適には、メチル基又はエチル基(C1-C2アルキル基)であり、更により好適には、メチル基である。
In the present invention, the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl, preferably having 1 to 4 linear or branched alkyl groups (C 1 -C 4 alkyl groups), more preferably methyl groups or ethyl groups (C 1 -C 2 alkyl groups), and even more preferably , A methyl group.
本発明において、「C1-C6ハロゲン化アルキル基」は、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C6アルキル基」に結合した基である。例えば、トリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル、2,2,2-トリフルオロエチル、2,2,2-トリクロロエチル、2-ブロモエチル、2-クロロエチル又は2-フルオロエチル基であり、好適には、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C4アルキル基」に結合した基(C1-C4ハロゲン化アルキル基)であり、より好適には、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C2アルキル基」に結合した基(C1-C2ハロゲン化アルキル基)であり、更により好適には、トリフルオロメチル基又はフルオロメチル基であり、特に好適には、フルオロメチル基である。
In the present invention, the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl or 2- A fluoroethyl group, and preferably a group (C 1 -C 4 halogenated alkyl group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkyl group”. More preferably, the same or different 1 to 5 “halogen atoms” are groups (C 1 -C 2 halogenated alkyl groups) bonded to the “C 1 -C 2 alkyl group”, Is more preferably a trifluoromethyl group or a fluoromethyl group, and particularly preferably a fluoromethyl group.
本発明において、「1又は2個のヒドロキシ基で置換されているC1-C6アルキル基」は、1又は2個のヒドロキシ基が前記「C1-C6アルキル基」に結合した基である。例えば、ヒドロキシメチル、2-ヒドロキシエチル、1-ヒドロキシエチル、3-ヒドロキシプロピル、1,2-ジヒドロキシエチル又は2,3-ジヒドロキシプロピル基であり、好適には、1又は2個のヒドロキシ基が前記「C1-C4アルキル基」に結合した基であり、より好適には、1又は2個のヒドロキシ基が前記「C1-C2アルキル基」に結合した基であり、更により好適には、ヒドロキシメチル基、2-ヒドロキシエチル基又は1,2-ジヒドロキシエチル基である。
In the present invention, the “C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups” is a group in which 1 or 2 hydroxy groups are bonded to the “C 1 -C 6 alkyl group”. is there. For example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl or 2,3-dihydroxypropyl group, and preferably one or two hydroxy groups A group bonded to the “C 1 -C 4 alkyl group”, more preferably a group in which one or two hydroxy groups are bonded to the “C 1 -C 2 alkyl group”, and even more preferably. Is a hydroxymethyl group, a 2-hydroxyethyl group or a 1,2-dihydroxyethyl group.
本発明において、「C1-C6アルキルチオ基」は、1個の前記「C1-C6アルキル基」が硫黄原子に結合した基であり、炭素数1乃至6個の直鎖又は分枝鎖アルキルチオ基である。例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、s-ブチルチオ、1-エチルプロピルチオ又はヘキシルチオ基であり、好適には、炭素数1乃至4個の直鎖又は分枝鎖アルキルチオ基(C1-C4アルキルチオ基)であり、より好適には、メチルチオ又はエチルチオ基(C1-C2アルキルチオ基)であり、更により好適には、メチルチオ基である。
In the present invention, the “C 1 -C 6 alkylthio group” is a group in which one “C 1 -C 6 alkyl group” is bonded to a sulfur atom, and is a straight chain or branched chain having 1 to 6 carbon atoms. It is a chain alkylthio group. For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, 1-ethylpropylthio or hexylthio group, preferably a linear or branched alkylthio group having 1 to 4 carbon atoms (C 1 -C 4 alkylthio group), more preferably methylthio or ethylthio group (C 1 -C 2 alkylthio group), and still more preferably methylthio group.
本発明において、「(C1-C6アルキルチオ)-(C1-C6アルキル)基」は、1個の前記「C1-C6アルキルチオ基」が前記「C1-C6アルキル基」に結合した基である。例えば、メチルチオメチル、エチルチオメチル、プロピルチオメチル、イソプロピルチオメチル、ブチルチオメチル又は2-メチルチオエチル基であり、好適には、1個の前記「C1-C4アルキルチオ基」が前記「C1-C4アルキル基」に結合した基((C1-C4アルキルチオ)-(C1-C4アルキル)基)であり、より好適には、1個の前記「C1-C2アルキルチオ基」が前記「C1-C2アルキル基」に結合した基((C1-C2アルキルチオ)-(C1-C2アルキル)基)であり、更により好適には、2-メチルチオエチル基である。
In the present invention, “(C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group” means that one “C 1 -C 6 alkylthio group” is the above “C 1 -C 6 alkyl group”. It is a group bonded to For example, it is a methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl or 2-methylthioethyl group, and preferably one of the “C 1 -C 4 alkylthio groups” is the “C 1 1- C 4 alkyl group ”((C 1 -C 4 alkylthio)-(C 1 -C 4 alkyl) group), more preferably one of the above-mentioned“ C 1 -C 2 alkylthio groups ”. Group ”is a group ((C 1 -C 2 alkylthio)-(C 1 -C 2 alkyl) group) bonded to the“ C 1 -C 2 alkyl group ”, and more preferably 2-methylthioethyl It is a group.
本発明において、「モノ-C1-C6アルキルアミノカルボニル基」は、1個の前記「C1-C6アルキル基」が結合したアミノ基がカルボニル基に結合した基である。例えば、メチルアミノカルボニル、エチルアミノカルボニル、プロピルアミノカルボニル、イソプロピルアミノカルボニル又はブチルアミノカルボニル基であり、好適には、1個の前記「C1-C4アルキル基」が結合したアミノ基がカルボニル基に結合した基(モノ-C1-C4アルキルアミノカルボニル基)であり、より好適には、メチルアミノカルボニル基又はエチルアミノカルボニル基(モノ-C1-C2アルキルアミノカルボニル基)であり、更により好適には、メチルアミノカルボニル基である。
In the present invention, "mono--C 1 -C 6 alkylaminocarbonyl group" is an amino group in which one of the "C 1 -C 6 alkyl group" is bonded is a group attached to a carbonyl group. For example, a methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl or butylaminocarbonyl group, preferably an amino group to which one of the above “C 1 -C 4 alkyl groups” is bonded is a carbonyl group A group bonded to (mono-C 1 -C 4 alkylaminocarbonyl group), more preferably a methylaminocarbonyl group or an ethylaminocarbonyl group (mono-C 1 -C 2 alkylaminocarbonyl group), Even more preferred is a methylaminocarbonyl group.
本発明において、「ジ-(C1-C6アルキル)アミノカルボニル基」は、同一又は異なる2個の前記「C1-C6アルキル基」が結合したアミノ基がカルボニル基に結合した基である。例えば、ジメチルアミノカルボニル、ジエチルアミノカルボニル、ジプロピルアミノカルボニル、N-エチル-N-メチルアミノカルボニル、N-メチル-N-プロピルアミノカルボニル又はN-ブチル-N-メチルアミノカルボニル基であり、好適には、同一又は異なる2個の前記「C1-C4アルキル基」が結合したアミノ基がカルボニル基に結合した基(ジ-(C1-C4アルキル)アミノカルボニル基)であり、より好適には、ジメチルアミノカルボニル基、ジエチルアミノカルボニル基又はN-エチル-N-メチルアミノカルボニル基(ジ-(C1-C2アルキル)アミノカルボニル基)であり、更により好適には、ジメチルアミノカルボニル基である。
In the present invention, the “di- (C 1 -C 6 alkyl) aminocarbonyl group” is a group in which two identical or different “C 1 -C 6 alkyl groups” are bonded to a carbonyl group. is there. For example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylaminocarbonyl group, preferably An amino group to which two identical or different “C 1 -C 4 alkyl groups” are bonded is a group bonded to a carbonyl group (di- (C 1 -C 4 alkyl) aminocarbonyl group), more preferably Is a dimethylaminocarbonyl group, a diethylaminocarbonyl group or an N-ethyl-N-methylaminocarbonyl group (di- (C 1 -C 2 alkyl) aminocarbonyl group), more preferably a dimethylaminocarbonyl group is there.
本発明において、「C2-C6アルケニル基」は、前記「C1-C6アルキル基」のうち、1個の二重結合を有する炭素数2乃至6個の基である。例えば、エテニル、1-プロペニル、2-プロペニル、1-メチルビニル、1-メチル-2-プロペニル、1-メチル-1-プロペニル、2-メチル-1-プロペニル、1-ブテニル、2-ブテニル、3-ブテニル、1-ペンテニル、4-ペンテニル、1-メチル-4-ペンテニル又は5-ヘキセニル基であり、好適には、炭素数2乃至4個のアルケニル基(C2-C4アルケニル基)であり、より好適には、1-メチルビニル基である。
In the present invention, the “C 2 -C 6 alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C 1 -C 6 alkyl group”. For example, ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 1-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl or 5-hexenyl group, preferably an alkenyl group having 2 to 4 carbon atoms (C 2 -C 4 alkenyl group) More preferably, it is a 1-methylvinyl group.
本発明において、「C1-C6アルコキシ基」は、前記「C1-C6アルキル基」が酸素原子に結合した基であり、炭素数1乃至6個の直鎖又は分枝鎖アルコキシ基である。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、s-ブトキシ、t-ブトキシ、ペントキシ、2-メチルブトキシ、3-エチルプロポキシ、ネオペントキシ、ヘキシルオキシ又は2,3-ジメチルブトキシ基であり、好適には、炭素数1乃至4個の直鎖又は分枝鎖アルコキシ基(C1-C4アルコキシ基)であり、より好適には、メトキシ基、エトキシ基、プロポキシ基又はイソプロポキシ基(C1-C3アルコキシ基)であり、更により好適には、メトキシ基又はエトキシ基(C1-C2アルコキシ基)であり、特に好適には、メトキシ基である。
In the present invention, the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 3-ethylpropoxy, neopentoxy, hexyloxy or 2,3-dimethylbutoxy group, Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy group), and more preferred is a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group (C 1 -C 3 alkoxy group), even more preferably a methoxy group or an ethoxy group (C 1 -C 2 alkoxy group), and particularly preferably a methoxy group.
本発明において、「C2-C7アルキルカルボニル基」は、1個の前記「C1-C6アルキル基」がカルボニル基に結合した基である。例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル又はバレリル基であり、好適には、1個の前記「C1-C4アルキル基」がカルボニル基に結合した基(C2-C5アルキルカルボニル基)であり、より好適には、アセチル基又はプロピオニル基(C2-C3アルキルカルボニル基)であり、更により好適には、アセチル基である。
In the present invention, a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group. For example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group, and preferably a group (C 2 -C 5 alkyl) in which one said “C 1 -C 4 alkyl group” is bonded to a carbonyl group A carbonyl group), more preferably an acetyl group or a propionyl group (C 2 -C 3 alkylcarbonyl group), and even more preferably an acetyl group.
本発明において、「C2-C7ハロゲン化アルキルカルボニル基」は、1個の前記「C1-C6ハロゲン化アルキル基」がカルボニル基に結合した基である。例えば、トリフルオロメチルカルボニル、トリクロロメチルカルボニル、ジフルオロメチルカルボニル、ジクロロメチルカルボニル、フルオロメチルカルボニル、2,2,2-トリフルオロエチルカルボニル、2,2,2-トリクロロエチルカルボニル又は2-フルオロエチルカルボニル基であり、好適には、1個の前記「C1-C4ハロゲン化アルキル基」がカルボニル基に結合した基(C2-C5ハロゲン化アルキルカルボニル基)であり、より好適には、1個の前記「C1-C2ハロゲン化アルキル基」がカルボニル基に結合した基(C2-C3ハロゲン化アルキルカルボニル基)であり、更により好適には、トリフルオロメチルカルボニル基である。
In the present invention, the “C 2 -C 7 halogenated alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a carbonyl group. For example, trifluoromethylcarbonyl, trichloromethylcarbonyl, difluoromethylcarbonyl, dichloromethylcarbonyl, fluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 2,2,2-trichloroethylcarbonyl or 2-fluoroethylcarbonyl group And is preferably a group in which one of the aforementioned “C 1 -C 4 halogenated alkyl groups” is bonded to a carbonyl group (C 2 -C 5 halogenated alkylcarbonyl group), more preferably 1 The aforementioned “C 1 -C 2 halogenated alkyl group” is a group (C 2 -C 3 halogenated alkylcarbonyl group) bonded to a carbonyl group, and more preferably a trifluoromethylcarbonyl group.
本発明において、「C2-C7アルコキシカルボニル基」は、1個の前記「C1-C6アルコキシ基」がカルボニル基に結合した基である。例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、s-ブトキシカルボニル又はt-ブトキシカルボニル基であり、好適には、1個の前記「C1-C4アルコキシ基」がカルボニル基に結合した基(C2-C5アルコキシカルボニル基)であり、より好適には、メトキシカルボニル基又はエトキシカルボニル基(C2-C3アルコキシカルボニル基)であり、更により好適には、メトキシカルボニル基である。
In the present invention, a “C 2 -C 7 alkoxycarbonyl group” is a group in which one of the above “C 1 -C 6 alkoxy groups” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group, preferably one of the above-mentioned “C 1 -C 4 alkoxy” Group ”is a group bonded to a carbonyl group (C 2 -C 5 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C 2 -C 3 alkoxycarbonyl group), and even more preferably Is a methoxycarbonyl group.
本発明において、「C1-C6ハロゲン化アルコキシ基」は、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C6アルコキシ基」に結合した基である。例えば、トリフルオロメトキシ、トリクロロメトキシ、ジフルオロメトキシ、ジクロロメトキシ、ジブロモメトキシ、フルオロメトキシ、2,2,2-トリフルオロエトキシ、2,2,2-トリクロロエトキシ、2-クロロエトキシ、2-フルオロエトキシ又はペンタフルオロエトキシ基であり、好適には、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C4アルコキシ基」に結合した基(C1-C4ハロゲン化アルコキシ基)であり、より好適には、同一又は異なる1乃至5個の前記「ハロゲン原子」が前記「C1-C2アルコキシ基」に結合した基(C1-C2ハロゲン化アルコキシ基)であり、更により好適には、トリフルオロメトキシ基である。
In the present invention, the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”. For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or A pentafluoroethoxy group, preferably a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group) More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 2 alkoxy group” (C 1 -C 2 halogenated alkoxy group), Even more preferred is a trifluoromethoxy group.
本発明において、「C1-C6アルキルスルホニル基」は、1個の前記「C1-C6アルキル基」がスルホニル基に結合した基であり、炭素数1乃至6個の直鎖又は分枝鎖アルキルスルホニル基である。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、イソブチルスルホニル、s-ブチルスルホニル又はペンチルスルホニル基であり、好適には、炭素数1乃至4個の直鎖又は分枝鎖アルキルスルホニル基(C1-C4アルキルスルホニル基)であり、より好適には、メチルスルホニル又はエチルスルホニル基(C1-C2アルキルスルホニル基)であり、更により好適には、メチルスルホニル基である。
In the present invention, a “C 1 -C 6 alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a sulfonyl group, and is a straight chain or branched group having 1 to 6 carbon atoms. It is a branched alkylsulfonyl group. For example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl or pentylsulfonyl group, preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms A group (C 1 -C 4 alkylsulfonyl group), more preferably a methylsulfonyl group or an ethylsulfonyl group (C 1 -C 2 alkylsulfonyl group), and even more preferably a methylsulfonyl group.
本発明において、「C1-C6ハロゲン化アルキルスルホニル基」は、1個の前記「C1-C6ハロゲン化アルキル基」がスルホニル基に結合した基であり、炭素数1乃至6個の直鎖又は分枝鎖ハロゲン化アルキルスルホニル基である。例えば、トリフルオロメチルスルホニル、トリクロロメチルスルホニル、ジフルオロメチルスルホニル、ジクロロメチルスルホニル、フルオロメチルスルホニル、2,2,2-トリフルオロエチルスルホニル又は2-フルオロエチルスルホニル基であり、好適には、炭素数1乃至4個の直鎖又は分枝鎖ハロゲン化アルキルスルホニル基(C1-C4ハロゲン化アルキルスルホニル基)であり、より好適には、炭素数1又は2個の直鎖又は分枝鎖ハロゲン化アルキルスルホニル基(C1-C2ハロゲン化アルキルスルホニル基)であり、更により好適には、トリフルオロメチルスルホニル基である。
In the present invention, the “C 1 -C 6 halogenated alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a sulfonyl group, and has 1 to 6 carbon atoms. A straight-chain or branched alkylsulfonyl halide group; For example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl or 2-fluoroethylsulfonyl group, preferably having 1 carbon atom Or a straight chain or branched chain alkylsulfonyl group having 4 to 4 straight chain or branched chain (C 1 -C 4 halogenated alkylsulfonyl group), more preferably a straight chain or branched chain halogenated group having 1 or 2 carbon atoms. An alkylsulfonyl group (C 1 -C 2 halogenated alkylsulfonyl group), and even more preferably a trifluoromethylsulfonyl group.
本発明において、「C3-C6シクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基である。好適には、シクロプロピル基である。
In the present invention, the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.
本発明において、「C3-C6シクロアルキルスルホニル基」は、シクロプロピルスルホニル基、シクロブチルスルホニル基、シクロペンチルスルホニル基又はシクロヘキシルスルホニル基である。好適には、シクロプロピルスルホニル基である。
In the present invention, the “C 3 -C 6 cycloalkylsulfonyl group” is a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group or a cyclohexylsulfonyl group. Preferred is a cyclopropylsulfonyl group.
本発明において、「(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基」は、1個の前記「C1-C6アルコキシ基」が前記「C1-C6アルキルスルホニル基」に結合した基である。例えば、メトキシメチルスルホニル、エトキシメチルスルホニル、プロポキシメチルスルホニル、イソプロポキシメチルスルホニル、ブトキシメチルスルホニル又はs-ブトキシメチルスルホニル基であり、好適には、1個の前記「C1-C4アルコキシ基」が前記「C1-C4アルキルスルホニル基」に結合した基((C1-C4アルコキシ)-(C1-C4アルキルスルホニル)基)であり、より好適には、1個の前記「C1-C2アルコキシ基」が前記「C1-C2アルキルスルホニル基」に結合した基((C1-C2アルコキシ)-(C1-C2アルキルスルホニル)基)であり、更により好適には、メトキシメチルスルホニル基である。
In the present invention, “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group” means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkylsulfonyl”. A group bonded to “group”. For example, a methoxymethylsulfonyl, ethoxymethylsulfonyl, propoxymethylsulfonyl, isopropoxymethylsulfonyl, butoxymethylsulfonyl or s-butoxymethylsulfonyl group, and preferably one of the above “C 1 -C 4 alkoxy groups” is A group ((C 1 -C 4 alkoxy)-(C 1 -C 4 alkylsulfonyl) group) bonded to the “C 1 -C 4 alkylsulfonyl group”, and more preferably one “C 1 -C 4 alkylsulfonyl group” The “1- C 2 alkoxy group” is a group ((C 1 -C 2 alkoxy)-(C 1 -C 2 alkylsulfonyl) group) bonded to the “C 1 -C 2 alkylsulfonyl group”, and more preferably Is a methoxymethylsulfonyl group.
本発明において、「(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基」は、1個の前記「C1-C6ハロゲン化アルコキシ基」が前記「C1-C6アルキルスルホニル基」に結合した基である。例えば、トリフルオロメトキシメチルスルホニル、トリクロロメトキシメチルスルホニル、ジフルオロメトキシメチルスルホニル、ジクロロメトキシメチルスルホニル又はフルオロメトキシメチルスルホニル基であり、好適には、1個の前記「C1-C4ハロゲン化アルコキシ基」が前記「C1-C4アルキルスルホニル基」に結合した基((C1-C4ハロゲン化アルコキシ)-(C1-C4アルキルスルホニル)基)であり、より好適には、1個の前記「C1-C2ハロゲン化アルコキシ基」が前記「C1-C2アルキルスルホニル基」に結合した基((C1-C2ハロゲン化アルコキシ)-(C1-C2アルキルスルホニル)基)であり、更により好適には、トリフルオロメトキシメチルスルホニル基である。
In the present invention, “(C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group” means that one “C 1 -C 6 halogenated alkoxy group” is the above “C 1- A group bonded to a “C 6 alkylsulfonyl group”. For example, it is a trifluoromethoxymethylsulfonyl, trichloromethoxymethylsulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethylsulfonyl or fluoromethoxymethylsulfonyl group, preferably one of the aforementioned “C 1 -C 4 halogenated alkoxy groups” Is a group ((C 1 -C 4 halogenated alkoxy)-(C 1 -C 4 alkylsulfonyl) group) bonded to the “C 1 -C 4 alkylsulfonyl group”, more preferably one A group ((C 1 -C 2 halogenated alkoxy)-(C 1 -C 2 alkylsulfonyl) group in which the “C 1 -C 2 halogenated alkoxy group” is bonded to the “C 1 -C 2 alkylsulfonyl group”; And more preferably a trifluoromethoxymethylsulfonyl group.
本発明において、「置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基」は、フェニル基又は置換基群Aから選択される基で独立に1乃至5個置換されているフェニル基である。好適には、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基であり、より好適には、3-メトキシフェニル基又は4-メチルスルホニルフェニル基である。
In the present invention, the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted. Preferable is a phenyl group substituted by one at 4-position or 3-position with a group selected from substituent group C, and more preferable is 3-methoxyphenyl group or 4-methylsulfonylphenyl group. .
本発明において、「置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基」は、ピリジル基、置換基群Aから選択される基で独立に1乃至3個置換されているピリジル基、ピラジニル基又は置換基群Aから選択される基で独立に1乃至3個置換されているピラジニル基である。好適には、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基であり、より好適には、2-メチルアミノカルボニル-5-ピリジル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基である。
In the present invention, “a pyridyl group or a pyrazinyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A” is independently a group selected from the pyridyl group and the substituent group A. 1 to 3 substituted pyridyl groups, pyrazinyl groups, or a pyrazinyl group independently substituted with 1 to 3 groups selected from substituent group A. Preferably, a 5-pyridyl group substituted at the 2-position with a group selected from Substituent Group C or 2-pyrazinyl substituted at the 5-position with a group selected from Substituent Group C More preferably a 2-methylaminocarbonyl-5-pyridyl group, a 2-methylsulfonyl-5-pyridyl group, a 2-methylaminosulfonyl-5-pyridyl group, and a 5-methylsulfonyl-2-pyrazinyl group. Or a 5-methylaminosulfonyl-2-pyrazinyl group.
本発明において、「置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基」は、C1-C6アルキル基又は置換基群Bから選択される基で独立に1乃至5個置換されているC1-C6アルキル基である。好適には、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基であり、より好適には、メチル基、エチル基、イソプロピル基、(1S)-2-フルオロ-1-メチルエチル基、ジフルオロメチル基又は1,3-ジフルオロー2-プロピル基である。
In the present invention, “a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group B” refers to a C 1 -C 6 alkyl group or the substituent group B C 1 -C 6 alkyl group independently substituted with 1 to 5 selected groups. Preferably, it is a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 halogen atoms, more preferably a methyl group, an ethyl group, an isopropyl group, (1S) -2-fluoro. A 1-methylethyl group, a difluoromethyl group or a 1,3-difluoro-2-propyl group;
本発明において、「3乃至6員環エーテル」は、オキシラン、オキセタン、テトラヒドロフラン又はテトラヒドロピランである。好適には、テトラヒドロフランである。
In the present invention, the “3- to 6-membered cyclic ether” is oxirane, oxetane, tetrahydrofuran or tetrahydropyran. Tetrahydrofuran is preferred.
本発明において、「酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環」は、C3-C6シクロアルキル基、3乃至6員環エーテル又は3乃至6員環アミンであり、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、オキシラン、オキセタン、テトラヒドロフラン、テトラヒドロピラン、アジリジン、アゼチジン、ピロリジン又はピペリジンである。好適には、シクロペンタン、テトラヒドロフラン又はピロリジンである。
In the present invention, the “3- to 6-membered saturated ring optionally containing one oxygen atom or nitrogen atom” is a C 3 -C 6 cycloalkyl group, a 3- to 6-membered ring ether, or a 3- to 6-membered ring amine, Cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine or piperidine. Preference is given to cyclopentane, tetrahydrofuran or pyrrolidine.
本発明において、「(C1-C6アルキル基、C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環」は、酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環又はC1-C6アルキル基、C3-C6シクロアルキル基及びオキソ基からなる群で独立に1乃至3個置換されている酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環である。例えば、前記「酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環」、シクロペンタノン、シクロヘキサノン、テトラヒドロ-2-フラノン、テトラヒドロ-2-ピロン、2-アゼチジノン、2-ピロリジノン、2-ピペリジノン、メチルシクロペンチル、メチルシクロヘキシル、メチルテトラヒドロフラン、メチルテトラヒドロピラン、メチルピロリジン、メチルピペリジン、1-メチル-2-ピロリジノン又は1-シクロプロピルピロリジン-2-オンであり、好適には、シクロプロパン、シクロペンタノン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロ-2-フラノン、1-メチル-2-ピロリジノン又は1-シクロプロピルピロリジン-2-オンであり、より好適には、シクロペンタノン、テトラヒドロフラン又は1-シクロプロピルピロリジン-2-オンである。
In the present invention, one to three independently substituted oxygen groups or one nitrogen atom may be substituted with a group consisting of “(C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group and oxo group)”. The “3- to 6-membered saturated ring which may be contained” means a 3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom, or a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group and an oxo group. A 3- to 6-membered saturated ring which may contain one oxygen atom or one nitrogen atom independently substituted by 1 to 3 groups. For example, the above “3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom”, cyclopentanone, cyclohexanone, tetrahydro-2-furanone, tetrahydro-2-pyrone, 2-azetidinone, 2-pyrrolidinone, 2 -Piperidinone, methylcyclopentyl, methylcyclohexyl, methyltetrahydrofuran, methyltetrahydropyran, methylpyrrolidine, methylpiperidine, 1-methyl-2-pyrrolidinone or 1-cyclopropylpyrrolidin-2-one, preferably cyclopropane, cyclo Pentanone, tetrahydrofuran, tetrahydropyran, tetrahydro-2-furanone, 1-methyl-2-pyrrolidinone or 1-cyclopropylpyrrolidin-2-one, more preferably cyclopentanone, tetrahydrofuran Down or 1-cyclopropyl-2-one.
本発明において、「R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい」は、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環(窒素原子を1個含み、更に1個の酸素原子又は窒素原子を含有してよい4乃至6員の完全還元型の飽和複素環基)であり、例えば、アゼチジン、ピロリジン、ピペリジン、モルホリン、ピペラジン、2-アゼチジノン、2-ピロリジノン、2-ピペリジノン、ジメチルモルホリン、メチルピペラジン又はジメチルピペラジンであり、好適には、アゼチジン、ピロリジン又はモルホリンである。
In the present invention, “1 to 3 which may be independently substituted with a group consisting of a C 1 -C 6 alkyl group and an oxo group together with the nitrogen atom to which R 4 and R 5 are bonded may be used. A 4 to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom ”is independently selected from the group consisting of a C 1 -C 6 alkyl group and an oxo group. 4 to 6-membered hetero-saturated ring which may be substituted by 3 to 4 (a 4- to 6-membered fully-reduced saturated heterocyclic ring which contains one nitrogen atom and further contains one oxygen atom or nitrogen atom) Group), for example, azetidine, pyrrolidine, piperidine, morpholine, piperazine, 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, dimethylmorpholine, methylpiperazine or dimethylpiperazine, and preferably Zechijin, pyrrolidine or morpholine.
本発明において、「式-V-NR6R7で表わされる基」は、「式-C(=O)-NR6R7で表わされる基」又は「式-SO2-NR6R7で表わされる基」である。
In the present invention, the “group represented by the formula —V—NR 6 R 7 ” is the “group represented by the formula —C (═O) —NR 6 R 7 ” or “the formula —SO 2 —NR 6 R 7” . Group represented ".
本発明において、「R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)」は、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環(窒素原子を1個含み、更に1個の酸素原子又は窒素原子を含有してよい4乃至6員の完全還元型の飽和複素環基)であり、例えば、アゼチジン、ピロリジン、ピペリジン、モルホリン、ピペラジン、ジメチルモルホリン、メチルピペラジン又はジメチルピペラジンであり、好適には、アゼチジン又は4-メチルピペラジンである。
In the present invention, “a 6 to 6-membered heterosaturated ring which may be independently substituted with one or two C 1 -C 6 alkyl groups together with the nitrogen atom to which R 6 and R 7 are bonded. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.) ”May be independently substituted with one or two C 1 -C 6 alkyl groups. To 6-membered heterosaturated ring (a 4- to 6-membered fully reduced saturated heterocyclic group containing one nitrogen atom and further containing one oxygen atom or nitrogen atom), such as azetidine, pyrrolidine , Piperidine, morpholine, piperazine, dimethylmorpholine, methylpiperazine or dimethylpiperazine, preferably azetidine or 4-methylpiperazine.
本発明において、好適なR1は、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基であり、一般式(I)が一般式(Ia)の場合、より好適なR1は、カルバモイル基である。一般式(I)が一般式(Ib)の場合、より好適なR1は、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基である。一般式(I)が一般式(Ic)の場合、より好適なR1は、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基である。
In the present invention, R 1 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group. And when general formula (I) is general formula (Ia), R 1 is more preferably a carbamoyl group. When the general formula (I) is the general formula (Ib), more preferable R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group. When the general formula (I) is the general formula (Ic), more preferable R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, or a (1S) -1,2-dihydroxyethyl group. is there.
本発明において、好適なR2は、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基(置換基群Cは、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群)であり、より好適なR2は、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基である。
In the present invention, R 2 is preferably a phenyl group substituted by one of the 4-position or 3-position with a group selected from Substituent Group C, and one 2-position of a group selected from Substituent Group C. A substituted 5-pyridyl group or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C (Substituent Group C is a C 1 -C 6 alkoxy group, C 1- A C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and each represents a hydrogen atom or C 1 -C 6; More preferably R 2 represents a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, a 2-methylsulfonyl-5. -Pyridyl group, 2-methylamino Sulfonyl-5-pyridyl group, a 5-methylsulfonyl-2-pyrazinyl or 5-methyl-aminosulfonyl-2-pyrazinyl group.
本発明において、Uが酸素原子の場合、好適なR3は、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環である。Uがカルボニル基の場合、好適なR3は、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)である。
In the present invention, when U is an oxygen atom, preferred R 3 is a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group) which may be independently substituted with 1 to 5 halogen atoms. A 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom. When U is a carbonyl group, preferred R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 may be the same or different and each represents a hydrogen atom or C 1 — A C 6 alkyl group).
本発明において、好適な式-NR4R5で表わされる基は、ジメチルアミノ基である。
In the present invention, the preferred group represented by the formula —NR 4 R 5 is a dimethylamino group.
本発明において、好適な式-U-R3で表わされる基は、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である。
In the present invention, preferable groups represented by the formula -UR 3 are methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3- A difluoro-2-propoxy group, a cyclopentanone-2-yloxy group, a tetrahydrofuran-3-yloxy group, a 1-cyclopropylpyrrolidin-2-one-3-yloxy group, an isopropylcarbonyl group or a dimethylaminocarbonyl group.
本発明において、好適な式-NR6R7で表わされる基は、メチルアミノ基である。
In the present invention, the preferred group represented by the formula —NR 6 R 7 is a methylamino group.
本発明において、好適なnは、1である。
In the present invention, n is preferably 1.
本発明において、好適な置換基群Aは、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、より好適な置換基群Aは、メトキシ基、メチルアミノカルボニル基、メチルスルホニル基又はメチルアミノスルホニル基である。
In the present invention, the preferred substituent group A includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group, and a group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) R 6 and R 7 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group.), And more preferred substituent group A includes a methoxy group, a methylaminocarbonyl group, a methyl group A sulfonyl group or a methylaminosulfonyl group.
本発明において、好適な置換基群Bは、ハロゲン原子であり、より好適な置換基群Bは、フッ素原子である。
In the present invention, a preferred substituent group B is a halogen atom, and a more preferred substituent group B is a fluorine atom.
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、全ての異性体(ケト-エノール異性体、ジアステレオ異性体、光学異性体、回転異性体等)を有する。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、その分子内に不斉炭素原子が存在するので、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式(I)で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
上記のような立体異性体は、光学活性な原料化合物を用いるか、又は不斉合成若しくは不斉誘導の手法を用いて本発明に係る化合物を合成するか、或いは合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。
For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、このような化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素(2H)、トリチウム(3H)、ヨウ素-125(125I)又は炭素-14(14C)などが挙げられる。また、前記化合物は、例えば、トリチウム(3H)、ヨウ素-125(125I)又は炭素-14(14C)などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
「その薬理上許容される塩」とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の一般式(I)を有する化合物は、塩基性の基を有する場合には酸と反応させることにより、又、酸性の基を有する場合には塩基と反応させることにより、塩にすることができる。
“The pharmacologically acceptable salt” refers to a salt that has no significant toxicity and can be used as a medicine. When the compound having the general formula (I) of the present invention has a basic group, it is reacted with an acid, and when it has an acidic group, it is reacted with a base to form a salt. Can do.
塩基性基に基づく塩としては、例えば、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩;メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなC1-C6アルキルスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩のようなアリ-ルスルホン酸塩、酢酸塩、りんご酸塩、フマ-ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩;及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。
Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
一方、酸性基に基づく塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩;アンモニウム塩のような無機塩、t-オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、N-メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、N,N’-ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、N-ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス(ヒドロキシメチル)アミノメタン塩のような有機塩等のアミン塩;及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。
On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明の塩に包含される。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also included in the salts of the present invention.
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also the present invention. Included in the salt.
本発明の一般式(I)を有する化合物又はその薬理上許容される塩は、好適には、本発明の一般式(I)を有する化合物である。
The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably a compound having the general formula (I) of the present invention.
本発明において、「メタボリックシンドローム」とは、インスリン抵抗性を基盤とし、複数の冠血管危険因子の集積により、冠動脈疾患のリスクが著しく増加した病態(生活習慣病である高脂血症、糖尿病、肥満、高血圧等)を意味する(Diabetes, Obesity and Metabolism, 9, 2007, 246-258、Journal of the American Medical Association, 285: 2486-2497 (2001)、Diabet. Med., 15: 539-553(1998))。
In the present invention, “metabolic syndrome” is based on insulin resistance, and a state in which the risk of coronary artery disease is significantly increased by accumulation of a plurality of coronary risk factors (lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc. (Diabetes, Obesity and Metabolism, 9, 2007, 246-258, Journal of the American Medical Association, oci285: 2486-2497 (2001), Diabet. Med., 15: 539-553 ( 1998)).
本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、優れたGK活性化作用を有しており、温血動物(好ましくは哺乳類動物であり、ヒトを含む)における、糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)及びメタボリックシンドロームからなる群から選ばれる疾患の予防及び/又は治療のための医薬として有用である。また、本発明により提供される一般式(I)で表される新規な化合物またはその薬理上許容される塩は、優れたGK活性化作用を有しており、温血動物(好ましくは哺乳類動物であり、ヒトを含む)における上記の疾患の予防及び/又は治療のための医薬の有効成分として有用である。好ましい疾患としては、糖尿病又は耐糖能異常である。好適には、上記の疾患の治療のための医薬として用いることができる。
The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammal, including humans). Diseases selected from the group consisting of diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and metabolic syndrome It is useful as a medicament for the prevention and / or treatment. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Preferred diseases are diabetes or impaired glucose tolerance. Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.
本発明の一般式(I)を有する化合物は、以下に記載するA法乃至U法に従って製造することができる。
The compound having the general formula (I) of the present invention can be produced according to Method A to Method U described below.
下記A法乃至U法の各工程の反応において使用される溶媒は、反応を阻害せず、出発原料をある程度溶解するものであれば特に限定はなく、例えば、下記溶媒群より選択される。溶媒群は、ペンタン、ヘキサン、オクタン、石油エーテル、リグロイン、シクロヘキサンのような炭化水素類;ホルムアミド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドン、N-メチル-2-ピロリジノン、ヘキサメチルリン酸トリアミドのようなアミド類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテル、シクロペンチルメチルエーテルのようなエーテル類;メタノール、エタノール、n-プロパノール、i-プロパノール、n-ブタノール、2-ブタノール、2-メチル-1-プロパノール、t-ブタノール、イソアミルアルコール、ジエチレングリコール、グリセリン、オクタノール、シクロヘキサノール、メチルセロソルブのようなアルコール類;ジメチルスルホキシドのようなスルホキシド類;スルホランのようなスルホン類;アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類;蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類;アセトン、2-ブタノン、4-メチル-2-ペンタノン、メチルイソブチルケトン、イソホロン、シクロヘキサノンのようなケトン類;ニトロエタン、ニトロベンゼンのようなニトロ化合物類;ジクロロメタン、1,2-ジクロロエタン、クロロベンゼン、ジクロロベンゼン、クロロホルム、四塩化炭素のようなハロゲン化炭化水素類;ベンゼン、トルエン、キシレンのような芳香族炭化水素類;酢酸、蟻酸、プロピオン酸、ブチリル酸、トリフルオロ酢酸のようなカルボン酸類;N-メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、N-メチルピペリジン、ピリジン、2,6-ルチジン、4-ピロリジノピリジン、ピコリン、4-ジメチルアミノピリジン、2,6-ジ(t-ブチル)-4-メチルピリジン、キノリン、N,N-ジメチルアニリン、N,N-ジエチルアニリン、1,5-ジアザビシクロ[4.3.0]ノナ-5-エン(DBN)、1,4-ジアザビシクロ[2.2.2]オクタン(DABCO)、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、ピペリジンのようなアミン類;水;及び、これらの混合溶媒からなる。
The solvent used in the reaction in each step of the following methods A to U is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ketones such as acetone, 2-butanone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, Halogenated hydrocarbons such as 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; acetic acid, formic acid, propionic acid, Carboxylic acids such as lauric acid and trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine , Picoline, 4-dimethylaminopyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3 .0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), An amine such as piperidine; water; and a mixed solvent thereof.
下記A法乃至U法の各工程の反応において使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム、炭酸リチウム、炭酸セシウムのようなアルカリ金属炭酸塩類;炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウムのようなアルカリ金属炭酸水素塩類;酢酸ナトリウム、酢酸カリウム、酢酸リチウム、酢酸セシウムのようなアルカリ金属酢酸塩類;水素化リチウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物類;水酸化ナトリウム、水酸化カリウム、水酸化バリウム、水酸化リチウムのようなアルカリ金属水酸化物類;弗化ナトリウム、弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類;ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム-t-ブトキシド、カリウムメトキシド、カリウムエトキシド、カリウム-t-ブトキシド、リチウムメトキシドのようなアルカリ金属アルコキシド類;ナトリウムトリメチルシロキシド、カリウムトリメチルシロキシド、リチウムトリメチルシロキシドのようなアルカリ金属トリアルキルシロキシド類;ナトリウムチオメトキシド、ナトリウムチオエトキシドのようなメルカプタンアルカリ金属類;N-メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、N,N-ジイソプロピルエチルアミン、ジシクロヘキシルアミン、N-メチルピペリジン、ピリジン、2,6-ルチジン、4-ピロリジノピリジン、ピコリン、4-ジメチルアミノピリジン、2,6-ジ(t-ブチル)-4-メチルピリジン、キノリン、N,N-ジメチルアニリン、N,N-ジエチルアニリン、1,5-ジアザビシクロ[4.3.0]ノナ-5-エン(DBN)、1,4-ジアザビシクロ[2.2.2]オクタン(DABCO)、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)のような有機塩基類;n-ブチルリチウム、リチウムジイソプロピルアミド、リチウム ビス(トリメチルシリル)アミドのような有機金属塩基類;又は、プロリンのようなアミノ酸である。
The base used in the reaction of each step of the following methods A to U is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxy Sodium-t-butoxide, potassium methoxide, Alkali metal alkoxides such as lithium ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; sodium thiomethoxide Mercaptan alkali metals such as sodium thioethoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4-dimethylaminopyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-die Ruaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU); organometallic bases such as n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or amino acids such as proline.
下記A法乃至U法の各工程の反応において使用される縮合剤は、例えば、O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスファート(HATU)、1-プロパンホスホン酸 環状無水物(T3P)、ジシクロヘキシルカルボジイミド(DCCD)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩(WSCI・HCl)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド 塩酸塩(EDCI)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(EDAC)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウム クロリド n水和物(DMT-MM)、クロロぎ酸イソブチル(IBCF)、1,1’-カルボニルビス-1H-イミダゾール(CDI)、シアノホスホン酸ジエチル(DEPC)、ジフェニルリン酸アジド(DPPA)、N-ヒドロキシサクシンイミド、N-ヒドロキシ-5-ノルボルネン-2,3-ジカルボキシイミド又はジピリジルジスルフィドであり、必要に応じて1-ヒドロキシベンゾトリアゾール(HOBt)又は1-ヒドロキシベンゾトリアゾール 一水和物(HOBt・H2O)を共存させることもできる。
The condensing agent used in the reaction in each step of the following methods A to U is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI · HCl), 1-ethyl -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC), 4- (4,6-dimethoxy-1,3,5- Triazin-2-yl) -4-methylmorpholinium chloride n-hydrate (DMT-MM), isobutyl chloroformate IBCF), 1,1′-carbonylbis-1H-imidazole (CDI), diethyl cyanophosphonate (DEPC), diphenyl phosphate azide (DPPA), N-hydroxysuccinimide, N-hydroxy-5-norbornene-2, It is 3-dicarboximide or dipyridyl disulfide, and 1-hydroxybenzotriazole (HOBt) or 1-hydroxybenzotriazole monohydrate (HOBt · H 2 O) can be coexisted as necessary.
下記A法乃至U法の各工程の反応において使用される脱メチル化剤は、例えば、ナトリウムチオメトキシド、ナトリウムチオエトキシド、ナトリウムチオフェノキシド、ヨードトリメチルシラン、塩化アルミニウム、臭化アルミニウム、三臭化ホウ素、三ヨウ化ホウ素、ヨウ化メチルマグネシウム、臭化水素である。
Examples of the demethylating agent used in the reaction of each step of the following methods A to U include sodium thiomethoxide, sodium thioethoxide, sodium thiophenoxide, iodotrimethylsilane, aluminum chloride, aluminum bromide, and three odors. Boron iodide, boron triiodide, methylmagnesium iodide, and hydrogen bromide.
下記A法乃至U法の各工程の反応において使用されるパラジウム触媒は、例えば、テトラキス(トリフェニルホスフィン)パラジウム(0)、パラジウム-活性炭素、酢酸パラジウム(II)、トリフルオロ酢酸パラジウム(II)、パラジウム黒、臭化パラジウム(II)、塩化パラジウム(II)、沃化パラジウム(II)、シアン化パラジウム(II)、硝酸パラジウム(II)、酸化パラジウム(II)、硫酸パラジウム(II)、ジクロロビス(アセトニトリル)パラジウム(II)、ジクロロビス(ベンゾニトリル)パラジウム(II)、ジクロロ(1,5-シクロオクタジエン)パラジウム(II)、アセチルアセトンパラジウム(II)、硫化パラジウム(II)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド、トリス(ジベンジリデンアセトン)ジパラジウム(0)、テトラキス(アセトニトリル)パラジウム(II)テトラフルオロボレート又は塩化アリールパラジウムダイマーのような0価のパラジウム触媒又は2価のパラジウム触媒である。
The palladium catalyst used in the reaction in each step of the following methods A to U is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II) , Palladium black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (Acetonitrile) palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium (II) sulfide, [1,1 ' -Bis (diphenylphosphino) ferrocene] Zero-valent or divalent palladium catalysts such as palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (acetonitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer. .
下記A法乃至U法の各工程の反応において使用される酸化剤は、例えば、m-クロロ過安息香酸、過酸化水素水、オキソン又は二酸化マンガンのような無機酸化剤である。
The oxidizing agent used in the reaction of each step of the following methods A to U is an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide solution, oxone or manganese dioxide.
下記A法乃至U法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。
In the reaction of each step of the following methods A to U, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
下記A法乃至U法の各工程の反応において、反応終了後、各目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、目的化合物を含む有機層を分離し、水等で洗浄後、無水硫酸マグネシウム、無水硫酸ナトリウム等で乾燥、ろ過後、溶剤を留去することによって得られる。得られた目的化合物は必要ならば、常法、例えば再結晶、再沈殿等の通常、有機化合物の分離精製に慣用されている方法を適宜組合せ、クロマトグラフィーを応用し、適切な溶離剤で溶出することによって分離、精製することができる。溶媒に不溶の目的化合物では、得られた固体の粗生成物を溶媒で洗浄して、精製することができる。また、各工程の目的化合物は精製することなくそのまま次の反応に使用することもできる。
In the reaction of each step of Method A to Method U below, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.
下記A法乃至U法の各工程の反応において、Meはメチル基を、iPrはイソプロピル基を、Acはアセチル基を、Bnはベンジル基を、Bocはt-ブトキシカルボニル基を示す。
In the reaction of each step of the following methods A to U, Me represents a methyl group, iPr represents an isopropyl group, Ac represents an acetyl group, Bn represents a benzyl group, and Boc represents a t-butoxycarbonyl group.
A法は、一般式(I)を有する化合物の中で、Uが酸素原子である一般式(Id)を有する化合物を製造する方法である。
Method A is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
本発明において、R2及びR3は、前述したものと同意義を示し、R8がC1-C6アルキル基(好適には、メチル基又はエチル基である。)を示し、R9、R10、R11及びR12は、水素原子又はR1の一つの基を示し、Xは、ハロゲン原子(好適には、塩素原子、臭素原子又はヨウ素原子であり、より好適には、臭素原子である。)を示し、Yは、ハロゲン原子、C1-C6アルキルスルホニルオキシ基、C1-C6アルコキシスルホニルオキシ基又はC6-C10アリールスルホニルオキシ基(好適には、ハロゲン原子であり、より好適には、フッ素原子又は塩素原子であり、更により好適には、フッ素原子である。)を示し、R2a、R3a、R9a、R10a、R11a及びR12aは、R2、R3、R9、R10、R11及びR12の基に置換基として含まれるアミノ基、ヒドロキシ基及び/又はカルボキシル基が、保護されてもよいアミノ基、ヒドロキシ基及び/又はカルボキシル基である他、R2、R3、R9、R10、R11及びR12の基の定義における基と同様の基を示す。
In the present invention, R 2 and R 3 are as defined above, R 8 represents a C 1 -C 6 alkyl group (preferably a methyl group or an ethyl group), R 9 , R 10 , R 11 and R 12 represent a hydrogen atom or one group of R 1 , and X is a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom Y represents a halogen atom, a C 1 -C 6 alkylsulfonyloxy group, a C 1 -C 6 alkoxysulfonyloxy group or a C 6 -C 10 arylsulfonyloxy group (preferably a halogen atom) R 2a , R 3a , R 9a , R 10a , R 11a, and R 12a are R, and more preferably a fluorine atom or a chlorine atom, and even more preferably a fluorine atom. 2, R 3 R 9, R 10, amino group contained as a substituent group of R 11 and R 12, hydroxy and / or carboxyl groups, addition is a protected amino group which may, hydroxyl and / or carboxyl group, The group similar to the group in the definition of group of R < 2 >, R < 3 >, R < 9 >, R < 10 >, R < 11 > and R < 12 > is shown.
第A1工程
本工程は、一般式(III)を有する化合物を製造する工程である。 Step A1 This step is a step of producing a compound having the general formula (III).
本工程は、一般式(III)を有する化合物を製造する工程である。 Step A1 This step is a step of producing a compound having the general formula (III).
本工程は、溶媒中、一般式(II)を有する化合物を、脱メチル化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (II) with a demethylating agent in a solvent.
本工程において使用される一般式(II)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類であり、より好適には、N,N-ジメチルホルムアミド又はN-メチル-2-ピロリジノンである。
The solvent used in this step is preferably an amide, more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidinone.
本工程において使用される脱メチル化剤は、好適には、ナトリウムチオメトキシドである。
The demethylating agent used in this step is preferably sodium thiomethoxide.
本工程における反応温度は、通常、50℃乃至140℃であり、好適には80℃乃至120℃である。
The reaction temperature in this step is usually 50 ° C. to 140 ° C., preferably 80 ° C. to 120 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至5時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
第A2工程
本工程は、一般式(V)を有する化合物を製造する工程である。 Step A2 This step is a step of producing a compound having the general formula (V).
本工程は、一般式(V)を有する化合物を製造する工程である。 Step A2 This step is a step of producing a compound having the general formula (V).
本工程は、溶媒中、塩基の存在下、一般式(III)を有する化合物を、一般式(IV)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (III) with a compound having the general formula (IV) in a solvent in the presence of a base.
本工程において使用される一般式(IV)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (IV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類又はニトリル類であり、より好適には、N,N-ジメチルホルムアミド又はアセトニトリルである。
The solvent used in this step is preferably an amide or a nitrile, and more preferably N, N-dimethylformamide or acetonitrile.
本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウム又は炭酸セシウムである。
The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate or cesium carbonate.
本工程における反応温度は、通常、-10℃乃至140℃であり、好適には0℃乃至120℃である。
The reaction temperature in this step is usually −10 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.
本工程における反応時間は、通常、0.5時間乃至72時間であり、好適には1時間乃至48時間である。
The reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 48 hours.
第A3工程
本工程は、一般式(VI)を有する化合物を製造する工程である。 Step A3 This step is a step of producing a compound having the general formula (VI).
本工程は、一般式(VI)を有する化合物を製造する工程である。 Step A3 This step is a step of producing a compound having the general formula (VI).
本工程は、溶媒中、一般式(V)を有する化合物を、脱メチル化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (V) with a demethylating agent in a solvent.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される脱メチル化剤は、好適には、三臭化ホウ素である。
The demethylating agent used in this step is preferably boron tribromide.
本工程における反応温度は、通常、-100℃乃至40℃であり、好適には-78℃乃至25℃である。
The reaction temperature in this step is usually −100 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.
本工程における反応時間は、通常、1時間乃至72時間であり、好適には12時間乃至36時間である。
The reaction time in this step is usually 1 hour to 72 hours, preferably 12 hours to 36 hours.
第A4工程
本工程は、一般式(VII)を有する化合物を製造する工程である。 Step A4 This step is a step of producing a compound having the general formula (VII).
本工程は、一般式(VII)を有する化合物を製造する工程である。 Step A4 This step is a step of producing a compound having the general formula (VII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(VI)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより行われる。
This step is performed by reacting a compound having the general formula (VI) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
本工程において使用される溶媒は、好適には、アミド類であり、より好適には、N,N-ジメチルホルムアミドである。
The solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
本工程において使用されるパラジウム触媒は、好適には、II価のパラジウム触媒であり、より好適には、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体である。
The palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
本工程において使用される無機塩基は、好適には、アルカリ金属酢酸塩類であり、より好適には、酢酸カリウムである。
The inorganic base used in this step is preferably an alkali metal acetate, and more preferably potassium acetate.
本工程における反応温度は、通常、50℃乃至130℃であり、好適には70℃乃至110℃である。
The reaction temperature in this step is usually 50 ° C to 130 ° C, preferably 70 ° C to 110 ° C.
本工程における反応時間は、通常、1時間乃至24時間であり、好適には2時間乃至10時間である。
The reaction time in this step is usually 1 to 24 hours, preferably 2 to 10 hours.
第A5工程
本工程は、一般式(IX)を有する化合物を製造する工程である。 Step A5 This step is a step of producing a compound having the general formula (IX).
本工程は、一般式(IX)を有する化合物を製造する工程である。 Step A5 This step is a step of producing a compound having the general formula (IX).
本工程は、溶媒中、トリフェニルホスフィン及びジエチルアゾジカルボキシラートの存在下、一般式(VII)を有する化合物を、一般式(VIII)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (VII) with a compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent.
本工程において使用される一般式(VIII)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (VIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、エーテル類、芳香族炭化水素類又はこれらの混合溶媒であり、より好適には、テトラヒドロフラン、トルエン又はテトラヒドロフランとトルエンの混合溶媒である。
The solvent used in this step is preferably an ether, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably tetrahydrofuran, toluene, or a mixed solvent of tetrahydrofuran and toluene.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至72時間であり、好適には1時間乃至36時間である。
The reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 36 hours.
第A6工程
本工程は、一般式(XI)を有する化合物を製造する工程である。 Step A6 This step is a step of producing a compound having the general formula (XI).
本工程は、一般式(XI)を有する化合物を製造する工程である。 Step A6 This step is a step of producing a compound having the general formula (XI).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(IX)を有する化合物を、一般式(X)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (IX) with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base.
本工程において使用される溶媒は、好適には、エーテル類、アルコール類、芳香族炭化水素類又はこれらの混合溶媒であり、より好適には、ジオキサン、エタノール、トルエン又はこれらの混合溶媒であり、更により好適には、ジオキサン又はエタノールとトルエンの混合溶媒である。
The solvent used in this step is preferably an ether, alcohol, aromatic hydrocarbon or a mixed solvent thereof, more preferably dioxane, ethanol, toluene or a mixed solvent thereof. Even more preferred is dioxane or a mixed solvent of ethanol and toluene.
本工程において使用されるパラジウム触媒は、好適には、II価のパラジウム触媒であり、より好適には、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体である。
The palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
本工程において使用される無機塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムであり、更により好適には、炭酸カリウム水溶液である。
The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
本工程における反応温度は、通常、25℃乃至100℃であり、好適には40℃乃至70℃である。
The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至5時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
第A7工程
本工程は、一般式(XII)を有する化合物を製造する工程である。 Step A7 This step is a step of producing a compound having the general formula (XII).
本工程は、一般式(XII)を有する化合物を製造する工程である。 Step A7 This step is a step of producing a compound having the general formula (XII).
本工程は、溶媒中、一般式(XI)を有する化合物を、酸と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XI) with an acid in a solvent.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される酸は、例えば、塩化水素ガス、臭化水素ガスのようなハロゲン化水素類;硫酸、臭化水素酸、塩酸のような鉱酸類;メタンスルホン酸、p-トルエンスルホン酸、p-トルエンスルホン酸ピリジニウム(PPTS)、カンファースルホン酸、トリフルオロメタンスルホン酸のような有機スルホン酸類;酢酸、蟻酸、トリフルオロ酢酸のようなカルボン酸類;塩化アルミ、塩化亜鉛、ヨウ化亜鉛、四塩化スズ、三塩化チタン、ボロントリフルオリド、ボロントリブロミドのようなルイス酸;又は、酸性イオン交換樹脂であり、好適には、カルボン酸類であり、より好適には、トリフルオロ酢酸である。
Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; methanesulfonic acid and p-toluenesulfonic acid , Organic sulfonic acids such as pyridinium p-toluenesulfonate (PPTS), camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid and trifluoroacetic acid; aluminum chloride, zinc chloride, zinc iodide, tetra Lewis acids such as tin chloride, titanium trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins, preferably carboxylic acids, and more preferably trifluoroacetic acid.
本工程における反応温度は、通常、-20℃乃至60℃であり、好適には0℃乃至40℃である。
The reaction temperature in this step is usually −20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.
本工程における反応時間は、通常、0.1時間乃至5時間であり、好適には0.5時間乃至3時間である。
The reaction time in this step is usually 0.1 to 5 hours, preferably 0.5 to 3 hours.
第A8工程
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step A8 This step is a step of producing a compound having the general formula (XIII).
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step A8 This step is a step of producing a compound having the general formula (XIII).
本工程は、溶媒中、一般式(XII)を有する化合物を、塩基と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XII) with a base in a solvent.
本工程において使用される溶媒は、好適には、アルコール類であり、より好適には、エタノールである。
The solvent used in this step is preferably an alcohol, and more preferably ethanol.
本工程において使用される塩基は、好適には、アルカリ金属水酸化物類であり、より好適には、水酸化ナトリウムであり、更により好適には、水酸化ナトリウム水溶液である。
The base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide, and even more preferably an aqueous sodium hydroxide solution.
本工程における反応温度は、通常、25℃乃至100℃であり、好適には50℃乃至80℃である。
The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 50 ° C to 80 ° C.
本工程における反応時間は、通常、0.1時間乃至24時間であり、好適には0.5時間乃至6時間である。
The reaction time in this step is usually 0.1 to 24 hours, preferably 0.5 to 6 hours.
第A9工程
本工程は、一般式(XV)を有する化合物を製造する工程である。 Step A9 This step is a step of producing a compound having the general formula (XV).
本工程は、一般式(XV)を有する化合物を製造する工程である。 Step A9 This step is a step of producing a compound having the general formula (XV).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(XIII)を有する化合物を、一般式(XIV)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base.
本工程において使用される一般式(XIV)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (XIV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アルコール類、ハロゲン化炭化水素類、アミド類又はこれらの混合溶媒であり、より好適には、メタノール、ジクロロメタン、N,N-ジメチルホルムアミド又はジクロロメタンとN,N-ジメチルホルムアミドの混合溶媒である。
The solvent used in this step is preferably an alcohol, a halogenated hydrocarbon, an amide or a mixed solvent thereof, more preferably methanol, dichloromethane, N, N-dimethylformamide or dichloromethane. It is a mixed solvent of N, N-dimethylformamide.
本工程において使用される縮合剤は、好適には、DMT-MM、HATU又はWSCI・HClである。WSCI・HClが使用される場合、必要に応じてHOBt又はHOBT・H2Oを共存させることもできる。
The condensing agent used in this step is preferably DMT-MM, HATU or WSCI · HCl. When WSCI · HCl is used, HOBt or HOBT · H 2 O can coexist if necessary.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、N-メチルモルホリン、N,N-ジイソプロピルエチルアミン又は4-ジメチルアミノピリジンである。
The base used in this step is preferably an organic base, and more preferably N-methylmorpholine, N, N-diisopropylethylamine or 4-dimethylaminopyridine.
本工程における反応温度は、通常、-20℃乃至60℃であり、好適には0℃乃至30℃である。
The reaction temperature in this step is usually −20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
本工程における反応時間は、通常、0.5時間乃至72時間であり、好適には1時間乃至24時間である。
The reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
第A10工程
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step A10 This step is a step of producing a compound having the general formula (Id).
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step A10 This step is a step of producing a compound having the general formula (Id).
本工程は、溶媒中、一般式(XV)を有する化合物を、塩基及びメタンスルホン酸無水物又はビス(2-メトキシエチル)アミノサルファー トリフルオリドと反応させた後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
In this step, a compound having the general formula (XV) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
本工程において使用される溶媒は、メタンスルホン酸無水物が使用される場合、好適には、エーテル類であり、より好適には、テトラヒドロフラン又はジメトキシエタンである。ビス(2-メトキシエチル)アミノサルファー トリフルオリドが使用される場合、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
When the methanesulfonic anhydride is used, the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran or dimethoxyethane. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される塩基は、メタンスルホン酸無水物が使用される場合、好適には、有機塩基類であり、より好適には、トリエチルアミンである。ビス(2-メトキシエチル)アミノサルファー トリフルオリドが使用される場合、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムである。
When the methanesulfonic anhydride is used, the base used in this step is preferably an organic base, and more preferably triethylamine. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably an alkali metal carbonate, more preferably potassium carbonate.
本工程における反応温度は、通常、-100℃乃至85℃であり、メタンスルホン酸無水物が使用される場合、好適には10℃乃至60℃である。ビス(2-メトキシエチル)アミノサルファー トリフルオリドが使用される場合、好適には-78℃乃至30℃である。
The reaction temperature in this step is usually −100 ° C. to 85 ° C., and when methanesulfonic anhydride is used, it is preferably 10 ° C. to 60 ° C. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably −78 ° C. to 30 ° C.
本工程における反応時間は、通常、0.5時間乃至72時間であり、好適には1時間乃至24時間である。
The reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
B法は、一般式(I)を有する化合物の中で、Uが酸素原子である一般式(Id)を有する化合物を製造する方法である。
Method B is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
本発明において、R2、R3、R8、R9、R10、R11、R12、R2a、R3a、R9a、R10a、R11a、R12a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are as described above. It shows the same meaning as the thing.
第B1工程
本工程は、一般式(XVI)を有する化合物を製造する工程である。 Step B1 This step is a step of producing a compound having the general formula (XVI).
本工程は、一般式(XVI)を有する化合物を製造する工程である。 Step B1 This step is a step of producing a compound having the general formula (XVI).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記A法第A2工程で得られる一般式(V)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより、前記A法の第A4工程と同様に行われる。
This step comprises reacting the compound having the general formula (V) obtained in Step A2 Step A2 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
第B2工程
本工程は、一般式(XVII)を有する化合物を製造する工程である。 Step B2 This step is a step of producing a compound having the general formula (XVII).
本工程は、一般式(XVII)を有する化合物を製造する工程である。 Step B2 This step is a step of producing a compound having the general formula (XVII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XVI)を有する化合物を、一般式(X)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
In this step, the compound having the general formula (XVI) is reacted with the compound having the general formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in step A6 of the method A. Done.
第B3工程
本工程は、一般式(XVIII)を有する化合物を製造する工程である。 Step B3 This step is a step of producing a compound having the general formula (XVIII).
本工程は、一般式(XVIII)を有する化合物を製造する工程である。 Step B3 This step is a step of producing a compound having the general formula (XVIII).
本工程は、溶媒中、一般式(XVII)を有する化合物を、塩基と反応させることにより、前記A法の第A8工程と同様に行われる。
This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XVII) with a base in a solvent.
第B4工程
本工程は、一般式(XIX)を有する化合物を製造する工程である。 Step B4 This step is a step of producing a compound having the general formula (XIX).
本工程は、一般式(XIX)を有する化合物を製造する工程である。 Step B4 This step is a step of producing a compound having the general formula (XIX).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(XVIII)を有する化合物を、一般式(XIV)を有する化合物と反応させることにより、前記A法の第A9工程と同様に行われる。
This step is performed by reacting a compound having the general formula (XVIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and Performed in the same manner as in step A9.
第B5工程
本工程は、一般式(XX)を有する化合物を製造する工程である。 Step B5 This step is a step of producing a compound having the general formula (XX).
本工程は、一般式(XX)を有する化合物を製造する工程である。 Step B5 This step is a step of producing a compound having the general formula (XX).
本工程は、溶媒中、一般式(XIX)を有する化合物を、塩基及びメタンスルホン酸無水物又はビス(2-メトキシエチル)アミノサルファー トリフルオリドと反応させることにより、前記A法の第A10工程と同様に行われる。
In this step, the compound having the general formula (XIX) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to form the step A10 of the above method A. The same is done.
第B6工程
本工程は、一般式(XXI)を有する化合物を製造する工程である。 Step B6 This step is a step of producing a compound having the general formula (XXI).
本工程は、一般式(XXI)を有する化合物を製造する工程である。 Step B6 This step is a step of producing a compound having the general formula (XXI).
本工程は、溶媒中、一般式(XX)を有する化合物を、脱メチル化剤と反応させることにより、前記A法の第A3工程と同様に行われる。
This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (XX) with a demethylating agent in a solvent.
第B7工程
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step B7 This step is a step of producing a compound having the general formula (Id).
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step B7 This step is a step of producing a compound having the general formula (Id).
本工程は、溶媒中、トリフェニルホスフィン及びジエチルアゾジカルボキシラートの存在下、一般式(XXI)を有する化合物を、一般式(VIII)を有する化合物と反応させることにより、前記A法の第A5工程と同様に行われた後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
In this step, the compound having the general formula (XXI) is reacted with the compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 After being carried out in the same manner as in the step, it is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a as desired.
第B8工程
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step B8 This step is a step of producing a compound having the general formula (Id).
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step B8 This step is a step of producing a compound having the general formula (Id).
本工程は、溶媒中、塩基の存在下、一般式(XXI)を有する化合物を、一般式(XXII)を有する化合物と反応させることにより行われた後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
This step is carried out by reacting a compound having the general formula (XXI) with a compound having the general formula (XXII) in a solvent in the presence of a base, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
本工程において使用される一般式(XXII)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (XXII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類又はケトン類であり、より好適には、N,N-ジメチルホルムアミド又は2-ブタノンである。
The solvent used in this step is preferably an amide or a ketone, and more preferably N, N-dimethylformamide or 2-butanone.
本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムである。
The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
本工程における反応温度は、通常、25℃乃至120℃であり、好適には40℃乃至80℃である。
The reaction temperature in this step is usually 25 ° C to 120 ° C, preferably 40 ° C to 80 ° C.
本工程における反応時間は、通常、1時間乃至72時間であり、好適には6時間乃至48時間である。
The reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 48 hours.
C法は、一般式(I)を有する化合物の中で、Uが酸素原子である一般式(Id)を有する化合物を製造する方法である。
Method C is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
本発明において、R2、R3、R9、R10、R11、R12、R2a、R3a、R9a、R10a、R11a、R12a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
第C1工程
本工程は、一般式(XXIII)を有する化合物を製造する工程である。 Step C1 This step is a step of producing a compound having the general formula (XXIII).
本工程は、一般式(XXIII)を有する化合物を製造する工程である。 Step C1 This step is a step of producing a compound having the general formula (XXIII).
本工程は、溶媒中、塩基の存在下、前記A法第A1工程で得られる一般式(III)を有する化合物を、一般式(XXII)を有する化合物と反応させることにより、前記B法の第B8工程と同様に行われる。
This step comprises reacting the compound having the general formula (III) obtained in the above-mentioned Method A, Step A1 with a compound having the general formula (XXII) in a solvent in the presence of a base, thereby Performed in the same manner as in step B8.
第C2工程
本工程は、一般式(XXIV)を有する化合物を製造する工程である。 Step C2 This step is a step of producing a compound having the general formula (XXIV).
本工程は、一般式(XXIV)を有する化合物を製造する工程である。 Step C2 This step is a step of producing a compound having the general formula (XXIV).
本工程は、溶媒中、一般式(XXIII)を有する化合物を、脱メチル化剤と反応させることにより、前記A法の第A1工程と同様に行われる。
This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XXIII) with a demethylating agent in a solvent.
第C3工程
本工程は、一般式(XXV)を有する化合物を製造する工程である。 Step C3 This step is a step of producing a compound having the general formula (XXV).
本工程は、一般式(XXV)を有する化合物を製造する工程である。 Step C3 This step is a step of producing a compound having the general formula (XXV).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XXIV)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより、前記A法の第A4工程と同様に行われる。
This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XXIV) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
第C4工程
本工程は、一般式(XXVII)を有する化合物を製造する工程である。 Step C4 This step is a step of producing a compound having the general formula (XXVII).
本工程は、一般式(XXVII)を有する化合物を製造する工程である。 Step C4 This step is a step of producing a compound having the general formula (XXVII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XXV)を有する化合物を、一般式(XXVI)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
In this step, the compound having the general formula (XXV) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
本工程において使用される一般式(XXVI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (XXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
第C5工程
本工程は、一般式(XXVIII)を有する化合物を製造する工程である。 Step C5 This step is a step of producing a compound having the general formula (XXVIII).
本工程は、一般式(XXVIII)を有する化合物を製造する工程である。 Step C5 This step is a step of producing a compound having the general formula (XXVIII).
本工程は、溶媒中、一般式(XXVII)を有する化合物を、酸と反応させることにより、前記A法の第A7工程と同様に行われる。
This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXVII) with an acid in a solvent.
第C6工程
本工程は、一般式(XXIX)を有する化合物を製造する工程である。 Step C6 This step is a step of producing a compound having the general formula (XXIX).
本工程は、一般式(XXIX)を有する化合物を製造する工程である。 Step C6 This step is a step of producing a compound having the general formula (XXIX).
本工程は、溶媒中、塩基の存在下、一般式(XXVIII)を有する化合物を、トリイソプロピルシリルクロリドと反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XXVIII) with triisopropylsilyl chloride in a solvent in the presence of a base.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、トリエチルアミン又はトリエチルアミンと4-ジメチルアミノピリジンの混合塩基である。
The base used in this step is preferably an organic base, and more preferably triethylamine or a mixed base of triethylamine and 4-dimethylaminopyridine.
本工程における反応温度は、通常、-10℃乃至40℃であり、好適には0℃乃至30℃である。
The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
本工程における反応時間は、通常、0.1時間乃至72時間であり、好適には0.5時間乃至24時間である。
The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
第C7工程
本工程は、一般式(XXX)を有する化合物を製造する工程である。 Step C7 This step is a step of producing a compound having the general formula (XXX).
本工程は、一般式(XXX)を有する化合物を製造する工程である。 Step C7 This step is a step of producing a compound having the general formula (XXX).
本工程は、水素雰囲気下、溶媒中、一般式(XXIX)を有する化合物を、パラジウム触媒の存在下、反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XXIX) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
本工程において使用される溶媒は、好適には、エーテル類、アルコール類、エステル類又はこれらの混合溶媒であり、より好適には、テトラヒドロフラン、メタノール、エタノール、酢酸エチル又はエタノールと酢酸エチルの混合溶媒である。
The solvent used in this step is preferably an ether, alcohol, ester or a mixed solvent thereof, more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. It is.
本工程において使用されるパラジウム触媒は、好適には、0価のパラジウム触媒であり、より好適には、パラジウム-活性炭素である。
The palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably palladium-activated carbon.
本工程における反応温度は、通常、-10℃乃至40℃であり、好適には0℃乃至30℃である。
The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
本工程における反応時間は、通常、0.1時間乃至72時間であり、好適には0.5時間乃至24時間である。
The reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
第C8工程
本工程は、一般式(XXXI)を有する化合物を製造する工程である。 Step C8 This step is a step of producing a compound having the general formula (XXXI).
本工程は、一般式(XXXI)を有する化合物を製造する工程である。 Step C8 This step is a step of producing a compound having the general formula (XXXI).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(XXX)を有する化合物を、一般式(XIV)を有する化合物と反応させることにより、前記A法の第A9工程と同様に行われる。
This step is performed by reacting a compound having the general formula (XXX) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base. Performed in the same manner as in step A9.
第C9工程
本工程は、一般式(XXXII)を有する化合物を製造する工程である。 Step C9 This step is a step of producing a compound having the general formula (XXXII).
本工程は、一般式(XXXII)を有する化合物を製造する工程である。 Step C9 This step is a step of producing a compound having the general formula (XXXII).
本工程は、溶媒中、一般式(XXXI)を有する化合物を、塩基及びメタンスルホン酸無水物又はビス(2-メトキシエチル)アミノサルファー トリフルオリドと反応させることにより、前記A法の第A10工程と同様に行われる。
This step comprises reacting the compound having the general formula (XXXI) with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, The same is done.
第C10工程
本工程は、一般式(XXXIII)を有する化合物を製造する工程である。 Step C10 This step is a step of producing a compound having the general formula (XXXIII).
本工程は、一般式(XXXIII)を有する化合物を製造する工程である。 Step C10 This step is a step of producing a compound having the general formula (XXXIII).
本工程は、溶媒中、一般式(XXXII)を有する化合物を、テトラブチルアンモニウムフルオリドと反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XXXII) with tetrabutylammonium fluoride in a solvent.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。
The solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
本工程における反応温度は、通常、-10℃乃至40℃であり、好適には0℃乃至30℃である。
The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至3時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
第C11工程
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step C11 This step is a step of producing a compound having the general formula (Id).
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step C11 This step is a step of producing a compound having the general formula (Id).
本工程は、溶媒中、塩基の存在下、一般式(XXXIII)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われた後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXIII) with a compound having the general formula (IV) in the presence of a base in a solvent. If necessary, the amino group, hydroxy group and / or carboxyl group-protecting group in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is removed.
D法は、前記A法第A9工程で用いる一般式(XIII)を有する化合物を製造する方法である。
Method D is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
本発明において、R2a、R3a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2a , R 3a , X and Y have the same meaning as described above.
第D1工程
本工程は、一般式(XXXIV)を有する化合物を製造する工程である。 Step D1 This step is a step of producing a compound having the general formula (XXXIV).
本工程は、一般式(XXXIV)を有する化合物を製造する工程である。 Step D1 This step is a step of producing a compound having the general formula (XXXIV).
本工程は、(i)又は(ii)で行われる。
This step is performed in (i) or (ii).
(i)本工程は、溶媒中、トリフェニルホスフィン及びジエチルアゾジカルボキシラートの存在下、前記A法第A3工程で得られる一般式(VI)を有する化合物を、一般式(VIII)を有する化合物と反応させることにより、前記A法の第A5工程と同様に行われる。
(I) In this step, in the presence of triphenylphosphine and diethylazodicarboxylate in a solvent, the compound having the general formula (VI) obtained in the above-mentioned Method A, Step A3 is converted to the compound having the general formula (VIII). Is carried out in the same manner as in step A5 of the method A.
(ii)本工程は、溶媒中、塩基の存在下、一般式(VI)を有する化合物を、一般式(XXII)を有する化合物と反応させることにより、前記B法の第B8工程と同様に行われる。
(Ii) This step is carried out in the same manner as in Step B8 of Method B above by reacting a compound having the general formula (VI) with a compound having the general formula (XXII) in the presence of a base in a solvent. Is called.
第D2工程
本工程は、一般式(XXXV)を有する化合物を製造する工程である。 Step D2 This step is a step of producing a compound having the general formula (XXXV).
本工程は、一般式(XXXV)を有する化合物を製造する工程である。 Step D2 This step is a step of producing a compound having the general formula (XXXV).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XXXIV)を有する化合物を、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより行われる。
In this step, a compound having the general formula (XXXIV) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) -1H-pyrrole-2-carboxylate.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、ジオキサンである。
The solvent used in this step is preferably an ether, and more preferably dioxane.
本工程において使用されるパラジウム触媒は、好適には、II価のパラジウム触媒であり、より好適には、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体である。
The palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
本工程において使用される無機塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムであり、更により好適には、炭酸カリウム水溶液である。
The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
本工程における反応温度は、通常、25℃乃至100℃であり、好適には40℃乃至70℃である。
The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至5時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
第D3工程
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step D3 This step is a step of producing a compound having the general formula (XIII).
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step D3 This step is a step of producing a compound having the general formula (XIII).
本工程は、水素雰囲気下、溶媒中、一般式(XXXV)を有する化合物を、パラジウム触媒の存在下、反応させることにより、前記C法の第C7工程と同様に行われる。
This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
E法は、前記A法第A9工程で用いる一般式(XIII)を有する化合物を製造する方法である。
Method E is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
本発明において、R8、R2a、R3a、X及びYは、前述したものと同意義を示す。
In the present invention, R 8 , R 2a , R 3a , X and Y have the same meaning as described above.
第E1工程
本工程は、一般式(XXXVI)を有する化合物を製造する工程である。 Step E1 This step is a step of producing a compound having the general formula (XXXVI).
本工程は、一般式(XXXVI)を有する化合物を製造する工程である。 Step E1 This step is a step of producing a compound having the general formula (XXXVI).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記C法第C3工程で得られる一般式(XXV)を有する化合物を、一般式(X)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
This step comprises reacting a compound having the general formula (XXV) obtained in the above-mentioned Method C, Step C3 with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A6 of method A.
第E2工程
本工程は、一般式(XXXVII)を有する化合物を製造する工程である。 Step E2 This step is a step of producing a compound having the general formula (XXXVII).
本工程は、一般式(XXXVII)を有する化合物を製造する工程である。 Step E2 This step is a step of producing a compound having the general formula (XXXVII).
本工程は、溶媒中、一般式(XXXVI)を有する化合物を、酸と反応させることにより、前記A法の第A7工程と同様に行われる。
This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXXVI) with an acid in a solvent.
第E3工程
本工程は、一般式(XXXVIII)を有する化合物を製造する工程である。 Step E3 This step is a step of producing a compound having the general formula (XXXVIII).
本工程は、一般式(XXXVIII)を有する化合物を製造する工程である。 Step E3 This step is a step of producing a compound having the general formula (XXXVIII).
本工程は、溶媒中、塩基の存在下、一般式(XXXVII)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXVII) with a compound having the general formula (IV) in the presence of a base in a solvent.
第E4工程
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step E4 This step is a step of producing a compound having the general formula (XIII).
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step E4 This step is a step of producing a compound having the general formula (XIII).
本工程は、溶媒中、一般式(XXXVIII)を有する化合物を、塩基と反応させることにより、前記A法の第A8工程と同様に行われる。
This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XXXVIII) with a base in a solvent.
F法は、前記A法第A9工程で用いる一般式(XIII)を有する化合物を製造する方法である。
Method F is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
本発明において、R2a、R3a及びYは、前述したものと同意義を示す。
In the present invention, R 2a , R 3a and Y have the same meaning as described above.
第F1工程
本工程は、一般式(XXXV)を有する化合物を製造する工程である。 Step F1 This step is a step of producing a compound having the general formula (XXXV).
本工程は、一般式(XXXV)を有する化合物を製造する工程である。 Step F1 This step is a step of producing a compound having the general formula (XXXV).
本工程は、溶媒中、塩基の存在下、前記C法第C5工程で得られる一般式(XXVIII)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
In this step, the compound having the general formula (XXVIII) obtained in the above-mentioned Method C, Step C5 is reacted with the compound having the general formula (IV) in a solvent in the presence of a base, thereby This is performed in the same manner as in step A2.
第F2工程
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step F2 This step is a step of producing a compound having the general formula (XIII).
本工程は、一般式(XIII)を有する化合物を製造する工程である。 Step F2 This step is a step of producing a compound having the general formula (XIII).
本工程は、水素雰囲気下、溶媒中、一般式(XXXV)を有する化合物を、パラジウム触媒の存在下、反応させることにより、前記C法の第C7工程と同様に行われる。
This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
G法は、前記B法第B4工程で用いる一般式(XVIII)を有する化合物を製造する方法である。
Method G is a method for producing a compound having the general formula (XVIII) used in Method B, Step B4.
本発明において、R2a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2a , X and Y are as defined above.
第G1工程
本工程は、化合物(XXXIX)を製造する工程である。 Step G1 This step is the step of producing compound (XXXIX).
本工程は、化合物(XXXIX)を製造する工程である。 Step G1 This step is the step of producing compound (XXXIX).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記A法第A1工程で得られる一般式(III)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより、前記A法の第A4工程と同様に行われる。
This step comprises reacting the compound having the general formula (III) obtained in Step A1 Step A1 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
第G2工程
本工程は、化合物(XL)を製造する工程である。 Step G2 This step is a step of producing compound (XL).
本工程は、化合物(XL)を製造する工程である。 Step G2 This step is a step of producing compound (XL).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、化合物(XXXIX)を、一般式(XXVI)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
This step is carried out in the same manner as in Step A6 of Method A above by reacting compound (XXXIX) with a compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent.
第G3工程
本工程は、一般式(XLI)を有する化合物を製造する工程である。 Step G3 This step is a step of producing a compound having the general formula (XLI).
本工程は、一般式(XLI)を有する化合物を製造する工程である。 Step G3 This step is a step of producing a compound having the general formula (XLI).
本工程は、溶媒中、塩基の存在下、化合物(XL)を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
This step is performed in the same manner as in Step A2 of Method A above by reacting compound (XL) with a compound having the general formula (IV) in a solvent in the presence of a base.
第G4工程
本工程は、一般式(XLII)を有する化合物を製造する工程である。 Step G4 This step is a step of producing a compound having the general formula (XLII).
本工程は、一般式(XLII)を有する化合物を製造する工程である。 Step G4 This step is a step of producing a compound having the general formula (XLII).
本工程は、溶媒中、一般式(XLI)を有する化合物を、酸と反応させることにより、前記A法の第A7工程と同様に行われる。
This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XLI) with an acid in a solvent.
第G5工程
本工程は、一般式(XVIII)を有する化合物を製造する工程である。 Step G5 This step is a step of producing a compound having the general formula (XVIII).
本工程は、一般式(XVIII)を有する化合物を製造する工程である。 Step G5 This step is a step of producing a compound having the general formula (XVIII).
本工程は、水素雰囲気下、溶媒中、一般式(XLII)を有する化合物を、パラジウム触媒の存在下、反応させることにより、前記C法の第C7工程と同様に行われる。
This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XLII) in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere.
H法は、前記C法第C6工程で用いる一般式(XXVIII)を有する化合物を製造する方法である。
Method H is a method for producing a compound having the general formula (XXVIII) used in Step C6 of Method C.
本発明において、R3a及びXは、前述したものと同意義を示す。
In the present invention, R 3a and X are as defined above.
第H1工程
本工程は、一般式(XXVIII)を有する化合物を製造する工程である。 Step H1 This step is a step of producing a compound having the general formula (XXVIII).
本工程は、一般式(XXVIII)を有する化合物を製造する工程である。 Step H1 This step is a step of producing a compound having the general formula (XXVIII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記C法第C2工程で得られる一般式(XXIV)を有する化合物を、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより、前記D法の第D2工程と同様に行われる。
In this step, in the presence of a palladium catalyst and an inorganic base in a solvent, the compound having the general formula (XXIV) obtained in the above-mentioned Method C, Step C2 is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
I法は、前記C法第C3工程で用いる一般式(XXIV)を有する化合物を製造する方法である。
Method I is a method for producing a compound having the general formula (XXIV) used in the above-mentioned Method C, Step C3.
本発明において、R3a及びXは、前述したものと同意義を示す。
In the present invention, R 3a and X are as defined above.
第I1工程
本工程は、一般式(XLIV)を有する化合物を製造する工程である。 Step I1 This step is a step of producing a compound having the general formula (XLIV).
本工程は、一般式(XLIV)を有する化合物を製造する工程である。 Step I1 This step is a step of producing a compound having the general formula (XLIV).
本工程は、溶媒中、トリフェニルホスフィン及びジエチルアゾジカルボキシラートの存在下、一般式(XLIII)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A5工程と同様に行われる。
In this step, the compound having the general formula (XLIII) is reacted with the compound having the general formula (IV) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 of the above method A It is performed in the same manner as the process.
本工程において使用される一般式(XLIII)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (XLIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
第I2工程
本工程は、一般式(XXIV)を有する化合物を製造する工程である。 Step I2 This step is a step of producing a compound having the general formula (XXIV).
本工程は、一般式(XXIV)を有する化合物を製造する工程である。 Step I2 This step is a step of producing a compound having the general formula (XXIV).
本工程は、溶媒中、塩基の存在下、一般式(XLIV)を有する化合物を、トリメチル ボレートと反応させ、更に酢酸及び酸化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XLIV) with trimethyl borate in a solvent in the presence of a base, and further with acetic acid and an oxidizing agent.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、ジエチルエーテルである。
The solvent used in this step is preferably an ether, and more preferably diethyl ether.
本工程において使用される塩基は、好適には、有機金属塩基類であり、より好適には、n-ブチルリチウムである。
The base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
本工程において使用される酸化剤は、好適には、無機酸化剤であり、より好適には、30%過酸化水素水である。
The oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably 30% hydrogen peroxide solution.
本工程における反応温度は、通常、-120℃乃至40℃であり、好適には-78℃乃至25℃である。
The reaction temperature in this step is usually −120 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.
本工程における反応時間は、通常、1時間乃至48時間であり、好適には6時間乃至24時間である。
The reaction time in this step is usually 1 hour to 48 hours, preferably 6 hours to 24 hours.
J法は、一般式(I)を有する化合物の中で、Uがカルボニル基である一般式(Ie)を有する化合物を製造する方法である。
Method J is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
本発明において、R2、R3、R8、R9、R10、R11、R12、R2a、R9a、R10a、R11a、R12a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
第J1工程
本工程は、一般式(XLVI)を有する化合物を製造する工程である。 Step J1 This step is a step of producing a compound having the general formula (XLVI).
本工程は、一般式(XLVI)を有する化合物を製造する工程である。 Step J1 This step is a step of producing a compound having the general formula (XLVI).
本工程は、溶媒中、塩基の存在下、一般式(XLV)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XLV) with a compound having the general formula (IV) in a solvent in the presence of a base.
本工程において使用される一般式(XLV)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (XLV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
第J2工程
本工程は、一般式(XLVIII)を有する化合物を製造する工程である。 Step J2 This step is a step of producing a compound having the general formula (XLVIII).
本工程は、一般式(XLVIII)を有する化合物を製造する工程である。 Step J2 This step is a step of producing a compound having the general formula (XLVIII).
本工程は、溶媒中、塩基の存在下、一般式(XLVI)を有する化合物を、トリフルオロメタンスルホン酸無水物(XLVII)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (XLVI) with a compound having trifluoromethanesulfonic anhydride (XLVII) in a solvent in the presence of a base.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、ピリジンである。
The base used in this step is preferably an organic base, and more preferably pyridine.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至6時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
第J3工程
本工程は、一般式(XLIX)を有する化合物を製造する工程である。 Step J3 This step is a step of producing a compound having the general formula (XLIX).
本工程は、一般式(XLIX)を有する化合物を製造する工程である。 Step J3 This step is a step of producing a compound having the general formula (XLIX).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XLVIII)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより、前記A法の第A4工程と同様に行われる。
This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XLVIII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
第J4工程
本工程は、一般式(L)を有する化合物を製造する工程である。 Step J4 This step is a step of producing a compound having the general formula (L).
本工程は、一般式(L)を有する化合物を製造する工程である。 Step J4 This step is a step of producing a compound having the general formula (L).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(XLIX)を有する化合物を、一般式(XXVI)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
In this step, the compound having the general formula (XLIX) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
第J5工程
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step J5 This step is a step of producing a compound having the general formula (LI).
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step J5 This step is a step of producing a compound having the general formula (LI).
本工程は、溶媒中、一般式(L)を有する化合物を、酸と反応させることにより、前記A法の第A7工程と同様に行われる。
This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (L) with an acid in a solvent.
第J6工程
本工程は、一般式(LII)を有する化合物を製造する工程である。 Step J6 This step is a step of producing a compound having the general formula (LII).
本工程は、一般式(LII)を有する化合物を製造する工程である。 Step J6 This step is a step of producing a compound having the general formula (LII).
本工程は、水素雰囲気下、溶媒中、一般式(LI)を有する化合物を、パラジウム触媒の存在下、反応させることにより、前記C法の第C7工程と同様に行われる。
This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LI) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
第J7工程
本工程は、一般式(LIII)を有する化合物を製造する工程である。 Step J7 This step is a step of producing a compound having the general formula (LIII).
本工程は、一般式(LIII)を有する化合物を製造する工程である。 Step J7 This step is a step of producing a compound having the general formula (LIII).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(LII)を有する化合物を、一般式(XIV)を有する化合物と反応させることにより、前記A法の第A9工程と同様に行われる。
This step is performed by reacting a compound having the general formula (LII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent or in the presence or absence of a base. Performed in the same manner as in step A9.
第J8工程
本工程は、一般式(LIV)を有する化合物を製造する工程である。 Step J8 This step is a step of producing a compound having the general formula (LIV).
本工程は、一般式(LIV)を有する化合物を製造する工程である。 Step J8 This step is a step of producing a compound having the general formula (LIV).
本工程は、溶媒中、一般式(LIII)を有する化合物を、塩基及びメタンスルホン酸無水物又はビス(2-メトキシエチル)アミノサルファー トリフルオリドと反応させることにより、前記A法の第A10工程と同様に行われる。
In this step, the compound having the general formula (LIII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
第J9工程
本工程は、一般式(Ie)を有する化合物を製造する工程である。 Step J9 This step is a step of producing a compound having the general formula (Ie).
本工程は、一般式(Ie)を有する化合物を製造する工程である。 Step J9 This step is a step of producing a compound having the general formula (Ie).
本工程は、一般式(LIV)を有する化合物のR8Oを、R3a(R3aは、前述したものと同意義を示す。)に変換した後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
In this step, R 8 O of the compound having the general formula (LIV) is converted to R 3a (R 3a is as defined above), and then R 2a , R 3a , R 9a as desired. , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
後記L法は、本第J9工程の一例である。
The L method described below is an example of the J9th step.
K法は、一般式(I)を有する化合物の中で、Uがカルボニル基である一般式(Ie)を有する化合物を製造する方法である。
Method K is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
本発明において、R2、R3、R9、R10、R11、R12、R2a、R3a、R9a、R10a、R11a、R12a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
第K1工程
本工程は、一般式(LVII)を有する化合物を製造する工程である。 Step K1 This step is a step of producing a compound having the general formula (LVII).
本工程は、一般式(LVII)を有する化合物を製造する工程である。 Step K1 This step is a step of producing a compound having the general formula (LVII).
本工程は、溶媒中、3,5-ジメトキシベンズアルデヒド(LV)を、一般式(LVI)を有する化合物と反応させることにより行われる。
This step is performed by reacting 3,5-dimethoxybenzaldehyde (LV) with a compound having the general formula (LVI) in a solvent.
本工程において使用される一般式(LVI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。
The solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
本工程における反応温度は、通常、-110℃乃至40℃であり、好適には-80℃乃至25℃である。
The reaction temperature in this step is usually −110 ° C. to 40 ° C., preferably −80 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至6時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
第K2工程
本工程は、一般式(LVIII)を有する化合物を製造する工程である。 Step K2 This step is a step of producing a compound having the general formula (LVIII).
本工程は、一般式(LVIII)を有する化合物を製造する工程である。 Step K2 This step is a step of producing a compound having the general formula (LVIII).
本工程は、溶媒中、一般式(LVII)を有する化合物を、酸化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LVII) with an oxidizing agent in a solvent.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される酸化剤は、好適には、無機酸化剤であり、より好適には、二酸化マンガンである。
The oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably manganese dioxide.
本工程における反応温度は、通常、0℃乃至60℃であり、好適には25℃乃至40℃である。
The reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 25 ° C. to 40 ° C.
本工程における反応時間は、通常、6時間乃至72時間であり、好適には12時間乃至36時間である。
The reaction time in this step is usually 6 hours to 72 hours, preferably 12 hours to 36 hours.
第K3工程
本工程は、一般式(LIX)を有する化合物を製造する工程である。 Step K3 This step is a step of producing a compound having the general formula (LIX).
本工程は、一般式(LIX)を有する化合物を製造する工程である。 Step K3 This step is a step of producing a compound having the general formula (LIX).
本工程は、溶媒中、一般式(LVIII)を有する化合物を、脱メチル化剤と反応させることにより、前記A法の第A1工程と同様に行われる。
This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (LVIII) with a demethylating agent in a solvent.
第K4工程
本工程は、一般式(LX)を有する化合物を製造する工程である。 Step K4 This step is a step of producing a compound having the general formula (LX).
本工程は、一般式(LX)を有する化合物を製造する工程である。 Step K4 This step is a step of producing a compound having the general formula (LX).
本工程は、溶媒中、塩基の存在下、一般式(LIX)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LIX) with a compound having the general formula (IV) in a solvent in the presence of a base.
第K5工程
本工程は、一般式(LXI)を有する化合物を製造する工程である。 Step K5 This step is a step of producing a compound having the general formula (LXI).
本工程は、一般式(LXI)を有する化合物を製造する工程である。 Step K5 This step is a step of producing a compound having the general formula (LXI).
本工程は、溶媒中、一般式(LX)を有する化合物を、脱メチル化剤と反応させることにより、前記A法の第A3工程と同様に行われる。
This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (LX) with a demethylating agent in a solvent.
第K6工程
本工程は、一般式(LXII)を有する化合物を製造する工程である。 Step K6 This step is a step of producing a compound having the general formula (LXII).
本工程は、一般式(LXII)を有する化合物を製造する工程である。 Step K6 This step is a step of producing a compound having the general formula (LXII).
本工程は、溶媒中、塩基の存在下、一般式(LXI)を有する化合物を、トリフルオロメタンスルホン酸無水物(XLVII)を有する化合物と反応させることにより、前記J法の第J2工程と同様に行われる。
In this step, the compound having the general formula (LXI) is reacted with the compound having trifluoromethanesulfonic anhydride (XLVII) in the presence of a base in a solvent in the same manner as in Step J2 of Method J above. Done.
第K7工程
本工程は、一般式(LXIII)を有する化合物を製造する工程である。 Step K7 This step is a step of producing a compound having the general formula (LXIII).
本工程は、一般式(LXIII)を有する化合物を製造する工程である。 Step K7 This step is a step of producing a compound having the general formula (LXIII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(LXII)を有する化合物を、ビス(ピナコラート)ジボロンと反応させることにより、前記A法の第A4工程と同様に行われる。
This step is performed in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (LXII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
第K8工程
本工程は、一般式(LXIV)を有する化合物を製造する工程である。 Step K8 This step is a step of producing a compound having the general formula (LXIV).
本工程は、一般式(LXIV)を有する化合物を製造する工程である。 Step K8 This step is a step of producing a compound having the general formula (LXIV).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(LXIII)を有する化合物を、一般式(XXVI)を有する化合物と反応させることにより、前記A法の第A6工程と同様に行われる。
In this step, the compound having the general formula (LXIII) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of Method A above. Done.
第K9工程
本工程は、一般式(LXV)を有する化合物を製造する工程である。 Step K9 This step is a step of producing a compound having the general formula (LXV).
本工程は、一般式(LXV)を有する化合物を製造する工程である。 Step K9 This step is a step of producing a compound having the general formula (LXV).
本工程は、溶媒中、一般式(LXIV)を有する化合物を、酸と反応させることにより、前記A法の第A7工程と同様に行われる。
This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (LXIV) with an acid in a solvent.
第K10工程
本工程は、一般式(LXVI)を有する化合物を製造する工程である。 Step K10 This step is a step of producing a compound having the general formula (LXVI).
本工程は、一般式(LXVI)を有する化合物を製造する工程である。 Step K10 This step is a step of producing a compound having the general formula (LXVI).
本工程は、水素雰囲気下、溶媒中、一般式(LXV)を有する化合物を、パラジウム触媒の存在下、反応させることにより、前記C法の第C7工程と同様に行われる。
This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
第K11工程
本工程は、一般式(LXVII)を有する化合物を製造する工程である。 Step K11 This step is a step of producing a compound having the general formula (LXVII).
本工程は、一般式(LXVII)を有する化合物を製造する工程である。 Step K11 This step is a step of producing a compound having the general formula (LXVII).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(LXVI)を有する化合物を、一般式(XIV)を有する化合物と反応させることにより、前記A法の第A9工程と同様に行われる。
This step comprises reacting a compound having the general formula (LXVI) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, Performed in the same manner as in step A9.
第K12工程
本工程は、一般式(Ie)を有する化合物を製造する工程である。 Step K12 This step is a step of producing a compound having the general formula (Ie).
本工程は、一般式(Ie)を有する化合物を製造する工程である。 Step K12 This step is a step of producing a compound having the general formula (Ie).
本工程は、溶媒中、一般式(LXVII)を有する化合物を、塩基及びメタンスルホン酸無水物又はビス(2-メトキシエチル)アミノサルファー トリフルオリドと反応させることにより、前記A法の第A10工程と同様に行われる。
In this step, the compound having the general formula (LXVII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
L法は、一般式(I)を有する化合物の中で、Uがカルボニル基であり、R3が式-NR4R5で表わされる基である一般式(If)を有する化合物を製造する方法である。
Method L is a method for producing a compound having the general formula (If) wherein U is a carbonyl group and R 3 is a group represented by the formula —NR 4 R 5 among the compounds having the general formula (I). It is.
本発明において、R2、R4、R5、R8、R9、R10、R11、R12、R2a、R9a、R10a、R11a及びR12aは、前述したものと同意義を示し、R4a及びR5aは、R4及びR5の基に置換基として含まれるアミノ基が、保護されてもよいアミノ基である他、R4及びR5の基の定義における基と同様の基を示す。
In the present invention, R 2 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a and R 12a are as defined above. R 4a and R 5a each represents an amino group contained as a substituent in the groups of R 4 and R 5 which may be protected, and groups in the definition of the groups of R 4 and R 5. Similar groups are shown.
第L1工程
本工程は、一般式(LXVIII)を有する化合物を製造する工程である。 Step L1 This step is a step of producing a compound having the general formula (LXVIII).
本工程は、一般式(LXVIII)を有する化合物を製造する工程である。 Step L1 This step is a step of producing a compound having the general formula (LXVIII).
本工程は、溶媒中、前記J法第J8工程で得られる一般式(LIV)を有する化合物を、塩基と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LIV) obtained in the above-mentioned J method, step J8, with a base in a solvent.
本工程において使用される溶媒は、好適には、エーテル類又はアルコール類であり、より好適には、テトラヒドロフラン又はエタノールである。
The solvent used in this step is preferably ethers or alcohols, and more preferably tetrahydrofuran or ethanol.
本工程において使用される塩基は、好適には、アルカリ金属水酸化物類であり、より好適には、水酸化ナトリウム又は水酸化リチウムであり、更により好適には、水酸化ナトリウム水溶液又は水酸化リチウム水溶液である。
The base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide or lithium hydroxide, and still more preferably an aqueous sodium hydroxide solution or hydroxide. Lithium aqueous solution.
本工程における反応温度は、通常、0℃乃至100℃であり、好適には25℃乃至70℃である。
The reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
本工程における反応時間は、通常、0.5時間乃至24時間であり、好適には1時間乃至12時間である。
The reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
第L2工程
本工程は、一般式(If)を有する化合物を製造する工程である。 Step L2 This step is a step of producing a compound having the general formula (If).
本工程は、一般式(If)を有する化合物を製造する工程である。 Step L2 This step is a step of producing a compound having the general formula (If).
本工程は、溶媒中、縮合剤の存在下、塩基の存在下又は非存在下、一般式(LXVIII)を有する化合物を、一般式(LXIX)を有する化合物と反応させた後、所望によりR2a、R4a、R5a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
In this step, a compound having the general formula (LXVIII) is reacted with a compound having the general formula (LXIX) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and then optionally R 2a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
本工程において使用される一般式(LXIX)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類、アルコール類又はハロゲン化炭化水素類であり、より好適には、N,N-ジメチルホルムアミド、メタノール又はジクロロメタンである。
The solvent used in this step is preferably amides, alcohols or halogenated hydrocarbons, and more preferably N, N-dimethylformamide, methanol or dichloromethane.
本工程において使用される縮合剤は、好適には、WSCI・HCl、DMT-MM又はHATUである。
The condensing agent used in this step is preferably WSCI · HCl, DMT-MM or HATU.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、トリエチルアミン、ジイソプロピルエチルアミン又はトリエチルアミンと4-ジメチルアミノピリジンの組み合わせである。
The base used in this step is preferably an organic base, and more preferably triethylamine, diisopropylethylamine or a combination of triethylamine and 4-dimethylaminopyridine.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、1時間乃至72時間であり、好適には6時間乃至36時間である。
The reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 36 hours.
M法は、前記J法第J6工程で用いる一般式(LI)を有する化合物を製造する方法である。
Method M is a method for producing a compound having the general formula (LI) used in the J method, J6 step.
本発明において、R8及びR2aは、前述したものと同意義を示す。
In the present invention, R 8 and R 2a have the same meaning as described above.
第M1工程
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step M1 This step is a step of producing a compound having the general formula (LI).
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step M1 This step is a step of producing a compound having the general formula (LI).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記J法第J2工程で得られる一般式(XLVIII)を有する化合物を、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより、前記D法の第D2工程と同様に行われる。
In this step, a compound having the general formula (XLVIII) obtained in the above-mentioned Method J, Step J2 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
N法は、前記A法第A6工程、前記B法第B2工程及び前記E法第E1工程で用いる一般式(X)を有する化合物を製造する方法である。
Method N is a method for producing a compound having the general formula (X) used in Method A, Step A6, Method B, Step B2, and Method E, Step E1.
本発明において、R8及びXは、前述したものと同意義を示す。
In the present invention, R 8 and X are as defined above.
第N1工程
本工程は、一般式(LXXI)を有する化合物を製造する工程である。 Step N1 This step is a step of producing a compound having the general formula (LXXI).
本工程は、一般式(LXXI)を有する化合物を製造する工程である。 Step N1 This step is a step of producing a compound having the general formula (LXXI).
本工程は、溶媒中、一般式(LXX)を有する化合物を、ハロゲン化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXX) with a halogenating agent in a solvent.
本工程において使用される一般式(LXX)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、エーテル類又はエーテル類とアルコール類の混合溶媒であり、より好適には、テトラヒドロフラン又はテトラヒドロフランとメタノールの混合溶媒である。
The solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
本工程において使用されるハロゲン化剤は、例えば、塩酸、臭化水素、ヨウ化水素のような無機酸;塩素、臭素、ヨウ素のようなハロゲン分子類又はN-クロロこはく酸イミド、N-ブロモこはく酸イミド、N-ヨードこはく酸イミドのようなこはく酸イミド類であり、好適には、こはく酸イミドであり、より好適には、N-ブロモこはく酸イミドである。
The halogenating agent used in this step is, for example, an inorganic acid such as hydrochloric acid, hydrogen bromide or hydrogen iodide; a halogen molecule such as chlorine, bromine or iodine, or N-chlorosuccinimide, N-bromo. Succinimides such as succinimide and N-iodosuccinimide, preferably succinimide, and more preferably N-bromosuccinimide.
本工程における反応温度は、通常、-100℃乃至40℃であり、好適には-78℃乃至25℃である。
The reaction temperature in this step is usually −100 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至24時間である。
The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
第N2工程
本工程は、一般式(X)を有する化合物を製造する工程である。 Step N2 This step is a step of producing a compound having the general formula (X).
本工程は、一般式(X)を有する化合物を製造する工程である。 Step N2 This step is a step of producing a compound having the general formula (X).
本工程は、溶媒中、塩基の存在下、一般式(LXXI)を有する化合物を、二炭酸ジ-t-ブチルと反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXI) with di-t-butyl dicarbonate in the presence of a base in a solvent.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、トリエチルアミン、4-ジメチルアミノピリジン又はこれらの混合塩基であり、更により好適には、トリエチルアミンと4-ジメチルアミノピリジンの混合塩基である。
The base used in this step is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl. A mixed base of aminopyridine.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至3時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
O法は、前記C法第C4工程、前記G法第G2工程、前記J法第J4工程及び前記K法第K8工程で用いる一般式(XXVI)を有する化合物を製造する方法である。
Method O is a method for producing a compound having the general formula (XXVI) used in Step C, Step C4, Method G, Step G2, Step J, Step J4 and Method K, Step K8.
本発明において、Xは、前述したものと同意義を示す。
In the present invention, X has the same meaning as described above.
第O1工程
本工程は、一般式(LXXIII)を有する化合物を製造する工程である。 Step O1 This step is a step of producing a compound having the general formula (LXXIII).
本工程は、一般式(LXXIII)を有する化合物を製造する工程である。 Step O1 This step is a step of producing a compound having the general formula (LXXIII).
本工程は、溶媒中、ピロール-1-カルボン酸 t-ブチル(LXXII)を、ハロゲン化剤と反応させることにより、前記N法の第N1工程と同様に行われる。
This step is carried out in the same manner as the Nth step of the N method by reacting pyrrole-1-carboxylate t-butyl (LXXII) with a halogenating agent in a solvent.
本工程において使用されるピロール-1-カルボン酸 t-ブチル(LXXII)は、公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The pyrrole-1-carboxylic acid t-butyl (LXXII) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
第O2工程
本工程は、一般式(XXVI)を有する化合物を製造する工程である。 Step O2 This step is a step of producing a compound having the general formula (XXVI).
本工程は、一般式(XXVI)を有する化合物を製造する工程である。 Step O2 This step is a step of producing a compound having the general formula (XXVI).
本工程は、溶媒中、塩基の存在下、一般式(LXXIII)を有する化合物を、一般式(LXXIV)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXIII) with a compound having the general formula (LXXIV) in a solvent in the presence of a base.
本工程において使用される一般式(LXXIV)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXIV) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、ジエチルエーテルである。
The solvent used in this step is preferably an ether, and more preferably diethyl ether.
本工程において使用される塩基は、好適には、有機金属塩基類であり、より好適には、n-ブチルリチウムである。
The base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
本工程における反応温度は、通常、-100℃乃至40℃であり、好適には-78℃乃至25℃である。
The reaction temperature in this step is usually −100 ° C. to 40 ° C., preferably −78 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至24時間であり、好適には1時間乃至12時間である。
The reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
P法は、前記D法第D2工程、前記H法第H1工程及び前記M法第M1工程で用いるベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(LXXVIII)を製造する方法である。
Method P is benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl used in Method D, Step D2, Method H, Step H1 and Method M, Step M1. ) -1H-pyrrole-2-carboxylate (LXXVIII).
本発明において、Yは、前述したものと同意義を示す。
In the present invention, Y has the same meaning as described above.
第P1工程
本工程は、ベンジル 1H-ピロール-2-カルボキシレート(LXXVII)を製造する工程である。 Step P1 This step is a step for producing benzyl 1H-pyrrole-2-carboxylate (LXXVII).
本工程は、ベンジル 1H-ピロール-2-カルボキシレート(LXXVII)を製造する工程である。 Step P1 This step is a step for producing benzyl 1H-pyrrole-2-carboxylate (LXXVII).
本工程は、溶媒中、塩基の存在下、ピロール-2-カルボン酸(LXXV)を、一般式(LXXVI)を有する化合物と反応させることにより行われる。
This step is performed by reacting pyrrole-2-carboxylic acid (LXXV) with a compound having the general formula (LXXVI) in a solvent in the presence of a base.
本工程において使用されるピロール-2-カルボン酸(LXXV)は、公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The pyrrole-2-carboxylic acid (LXXV) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
本工程において使用される一般式(LXXVI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類であり、より好適には、N,N-ジメチルホルムアミドである。
The solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムである。
The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
本工程における反応温度は、通常、-10℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −10 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至24時間である。
The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
第P2工程
本工程は、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(LXXVIII)を製造する工程である。 Step P2 This step is a step for producing benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (LXXVIII). .
本工程は、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(LXXVIII)を製造する工程である。 Step P2 This step is a step for producing benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (LXXVIII). .
本工程は、溶媒中、イリジウム触媒及び4,4´-ジ-t-ブチル-2,2´-ジピリジルの存在下、ベンジル 1H-ピロール-2-カルボキシレート(LXXVII)を、ビス(ピナコラート)ジボロンと反応させることにより行われる。
In this step, benzyl 1H-pyrrole-2-carboxylate (LXXVII) is converted to bis (pinacolato) diboron in the presence of an iridium catalyst and 4,4′-di-t-butyl-2,2′-dipyridyl in a solvent. By reacting with.
本工程において使用される溶媒は、好適には、炭化水素類であり、より好適には、ヘキサンである。
The solvent used in this step is preferably a hydrocarbon, and more preferably hexane.
本工程において使用されるイリジウム触媒は、好適には、メトキシ(シクロオクタジエン)イリジウム(I)ダイマーである。
The iridium catalyst used in this step is preferably methoxy (cyclooctadiene) iridium (I) dimer.
本工程における反応温度は、通常、0℃乃至70℃であり、好適には25℃乃至60℃である。
The reaction temperature in this step is usually 0 ° C. to 70 ° C., preferably 25 ° C. to 60 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至6時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
Q法は、一般式(I)を有する化合物の中で、Uが酸素原子である一般式(Id)を有する化合物を製造する方法である。
Method Q is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
本発明において、R2、R3、R8、R9、R10、R11、R12、R2a、R3a、R9a、R10a、R11a、R12a及びYは、前述したものと同意義を示す。
In the present invention, R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a and Y are as described above. Shows the same significance.
第Q1工程
本工程は、一般式(LXXX)を有する化合物を製造する工程である。 Step Q1 This step is a step of producing a compound having the general formula (LXXX).
本工程は、一般式(LXXX)を有する化合物を製造する工程である。 Step Q1 This step is a step of producing a compound having the general formula (LXXX).
本工程は、溶媒中、縮合剤及び塩基の存在下、前記A法第A8工程で得られる一般式(XIII)を有する化合物を、一般式(LXXIX)を有する化合物と反応させることにより、前記A法の第A9工程と同様に行われる。
In this step, in the presence of a condensing agent and a base in a solvent, the compound having the general formula (XIII) obtained in the above-mentioned Method A, Step A8 is reacted with a compound having the general formula (LXXIX), thereby This is carried out in the same manner as in step A9 of the law.
本工程において使用される一般式(LXXIX)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
第Q2工程
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step Q2 This step is a step of producing a compound having the general formula (Id).
本工程は、一般式(Id)を有する化合物を製造する工程である。 Step Q2 This step is a step of producing a compound having the general formula (Id).
本工程は、溶媒中、一般式(LXXX)を有する化合物を、塩基と反応させた後、所望によりR2a、R3a、R9a、R10a、R11a及びR12aにおけるアミノ基、ヒドロキシ基及び/又はカルボキシル基の保護基を除去することにより行われる。
In this step, a compound having the general formula (LXXX) is reacted with a base in a solvent, and then optionally, an amino group, a hydroxy group, and R 2a , R 3a , R 9a , R 10a , R 11a and R 12a It is carried out by removing the protecting group of the carboxyl group.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、テトラヒドロフランである。
The solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
本工程において使用される塩基は、好適には、アルカリ金属水素化物類であり、より好適には、水素化ナトリウムである。
The base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.5時間乃至48時間であり、好適には1時間乃至24時間である。
The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
R法は、前記J法第J6工程で用いる一般式(LI)を有する化合物を製造する方法である。
Method R is a method for producing a compound having the general formula (LI) used in Method J, Step J6.
本発明において、R8、R2a及びXは、前述したものと同意義を示す。
In the present invention, R 8 , R 2a and X are as defined above.
第R1工程
本工程は、一般式(LXXXII)を有する化合物を製造する工程である。 Step R1 This step is a step of producing a compound having the general formula (LXXXII).
本工程は、一般式(LXXXII)を有する化合物を製造する工程である。 Step R1 This step is a step of producing a compound having the general formula (LXXXII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(LXXXI)を有する化合物を、ベンジル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより、前記D法の第D2工程と同様に行われる。
In this step, a compound having the general formula (LXXXI) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is performed in the same manner as in Step D2 of Method D above.
本工程において使用される一般式(LXXXI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXXI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
第R2工程
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step R2 This step is a step of producing a compound having the general formula (LI).
本工程は、一般式(LI)を有する化合物を製造する工程である。 Step R2 This step is a step of producing a compound having the general formula (LI).
本工程は、溶媒中、銅触媒、塩基及びモレキュラーシーヴス4Aの存在下、一般式(LXXXII)を有する化合物を、一般式(LXXXIII)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXXII) with a compound having the general formula (LXXXIII) in the presence of a copper catalyst, a base and molecular sieves 4A in a solvent.
本工程において使用される一般式(LXXXIII)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXXIII) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程において使用される銅触媒は、好適には、酢酸銅(II)である。
The copper catalyst used in this step is preferably copper (II) acetate.
本工程において使用される塩基は、好適には、有機塩基類であり、より好適には、トリエチルアミンである。
The base used in this step is preferably an organic base, and more preferably triethylamine.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、12時間乃至360時間であり、好適には24時間乃至240時間である。
The reaction time in this step is usually 12 hours to 360 hours, preferably 24 hours to 240 hours.
S法は、前記K法第K11工程で用いる一般式(LXVI)を有する化合物を製造する方法である。
Method S is a method for producing a compound having the general formula (LXVI) used in Method K, Step K11.
本発明において、R2a及びR3aは、前述したものと同意義を示す。
In the present invention, R 2a and R 3a have the same meaning as described above.
第S1工程
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step S1 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step S1 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、前記K法第K6工程で得られる一般式(LXII)を有する化合物を、メチル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより行われる。
In this step, a compound having the general formula (LXII) obtained in Step K6, Step K6 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to methyl 5- (4,4,5,5-tetramethyl-1, Performed by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
本工程において使用される溶媒は、好適には、エーテル類であり、より好適には、ジオキサンである。
The solvent used in this step is preferably an ether, and more preferably dioxane.
本工程において使用されるパラジウム触媒は、好適には、II価のパラジウム触媒であり、より好適には、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体である。
The palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
本工程において使用される無機塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸カリウムであり、更により好適には、炭酸カリウム水溶液である。
The inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
本工程における反応温度は、通常、25℃乃至100℃であり、好適には40℃乃至70℃である。
The reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
本工程における反応時間は、通常、0.5時間乃至12時間であり、好適には1時間乃至5時間である。
The reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
第S2工程
本工程は、一般式(LXVI)を有する化合物を製造する工程である。 Step S2 This step is a step of producing a compound having the general formula (LXVI).
本工程は、一般式(LXVI)を有する化合物を製造する工程である。 Step S2 This step is a step of producing a compound having the general formula (LXVI).
本工程は、溶媒中、一般式(LXXXIV)を有する化合物を、塩基と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXXIV) with a base in a solvent.
本工程において使用される溶媒は、好適には、エーテル類又はエーテル類とアルコール類の混合溶媒であり、より好適には、テトラヒドロフラン又はテトラヒドロフランとメタノールの混合溶媒である。
The solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
本工程において使用される塩基は、好適には、アルカリ金属水酸化物類であり、より好適には、水酸化リチウムであり、更により好適には、水酸化リチウム水溶液である。
The base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide, and even more preferably an aqueous lithium hydroxide solution.
本工程における反応温度は、通常、0℃乃至100℃であり、好適には25℃乃至70℃である。
The reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
本工程における反応時間は、通常、0.5時間乃至24時間であり、好適には1時間乃至12時間である。
The reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
T法は、前記S法第S2工程で用いる一般式(LXXXIV)を有する化合物を製造する方法である。
Method T is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
本発明において、R2a、R3a及びXは、前述したものと同意義を示す。
In the present invention, R 2a , R 3a and X are as defined above.
第T1工程
本工程は、一般式(LXXXVII)を有する化合物を製造する工程である。 Step T1 This step is a step of producing a compound having the general formula (LXXXVII).
本工程は、一般式(LXXXVII)を有する化合物を製造する工程である。 Step T1 This step is a step of producing a compound having the general formula (LXXXVII).
本工程は、溶媒中、塩基の存在下、一般式(LXXXV)を有する化合物を、一般式(LXXXVI)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXXV) with a compound having the general formula (LXXXVI) in the presence of a base in a solvent.
本工程において使用される一般式(LXXXV)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXXV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される一般式(LXXXVI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、アミド類であり、より好適には、N,N-ジメチルホルムアミドである。
The solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
本工程において使用される塩基は、好適には、アルカリ金属炭酸塩類であり、より好適には、炭酸セシウムである。
The base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
本工程における反応温度は、通常、60℃乃至180℃であり、好適には100℃乃至150℃である。
The reaction temperature in this step is usually 60 ° C to 180 ° C, preferably 100 ° C to 150 ° C.
本工程における反応時間は、通常、1時間乃至48時間であり、好適には12時間乃至36時間である。
The reaction time in this step is usually 1 hour to 48 hours, preferably 12 hours to 36 hours.
第T2工程
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step T2 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step T2 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(LXXXVII)を有する化合物を、メチル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより、前記S法の第S1工程と同様に行われる。
In this step, a compound having the general formula (LXXXVII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.
U法は、前記S法第S2工程で用いる一般式(LXXXIV)を有する化合物を製造する方法である。
Method U is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
本発明において、R2a、R3a、X及びYは、前述したものと同意義を示す。
In the present invention, R 2a , R 3a , X and Y have the same meaning as described above.
第U1工程
本工程は、一般式(LXXXIX)を有する化合物を製造する工程である。 Step U1 This step is a step of producing a compound having the general formula (LXXXIX).
本工程は、一般式(LXXXIX)を有する化合物を製造する工程である。 Step U1 This step is a step of producing a compound having the general formula (LXXXIX).
本工程は、酸の存在下、一般式(LXXXVIII)を有する化合物を、無水酢酸と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXXVIII) with acetic anhydride in the presence of an acid.
本工程において使用される一般式(LXXXVIII)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXXXVIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される酸は、例えば、塩化水素ガス、臭化水素ガスのようなハロゲン化水素類;硫酸、臭化水素酸、塩酸のような鉱酸類;酢酸、蟻酸、トリフルオロ酢酸のようなカルボン酸類であり、好適には、鉱酸類であり、より好適には、硫酸である。
Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; acetic acid, formic acid and trifluoroacetic acid. Carboxylic acids, preferably mineral acids, and more preferably sulfuric acid.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至3時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
第U2工程
本工程は、一般式(LXL)を有する化合物を製造する工程である。 Step U2 This step is a step of producing a compound having the general formula (LXL).
本工程は、一般式(LXL)を有する化合物を製造する工程である。 Step U2 This step is a step of producing a compound having the general formula (LXL).
本工程は、一般式(LXXXIX)を有する化合物を、塩素化剤と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXXXIX) with a chlorinating agent.
本工程において使用される塩素化剤は、例えば、塩酸のような無機酸;塩素のようなハロゲン分子類;三塩化リン、五塩化リン、オキシ塩化リンのようなリン試薬類;塩化オキサリルのようなシュウ酸塩化物類;塩化チオニルのようなスルフィン酸試薬類;又は、塩化スルホニル、トルエンスルホン酸クロリドのようなスルホン酸試薬類であり、好適には、スルフィン酸試薬類又はシュウ酸塩化物類であり、より好適には、塩化チオニル又は塩化オキサリルであり、更により好適には、塩化チオニルである。
The chlorinating agent used in this step is, for example, an inorganic acid such as hydrochloric acid; a halogen molecule such as chlorine; a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride; Oxalic acid chlorides; sulfinic acid reagents such as thionyl chloride; or sulfonic acid reagents such as sulfonyl chloride and toluenesulfonic acid chloride, preferably sulfinic acid reagents or oxalate chlorides More preferred is thionyl chloride or oxalyl chloride, and even more preferred is thionyl chloride.
本工程における反応温度は、通常、-20℃乃至100℃であり、好適には25℃乃至80℃である。
The reaction temperature in this step is usually −20 ° C. to 100 ° C., preferably 25 ° C. to 80 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至3時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
第U3工程
本工程は、一般式(LXLII)を有する化合物を製造する工程である。 Step U3 This step is a step of producing a compound having the general formula (LXLII).
本工程は、一般式(LXLII)を有する化合物を製造する工程である。 Step U3 This step is a step of producing a compound having the general formula (LXLII).
本工程は、溶媒中、一般式(LXL)を有する化合物を、一般式(LXLI)を有する化合物と反応させることにより行われる。
This step is performed by reacting a compound having the general formula (LXL) with a compound having the general formula (LXLI) in a solvent.
本工程において使用される一般式(LXLI)を有する化合物は、公知化合物であるか、或いは公知化合物を出発原料に公知の方法又はそれに類似した方法に従って容易に製造される。
The compound having the general formula (LXLI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
本工程において使用される溶媒は、好適には、ハロゲン化炭化水素類であり、より好適には、ジクロロメタンである。
The solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
本工程における反応温度は、通常、-20℃乃至40℃であり、好適には0℃乃至25℃である。
The reaction temperature in this step is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
本工程における反応時間は、通常、0.1時間乃至12時間であり、好適には0.5時間乃至6時間である。
The reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
第U4工程
本工程は、一般式(LXLIII)を有する化合物を製造する工程である。 Step U4 This step is a step of producing a compound having the general formula (LXLIII).
本工程は、一般式(LXLIII)を有する化合物を製造する工程である。 Step U4 This step is a step of producing a compound having the general formula (LXLIII).
本工程は、溶媒中、パラジウム触媒及び無機塩基の存在下、一般式(LXLII)を有する化合物を、メチル 5-(4,4,5,5-テトラメチルー1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレートと反応させることにより、前記S法の第S1工程と同様に行われる。
In this step, a compound having the general formula (LXLII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.
第U5工程
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step U5 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、一般式(LXXXIV)を有する化合物を製造する工程である。 Step U5 This step is a step of producing a compound having the general formula (LXXXIV).
本工程は、溶媒中、塩基の存在下、一般式(LXLIII)を有する化合物を、一般式(IV)を有する化合物と反応させることにより、前記A法の第A2工程と同様に行われる。
This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LXLIII) with a compound having the general formula (IV) in a solvent in the presence of a base.
上記において、R2a、R3a、R4a、R5a、R9a、R10a、R11a及びR12aの定義における「保護されてもよいアミノ基」、「保護されてもよいヒドロキシ基」及び「保護されてもよいカルボキシル基」の保護基とは、加水素分解、加水分解、電気分解、光分解のような化学的方法により開裂し得る保護基をいい、有機合成化学で一般的に用いられる保護基を示す(例えば、T. W. Greeneら,Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999年)参照)。
In the above, R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a in the definition of “amino group which may be protected”, “hydroxy group which may be protected” and “ The protecting group of “optionally protected carboxyl group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).
上記において、R2a、R3a、R9a、R10a、R11a及びR12aの定義における「保護されてもよいヒドロキシ基」の「保護基」は、有機合成化学の分野で使用されるヒドロキシ基の保護基であれば特に限定はされないが、例えば、ホルミル基、前記「C2-C7アルキルカルボニル基」、前記「C2-C7ハロゲン化アルキルカルボニル基」、メトキシアセチルのようなアルコキシアルキルカルボニル基、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、イソクロトノイル、(E)-2-メチル-2-ブテノイルのような不飽和アルキルカルボニル基等の「アルキルカルボニル基」;ベンゾイル、α-ナフトイル、β-ナフトイルのようなアリールカルボニル基、2-ブロモベンゾイル、4-クロロベンゾイルのようなハロゲン化アリールカルボニル基、2,4,6-トリメチルベンゾイル、4-トルオイルのようなC1-C6アルキル化アリ-ルカルボニル基、4-アニソイルのようなC1-C6アルコキシ化アリールカルボニル基、4-ニトロベンゾイル、2-ニトロベンゾイルのようなニトロ化アリールカルボニル基、2-(メトキシカルボニル)ベンゾイルのようなC2-C7アルコキシカルボニル化アリールカルボニル基、4-フェニルベンゾイルのようなアリール化アリールカルボニル基等の「アリールカルボニル基」;前記「C2-C7アルコキシカルボニル基」、2,2,2-トリクロロエトキシカルボニル、2-トリメチルシリルエトキシカルボニルのようなハロゲン又はトリ-(C1-C6アルキル)シリル基で置換されたC2-C7アルコキシカルボニル基等の「アルコキシカルボニル基」;テトラヒドロピラン-2-イル、3-ブロモテトラヒドロピラン-2-イル、4-メトキシテトラヒドロピラン-4-イル、テトラヒドロチオピラン-2-イル、4-メトキシテトラヒドロチオピラン-4-イルのような「テトラヒドロピラニル又はテトラヒドロチオピラニル基」;テトラヒドロフラン-2-イル、テトラヒドロチオフラン-2-イルのような「テトラヒドロフラニル又はテトラヒドロチオフラニル基」;トリメチルシリル、トリエチルシリル、イソプロピルジメチルシリル、t-ブチルジメチルシリル、メチルジイソプロピルシリル、メチルジ-t-ブチルシリル、トリイソプロピルシリルのようなトリ-(C1-C6アルキル)シリル基、ジフェニルメチルシリル、ジフェニルブチルシリル、ジフェニルイソプロピルシリル、フェニルジイソプロピルシリルのような(C1-C6アルキル)ジアリールシリル又はジ-(C1-C6アルキル)アリールシリル基等の「シリル基」;メトキシメチル、1,1-ジメチル-1-メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、t-ブトキシメチルのような(C1-C6アルコキシ)メチル基、2-メトキシエトキシメチルのような(C1-C6アルコキシ)-(C1-C6アルコキシ)メチル基、2,2,2-トリクロロエトキシメチル、ビス(2-クロロエトキシ)メチルのような(C1-C6ハロゲン化アルコキシ)メチル等の「アルコキシメチル基」;1-エトキシエチル、1-(イソプロポキシ)エチルのような(C1-C6アルコキシ)エチル基、2,2,2-トリクロロエチルのようなハロゲン化エチル基等の「置換エチル基」;ベンジル、α-ナフチルメチル、β-ナフチルメチル、ジフェニルメチル、トリフェニルメチル、α-ナフチルジフェニルメチル、9-アンスリルメチルのような1乃至3個のアリ-ル基で置換されたC1-C6アルキル基、4-メチルベンジル、2,4,6-トリメチルベンジル、3,4,5-トリメチルベンジル、4-メトキシベンジル、4-メトキシフェニルジフェニルメチル、2-ニトロベンジル、4-ニトロベンジル、4-クロロベンジル、4-ブロモベンジル、4-シアノベンジルのようなC1-C6アルキル、C1-C6アルコキシ、ニトロ、ハロゲン、シアノ基でアリ-ル環が置換された1乃至3個のアリ-ル基で置換されたC1-C6アルキル基等の「アラルキル基」;ビニルオキシカルボニル、アリルオキシカルボニルのような「アルケニルオキシカルボニル基」;ベンジルオキシカルボニル、4-メトキシベンジルオキシカルボニル、3,4-ジメトキシベンジルオキシカルボニル、2-ニトロベンジルオキシカルボニル、4-ニトロベンジルオキシカルボニルのような、1又は2個のC1-C6アルコキシ又はニトロ基でアリ-ル環が置換されていてもよい「アラルキルオキシカルボニル基」であり、好適には、アルキルカルボニル基、シリル基又はアラルキル基である。
In the above, “protective group” of “optionally protected hydroxy group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a hydroxy group used in the field of synthetic organic chemistry The protecting group is not particularly limited, and examples thereof include a formyl group, the “C 2 -C 7 alkylcarbonyl group”, the “C 2 -C 7 halogenated alkylcarbonyl group”, and an alkoxyalkyl such as methoxyacetyl. “Alkylcarbonyl groups” such as carbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, α-naphthoyl, β-naphthoyl Arylcarbonyl groups such as 2-bromobenzoyl, 4-chloro Halogenated arylcarbonyl groups such as Nzoiru, 2,4,6-trimethylbenzoyl, 4-C 1 -C 6 alkylated ants such as toluoyl - ylcarbonyl group, C 1 -C 6 alkoxy such as 4-anisoyl Arylcarbonyl groups, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C 2 -C 7 alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, 4-phenylbenzoyl An “arylcarbonyl group” such as an arylated arylcarbonyl group; a halogen such as the aforementioned “C 2 -C 7 alkoxycarbonyl group”, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or tri- ( C 1 -C 6 alkyl) silyl An “alkoxycarbonyl group” such as a C 2 -C 7 alkoxycarbonyl group substituted with a group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothio “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as pyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl” or tetrahydrothiofuranyl group "; trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, t- butyl dimethylsilyl, methyl diisopropylsilyl, methyldi -t- butylsilyl, tri as triisopropylsilyl - (C 1 -C 6 alkyl) "Silyl groups such as (C 1 -C 6 alkyl) aryl silyl group - Lil group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, (C 1 -C 6 alkyl) diarylsilyl or di- such as phenyl diisopropylsilyl A (C 1 -C 6 alkoxy) methyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxy such as ethoxymethyl (C 1 -C 6 alkoxy) - (C 1 -C 6 alkoxy) methyl group, 2,2,2-trichloroethoxymethyl, such as bis (2-chloroethoxy) methyl (C 1 - C 6 halogenated alkoxy) "alkoxymethyl group" such as methyl; 1 Ethoxyethyl, 1- (isopropoxy) such as ethyl (C 1 -C 6 alkoxy) ethyl group, "substituted ethyl group" such as a halogenated ethyl group such as 2,2,2-trichloroethyl; benzyl, alpha A C 1 -C 6 alkyl group substituted by 1 to 3 aryl groups such as naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl , 4-bromobenzyl, C 1 -C 6 alkyl such as 4-cyanobenzyl, C 1 -C 6 alkoxy, nitro (B) an aralkyl group such as a C 1 -C 6 alkyl group substituted with 1 to 3 aryl groups in which the aryl ring is substituted with a halogen, cyano group; vinyloxycarbonyl, allyloxycarbonyl Such as “alkenyloxycarbonyl group”; 1 or 2 such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with a C 1 -C 6 alkoxy group or a nitro group, preferably an alkylcarbonyl group, a silyl group, or an aralkyl group.
上記において、R2a、R3a、R9a、R10a、R11a及びR12aの定義における「保護されてもよいカルボキシル基」の「保護基」は、有機合成化学の分野で使用されるカルボキシル基の保護基であれば特に限定はされないが、例えば、前記「C1-C6アルキル基」;前記「C2-C6アルケニル基」;エチニル、1-プロピニル、2-プロピニル、1-メチル-2-プロピニル、1-ブチニルのようなC2-C6アルキニル基;前記「C1-C6ハロゲン化アルキル基」;ヒドロキシメチル、2-ヒドロキシエチルのようなC1-C6ヒドロキシアルキル基;アセチルメチルのような(C2-C7アルキルカルボニル)-(C1-C6アルキル基);前記「アラルキル基」;又は前記「シリル基」であり、好適には、C1-C6アルキル基又はアラルキル基である。
In the above, “protective group” of “optionally protected carboxyl group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a carboxyl group used in the field of synthetic organic chemistry The protecting group is not particularly limited, but for example, the “C 1 -C 6 alkyl group”; the “C 2 -C 6 alkenyl group”; ethynyl, 1-propynyl, 2-propynyl, 1-methyl- A C 2 -C 6 alkynyl group such as 2-propynyl and 1-butynyl; the aforementioned “C 1 -C 6 halogenated alkyl group”; a C 1 -C 6 hydroxyalkyl group such as hydroxymethyl and 2-hydroxyethyl; (C 2 -C 7 alkylcarbonyl)-(C 1 -C 6 alkyl group) such as acetylmethyl; said “aralkyl group”; or “silyl group” And preferably a C 1 -C 6 alkyl group or an aralkyl group.
上記において、R2a、R3a、R4a、R5a、R9a、R10a、R11a及びR12aの定義における「保護されてもよいアミノ基」の「保護基」は、有機合成化学の分野で使用されるアミノ基の保護基であれば特に限定はされないが、例えば、前記「ヒドロキシ基の保護基」における、「アルキルカルボニル基」;「アリールカルボニル基」;「アルコキシカルボニル基」;「シリル基」;「アラルキル基」;「アルケニルオキシカルボニル基」;又は「アラルキルオキシカルボニル基」と同様な基を示すか或いはN,N-ジメチルアミノメチレン、ベンジリデン、4-メトキシベンジリデン、4-ニトロベンジリデン、サリシリデン、5-クロロサリシリデン、ジフェニルメチレン、(5-クロロ-2-ヒドロキシフェニル)フェニルメチレンのような「シッフ塩基を形成する置換されたメチレン基」であり、好適には、アルキルカルボニル基、アリールカルボニル基又はアルコキシカルボニル基であり、より好適には、アルコキシカルボニル基である。
In the above, “protecting group” of “amino group which may be protected” in the definition of R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a is a field of synthetic organic chemistry. There is no particular limitation as long as it is an amino-protecting group used in the above, for example, “alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; A group similar to the “aralkyloxycarbonyl group” or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, Salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) E) a “substituted methylene group forming a Schiff base” such as phenylmethylene, preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group .
保護・脱保護が必要な工程は、既知の方法(例えば、”Protective Groups in Organic Synthesis” (Theodora W. Greene、Peter G. M.Wuts著、 1999年、Wiley-Interscience Publication発行)等に記載の方法)に準じて行われる。
Processes that require protection / deprotection are described in known methods (eg “Protective Groups Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, W1999, published by Wiley-Interscience Publication)). Method).
本発明の化合物又はその薬理上許容される塩は、種々の形態で投与することができる。その投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、乳剤、丸剤、散剤、シロップ剤(液剤)等による経口投与、または注射剤(静脈内、筋肉内、皮下または腹腔内投与)、点滴剤、坐剤(直腸投与)等による非経口投与を挙げることができる。これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤等の医薬の製剤技術分野において通常使用し得る補助剤を用いて製剤化することができる。
The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration). These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It can be formulated with the resulting adjuvant.
錠剤として使用する場合、担体として、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤;水、エタノール、プロパノール、単シロップ、グルコース液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤;乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤;白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤;第4級アンモニウム塩類、ラウリル硫酸ナトリウム等の吸収促進剤;グリセリン、デンプン等の保湿剤;デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤;精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の潤沢剤等を使用することができる。また、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。
When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrating agents such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
丸剤として使用する場合、担体として、例えば、グルコース、乳糖、カカオバター、デンプン、硬化植物油、カオリン、タルク等の賦形剤;アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤;ラミナラン、寒天等の崩壊剤等を使用することができる。
When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
坐剤として使用する場合、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオバター、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセリド等を挙げることができる。
When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
注射剤として使用する場合、液剤、乳剤または懸濁剤として使用することができる。これらの液剤、乳剤または懸濁剤は、殺菌され、血液と等張であることが好ましい。これら液剤、乳剤または懸濁剤の製造に用いる溶媒は、医療用の希釈剤として使用できるものであれば特に限定はなく、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するのに充分な量の食塩、グルコースまたはグリセリンを製剤中に含んでいてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を含んでいてもよい。
When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
また、上記の製剤には、必要に応じて、着色剤、保存剤、香料、風味剤、甘味剤等を含めることもでき、更に、他の医薬品を含めることもできる。
In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
上記製剤に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常、全組成物中0.5乃至70重量%、好ましくは1乃至30重量%含む。
The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
その使用量は患者(温血動物、特に人間)の症状、年齢等により異なるが、経口投与の場合には、1日あたり、上限として2000mg(好ましくは100mg)であり、下限として0.1mg(好ましくは1mg、さらに好ましくは10mg)を成人に対して、1日当り1乃至6回症状に応じて投与することが望ましい。
The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
以下、実施例および試験例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
実施例のカラムクロマトグラフィーにおける溶出はTLC(Thin Layer Chromatography,薄層クロマトグラフィー)による観察下に行われた。TLC観察においては、TLCプレートとしてメルク社製のTLCプレートシリカゲル60F254または富士シリシア化学社製のNH-TLCプレートを、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてUV検出器を採用した。カラム用シリカゲルは同じくメルク社製のシリカゲルSK-85(230~400メッシュ)、もしくは富士シリシア化学社製のシリカゲルFL100Bを用いた。通常のカラムクロマトグラフィーの他に、モリテックス社の自動クロマトグラフィー装置(Purif-α2)とディスポーザブルカラム(Purif-pack SIシリーズまたはNHシリーズ)を適宜使用した。プレパラティブTLCによる精製にはメルク社製のシリカゲル60F254、0.5mm厚、プレート20×20cmを用いた。尚、実施例で用いる略号は、次のような意義を有する。
mg:ミリグラム、g:グラム、mL:ミリリットル、MHz:メガヘルツ、HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N´,N´-テトラメチルウロニウム ヘキサフルオロホスファート、WSCI・HCl:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩、HOBT・H2O:1-ヒドロキシベンゾトリアゾール一水和物、DMT-MM:4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウム クロリド n水和物。 Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, the TLC plate silica gel 60F 254 manufactured by Merck or the NH-TLC plate manufactured by Fuji Silysia Chemical Co. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the detection method. A UV detector was adopted. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to the usual column chromatography, an automatic chromatography device (Purif-α2) manufactured by Moritex and a disposable column (Purif-pack SI series or NH series) were appropriately used. The purification by preparative TLC manufactured by Merck silica gel 60F 254, 0.5 mm thick, was used plates 20 × 20 cm. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz, HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate WSCI.HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBT.H 2 O: 1-hydroxybenzotriazole monohydrate, DMT-MM: 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate.
mg:ミリグラム、g:グラム、mL:ミリリットル、MHz:メガヘルツ、HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N´,N´-テトラメチルウロニウム ヘキサフルオロホスファート、WSCI・HCl:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩、HOBT・H2O:1-ヒドロキシベンゾトリアゾール一水和物、DMT-MM:4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウム クロリド n水和物。 Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, the TLC plate silica gel 60F 254 manufactured by Merck or the NH-TLC plate manufactured by Fuji Silysia Chemical Co. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the detection method. A UV detector was adopted. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used. In addition to the usual column chromatography, an automatic chromatography device (Purif-α2) manufactured by Moritex and a disposable column (Purif-pack SI series or NH series) were appropriately used. The purification by preparative TLC manufactured by Merck silica gel 60F 254, 0.5 mm thick, was used plates 20 × 20 cm. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz, HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate WSCI.HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBT.H 2 O: 1-hydroxybenzotriazole monohydrate, DMT-MM: 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate.
以下の実施例において、核磁気共鳴(以下、1H-NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をm、ブロードをbrで示した。
In the following examples, nuclear magnetic resonance (hereinafter, 1 H-NMR) spectra are described with chemical shift values in terms of δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, m for multiple lines, and br for broad lines.
質量分析(以下、MS)は、FAB(Fast Atom Bombardment) 法、EI(Electron Ionization)法、もしくはESI(Electron Spray Ionization)法で行った。
Mass spectrometry (hereinafter referred to as “MS”) was performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method.
(実施例1)
2-[5-(3-{[(2S)-1-フルオロプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール Example 1
2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole
2-[5-(3-{[(2S)-1-フルオロプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール Example 1
2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole
(1a)3-ブロモ-5-メトキシフェノール
1-ブロモ-3,5-ジメトキシベンゼン(18.74g,86.3mmol)を1-メチル-2-ピロリドン(100mL)に溶解し、ナトリウムチオメトキシド(6.74g,96.2mmol)を加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却し、1規定塩酸(200mL)を加え、ジエチルエーテル(500mL)で抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~25%)を用いて精製することにより、白色固体の目的化合物(15.03g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.77 (3H, s), 4.82 (1H, s), 6.33 (1H, t, J = 2.4 Hz), 6.61 (1H, t, J = 2.0 Hz), 6.66 (1H, t, J = 2.0 Hz).
(1b)1-ブロモ-3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]ベンゼン
実施例(1a)で合成した化合物(10.45g,60.0mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、炭酸カリウム(25.00g,181mmol)を加え、窒素雰囲気下100℃で36時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、0.1規定塩酸(500mL)を加え、ジエチルエーテル(400mL)と酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた固体をジエチルエーテルで洗浄することにより、淡茶色固体の目的化合物(18.30g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.80 (3H, s), 6.56 (1H, t, J = 2.4 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.92 (2H, d, J = 9.0 Hz).
(1c)3-ブロモ-5-[4-(メチルスルホニル)フェノキシ]フェノール
実施例(1b)で合成した化合物(18.29g,51.2mmol)を塩化メチレン(400mL)に溶解して-78℃へ冷却し、窒素雰囲気下に滴下ロートを用いて三臭化ホウ素(1.0mol/L塩化メチレン溶液,100mL,100mmol)を30分かけて加えた。-78℃で2時間撹拌した後、自然に昇温させ室温で一晩撹拌した。氷浴で冷却しながら飽和炭酸水素ナトリウム水溶液を加えて反応液を中和し、塩化メチレン(500mL)とメタノール(50mL)の混合溶媒で2回抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、淡黄色固体の目的化合物(16.89g,収率96%)を得た。
1H-NMR (DMSO-D6, 400MHz):δ3.19 (3H, s), 6.49 (1H, t, J = 2.1 Hz), 6.77 (1H, t, J = 2.0 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s)。 (1a) 3-Bromo-5-methoxyphenol 1-Bromo-3,5-dimethoxybenzene (18.74 g, 86.3 mmol) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide ( 6.74 g, 96.2 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (500 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 25%) to give the target compound (15.03 g, Yield 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.77 (3H, s), 4.82 (1H, s), 6.33 (1H, t, J = 2.4 Hz), 6.61 (1H, t, J = 2.0 Hz) , 6.66 (1H, t, J = 2.0 Hz).
(1b) 1-Bromo-3-methoxy-5- [4- (methylsulfonyl) phenoxy] benzene The compound synthesized in Example (1a) (10.45 g, 60.0 mmol) was converted to N, N-dimethylformamide (100 mL). ), Potassium carbonate (25.00 g, 181 mmol) was added, and the mixture was stirred at 100 ° C. for 36 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 0.1N hydrochloric acid (500 mL) was added, and the mixture was extracted twice with diethyl ether (400 mL) and ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to obtain the target compound (18.30 g, yield 79%) as a light brown solid.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.80 (3H, s), 6.56 (1H, t, J = 2.4 Hz), 6.81 (1H, t, J = 2.0 Hz) , 6.92 (1H, t, J = 2.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.92 (2H, d, J = 9.0 Hz).
(1c) 3-Bromo-5- [4- (methylsulfonyl) phenoxy] phenol The compound (18.29 g, 51.2 mmol) synthesized in Example (1b) was dissolved in methylene chloride (400 mL) and dissolved at −78 ° C. Then, boron tribromide (1.0 mol / L methylene chloride solution, 100 mL, 100 mmol) was added over 30 minutes using a dropping funnel under a nitrogen atmosphere. After stirring at −78 ° C. for 2 hours, the temperature was naturally raised and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added while cooling in an ice bath to neutralize the reaction solution, and the mixture was extracted twice with a mixed solvent of methylene chloride (500 mL) and methanol (50 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (16.89 g, yield 96%) as a pale yellow solid.
1 H-NMR (DMSO-D 6 , 400 MHz): δ 3.19 (3H, s), 6.49 (1H, t, J = 2.1 Hz), 6.77 (1H, t, J = 2.0 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s).
1-ブロモ-3,5-ジメトキシベンゼン(18.74g,86.3mmol)を1-メチル-2-ピロリドン(100mL)に溶解し、ナトリウムチオメトキシド(6.74g,96.2mmol)を加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却し、1規定塩酸(200mL)を加え、ジエチルエーテル(500mL)で抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~25%)を用いて精製することにより、白色固体の目的化合物(15.03g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.77 (3H, s), 4.82 (1H, s), 6.33 (1H, t, J = 2.4 Hz), 6.61 (1H, t, J = 2.0 Hz), 6.66 (1H, t, J = 2.0 Hz).
(1b)1-ブロモ-3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]ベンゼン
実施例(1a)で合成した化合物(10.45g,60.0mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、炭酸カリウム(25.00g,181mmol)を加え、窒素雰囲気下100℃で36時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、0.1規定塩酸(500mL)を加え、ジエチルエーテル(400mL)と酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた固体をジエチルエーテルで洗浄することにより、淡茶色固体の目的化合物(18.30g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.80 (3H, s), 6.56 (1H, t, J = 2.4 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.92 (2H, d, J = 9.0 Hz).
(1c)3-ブロモ-5-[4-(メチルスルホニル)フェノキシ]フェノール
実施例(1b)で合成した化合物(18.29g,51.2mmol)を塩化メチレン(400mL)に溶解して-78℃へ冷却し、窒素雰囲気下に滴下ロートを用いて三臭化ホウ素(1.0mol/L塩化メチレン溶液,100mL,100mmol)を30分かけて加えた。-78℃で2時間撹拌した後、自然に昇温させ室温で一晩撹拌した。氷浴で冷却しながら飽和炭酸水素ナトリウム水溶液を加えて反応液を中和し、塩化メチレン(500mL)とメタノール(50mL)の混合溶媒で2回抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、淡黄色固体の目的化合物(16.89g,収率96%)を得た。
1H-NMR (DMSO-D6, 400MHz):δ3.19 (3H, s), 6.49 (1H, t, J = 2.1 Hz), 6.77 (1H, t, J = 2.0 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s)。 (1a) 3-Bromo-5-methoxyphenol 1-Bromo-3,5-dimethoxybenzene (18.74 g, 86.3 mmol) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide ( 6.74 g, 96.2 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (500 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 25%) to give the target compound (15.03 g, Yield 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.77 (3H, s), 4.82 (1H, s), 6.33 (1H, t, J = 2.4 Hz), 6.61 (1H, t, J = 2.0 Hz) , 6.66 (1H, t, J = 2.0 Hz).
(1b) 1-Bromo-3-methoxy-5- [4- (methylsulfonyl) phenoxy] benzene The compound synthesized in Example (1a) (10.45 g, 60.0 mmol) was converted to N, N-dimethylformamide (100 mL). ), Potassium carbonate (25.00 g, 181 mmol) was added, and the mixture was stirred at 100 ° C. for 36 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 0.1N hydrochloric acid (500 mL) was added, and the mixture was extracted twice with diethyl ether (400 mL) and ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to obtain the target compound (18.30 g, yield 79%) as a light brown solid.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.80 (3H, s), 6.56 (1H, t, J = 2.4 Hz), 6.81 (1H, t, J = 2.0 Hz) , 6.92 (1H, t, J = 2.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.92 (2H, d, J = 9.0 Hz).
(1c) 3-Bromo-5- [4- (methylsulfonyl) phenoxy] phenol The compound (18.29 g, 51.2 mmol) synthesized in Example (1b) was dissolved in methylene chloride (400 mL) and dissolved at −78 ° C. Then, boron tribromide (1.0 mol / L methylene chloride solution, 100 mL, 100 mmol) was added over 30 minutes using a dropping funnel under a nitrogen atmosphere. After stirring at −78 ° C. for 2 hours, the temperature was naturally raised and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added while cooling in an ice bath to neutralize the reaction solution, and the mixture was extracted twice with a mixed solvent of methylene chloride (500 mL) and methanol (50 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (16.89 g, yield 96%) as a pale yellow solid.
1 H-NMR (DMSO-D 6 , 400 MHz): δ 3.19 (3H, s), 6.49 (1H, t, J = 2.1 Hz), 6.77 (1H, t, J = 2.0 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 9.0 Hz), 10.27 (1H, s).
(1d)3-[4-(メチルスルホニル)フェノキシ]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(1c)で合成した化合物(10.10g,29.4mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、ビス(ピナコラート)ジボロン(11.09g,43.7mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(722mg,0.884mmol)、酢酸カリウム(14.92g,152mmol)を加え、窒素雰囲気下90℃で5時間撹拌した。反応液を室温まで冷却し後に酢酸エチル(400mL)で反応液を希釈し、不溶物をセライト濾過により除去した。濾液に水(400mL)を加えて分液し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することにより、白色固体の目的化合物(11.88g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (12H, s), 3.06 (3H, s), 5.16 (1H, s), 6.69 (1H, t, J = 2.4 Hz), 7.06-7.12 (4H, m), 7.87 (2H, t, J = 9.0 Hz).
(1e)2-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
実施例(1d)で合成した化合物(13.20g,33.8mmol)をテトラヒドロフラン(300mL)に溶解し、(R)-(-)-1-メトキシ-2-プロパノール(3.70mL,37.8mmol)、トリフェニルホスフィン(9.78g,37.3mmol)を加えて0℃に冷却した。窒素雰囲気下にアゾジカルボン酸ジエチル(40%トルエン溶液,16.2mL,37.2mmol)を10分かけて滴下し、0℃で30分間撹拌した後、自然に昇温させ室温で一晩撹拌した。水(300mL)と酢酸エチル(300mL)を加え分液した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、無色油状の目的化合物(11.94g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.31 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05-7.09 (3H, m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz).
(1f)エチル 5-ブロモ-1H-ピロール-2-カルボキシレート
エチル 1H-ピロール-2-カルボキシレート(5.10g,30.7mmol)をテトラヒドロフラン(120mL)とメタノール(60mL)の混合溶媒に溶解し0℃に冷却した。N-ブロモスクシンイミド(6.52g,30.7mmol)を加え、窒素雰囲気下室温で18時間撹拌した。水(150mL)と酢酸エチル(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(3.20g,収率40%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 6.21 (1H, dd, J = 3.9, 2.7 Hz), 6.82 (1H, dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs)。 (1d) 3- [4- (Methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol Synthesized in Example (1c) The compound (10.10 g, 29.4 mmol) was dissolved in N, N-dimethylformamide (100 mL) and bis (pinacolato) diboron (11.09 g, 43.7 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride A dichloromethane complex (722 mg, 0.884 mmol) and potassium acetate (14.92 g, 152 mmol) were added, and the mixture was stirred at 90 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and insolubles were removed by celite filtration. Water (400 mL) was added to the filtrate for liquid separation, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the target compound (11.88 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (12H, s), 3.06 (3H, s), 5.16 (1H, s), 6.69 (1H, t, J = 2.4 Hz), 7.06-7.12 (4H , m), 7.87 (2H, t, J = 9.0 Hz).
(1e) 2- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1, 3,2-Dioxaborolane The compound (13.20 g, 33.8 mmol) synthesized in Example (1d) was dissolved in tetrahydrofuran (300 mL), and (R)-(−)-1-methoxy-2-propanol (3. 70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added and cooled to 0 ° C. Under a nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes, stirred at 0 ° C. for 30 minutes, then allowed to warm naturally and stirred overnight at room temperature. . Water (300 mL) and ethyl acetate (300 mL) were added for liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -40%) to give the desired compound (11.94 g, Yield 76%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.31 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05-7.09 (3H , m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz).
(1f) Ethyl 5-bromo-1H-pyrrole-2-carboxylate Ethyl 1H-pyrrole-2-carboxylate (5.10 g, 30.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (120 mL) and methanol (60 mL). Cooled to 0 ° C. N-bromosuccinimide (6.52 g, 30.7 mmol) was added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (150 mL) and ethyl acetate (200 mL) were added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (3.20 g, 3.20 g, Yield 40%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.36 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 6.21 (1H, dd, J = 3.9, 2.7 Hz) , 6.82 (1H, dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs).
実施例(1c)で合成した化合物(10.10g,29.4mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、ビス(ピナコラート)ジボロン(11.09g,43.7mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(722mg,0.884mmol)、酢酸カリウム(14.92g,152mmol)を加え、窒素雰囲気下90℃で5時間撹拌した。反応液を室温まで冷却し後に酢酸エチル(400mL)で反応液を希釈し、不溶物をセライト濾過により除去した。濾液に水(400mL)を加えて分液し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することにより、白色固体の目的化合物(11.88g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (12H, s), 3.06 (3H, s), 5.16 (1H, s), 6.69 (1H, t, J = 2.4 Hz), 7.06-7.12 (4H, m), 7.87 (2H, t, J = 9.0 Hz).
(1e)2-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
実施例(1d)で合成した化合物(13.20g,33.8mmol)をテトラヒドロフラン(300mL)に溶解し、(R)-(-)-1-メトキシ-2-プロパノール(3.70mL,37.8mmol)、トリフェニルホスフィン(9.78g,37.3mmol)を加えて0℃に冷却した。窒素雰囲気下にアゾジカルボン酸ジエチル(40%トルエン溶液,16.2mL,37.2mmol)を10分かけて滴下し、0℃で30分間撹拌した後、自然に昇温させ室温で一晩撹拌した。水(300mL)と酢酸エチル(300mL)を加え分液した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、無色油状の目的化合物(11.94g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.31 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05-7.09 (3H, m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz).
(1f)エチル 5-ブロモ-1H-ピロール-2-カルボキシレート
エチル 1H-ピロール-2-カルボキシレート(5.10g,30.7mmol)をテトラヒドロフラン(120mL)とメタノール(60mL)の混合溶媒に溶解し0℃に冷却した。N-ブロモスクシンイミド(6.52g,30.7mmol)を加え、窒素雰囲気下室温で18時間撹拌した。水(150mL)と酢酸エチル(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(3.20g,収率40%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 6.21 (1H, dd, J = 3.9, 2.7 Hz), 6.82 (1H, dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs)。 (1d) 3- [4- (Methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol Synthesized in Example (1c) The compound (10.10 g, 29.4 mmol) was dissolved in N, N-dimethylformamide (100 mL) and bis (pinacolato) diboron (11.09 g, 43.7 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride A dichloromethane complex (722 mg, 0.884 mmol) and potassium acetate (14.92 g, 152 mmol) were added, and the mixture was stirred at 90 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and insolubles were removed by celite filtration. Water (400 mL) was added to the filtrate for liquid separation, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the target compound (11.88 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (12H, s), 3.06 (3H, s), 5.16 (1H, s), 6.69 (1H, t, J = 2.4 Hz), 7.06-7.12 (4H , m), 7.87 (2H, t, J = 9.0 Hz).
(1e) 2- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1, 3,2-Dioxaborolane The compound (13.20 g, 33.8 mmol) synthesized in Example (1d) was dissolved in tetrahydrofuran (300 mL), and (R)-(−)-1-methoxy-2-propanol (3. 70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added and cooled to 0 ° C. Under a nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes, stirred at 0 ° C. for 30 minutes, then allowed to warm naturally and stirred overnight at room temperature. . Water (300 mL) and ethyl acetate (300 mL) were added for liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -40%) to give the desired compound (11.94 g, Yield 76%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.31 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 3.05 (3H, s), 3.40 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.58-4.62 (1H, m), 6.76 (1H, t, J = 2.4 Hz), 7.05-7.09 (3H , m), 7.24 (1H, d, J = 2.4 Hz), 7.87 (2H, d, J = 9.0 Hz).
(1f) Ethyl 5-bromo-1H-pyrrole-2-carboxylate Ethyl 1H-pyrrole-2-carboxylate (5.10 g, 30.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (120 mL) and methanol (60 mL). Cooled to 0 ° C. N-bromosuccinimide (6.52 g, 30.7 mmol) was added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (150 mL) and ethyl acetate (200 mL) were added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (3.20 g, 3.20 g, Yield 40%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.36 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 6.21 (1H, dd, J = 3.9, 2.7 Hz) , 6.82 (1H, dd, J = 3.9, 2.7 Hz), 9.21 (1H, brs).
(1g)1-t-ブチル 2-エチル 5-ブロモ-1H-ピロール-1,2-ジカルボキシレート
実施例(1f)で合成した化合物(3.20g,14.7mmol)を塩化メチレン(100mL)に溶解し、ジ-t-ブチル ジカルボナート(3.85g,17.6mmol)、トリエチルアミン(4.10mL,19.4mmol)及び4-ジメチルアミノピリジン(180mg,1.47mmol)を加え、窒素雰囲気下室温で1時間撹拌した。水(100mL)を加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することにより、無色油状の目的化合物(4.37g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 4.30 (2H, q, J = 7.0 Hz), 6.23 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz).
(1h)1-t-ブチル 2-エチル 5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(1e)で合成した化合物(8.73g,18.9mmol)と、実施例(1g)で合成した化合物(8.37g,26.3mmol)をトルエン(180mL)とエタノール(77mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(770mg,0.94mmol)、炭酸カリウム水溶液(2mol/L,23.7mL,47.2mmol)を加え、窒素雰囲気下100℃で1時間撹拌した。反応液を室温まで冷却後に水(200mL)を加え、酢酸エチル(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色油状の目的化合物(9.44g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.31 (3H, d, J = 6.3 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 3.05 (3H, s), 3.39 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.53 (1H, m), 6.22 (1H, d, J = 3.9 Hz), 6.65 (1H, m), 6.73 (1H, m), 6.88 (1H, m), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(1i)エチル 5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(1h)で合成した化合物(9.44g,16.5mmol)を塩化メチレン(90mL)に溶解し0℃に冷却した。窒素雰囲気下に撹拌しながらトリフルオロ酢酸(45mL)を滴下し、室温で1時間撹拌した。減圧下溶媒を留去後に酢酸エチル(300mL)で希釈し、飽和炭酸水素ナトリウム水溶液(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色固体の目的化合物(6.34g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J = 6.3 Hz), 1.37 (2H, t, J = 7.0 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.51 (1H, dd, J = 10.2, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.34 (2H, q, J = 7.0 Hz), 4.58 (1H, m), 6.51 (1H, dd, J = 4.0, 2.5 Hz), 6.58 (1H, m), 6.86 (1H, m), 6.93 (1H, dd, J = 4.0, 2.5 Hz), 7.01 (1H, m), 7.13 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.41 (1H, brs).
MS (ESI) m/z: 474.16048 (M+H)+。 (1 g) 1-tert-butyl 2-ethyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (1f) (3.20 g, 14.7 mmol) was dissolved in methylene chloride (100 mL). Di-t-butyl dicarbonate (3.85 g, 17.6 mmol), triethylamine (4.10 mL, 19.4 mmol) and 4-dimethylaminopyridine (180 mg, 1.47 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 1 hour. Water (100 mL) was added and extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oily target compound (4.37 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 4.30 (2H, q, J = 7.0 Hz), 6.23 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz).
(1h) 1-tert-butyl 2-ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1 , 2-Dicarboxylate Compound (8.73 g, 18.9 mmol) synthesized in Example (1e) and compound (8.37 g, 26.3 mmol) synthesized in Example (1 g) were combined with toluene (180 mL). Dissolved in a mixed solvent of ethanol (77 mL), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (770 mg, 0.94 mmol), aqueous potassium carbonate solution (2 mol / L, 23. 7 mL, 47.2 mmol) was added and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (9.44 g) as a pale yellow oil. Yield 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.31 (3H, d, J = 6.3 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 3.05 (3H, s) , 3.39 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.53 ( 1H, m), 6.22 (1H, d, J = 3.9 Hz), 6.65 (1H, m), 6.73 (1H, m), 6.88 (1H, m), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(1i) Ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Example (1h) ) (9.44 g, 16.5 mmol) was dissolved in methylene chloride (90 mL) and cooled to 0 ° C. While stirring in a nitrogen atmosphere, trifluoroacetic acid (45 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the mixture was diluted with ethyl acetate (300 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (6.34 g) as a pale yellow solid. Yield 81%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.37 (2H, t, J = 7.0 Hz), 3.07 (3H, s), 3.41 (3H, s) , 3.51 (1H, dd, J = 10.2, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.34 (2H, q, J = 7.0 Hz), 4.58 (1H, m), 6.51 ( 1H, dd, J = 4.0, 2.5 Hz), 6.58 (1H, m), 6.86 (1H, m), 6.93 (1H, dd, J = 4.0, 2.5 Hz), 7.01 (1H, m), 7.13 (2H , d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.41 (1H, brs).
MS (ESI) m / z: 474.16048 (M + H) <+> .
実施例(1f)で合成した化合物(3.20g,14.7mmol)を塩化メチレン(100mL)に溶解し、ジ-t-ブチル ジカルボナート(3.85g,17.6mmol)、トリエチルアミン(4.10mL,19.4mmol)及び4-ジメチルアミノピリジン(180mg,1.47mmol)を加え、窒素雰囲気下室温で1時間撹拌した。水(100mL)を加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することにより、無色油状の目的化合物(4.37g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 4.30 (2H, q, J = 7.0 Hz), 6.23 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz).
(1h)1-t-ブチル 2-エチル 5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(1e)で合成した化合物(8.73g,18.9mmol)と、実施例(1g)で合成した化合物(8.37g,26.3mmol)をトルエン(180mL)とエタノール(77mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(770mg,0.94mmol)、炭酸カリウム水溶液(2mol/L,23.7mL,47.2mmol)を加え、窒素雰囲気下100℃で1時間撹拌した。反応液を室温まで冷却後に水(200mL)を加え、酢酸エチル(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色油状の目的化合物(9.44g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.31 (3H, d, J = 6.3 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 3.05 (3H, s), 3.39 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.53 (1H, m), 6.22 (1H, d, J = 3.9 Hz), 6.65 (1H, m), 6.73 (1H, m), 6.88 (1H, m), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(1i)エチル 5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(1h)で合成した化合物(9.44g,16.5mmol)を塩化メチレン(90mL)に溶解し0℃に冷却した。窒素雰囲気下に撹拌しながらトリフルオロ酢酸(45mL)を滴下し、室温で1時間撹拌した。減圧下溶媒を留去後に酢酸エチル(300mL)で希釈し、飽和炭酸水素ナトリウム水溶液(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色固体の目的化合物(6.34g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J = 6.3 Hz), 1.37 (2H, t, J = 7.0 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.51 (1H, dd, J = 10.2, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.34 (2H, q, J = 7.0 Hz), 4.58 (1H, m), 6.51 (1H, dd, J = 4.0, 2.5 Hz), 6.58 (1H, m), 6.86 (1H, m), 6.93 (1H, dd, J = 4.0, 2.5 Hz), 7.01 (1H, m), 7.13 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.41 (1H, brs).
MS (ESI) m/z: 474.16048 (M+H)+。 (1 g) 1-tert-butyl 2-ethyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (1f) (3.20 g, 14.7 mmol) was dissolved in methylene chloride (100 mL). Di-t-butyl dicarbonate (3.85 g, 17.6 mmol), triethylamine (4.10 mL, 19.4 mmol) and 4-dimethylaminopyridine (180 mg, 1.47 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 1 hour. Water (100 mL) was added and extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oily target compound (4.37 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, t, J = 7.0 Hz), 1.63 (9H, s), 4.30 (2H, q, J = 7.0 Hz), 6.23 (1H, d, J = 3.9 Hz), 6.83 (1H, d, J = 3.9 Hz).
(1h) 1-tert-butyl 2-ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1 , 2-Dicarboxylate Compound (8.73 g, 18.9 mmol) synthesized in Example (1e) and compound (8.37 g, 26.3 mmol) synthesized in Example (1 g) were combined with toluene (180 mL). Dissolved in a mixed solvent of ethanol (77 mL), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (770 mg, 0.94 mmol), aqueous potassium carbonate solution (2 mol / L, 23. 7 mL, 47.2 mmol) was added and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (9.44 g) as a pale yellow oil. Yield 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.31 (3H, d, J = 6.3 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.46 (9H, s), 3.05 (3H, s) , 3.39 (3H, s), 3.48 (1H, dd, J = 10.2, 4.3 Hz), 3.57 (1H, dd, J = 10.2, 5.9 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.53 ( 1H, m), 6.22 (1H, d, J = 3.9 Hz), 6.65 (1H, m), 6.73 (1H, m), 6.88 (1H, m), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(1i) Ethyl 5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Example (1h) ) (9.44 g, 16.5 mmol) was dissolved in methylene chloride (90 mL) and cooled to 0 ° C. While stirring in a nitrogen atmosphere, trifluoroacetic acid (45 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the mixture was diluted with ethyl acetate (300 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (6.34 g) as a pale yellow solid. Yield 81%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.37 (2H, t, J = 7.0 Hz), 3.07 (3H, s), 3.41 (3H, s) , 3.51 (1H, dd, J = 10.2, 3.9 Hz), 3.60 (1H, dd, J = 10.2, 6.3 Hz), 4.34 (2H, q, J = 7.0 Hz), 4.58 (1H, m), 6.51 ( 1H, dd, J = 4.0, 2.5 Hz), 6.58 (1H, m), 6.86 (1H, m), 6.93 (1H, dd, J = 4.0, 2.5 Hz), 7.01 (1H, m), 7.13 (2H , d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.41 (1H, brs).
MS (ESI) m / z: 474.16048 (M + H) <+> .
(1j)5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(1i)で合成した化合物(4.36g, 9.2mmol)をエタノール(100mL)に溶解し、4規定水酸化ナトリウム水溶液(23mL, 92mmol)を加え、窒素雰囲気下1時間加熱還流した。反応液に2規定塩酸(45mL)を加え中和し、減圧下溶媒を留去した。1規定塩酸で酸性とし、酢酸エチル(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色固体の目的物(4.06g, 収率99%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, d, J = 6.3 Hz,), 3.07 (3H, s), 3.46 (3H, s), 3.55 (1H, dd, J = 10.4, 4.2 Hz), 3.66 (1H, dd, J = 10.5, 6.3 Hz), 4.70-4.75 (1H, m), 6.53 (1H, dd, J = 3.9, 2.6 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 1.6 Hz,), 7.04 (1H, dd, J = 3.9, 2.3 Hz), 7.25 (1H, m), 7.14 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.13 (1H, brs).
(1k)N-(2-クロロエチル)-5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(1j)で合成した化合物(150mg,0.34mmol)、2-クロロエチルアミン塩酸塩(78mg,0.68mmol)及び4-ジメチルアミノピリジン(41mg, 0.34mmol)を塩化メチレン(15mL)に溶解し、室温でWSCI・HCl(71mg, 0.37mmol)を加え、窒素雰囲気下2時間撹拌した。反応液を塩化メチレン(150mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製し、白色固体の目的物(105mg,収率62%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.42 (3H, s), 3.51 (1H, dd, J = 10.3, 4.0 Hz), 3.59 (1H, dd, J = 10.4, 6.1 Hz), 3.70 (2H, t, J = 5.4 Hz), 3.77 (2H, t, J = 5.4 Hz), 4.55-4.59 (1H, m), 6.26-6.29 (1H, brm), 6.50 (1H, dd, J = 3.9, 2.9 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.63 (1H, dd, J = 3.8, 2.5 Hz), 6.83 (1H, t, J = 1.7Hz), 6.99 (1H, t, J = 2.0 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.52 (1H, brs).
(1l)2-(5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(1k)で合成した化合物(177mg,0.349mmol)をテトラヒドロフラン(5mL)に溶解し、0℃に冷却した。水素化ナトリウム(40mg,0.917mmol)を加え、室温まで昇温し19時間撹拌した。反応液を0℃に冷却後水(5mL)を加え、酢酸エチル(10mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的化合物(118mg,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.50 (1H, dd, J = 10.2, 3.9 Hz), 3.59 (1H, dd, J = 10.2, 6.3 Hz), 3.98 (2H, t, J = 9.4 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.56 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, brt, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.83 (1H, brt, J = 2.0 Hz), 7.00 (1H, brt, J = 2.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 471.16050(M+H)+。 (1j) 5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Example (1i) The compound synthesized in step (4.36 g, 9.2 mmol) was dissolved in ethanol (100 mL), 4N aqueous sodium hydroxide solution (23 mL, 92 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction solution was neutralized with 2N hydrochloric acid (45 mL), and the solvent was distilled off under reduced pressure. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (4.06 g, yield 99%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz,), 3.07 (3H, s), 3.46 (3H, s), 3.55 (1H, dd, J = 10.4, 4.2 Hz), 3.66 (1H, dd, J = 10.5, 6.3 Hz), 4.70-4.75 (1H, m), 6.53 (1H, dd, J = 3.9, 2.6 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 1.6 Hz,), 7.04 (1H, dd, J = 3.9, 2.3 Hz), 7.25 (1H, m), 7.14 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.13 (1H, brs).
(1k) N- (2-chloroethyl) -5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2 -Carboxamide Compound (150 mg, 0.34 mmol) synthesized in Example (1j), 2-chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) were dissolved in methylene chloride (15 mL). ), WSCI · HCl (71 mg, 0.37 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the desired product (105 mg, yield 62%) as a white solid. )
1 H-NMR (CDCl 3 , 500 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.42 (3H, s), 3.51 (1H, dd, J = 10.3, 4.0 Hz ), 3.59 (1H, dd, J = 10.4, 6.1 Hz), 3.70 (2H, t, J = 5.4 Hz), 3.77 (2H, t, J = 5.4 Hz), 4.55-4.59 (1H, m), 6.26 -6.29 (1H, brm), 6.50 (1H, dd, J = 3.9, 2.9 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.63 (1H, dd, J = 3.8, 2.5 Hz), 6.83 ( 1H, t, J = 1.7Hz), 6.99 (1H, t, J = 2.0 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.52 (1H, brs).
(1l) 2- (5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4 , 5-Dihydro-1,3-oxazole The compound synthesized in Example (1k) (177 mg, 0.349 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 ° C. Sodium hydride (40 mg, 0.917 mmol) was added, and the mixture was warmed to room temperature and stirred for 19 hours. The reaction mixture was cooled to 0 ° C., water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (118 mg, yield) as a white solid. 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.50 (1H, dd, J = 10.2, 3.9 Hz), 3.59 (1H, dd, J = 10.2, 6.3 Hz), 3.98 (2H, t, J = 9.4 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.56 (1H, m), 6.50 ( 1H, d, J = 3.9 Hz), 6.56 (1H, brt, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.83 (1H, brt, J = 2.0 Hz), 7.00 (1H, brt, J = 2.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 471.16050 (M + H) <+> .
実施例(1i)で合成した化合物(4.36g, 9.2mmol)をエタノール(100mL)に溶解し、4規定水酸化ナトリウム水溶液(23mL, 92mmol)を加え、窒素雰囲気下1時間加熱還流した。反応液に2規定塩酸(45mL)を加え中和し、減圧下溶媒を留去した。1規定塩酸で酸性とし、酢酸エチル(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色固体の目的物(4.06g, 収率99%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, d, J = 6.3 Hz,), 3.07 (3H, s), 3.46 (3H, s), 3.55 (1H, dd, J = 10.4, 4.2 Hz), 3.66 (1H, dd, J = 10.5, 6.3 Hz), 4.70-4.75 (1H, m), 6.53 (1H, dd, J = 3.9, 2.6 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 1.6 Hz,), 7.04 (1H, dd, J = 3.9, 2.3 Hz), 7.25 (1H, m), 7.14 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.13 (1H, brs).
(1k)N-(2-クロロエチル)-5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(1j)で合成した化合物(150mg,0.34mmol)、2-クロロエチルアミン塩酸塩(78mg,0.68mmol)及び4-ジメチルアミノピリジン(41mg, 0.34mmol)を塩化メチレン(15mL)に溶解し、室温でWSCI・HCl(71mg, 0.37mmol)を加え、窒素雰囲気下2時間撹拌した。反応液を塩化メチレン(150mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製し、白色固体の目的物(105mg,収率62%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.42 (3H, s), 3.51 (1H, dd, J = 10.3, 4.0 Hz), 3.59 (1H, dd, J = 10.4, 6.1 Hz), 3.70 (2H, t, J = 5.4 Hz), 3.77 (2H, t, J = 5.4 Hz), 4.55-4.59 (1H, m), 6.26-6.29 (1H, brm), 6.50 (1H, dd, J = 3.9, 2.9 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.63 (1H, dd, J = 3.8, 2.5 Hz), 6.83 (1H, t, J = 1.7Hz), 6.99 (1H, t, J = 2.0 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.52 (1H, brs).
(1l)2-(5-{3-[(1S)-2-メトキシ-1-メチルエトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(1k)で合成した化合物(177mg,0.349mmol)をテトラヒドロフラン(5mL)に溶解し、0℃に冷却した。水素化ナトリウム(40mg,0.917mmol)を加え、室温まで昇温し19時間撹拌した。反応液を0℃に冷却後水(5mL)を加え、酢酸エチル(10mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的化合物(118mg,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.50 (1H, dd, J = 10.2, 3.9 Hz), 3.59 (1H, dd, J = 10.2, 6.3 Hz), 3.98 (2H, t, J = 9.4 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.56 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, brt, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.83 (1H, brt, J = 2.0 Hz), 7.00 (1H, brt, J = 2.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 471.16050(M+H)+。 (1j) 5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Example (1i) The compound synthesized in step (4.36 g, 9.2 mmol) was dissolved in ethanol (100 mL), 4N aqueous sodium hydroxide solution (23 mL, 92 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction solution was neutralized with 2N hydrochloric acid (45 mL), and the solvent was distilled off under reduced pressure. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (4.06 g, yield 99%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz,), 3.07 (3H, s), 3.46 (3H, s), 3.55 (1H, dd, J = 10.4, 4.2 Hz), 3.66 (1H, dd, J = 10.5, 6.3 Hz), 4.70-4.75 (1H, m), 6.53 (1H, dd, J = 3.9, 2.6 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 1.6 Hz,), 7.04 (1H, dd, J = 3.9, 2.3 Hz), 7.25 (1H, m), 7.14 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 10.13 (1H, brs).
(1k) N- (2-chloroethyl) -5- {3-[(1S) -2-methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2 -Carboxamide Compound (150 mg, 0.34 mmol) synthesized in Example (1j), 2-chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) were dissolved in methylene chloride (15 mL). ), WSCI · HCl (71 mg, 0.37 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the desired product (105 mg, yield 62%) as a white solid. )
1 H-NMR (CDCl 3 , 500 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.42 (3H, s), 3.51 (1H, dd, J = 10.3, 4.0 Hz ), 3.59 (1H, dd, J = 10.4, 6.1 Hz), 3.70 (2H, t, J = 5.4 Hz), 3.77 (2H, t, J = 5.4 Hz), 4.55-4.59 (1H, m), 6.26 -6.29 (1H, brm), 6.50 (1H, dd, J = 3.9, 2.9 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.63 (1H, dd, J = 3.8, 2.5 Hz), 6.83 ( 1H, t, J = 1.7Hz), 6.99 (1H, t, J = 2.0 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.52 (1H, brs).
(1l) 2- (5- {3-[(1S) -2-Methoxy-1-methylethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4 , 5-Dihydro-1,3-oxazole The compound synthesized in Example (1k) (177 mg, 0.349 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 ° C. Sodium hydride (40 mg, 0.917 mmol) was added, and the mixture was warmed to room temperature and stirred for 19 hours. The reaction mixture was cooled to 0 ° C., water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (118 mg, yield) as a white solid. 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 3.07 (3H, s), 3.41 (3H, s), 3.50 (1H, dd, J = 10.2, 3.9 Hz), 3.59 (1H, dd, J = 10.2, 6.3 Hz), 3.98 (2H, t, J = 9.4 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.56 (1H, m), 6.50 ( 1H, d, J = 3.9 Hz), 6.56 (1H, brt, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.83 (1H, brt, J = 2.0 Hz), 7.00 (1H, brt, J = 2.0 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 471.16050 (M + H) <+> .
(1m)(2S)-2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロパン-1-オール
実施例(1l)で合成した化合物(3.17g,6.74mmol)を塩化メチレン(100mL)に溶解して-78℃へ冷却し、窒素雰囲気下、三臭化ホウ素(1.0mol/L塩化メチレン溶液,7.07mL,7.07mmol)を加えた。自然に昇温させ室温で30分撹拌後、飽和炭酸水素ナトリウム水溶液を加えて反応液を中和し、塩化メチレン(200mL)で抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣を酢酸エチル(100mL)、エタノール(50mL)で洗浄し、白色固体の目的物(1.96g,収率64%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.29 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.79 (2H, d, J = 5.9 Hz), 4.00 (2H, t, J = 9.3 Hz), 4.42 (2H, t, J = 9.4 Hz), 4.58-4.63 (1H, m), 6.40 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.8 Hz), 6.79 (1H, t, J = 1.7 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz).
MS (ESI) m/z: 457.14357 (M+H)+.
(1n)2-[5-(3-{[(2S)-1-フルオロプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール
実施例(1m)で合成した化合物(80mg,0.175mmol)を塩化メチレン(10.0mL)に溶解し、三フッ化N,N-ジエチルアミノ硫黄(0.05mL,0.378mmol)を0℃で加え、窒素雰囲気下室温で2時間半撹拌した。この反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(20mL)で抽出した。有機層を1規定水酸化ナトリウム水溶液(10mL)で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~75%)を用いて精製することにより、白色固体の目的化合物(48mg,収率60%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (3H, dd, J = 6.5, 1.4 Hz), 3.04 (3H, s), 3.97 (2H, t, J = 9.4 Hz), 4.38 (2H, t, J = 9.4 Hz), 4.43 (1H, d, J = 4.7 Hz), 4.54 (1H, d, J = 5.1 Hz), 4.60-4.68 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 459.13825 (M+H)+。 (1m) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propan-1-ol The compound synthesized in Example (1l) (3.17 g, 6.74 mmol) was dissolved in methylene chloride (100 mL) and cooled to -78 ° C. Boron bromide (1.0 mol / L methylene chloride solution, 7.07 mL, 7.07 mmol) was added. The mixture was naturally warmed and stirred at room temperature for 30 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (200 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate (100 mL) and ethanol (50 mL) to obtain the desired product (1.96 g, yield 64%) as a white solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.29 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.79 (2H, d, J = 5.9 Hz), 4.00 (2H, t, J = 9.3 Hz), 4.42 (2H, t, J = 9.4 Hz), 4.58-4.63 (1H, m), 6.40 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.75 (1H, d, J = 3.8 Hz), 6.79 (1H, t, J = 1.7 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 457.14357 (M + H) + .
(1n) 2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (1m) (80 mg, 0.175 mmol) was dissolved in methylene chloride (10.0 mL), and N, N-diethylaminosulfur trifluoride was dissolved. (0.05 mL, 0.378 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 and a half hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution (10 mL) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -75%) to give the target compound (48 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, dd, J = 6.5, 1.4 Hz), 3.04 (3H, s), 3.97 (2H, t, J = 9.4 Hz), 4.38 (2H, t , J = 9.4 Hz), 4.43 (1H, d, J = 4.7 Hz), 4.54 (1H, d, J = 5.1 Hz), 4.60-4.68 (1H, m), 6.48 (1H, d, J = 3.9 Hz) ), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 459.13825 (M + H) <+> .
実施例(1l)で合成した化合物(3.17g,6.74mmol)を塩化メチレン(100mL)に溶解して-78℃へ冷却し、窒素雰囲気下、三臭化ホウ素(1.0mol/L塩化メチレン溶液,7.07mL,7.07mmol)を加えた。自然に昇温させ室温で30分撹拌後、飽和炭酸水素ナトリウム水溶液を加えて反応液を中和し、塩化メチレン(200mL)で抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣を酢酸エチル(100mL)、エタノール(50mL)で洗浄し、白色固体の目的物(1.96g,収率64%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.29 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.79 (2H, d, J = 5.9 Hz), 4.00 (2H, t, J = 9.3 Hz), 4.42 (2H, t, J = 9.4 Hz), 4.58-4.63 (1H, m), 6.40 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.8 Hz), 6.79 (1H, t, J = 1.7 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz).
MS (ESI) m/z: 457.14357 (M+H)+.
(1n)2-[5-(3-{[(2S)-1-フルオロプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール
実施例(1m)で合成した化合物(80mg,0.175mmol)を塩化メチレン(10.0mL)に溶解し、三フッ化N,N-ジエチルアミノ硫黄(0.05mL,0.378mmol)を0℃で加え、窒素雰囲気下室温で2時間半撹拌した。この反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(20mL)で抽出した。有機層を1規定水酸化ナトリウム水溶液(10mL)で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~75%)を用いて精製することにより、白色固体の目的化合物(48mg,収率60%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (3H, dd, J = 6.5, 1.4 Hz), 3.04 (3H, s), 3.97 (2H, t, J = 9.4 Hz), 4.38 (2H, t, J = 9.4 Hz), 4.43 (1H, d, J = 4.7 Hz), 4.54 (1H, d, J = 5.1 Hz), 4.60-4.68 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 459.13825 (M+H)+。 (1m) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propan-1-ol The compound synthesized in Example (1l) (3.17 g, 6.74 mmol) was dissolved in methylene chloride (100 mL) and cooled to -78 ° C. Boron bromide (1.0 mol / L methylene chloride solution, 7.07 mL, 7.07 mmol) was added. The mixture was naturally warmed and stirred at room temperature for 30 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (200 mL). The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate (100 mL) and ethanol (50 mL) to obtain the desired product (1.96 g, yield 64%) as a white solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.29 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.79 (2H, d, J = 5.9 Hz), 4.00 (2H, t, J = 9.3 Hz), 4.42 (2H, t, J = 9.4 Hz), 4.58-4.63 (1H, m), 6.40 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.75 (1H, d, J = 3.8 Hz), 6.79 (1H, t, J = 1.7 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 457.14357 (M + H) + .
(1n) 2- [5- (3-{[(2S) -1-fluoropropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (1m) (80 mg, 0.175 mmol) was dissolved in methylene chloride (10.0 mL), and N, N-diethylaminosulfur trifluoride was dissolved. (0.05 mL, 0.378 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 and a half hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution (10 mL) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -75%) to give the target compound (48 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, dd, J = 6.5, 1.4 Hz), 3.04 (3H, s), 3.97 (2H, t, J = 9.4 Hz), 4.38 (2H, t , J = 9.4 Hz), 4.43 (1H, d, J = 4.7 Hz), 4.54 (1H, d, J = 5.1 Hz), 4.60-4.68 (1H, m), 6.48 (1H, d, J = 3.9 Hz) ), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 459.13825 (M + H) <+> .
(実施例2)
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(1-プロペン-2-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 2)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3 -Oxazole
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(1-プロペン-2-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 2)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3 -Oxazole
(2a)(2S)-2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロピル メタンスルホネート
実施例(1m)で合成した化合物(106mg,0.23mmol)をテトラヒドロフラン(5.0mL)に溶解し、メタンスルホン酸無水物(65mg,0.37mmol)、トリエチルアミン(0.06mL,0.43mmol)を加え、窒素雰囲気下室温で一時間半撹拌した。反応液に飽和塩化アンモニウム水溶液(20mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~100%)を用いて精製することにより、白色固体の目的化合物(109mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.40 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.08 (3H, s), 4.00 (2H, t, J = 9.4 Hz), 4.35 (2H, ddd, J = 21.6, 11.0, 5.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.67-4.75 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.14 (2H, dt, J = 9.4, 2.5 Hz), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
(2b)2-[5-(3-{[(2S)-1-ヨードプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール
実施例(2a)で合成した化合物(504mg,0.94mmol)をアセトン(15.0mL)に溶解し、ヨウ化ナトリウム(320mg,2.13mmol)を加え、窒素雰囲気下加熱還流で一日撹拌した。反応液に水(40mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40~100%)を用いて精製することにより、白色固体の目的化合物(443mg,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.48 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (1H, dd, J = 10.4, 6.1 Hz), 3.39 (1H, dd, J = 10.4, 4.9 Hz), 4.00 (2H, t, J = 9.2 Hz), 4.40-4.44 (1H, m), 4.41 (2H, t, J = 9.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.14 (2H, dd, J = 6.6, 2.0 Hz), 7.92 (2H, dd, J = 6.6, 2.0 Hz).
(2c)2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(1-プロペン-2-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(2b)で合成した化合物(93mg,0.16mmol)をN,N-ジメチルホルムアミド(10.0mL)に溶解し、ナトリウムエトキシド(500mg,7.34mmol)を加え、窒素雰囲気下80℃で一日撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0~2%)を用いて精製することにより、黄色固体の目的化合物(34mg,収率47%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.99 (3H, s), 3.07 (3H, s), 4.01 (2H, t, J = 9.2 Hz), 4.19 (1H, s), 4.33 (1H, s), 4.43 (2H, t, J = 9.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.67 (1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.00 (1H, s), 7.09 (1H, s), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m/z: 439.13042 (M+H)+。 (2a) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propyl methanesulfonate The compound (106 mg, 0.23 mmol) synthesized in Example (1m) was dissolved in tetrahydrofuran (5.0 mL), methanesulfonic anhydride (65 mg, 0.37 mmol), triethylamine ( 0.06 mL, 0.43 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (109 mg, yield) as a white solid. 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.40 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.08 (3H, s), 4.00 (2H, t, J = 9.4 Hz), 4.35 (2H, ddd, J = 21.6, 11.0, 5.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.67-4.75 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.14 (2H , dt, J = 9.4, 2.5 Hz), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
(2b) 2- [5- (3-{[(2S) -1-iodopropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (2a) (504 mg, 0.94 mmol) was dissolved in acetone (15.0 mL), and sodium iodide (320 mg, 2.13 mmol) was dissolved. Was added, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40-100%) to give the target compound (443 mg, yield 83) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.48 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (1H, dd, J = 10.4, 6.1 Hz), 3.39 (1H, dd , J = 10.4, 4.9 Hz), 4.00 (2H, t, J = 9.2 Hz), 4.40-4.44 (1H, m), 4.41 (2H, t, J = 9.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz ), 7.14 (2H, dd, J = 6.6, 2.0 Hz), 7.92 (2H, dd, J = 6.6, 2.0 Hz).
(2c) 2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro- 1,3-oxazole The compound (93 mg, 0.16 mmol) synthesized in Example (2b) was dissolved in N, N-dimethylformamide (10.0 mL), sodium ethoxide (500 mg, 7.34 mmol) was added, The mixture was stirred at 80 ° C. for 1 day under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0-2%) to give the target compound (34 mg, yield 47) as a yellow solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.99 (3H, s), 3.07 (3H, s), 4.01 (2H, t, J = 9.2 Hz), 4.19 (1H, s), 4.33 (1H, s ), 4.43 (2H, t, J = 9.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.67 (1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.00 (1H, s ), 7.09 (1H, s), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 439.13042 (M + H) <+> .
実施例(1m)で合成した化合物(106mg,0.23mmol)をテトラヒドロフラン(5.0mL)に溶解し、メタンスルホン酸無水物(65mg,0.37mmol)、トリエチルアミン(0.06mL,0.43mmol)を加え、窒素雰囲気下室温で一時間半撹拌した。反応液に飽和塩化アンモニウム水溶液(20mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~100%)を用いて精製することにより、白色固体の目的化合物(109mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.40 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.08 (3H, s), 4.00 (2H, t, J = 9.4 Hz), 4.35 (2H, ddd, J = 21.6, 11.0, 5.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.67-4.75 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.14 (2H, dt, J = 9.4, 2.5 Hz), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
(2b)2-[5-(3-{[(2S)-1-ヨードプロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール
実施例(2a)で合成した化合物(504mg,0.94mmol)をアセトン(15.0mL)に溶解し、ヨウ化ナトリウム(320mg,2.13mmol)を加え、窒素雰囲気下加熱還流で一日撹拌した。反応液に水(40mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40~100%)を用いて精製することにより、白色固体の目的化合物(443mg,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.48 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (1H, dd, J = 10.4, 6.1 Hz), 3.39 (1H, dd, J = 10.4, 4.9 Hz), 4.00 (2H, t, J = 9.2 Hz), 4.40-4.44 (1H, m), 4.41 (2H, t, J = 9.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.14 (2H, dd, J = 6.6, 2.0 Hz), 7.92 (2H, dd, J = 6.6, 2.0 Hz).
(2c)2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(1-プロペン-2-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(2b)で合成した化合物(93mg,0.16mmol)をN,N-ジメチルホルムアミド(10.0mL)に溶解し、ナトリウムエトキシド(500mg,7.34mmol)を加え、窒素雰囲気下80℃で一日撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0~2%)を用いて精製することにより、黄色固体の目的化合物(34mg,収率47%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.99 (3H, s), 3.07 (3H, s), 4.01 (2H, t, J = 9.2 Hz), 4.19 (1H, s), 4.33 (1H, s), 4.43 (2H, t, J = 9.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.67 (1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.00 (1H, s), 7.09 (1H, s), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m/z: 439.13042 (M+H)+。 (2a) (2S) -2- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) ) Phenoxy] phenoxy} propyl methanesulfonate The compound (106 mg, 0.23 mmol) synthesized in Example (1m) was dissolved in tetrahydrofuran (5.0 mL), methanesulfonic anhydride (65 mg, 0.37 mmol), triethylamine ( 0.06 mL, 0.43 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (109 mg, yield) as a white solid. 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.40 (3H, d, J = 6.3 Hz), 3.06 (3H, s), 3.08 (3H, s), 4.00 (2H, t, J = 9.4 Hz), 4.35 (2H, ddd, J = 21.6, 11.0, 5.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.67-4.75 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.14 (2H , dt, J = 9.4, 2.5 Hz), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
(2b) 2- [5- (3-{[(2S) -1-iodopropan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole The compound synthesized in Example (2a) (504 mg, 0.94 mmol) was dissolved in acetone (15.0 mL), and sodium iodide (320 mg, 2.13 mmol) was dissolved. Was added, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40-100%) to give the target compound (443 mg, yield 83) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.48 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.32 (1H, dd, J = 10.4, 6.1 Hz), 3.39 (1H, dd , J = 10.4, 4.9 Hz), 4.00 (2H, t, J = 9.2 Hz), 4.40-4.44 (1H, m), 4.41 (2H, t, J = 9.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.8 Hz), 6.94 (1H, t, J = 1.8 Hz ), 7.14 (2H, dd, J = 6.6, 2.0 Hz), 7.92 (2H, dd, J = 6.6, 2.0 Hz).
(2c) 2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (1-propen-2-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro- 1,3-oxazole The compound (93 mg, 0.16 mmol) synthesized in Example (2b) was dissolved in N, N-dimethylformamide (10.0 mL), sodium ethoxide (500 mg, 7.34 mmol) was added, The mixture was stirred at 80 ° C. for 1 day under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0-2%) to give the target compound (34 mg, yield 47) as a yellow solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.99 (3H, s), 3.07 (3H, s), 4.01 (2H, t, J = 9.2 Hz), 4.19 (1H, s), 4.33 (1H, s ), 4.43 (2H, t, J = 9.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.67 (1H, s), 6.77 (1H, d, J = 3.9 Hz), 7.00 (1H, s ), 7.09 (1H, s), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 439.13042 (M + H) <+> .
(実施例3)
2-[5-(3-{[(2S)-1-(メチルスルファニル)プロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール (Example 3)
2- [5- (3-{[(2S) -1- (methylsulfanyl) propan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole
2-[5-(3-{[(2S)-1-(メチルスルファニル)プロパン-2-イル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール (Example 3)
2- [5- (3-{[(2S) -1- (methylsulfanyl) propan-2-yl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole
実施例(2a)で合成した化合物(56mg,0.11mmol)をテトラヒドロフラン(10mL)に溶解し、ナトリウムチオメトキシド(25mg,0.36mmol)を加え、窒素雰囲気下室温で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(20mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~70%)を用いて精製することにより、白色固体の目的化合物(31mg,収率61%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd, J = 13.7, 5.5 Hz), 3.07 (3H, s), 3.97 (2H, t, J = 9.0 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.55 (1H, br s), 6.50 (1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.75 (1H, d, J = 3.5 Hz), 6.83 (1H, s), 6.96 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.2 Hz).
MS (ESI) m/z: 487.13473 (M+H)+。 The compound synthesized in Example (2a) (56 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL), sodium thiomethoxide (25 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound as a white solid (31 mg, yield). 61%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd , J = 13.7, 5.5 Hz), 3.07 (3H, s), 3.97 (2H, t, J = 9.0 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.55 (1H, br s), 6.50 ( 1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.75 (1H, d, J = 3.5 Hz), 6.83 (1H, s), 6.96 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.2 Hz).
MS (ESI) m / z: 487.13473 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd, J = 13.7, 5.5 Hz), 3.07 (3H, s), 3.97 (2H, t, J = 9.0 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.55 (1H, br s), 6.50 (1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.75 (1H, d, J = 3.5 Hz), 6.83 (1H, s), 6.96 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.2 Hz).
MS (ESI) m/z: 487.13473 (M+H)+。 The compound synthesized in Example (2a) (56 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL), sodium thiomethoxide (25 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound as a white solid (31 mg, yield). 61%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 2.18 (3H, s), 2.70 (1H, dd, J = 13.5, 6.1 Hz), 2.85 (1H, dd , J = 13.7, 5.5 Hz), 3.07 (3H, s), 3.97 (2H, t, J = 9.0 Hz), 4.40 (2H, t, J = 9.4 Hz), 4.55 (1H, br s), 6.50 ( 1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.75 (1H, d, J = 3.5 Hz), 6.83 (1H, s), 6.96 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.2 Hz).
MS (ESI) m / z: 487.13473 (M + H) <+> .
(実施例4)
2-[5-(3-[4-(メチルスルホニル)フェノキシ]-5-{[(2S)-1-(メチルスルホニル)プロパン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール Example 4
2- [5- (3- [4- (Methylsulfonyl) phenoxy] -5-{[(2S) -1- (methylsulfonyl) propan-2-yl] oxy} phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole
2-[5-(3-[4-(メチルスルホニル)フェノキシ]-5-{[(2S)-1-(メチルスルホニル)プロパン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール Example 4
2- [5- (3- [4- (Methylsulfonyl) phenoxy] -5-{[(2S) -1- (methylsulfonyl) propan-2-yl] oxy} phenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazole
(実施例3)で合成した化合物(150mg,0.31mmol)を塩化メチレン(5.0mL)に溶解し、m-クロロ過安息香酸(約65%,170mg,約0.64mmol)を0℃で加え、窒素雰囲気下室温で一時間撹拌した。飽和炭酸水素ナトリウム水溶液(10mL)を加え、塩化メチレン(15mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~90%)を用いて精製することにより、白色固体の目的化合物(95mg,収率60%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.45 (3H, d, J = 6.3 Hz), 3.01 (3H, s), 3.08 (3H, s), 3.16 (1H, dd, J = 15.1, 1.8 Hz), 3.54 (1H, dd, J = 15.1, 8.8 Hz), 3.98 (2H, t, J = 9.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.99-5.06 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.8 Hz), 7.02 (1H, t, J = 1.8 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 519.12522 (M+H)+。 The compound synthesized in Example 3 (150 mg, 0.31 mmol) was dissolved in methylene chloride (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (15 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -90%) to give the desired compound (95 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.45 (3H, d, J = 6.3 Hz), 3.01 (3H, s), 3.08 (3H, s), 3.16 (1H, dd, J = 15.1, 1.8 Hz ), 3.54 (1H, dd, J = 15.1, 8.8 Hz), 3.98 (2H, t, J = 9.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.99-5.06 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.8 Hz), 7.02 (1H , t, J = 1.8 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 519.12522 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.45 (3H, d, J = 6.3 Hz), 3.01 (3H, s), 3.08 (3H, s), 3.16 (1H, dd, J = 15.1, 1.8 Hz), 3.54 (1H, dd, J = 15.1, 8.8 Hz), 3.98 (2H, t, J = 9.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.99-5.06 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.8 Hz), 7.02 (1H, t, J = 1.8 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 519.12522 (M+H)+。 The compound synthesized in Example 3 (150 mg, 0.31 mmol) was dissolved in methylene chloride (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (15 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -90%) to give the desired compound (95 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.45 (3H, d, J = 6.3 Hz), 3.01 (3H, s), 3.08 (3H, s), 3.16 (1H, dd, J = 15.1, 1.8 Hz ), 3.54 (1H, dd, J = 15.1, 8.8 Hz), 3.98 (2H, t, J = 9.2 Hz), 4.41 (2H, t, J = 9.4 Hz), 4.99-5.06 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.8 Hz), 7.02 (1H , t, J = 1.8 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 519.12522 (M + H) <+> .
(実施例5)
2-(5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 5)
2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
2-(5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 5)
2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
(5a)2-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン
実施例(1b)で合成した化合物(22.8g,63.8mmol)、ビス(ピナコラート)ジボロン(24.3g,95.7mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.56g,1.91mmol)、酢酸カリウム(31.3g,319mmol)を用い、実施例(1d)と同様の方法で淡黄色油状の目的化合物(24.8g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (12H, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J=2.4Hz), 7.07 (2H, d, J=9.0Hz), 7.08(1H, m), 7.20 (1H, d, J=2.8Hz), 7.87(2H, d, J=9.0Hz).
(5b)1-t-ブチル 2-エチル 5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(5a)で合成した化合物(24.8g,61.3mmol)、実施例(1g)で合成した化合物(20.1g,63.2mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(2.50g,3.06mmol)、炭酸カリウム水溶液(2mol/L,80.0mL,160mmol)を用い、実施例(1h)と同様の方法で褐色油状の目的化合物(23.9g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.35 (3H, t, J=7.0Hz), 1.46 (9H, s), 3.05 (3H, s), 3.81 (3H, s), 4.32 (2H, q, J=7.0Hz), 6.22 (1H, d, J=3.9Hz), 6.62 (1H, t, J=2.4Hz), 6.74 (1H, t, J=2.0Hz), 6.85 (1H, t, J=2.4Hz), 6.89 (1H, d, J=3.9 Hz), 7.12 (1H, d, J=.9.0 Hz), 7.89 (2H, d, J=9.0 Hz).
(5c)5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(5b)で合成した化合物(23.9g, 46.4mmol)をエタノール(100mL)に溶解し、5規定水酸化ナトリウム水溶液(100mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(260mL)を加え、酢酸エチル(300mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色固体の目的物(18.3g, 収率~100%)を得た。 (5a) 2- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesized in Example (1b) Compound (22.8 g, 63.8 mmol), bis (pinacolato) diboron (24.3 g, 95.7 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1. 56 g, 1.91 mmol) and potassium acetate (31.3 g, 319 mmol) were used to obtain the target compound (24.8 g, yield 96%) as a pale yellow oil in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (12H, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J = 2.4 Hz), 7.07 (2H, d, J = 9.0Hz), 7.08 (1H, m), 7.20 (1H, d, J = 2.8Hz), 7.87 (2H, d, J = 9.0Hz).
(5b) 1-tert-butyl 2-ethyl 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate synthesized in Example (5a) Compound (24.8 g, 61.3 mmol), compound synthesized in Example (1 g) (20.1 g, 63.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (2.50 g, 3.06 mmol) and an aqueous potassium carbonate solution (2 mol / L, 80.0 mL, 160 mmol), the target compound (23.9 g, yield) was obtained in the same manner as in Example (1h). 76%).
1 H-NMR (CDCl 3 , 400MHz): δ1.35 (3H, t, J = 7.0Hz), 1.46 (9H, s), 3.05 (3H, s), 3.81 (3H, s), 4.32 (2H, q, J = 7.0Hz), 6.22 (1H, d, J = 3.9Hz), 6.62 (1H, t, J = 2.4Hz), 6.74 (1H, t, J = 2.0Hz), 6.85 (1H, t, J = 2.4Hz), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = .9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(5c) 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (5b) (23.9 g, 46.4 mmol) Was dissolved in ethanol (100 mL), 5N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N hydrochloric acid (260 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (18.3 g, yield˜100%) as a white solid.
実施例(1b)で合成した化合物(22.8g,63.8mmol)、ビス(ピナコラート)ジボロン(24.3g,95.7mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.56g,1.91mmol)、酢酸カリウム(31.3g,319mmol)を用い、実施例(1d)と同様の方法で淡黄色油状の目的化合物(24.8g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (12H, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J=2.4Hz), 7.07 (2H, d, J=9.0Hz), 7.08(1H, m), 7.20 (1H, d, J=2.8Hz), 7.87(2H, d, J=9.0Hz).
(5b)1-t-ブチル 2-エチル 5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(5a)で合成した化合物(24.8g,61.3mmol)、実施例(1g)で合成した化合物(20.1g,63.2mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(2.50g,3.06mmol)、炭酸カリウム水溶液(2mol/L,80.0mL,160mmol)を用い、実施例(1h)と同様の方法で褐色油状の目的化合物(23.9g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.35 (3H, t, J=7.0Hz), 1.46 (9H, s), 3.05 (3H, s), 3.81 (3H, s), 4.32 (2H, q, J=7.0Hz), 6.22 (1H, d, J=3.9Hz), 6.62 (1H, t, J=2.4Hz), 6.74 (1H, t, J=2.0Hz), 6.85 (1H, t, J=2.4Hz), 6.89 (1H, d, J=3.9 Hz), 7.12 (1H, d, J=.9.0 Hz), 7.89 (2H, d, J=9.0 Hz).
(5c)5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(5b)で合成した化合物(23.9g, 46.4mmol)をエタノール(100mL)に溶解し、5規定水酸化ナトリウム水溶液(100mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(260mL)を加え、酢酸エチル(300mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色固体の目的物(18.3g, 収率~100%)を得た。 (5a) 2- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesized in Example (1b) Compound (22.8 g, 63.8 mmol), bis (pinacolato) diboron (24.3 g, 95.7 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1. 56 g, 1.91 mmol) and potassium acetate (31.3 g, 319 mmol) were used to obtain the target compound (24.8 g, yield 96%) as a pale yellow oil in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (12H, s), 3.05 (3H, s), 3.84 (3H, s), 6.73 (1H, t, J = 2.4 Hz), 7.07 (2H, d, J = 9.0Hz), 7.08 (1H, m), 7.20 (1H, d, J = 2.8Hz), 7.87 (2H, d, J = 9.0Hz).
(5b) 1-tert-butyl 2-ethyl 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate synthesized in Example (5a) Compound (24.8 g, 61.3 mmol), compound synthesized in Example (1 g) (20.1 g, 63.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (2.50 g, 3.06 mmol) and an aqueous potassium carbonate solution (2 mol / L, 80.0 mL, 160 mmol), the target compound (23.9 g, yield) was obtained in the same manner as in Example (1h). 76%).
1 H-NMR (CDCl 3 , 400MHz): δ1.35 (3H, t, J = 7.0Hz), 1.46 (9H, s), 3.05 (3H, s), 3.81 (3H, s), 4.32 (2H, q, J = 7.0Hz), 6.22 (1H, d, J = 3.9Hz), 6.62 (1H, t, J = 2.4Hz), 6.74 (1H, t, J = 2.0Hz), 6.85 (1H, t, J = 2.4Hz), 6.89 (1H, d, J = 3.9 Hz), 7.12 (1H, d, J = .9.0 Hz), 7.89 (2H, d, J = 9.0 Hz).
(5c) 5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (5b) (23.9 g, 46.4 mmol) Was dissolved in ethanol (100 mL), 5N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N hydrochloric acid (260 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (18.3 g, yield˜100%) as a white solid.
(5d)N-(2-ヒドロキシエチル)-5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(5c)で合成した化合物(10.36g,26.7mmol)をメタノール(250mL)に溶解し、2-アミノエタノール(3.23mL,53.5mmol)、DMT-MM(11.7g, 42.3mmol)を加え、窒素雰囲気下室温で19時間撹拌した。減圧下溶媒を留去し、水(200mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=80%~100%)を用いて精製し、白色固体の目的物(11.6g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.59 (2H, dd, J=5.1, 10.2Hz), 3.80 (2H, t, J=5.1Hz), 3.84 (3H, s), 6.49 (2H, m), 6.54 (1H, t, J=2.4Hz), 6.61(1H, d, J=3.5Hz), 6.84 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J=9.0Hz), 7.90 (2H, d, J=9.0Hz), 9.73 (1H, brs).
(5e)2-(5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(5d)で合成した化合物(11.5g,26.7mmol)をテトラヒドロフラン(200mL)に溶解し、メタンスルホン酸無水物(7.00g,40.2mmol)、トリエチルアミン(15.0mL, 108mol)を加え、窒素雰囲気下室温で50時間撹拌した。飽和炭酸水素ナトリウム水溶液(200mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~90%)を用いて精製することにより、白色固体の目的物(8.90g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J=9.4Hz), 4.41 (2H, t, J=9.4Hz), 6.52 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.76 (1H, d, J=3.9Hz), 6.83 (1H, t, J=2.4Hz), 6.94 (1H, t, J=2.4Hz), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 413.11712(M+H)+。 (5d) N- (2-hydroxyethyl) -5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide Compound synthesized in Example (5c) ( 10.36 g, 26.7 mmol) was dissolved in methanol (250 mL), 2-aminoethanol (3.23 mL, 53.5 mmol) and DMT-MM (11.7 g, 42.3 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 19 hours. The solvent was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 80% to 100%) to obtain the desired product (11.6 g, yield) as a white solid. To 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.59 (2H, dd, J = 5.1, 10.2 Hz), 3.80 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 6.49 (2H, m), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.5Hz), 6.84 (1H, brs), 6.94 (1H, brs), 7.13 ( 2H, d, J = 9.0Hz), 7.90 (2H, d, J = 9.0Hz), 9.73 (1H, brs).
(5e) 2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole Examples The compound synthesized in 5d) (11.5 g, 26.7 mmol) was dissolved in tetrahydrofuran (200 mL), methanesulfonic anhydride (7.00 g, 40.2 mmol) and triethylamine (15.0 mL, 108 mol) were added, The mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -90%) to give the desired product as a white solid (8.90 g, Yield 81%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4 Hz) , 6.52 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.76 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.4Hz), 6.94 (1H, t, J = 2.4Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 413.11712 (M + H) <+> .
実施例(5c)で合成した化合物(10.36g,26.7mmol)をメタノール(250mL)に溶解し、2-アミノエタノール(3.23mL,53.5mmol)、DMT-MM(11.7g, 42.3mmol)を加え、窒素雰囲気下室温で19時間撹拌した。減圧下溶媒を留去し、水(200mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=80%~100%)を用いて精製し、白色固体の目的物(11.6g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.59 (2H, dd, J=5.1, 10.2Hz), 3.80 (2H, t, J=5.1Hz), 3.84 (3H, s), 6.49 (2H, m), 6.54 (1H, t, J=2.4Hz), 6.61(1H, d, J=3.5Hz), 6.84 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J=9.0Hz), 7.90 (2H, d, J=9.0Hz), 9.73 (1H, brs).
(5e)2-(5-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール
実施例(5d)で合成した化合物(11.5g,26.7mmol)をテトラヒドロフラン(200mL)に溶解し、メタンスルホン酸無水物(7.00g,40.2mmol)、トリエチルアミン(15.0mL, 108mol)を加え、窒素雰囲気下室温で50時間撹拌した。飽和炭酸水素ナトリウム水溶液(200mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~90%)を用いて精製することにより、白色固体の目的物(8.90g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J=9.4Hz), 4.41 (2H, t, J=9.4Hz), 6.52 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.76 (1H, d, J=3.9Hz), 6.83 (1H, t, J=2.4Hz), 6.94 (1H, t, J=2.4Hz), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 413.11712(M+H)+。 (5d) N- (2-hydroxyethyl) -5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide Compound synthesized in Example (5c) ( 10.36 g, 26.7 mmol) was dissolved in methanol (250 mL), 2-aminoethanol (3.23 mL, 53.5 mmol) and DMT-MM (11.7 g, 42.3 mmol) were added, and the mixture was added at room temperature under a nitrogen atmosphere. For 19 hours. The solvent was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 80% to 100%) to obtain the desired product (11.6 g, yield) as a white solid. To 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.59 (2H, dd, J = 5.1, 10.2 Hz), 3.80 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 6.49 (2H, m), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.5Hz), 6.84 (1H, brs), 6.94 (1H, brs), 7.13 ( 2H, d, J = 9.0Hz), 7.90 (2H, d, J = 9.0Hz), 9.73 (1H, brs).
(5e) 2- (5- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole Examples The compound synthesized in 5d) (11.5 g, 26.7 mmol) was dissolved in tetrahydrofuran (200 mL), methanesulfonic anhydride (7.00 g, 40.2 mmol) and triethylamine (15.0 mL, 108 mol) were added, The mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -90%) to give the desired product as a white solid (8.90 g, Yield 81%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.84 (3H, s), 3.99 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4 Hz) , 6.52 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.76 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.4Hz), 6.94 (1H, t, J = 2.4Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 413.11712 (M + H) <+> .
(実施例6)
メチル 2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロパノエート (Example 6)
Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} propanoate
メチル 2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロパノエート (Example 6)
Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} propanoate
(6a)3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノール
実施例(5e)で合成した化合物(2.93g,7.10mmol)を塩化メチレン(70mL)に溶解し、0℃にて三臭化ホウ素 (1.0mol/L塩化メチレン溶液,23.0mL,23.0mmol)を加え、窒素雰囲気下室温で4日間撹拌した。飽和炭酸水素ナトリウム水溶液(100mL)を加え、テトラヒドロフラン(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~10%)を用いて精製することにより、白色固体の目的物(2.70g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 4.07 (2H, t, J=9.4Hz), 4.52 (2H, t, J=9.4Hz), 6.44 (1H, t, J=2.0Hz), 6.47 (1H, d, J=3.9Hz), 6.78 (1H, d, J=3.9Hz), 6.85 (1H, t, J=2.0Hz), 7.15 (2H, d, J=9.0 Hz), 7.31 (1H, m), 7.91 (2H, d, J=9.0Hz).
(6b)メチル 2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロパノエート
実施例(6a)で合成した化合物(600mg,1.51mmol)を2-ブタノン(20mL)に溶解し、メチル 2-ブロモプロパノエート(340μL,3.05mmol)、炭酸カリウム(625mg,4.52mmol)を加え、窒素雰囲気下で19時間加熱還流した。室温まで冷却し、セライト濾過により不溶物を除去した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的物(302mg,収率41%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.64 (3H, d, J=6.7Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J=9.4Hz), 4.40 (2H, t, J=9.4Hz), 4.80 (1H, q, J=6.7Hz), 6.48 (1H, brs), 6.50 (1H, d, J=3.9Hz), 6.76 (1H, d, J=3.9Hz), 6.86 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 485.13825(M+H)+。 (6a) 3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenol Examples ( 5e) was dissolved in methylene chloride (70 mL), and boron tribromide (1.0 mol / L methylene chloride solution, 23.0 mL, 23.0 mmol) was dissolved at 0 ° C. ) And stirred at room temperature for 4 days under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted 3 times with tetrahydrofuran (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 10%) to give the desired product as a white solid (2.70 g, Yield 95%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 4.07 (2H, t, J = 9.4 Hz), 4.52 (2H, t, J = 9.4 Hz), 6.44 (1H, t, J = 2.0Hz), 6.47 (1H, d, J = 3.9Hz), 6.78 (1H, d, J = 3.9Hz), 6.85 (1H, t, J = 2.0Hz), 7.15 (2H, d, J = 9.0 Hz), 7.31 (1H, m), 7.91 (2H, d, J = 9.0Hz).
(6b) Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} propanoate The compound synthesized in Example (6a) (600 mg, 1.51 mmol) was dissolved in 2-butanone (20 mL), methyl 2-bromopropanoate (340 μL, 3.05 mmol), potassium carbonate (625 mg, 4.52 mmol) was added, and the mixture was refluxed for 19 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -100%) to give the desired product (302 mg, yield) as a white solid. 41%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.64 (3H, d, J = 6.7 Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J = 9.4 Hz) , 4.40 (2H, t, J = 9.4Hz), 4.80 (1H, q, J = 6.7Hz), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 485.13825 (M + H) <+> .
実施例(5e)で合成した化合物(2.93g,7.10mmol)を塩化メチレン(70mL)に溶解し、0℃にて三臭化ホウ素 (1.0mol/L塩化メチレン溶液,23.0mL,23.0mmol)を加え、窒素雰囲気下室温で4日間撹拌した。飽和炭酸水素ナトリウム水溶液(100mL)を加え、テトラヒドロフラン(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~10%)を用いて精製することにより、白色固体の目的物(2.70g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 4.07 (2H, t, J=9.4Hz), 4.52 (2H, t, J=9.4Hz), 6.44 (1H, t, J=2.0Hz), 6.47 (1H, d, J=3.9Hz), 6.78 (1H, d, J=3.9Hz), 6.85 (1H, t, J=2.0Hz), 7.15 (2H, d, J=9.0 Hz), 7.31 (1H, m), 7.91 (2H, d, J=9.0Hz).
(6b)メチル 2-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}プロパノエート
実施例(6a)で合成した化合物(600mg,1.51mmol)を2-ブタノン(20mL)に溶解し、メチル 2-ブロモプロパノエート(340μL,3.05mmol)、炭酸カリウム(625mg,4.52mmol)を加え、窒素雰囲気下で19時間加熱還流した。室温まで冷却し、セライト濾過により不溶物を除去した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的物(302mg,収率41%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.64 (3H, d, J=6.7Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J=9.4Hz), 4.40 (2H, t, J=9.4Hz), 4.80 (1H, q, J=6.7Hz), 6.48 (1H, brs), 6.50 (1H, d, J=3.9Hz), 6.76 (1H, d, J=3.9Hz), 6.86 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 485.13825(M+H)+。 (6a) 3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenol Examples ( 5e) was dissolved in methylene chloride (70 mL), and boron tribromide (1.0 mol / L methylene chloride solution, 23.0 mL, 23.0 mmol) was dissolved at 0 ° C. ) And stirred at room temperature for 4 days under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted 3 times with tetrahydrofuran (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 10%) to give the desired product as a white solid (2.70 g, Yield 95%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 4.07 (2H, t, J = 9.4 Hz), 4.52 (2H, t, J = 9.4 Hz), 6.44 (1H, t, J = 2.0Hz), 6.47 (1H, d, J = 3.9Hz), 6.78 (1H, d, J = 3.9Hz), 6.85 (1H, t, J = 2.0Hz), 7.15 (2H, d, J = 9.0 Hz), 7.31 (1H, m), 7.91 (2H, d, J = 9.0Hz).
(6b) Methyl 2- {3- [5- (4,5-dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} propanoate The compound synthesized in Example (6a) (600 mg, 1.51 mmol) was dissolved in 2-butanone (20 mL), methyl 2-bromopropanoate (340 μL, 3.05 mmol), potassium carbonate (625 mg, 4.52 mmol) was added, and the mixture was refluxed for 19 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -100%) to give the desired product (302 mg, yield) as a white solid. 41%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.64 (3H, d, J = 6.7 Hz), 3.07 (3H, s), 3.77 (3H, s), 3.97 (2H, t, J = 9.4 Hz) , 4.40 (2H, t, J = 9.4Hz), 4.80 (1H, q, J = 6.7Hz), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.94 (1H, brs), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 485.13825 (M + H) <+> .
(実施例7)
3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-2-オン (Example 7)
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} butane- 2-on
3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-2-オン (Example 7)
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} butane- 2-on
実施例(6a)で合成した化合物(200mg,0.502mmol)、3-ブロモ-2-ブタノン(110μL,1.05mmol)、炭酸カリウム(210mg,1.52mmol)を用い、実施例(6b)と同様の方法で白色固体の目的物(31.0mg,収率13%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.52 (3H, d, J=7.0Hz), 2.20 (3H, s), 3.08 (3H, s), 3.97 (2H, t, J=9.4Hz), 4.40 (2H, t, J=9.4Hz), 4.66 (1H, q, J=7.0Hz), 6.46 (1H, t, J=2.4Hz), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.87 (1H, t, J=2.0Hz), 6.91 (1H, t, J=2.0Hz), 7.12 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 469.14333(M+H)+。 Using the compound (200 mg, 0.502 mmol) synthesized in Example (6a), 3-bromo-2-butanone (110 μL, 1.05 mmol), and potassium carbonate (210 mg, 1.52 mmol), The target product (31.0 mg, yield 13%) as a white solid was obtained in the same manner.
1 H-NMR (CDCl 3 , 400MHz): δ1.52 (3H, d, J = 7.0Hz), 2.20 (3H, s), 3.08 (3H, s), 3.97 (2H, t, J = 9.4Hz) , 4.40 (2H, t, J = 9.4Hz), 4.66 (1H, q, J = 7.0Hz), 6.46 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.91 (2H , d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.52 (3H, d, J=7.0Hz), 2.20 (3H, s), 3.08 (3H, s), 3.97 (2H, t, J=9.4Hz), 4.40 (2H, t, J=9.4Hz), 4.66 (1H, q, J=7.0Hz), 6.46 (1H, t, J=2.4Hz), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.87 (1H, t, J=2.0Hz), 6.91 (1H, t, J=2.0Hz), 7.12 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 469.14333(M+H)+。 Using the compound (200 mg, 0.502 mmol) synthesized in Example (6a), 3-bromo-2-butanone (110 μL, 1.05 mmol), and potassium carbonate (210 mg, 1.52 mmol), The target product (31.0 mg, yield 13%) as a white solid was obtained in the same manner.
1 H-NMR (CDCl 3 , 400MHz): δ1.52 (3H, d, J = 7.0Hz), 2.20 (3H, s), 3.08 (3H, s), 3.97 (2H, t, J = 9.4Hz) , 4.40 (2H, t, J = 9.4Hz), 4.66 (1H, q, J = 7.0Hz), 6.46 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.91 (2H , d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
(実施例8)
2-(5-{3-イソプロポキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 8)
2- (5- {3-Isopropoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
2-(5-{3-イソプロポキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 8)
2- (5- {3-Isopropoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
実施例(6a)で合成した化合物(340mg,0.853mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、2-ブロモプロパン(160μL,1.70mmol)、炭酸カリウム(360mg,2.60mmol)を加え、窒素雰囲気下80℃で2日間攪拌した。室温まで冷却し、セライト濾過により不溶物を除去した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~90%)を用いて精製することにより、白色固体の目的物(318mg,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (6H, d, J=6.3Hz), 3.07 (3H, s), 3.95 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.55 (1H, m), 6.50 (1H, m), 6.75 (1H, d, J=3.5Hz), 6.81 (1H, t, J=2.0Hz), 6.94 (1H, t, J=2.0Hz), 7.12 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6Hz).
MS (ESI) m/z: 441.14842(M+H)+。 The compound (340 mg, 0.853 mmol) synthesized in Example (6a) was dissolved in N, N-dimethylformamide (10 mL), 2-bromopropane (160 μL, 1.70 mmol), potassium carbonate (360 mg, 2.60 mmol). ) And stirred at 80 ° C. under a nitrogen atmosphere for 2 days. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -90%) to give the desired product (318 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400MHz): δ1.34 (6H, d, J = 6.3Hz), 3.07 (3H, s), 3.95 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.55 (1H, m), 6.50 (1H, m), 6.75 (1H, d, J = 3.5Hz), 6.81 (1H, t, J = 2.0Hz), 6.94 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 441.14842 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.34 (6H, d, J=6.3Hz), 3.07 (3H, s), 3.95 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.55 (1H, m), 6.50 (1H, m), 6.75 (1H, d, J=3.5Hz), 6.81 (1H, t, J=2.0Hz), 6.94 (1H, t, J=2.0Hz), 7.12 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6Hz).
MS (ESI) m/z: 441.14842(M+H)+。 The compound (340 mg, 0.853 mmol) synthesized in Example (6a) was dissolved in N, N-dimethylformamide (10 mL), 2-bromopropane (160 μL, 1.70 mmol), potassium carbonate (360 mg, 2.60 mmol). ) And stirred at 80 ° C. under a nitrogen atmosphere for 2 days. The mixture was cooled to room temperature, and insoluble matters were removed by celite filtration. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -90%) to give the desired product (318 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400MHz): δ1.34 (6H, d, J = 6.3Hz), 3.07 (3H, s), 3.95 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.55 (1H, m), 6.50 (1H, m), 6.75 (1H, d, J = 3.5Hz), 6.81 (1H, t, J = 2.0Hz), 6.94 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 441.14842 (M + H) <+> .
(実施例9)
3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ジヒドロフラン-2(3H)-オン Example 9
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} dihydrofuran -2 (3H) -ON
3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ジヒドロフラン-2(3H)-オン Example 9
3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] phenoxy} dihydrofuran -2 (3H) -ON
実施例(6a)で合成した化合物(220mg,0.552mmol)、α-ブロモ-γ-ブチロラクトン(110μL,1.19mmol)、炭酸カリウム(230mg,1.66mmol)を用い、実施例(6b)と同様の方法で白色固体の目的物(175mg,収率66%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.48 (1H, m), 2.72 (1H, m), 3.07 (3H, s), 3.93 (2H, t, J=9.4Hz), 4.36 (1H, m), 4.38 (2H, t, J=9.4Hz), 4.52 (1H, m), 4.99 (1H, t, J=7.8Hz), 6.51 (1H, d, J=3.9Hz), 6.66 (1H, t, J=2.4Hz), 6.74 (1H, d, J=3.9Hz), 6.92 (1H, t, J=2.4Hz), 7.08 (1H, t, J=2.0Hz), 7.12 (2H, d, J=9.0 Hz), 7.90 (2H, d, J=9.0Hz).
MS (ESI) m/z: 483.12260(M+H)+。 Using the compound (220 mg, 0.552 mmol) synthesized in Example (6a), α-bromo-γ-butyrolactone (110 μL, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol), and Example (6b) The target product (175 mg, 66% yield) was obtained in the same manner as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.48 (1H, m), 2.72 (1H, m), 3.07 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.36 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.52 (1H, m), 4.99 (1H, t, J = 7.8Hz), 6.51 (1H, d, J = 3.9Hz), 6.66 (1H, t, J = 2.4Hz), 6.74 (1H, d, J = 3.9Hz), 6.92 (1H, t, J = 2.4Hz), 7.08 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 483.12260 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ2.48 (1H, m), 2.72 (1H, m), 3.07 (3H, s), 3.93 (2H, t, J=9.4Hz), 4.36 (1H, m), 4.38 (2H, t, J=9.4Hz), 4.52 (1H, m), 4.99 (1H, t, J=7.8Hz), 6.51 (1H, d, J=3.9Hz), 6.66 (1H, t, J=2.4Hz), 6.74 (1H, d, J=3.9Hz), 6.92 (1H, t, J=2.4Hz), 7.08 (1H, t, J=2.0Hz), 7.12 (2H, d, J=9.0 Hz), 7.90 (2H, d, J=9.0Hz).
MS (ESI) m/z: 483.12260(M+H)+。 Using the compound (220 mg, 0.552 mmol) synthesized in Example (6a), α-bromo-γ-butyrolactone (110 μL, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol), and Example (6b) The target product (175 mg, 66% yield) was obtained in the same manner as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.48 (1H, m), 2.72 (1H, m), 3.07 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.36 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.52 (1H, m), 4.99 (1H, t, J = 7.8Hz), 6.51 (1H, d, J = 3.9Hz), 6.66 (1H, t, J = 2.4Hz), 6.74 (1H, d, J = 3.9Hz), 6.92 (1H, t, J = 2.4Hz), 7.08 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 483.12260 (M + H) <+> .
(実施例10)
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(テトラヒドロフラン-3-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 10)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (tetrahydrofuran-3-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-(テトラヒドロフラン-3-イルオキシ)フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 10)
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5- (tetrahydrofuran-3-yloxy) phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1,3-oxazole
テトラヒドロ-3-フラノール(130μL,1.61mmol)、トリフェニルホスフィン(410mg,1.56mmol)をテトラヒドロフラン(10mL)に溶解し、0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,720μL,1.58mmol)を滴下した。反応液に実施例(6a)で合成した化合物(250mg,0.627mmol)をテトラヒドロフラン(10mL)に溶解して加え、窒素雰囲気下室温で14時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製することにより、白色固体の目的物(277mg,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.11-2.25 (2H, m), 3.07 (3H, s), 3.87-4.02 (4H, m), 3.94 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.92 (1H, m), 6.48 (1H, brs), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.86 (1H, brs), 6.92 (1H, brs), 7.12 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6Hz).
MS (ESI) m/z: 469.14333(M+H)+。 Tetrahydro-3-furanol (130 μL, 1.61 mmol) and triphenylphosphine (410 mg, 1.56 mmol) are dissolved in tetrahydrofuran (10 mL), and at 0 ° C. diethyl azodicarboxylate (40% toluene solution, 720 μL, 1). 58 mmol) was added dropwise. The compound synthesized in Example (6a) (250 mg, 0.627 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, followed by stirring at room temperature for 14 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -80%) to give the desired product (277 mg, yield) as a white solid. 94%).
1 H-NMR (CDCl 3 , 400MHz): δ2.11-2.25 (2H, m), 3.07 (3H, s), 3.87-4.02 (4H, m), 3.94 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.92 (1H, m), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.92 (1H, brs), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ2.11-2.25 (2H, m), 3.07 (3H, s), 3.87-4.02 (4H, m), 3.94 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.92 (1H, m), 6.48 (1H, brs), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.86 (1H, brs), 6.92 (1H, brs), 7.12 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6Hz).
MS (ESI) m/z: 469.14333(M+H)+。 Tetrahydro-3-furanol (130 μL, 1.61 mmol) and triphenylphosphine (410 mg, 1.56 mmol) are dissolved in tetrahydrofuran (10 mL), and at 0 ° C. diethyl azodicarboxylate (40% toluene solution, 720 μL, 1). 58 mmol) was added dropwise. The compound synthesized in Example (6a) (250 mg, 0.627 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, followed by stirring at room temperature for 14 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 50% -80%) to give the desired product (277 mg, yield) as a white solid. 94%).
1 H-NMR (CDCl 3 , 400MHz): δ2.11-2.25 (2H, m), 3.07 (3H, s), 3.87-4.02 (4H, m), 3.94 (2H, t, J = 9.4Hz), 4.39 (2H, t, J = 9.4Hz), 4.92 (1H, m), 6.48 (1H, brs), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.86 (1H, brs), 6.92 (1H, brs), 7.12 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
(実施例11)
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール Example 11
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1 , 3-Oxazole
2-(5-{3-[4-(メチルスルホニル)フェノキシ]-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール Example 11
2- (5- {3- [4- (Methylsulfonyl) phenoxy] -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro-1 , 3-Oxazole
(3R)-テトラヒドロ-3-フラノール(76.0μL,0.946mmol)、トリフェニルホスフィン(250mg,0.953mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,430μL,0.946mmol)、実施例(6a)で合成した化合物(150mg,0.376mmol)を用い、(実施例10)と同様の方法で白色固体の目的物(130mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.12-2.25 (2H, m), 3.07 (3H, s), 3.88-4.03 (6H, m), 4.40 (2H, t, J=9.4Hz), 4.93 (1H, m), 6.48 (1H, t, J=2.4Hz), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.84 (1H, t, J=2.0Hz), 6.91 (1H, t, J=2.0Hz), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 469.14333(M+H)+。 (3R) -tetrahydro-3-furanol (76.0 μL, 0.946 mmol), triphenylphosphine (250 mg, 0.953 mmol), diethyl azodicarboxylate (40% toluene solution, 430 μL, 0.946 mmol), Example ( Using the compound (150 mg, 0.376 mmol) synthesized in 6a), a white solid target product (130 mg, yield 74%) was obtained in the same manner as in (Example 10).
1 H-NMR (CDCl 3 , 400 MHz): δ2.12-2.25 (2H, m), 3.07 (3H, s), 3.88-4.03 (6H, m), 4.40 (2H, t, J = 9.4Hz), 4.93 (1H, m), 6.48 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.84 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ2.12-2.25 (2H, m), 3.07 (3H, s), 3.88-4.03 (6H, m), 4.40 (2H, t, J=9.4Hz), 4.93 (1H, m), 6.48 (1H, t, J=2.4Hz), 6.50 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.84 (1H, t, J=2.0Hz), 6.91 (1H, t, J=2.0Hz), 7.13 (2H, d, J=9.0 Hz), 7.91 (2H, d, J=9.0Hz).
MS (ESI) m/z: 469.14333(M+H)+。 (3R) -tetrahydro-3-furanol (76.0 μL, 0.946 mmol), triphenylphosphine (250 mg, 0.953 mmol), diethyl azodicarboxylate (40% toluene solution, 430 μL, 0.946 mmol), Example ( Using the compound (150 mg, 0.376 mmol) synthesized in 6a), a white solid target product (130 mg, yield 74%) was obtained in the same manner as in (Example 10).
1 H-NMR (CDCl 3 , 400 MHz): δ2.12-2.25 (2H, m), 3.07 (3H, s), 3.88-4.03 (6H, m), 4.40 (2H, t, J = 9.4Hz), 4.93 (1H, m), 6.48 (1H, t, J = 2.4Hz), 6.50 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.84 (1H, t, J = 2.0Hz), 6.91 (1H, t, J = 2.0Hz), 7.13 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 469.14333 (M + H) <+> .
(実施例12)
2-(5-{3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 12)
2- (5- {3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro -1,3-oxazole
2-(5-{3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール (Example 12)
2- (5- {3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrol-2-yl) -4,5-dihydro -1,3-oxazole
1,3-ジフルオロ-2-プロパノール(100μL,1.29mmol)、トリフェニルホスフィン(330mg,1.26mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,570μL,1.26mmol)、実施例(6a)で合成した化合物(200mg,0.502mmol)を用い、(実施例10)と同様の方法で白色固体の目的物(178mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.94 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.57-4.76 (5H, m), 6.51 (1H, d, J=3.5Hz), 6.60 (1H, t, J=2.4Hz), 6.75 (1H, d, J=3.5Hz), 6.90 (1H, t, J=2.0Hz), 7.02 (1H, t, J=2.0Hz), 7.12 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6Hz).
MS (ESI) m/z: 477.12957(M+H)+。 1,3-difluoro-2-propanol (100 μL, 1.29 mmol), triphenylphosphine (330 mg, 1.26 mmol), diethyl azodicarboxylate (40% toluene solution, 570 μL, 1.26 mmol), Example (6a) Using the compound synthesized in Step (200 mg, 0.502 mmol), the target product (178 mg, yield 74%) was obtained as a white solid in the same manner as in Example 10.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.94 (2H, t, J = 9.4 Hz), 4.39 (2H, t, J = 9.4 Hz), 4.57-4.76 (5H, m), 6.51 (1H, d, J = 3.5Hz), 6.60 (1H, t, J = 2.4Hz), 6.75 (1H, d, J = 3.5Hz), 6.90 (1H, t, J = 2.0Hz) , 7.02 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 477.12957 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ3.07 (3H, s), 3.94 (2H, t, J=9.4Hz), 4.39 (2H, t, J=9.4Hz), 4.57-4.76 (5H, m), 6.51 (1H, d, J=3.5Hz), 6.60 (1H, t, J=2.4Hz), 6.75 (1H, d, J=3.5Hz), 6.90 (1H, t, J=2.0Hz), 7.02 (1H, t, J=2.0Hz), 7.12 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6Hz).
MS (ESI) m/z: 477.12957(M+H)+。 1,3-difluoro-2-propanol (100 μL, 1.29 mmol), triphenylphosphine (330 mg, 1.26 mmol), diethyl azodicarboxylate (40% toluene solution, 570 μL, 1.26 mmol), Example (6a) Using the compound synthesized in Step (200 mg, 0.502 mmol), the target product (178 mg, yield 74%) was obtained as a white solid in the same manner as in Example 10.
1 H-NMR (CDCl 3 , 400 MHz): δ3.07 (3H, s), 3.94 (2H, t, J = 9.4 Hz), 4.39 (2H, t, J = 9.4 Hz), 4.57-4.76 (5H, m), 6.51 (1H, d, J = 3.5Hz), 6.60 (1H, t, J = 2.4Hz), 6.75 (1H, d, J = 3.5Hz), 6.90 (1H, t, J = 2.0Hz) , 7.02 (1H, t, J = 2.0Hz), 7.12 (2H, d, J = 8.6Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 477.12957 (M + H) <+> .
(実施例13)
(2R,3S)-3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-2-オール (Example 13)
(2R, 3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) Phenoxy] phenoxy} butan-2-ol
(2R,3S)-3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-2-オール (Example 13)
(2R, 3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) Phenoxy] phenoxy} butan-2-ol
公知{Tetrahedron Letters(テトラへドロン レターズ)38巻、5号、773-776項(1997年)}の(1R,2R)-2-ヒドロキシ-1-メチルプロピル ベンゾエート(270mg,1.39mmol)、トリフェニルホスフィン(360mg,1.37mmol)をテトラヒドロフラン(5mL)に溶解し、0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,630μL,1.39mmol)を滴下した。反応液に実施例(6a)で合成した化合物(220mg,0.552mmol)をテトラヒドロフラン(10mL)に溶解して加え、窒素雰囲気下室温で3時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製した。
(1R, 2R) -2-hydroxy-1-methylpropyl benzoate (270 mg, 1.39 mmol), tritium of {Tetrahedron Letters, Vol. 38, No. 5, Item 773-776 (1997)} Phenylphosphine (360 mg, 1.37 mmol) was dissolved in tetrahydrofuran (5 mL), and diethyl azodicarboxylate (40% toluene solution, 630 μL, 1.39 mmol) was added dropwise at 0 ° C. The compound synthesized in Example (6a) (220 mg, 0.552 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%).
得られた粗精製物をメタノール(10mL)に溶解し、炭酸カリウム(230mg,1.66mmol)を加え窒素雰囲気下で1時間加熱還流した。セライト濾過により不溶物を除去し、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=70%~100%)を用いて精製することにより、白色固体の目的物(154mg,収率59%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.28 (3H, d, J=6.3Hz), 1.29 (3H, d, J=6.3Hz), 3.06 (3H, s), 3.93 (2H, t, J=9.4Hz), 4.03 (1H, m), 4.38 (2H, t, J=9.4Hz), 4.41 (1H, m), 6.44 (1H, d, J=3.9Hz), 6.45 (1H, m), 6.73 (1H, d, J=3.9Hz), 6.83 (1H, t, J=2.0Hz), 7.01 (1H, t, J=2.0Hz), 7.06 (2H, d, J=9.0 Hz), 7.87 (2H, d, J=9.0Hz).
MS (ESI) m/z: 471.15898(M+H)+。 The obtained crude product was dissolved in methanol (10 mL), potassium carbonate (230 mg, 1.66 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. Insoluble matter was removed by Celite filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give white A solid target product (154 mg, yield 59%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.28 (3H, d, J = 6.3Hz), 1.29 (3H, d, J = 6.3Hz), 3.06 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.03 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.41 (1H, m), 6.44 (1H, d, J = 3.9Hz), 6.45 (1H, m) , 6.73 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.06 (2H, d, J = 9.0 Hz), 7.87 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.28 (3H, d, J=6.3Hz), 1.29 (3H, d, J=6.3Hz), 3.06 (3H, s), 3.93 (2H, t, J=9.4Hz), 4.03 (1H, m), 4.38 (2H, t, J=9.4Hz), 4.41 (1H, m), 6.44 (1H, d, J=3.9Hz), 6.45 (1H, m), 6.73 (1H, d, J=3.9Hz), 6.83 (1H, t, J=2.0Hz), 7.01 (1H, t, J=2.0Hz), 7.06 (2H, d, J=9.0 Hz), 7.87 (2H, d, J=9.0Hz).
MS (ESI) m/z: 471.15898(M+H)+。 The obtained crude product was dissolved in methanol (10 mL), potassium carbonate (230 mg, 1.66 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. Insoluble matter was removed by Celite filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give white A solid target product (154 mg, yield 59%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.28 (3H, d, J = 6.3Hz), 1.29 (3H, d, J = 6.3Hz), 3.06 (3H, s), 3.93 (2H, t, J = 9.4Hz), 4.03 (1H, m), 4.38 (2H, t, J = 9.4Hz), 4.41 (1H, m), 6.44 (1H, d, J = 3.9Hz), 6.45 (1H, m) , 6.73 (1H, d, J = 3.9Hz), 6.83 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.06 (2H, d, J = 9.0 Hz), 7.87 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) <+> .
(実施例14)
(3S)-3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-1-オール (Example 14)
(3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} butan-1-ol
(3S)-3-{3-[5-(4,5-ジヒドロ-1,3-オキサゾール-2-イル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]フェノキシ}ブタン-1-オール (Example 14)
(3S) -3- {3- [5- (4,5-Dihydro-1,3-oxazol-2-yl) -1H-pyrrol-2-yl] -5- [4- (methylsulfonyl) phenoxy] Phenoxy} butan-1-ol
公知{Synthesis(シンセシス)9巻、1357-1360項(2003年)}の(2R)-4-{[(1,1-ジメチルエチル)ジフェニルシリル]オキシ}-2-ブタノール(460mg,1.40mmol)、トリフェニルホスフィン(360mg,1.37mmol)をテトラヒドロフラン(5mL)に溶解し、0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,630μL,1.39mmol)を滴下した。反応液に実施例(6a)で合成した化合物(220mg,0.552mmol)をテトラヒドロフラン(10mL)に溶解して加え、窒素雰囲気下室温で6時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製した。
{2R) -4-{[(1,1-dimethylethyl) diphenylsilyl] oxy} -2-butanol (460 mg, 1.40 mmol) of {{Synthesis 9], 1357-1360 (2003)} ), Triphenylphosphine (360 mg, 1.37 mmol) was dissolved in tetrahydrofuran (5 mL), and diethyl azodicarboxylate (40% toluene solution, 630 μL, 1.39 mmol) was added dropwise at 0 ° C. The compound synthesized in Example (6a) (220 mg, 0.552 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%).
得られた粗精製物をテトラヒドロフラン(10mL)に溶解し、テトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液,560μL,0.560mmol)を加え、窒素雰囲気下室温で1時間撹拌した。水(10mL)を加え、酢酸エチル(20mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=70%~100%)を用いて精製することにより、白色固体の目的化合物(121mg,収率47%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J=6.3Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.88 (2H, m), 3.94 (2H, t, J=9.4Hz), 4.38 (2H, t, J=9.4Hz), 4.63 (1H, m), 6.44-6.48 (2H, m), 6.73 (1H, d, J=3.5Hz), 6.83 (1H, t, J=2.0Hz), 7.03 (1H, brs), 7.10 (2H, d, J=9.0 Hz), 7.88 (2H, d, J=9.0Hz).
MS (ESI) m/z: 471.15898(M+H)+。 The obtained crude product was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 560 μL, 0.560 mmol) was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water (10 mL) was added and extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the target compound (121 mg, yield) as a white solid. 47%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.88 ( 2H, m), 3.94 (2H, t, J = 9.4Hz), 4.38 (2H, t, J = 9.4Hz), 4.63 (1H, m), 6.44-6.48 (2H, m), 6.73 (1H, d , J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 7.03 (1H, brs), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.33 (3H, d, J=6.3Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.88 (2H, m), 3.94 (2H, t, J=9.4Hz), 4.38 (2H, t, J=9.4Hz), 4.63 (1H, m), 6.44-6.48 (2H, m), 6.73 (1H, d, J=3.5Hz), 6.83 (1H, t, J=2.0Hz), 7.03 (1H, brs), 7.10 (2H, d, J=9.0 Hz), 7.88 (2H, d, J=9.0Hz).
MS (ESI) m/z: 471.15898(M+H)+。 The obtained crude product was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 560 μL, 0.560 mmol) was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water (10 mL) was added and extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the target compound (121 mg, yield) as a white solid. 47%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (3H, d, J = 6.3 Hz), 1.85 (1H, m), 2.04 (1H, m), 3.06 (3H, s), 3.77-3.88 ( 2H, m), 3.94 (2H, t, J = 9.4Hz), 4.38 (2H, t, J = 9.4Hz), 4.63 (1H, m), 6.44-6.48 (2H, m), 6.73 (1H, d , J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 7.03 (1H, brs), 7.10 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J = 9.0Hz).
MS (ESI) m / z: 471.15898 (M + H) <+> .
(実施例15)
2-[5-(3-{[(1S)-3-フルオロ-1-メチルプロピル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール (Example 15)
2- [5- (3-{[(1S) -3-Fluoro-1-methylpropyl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole
2-[5-(3-{[(1S)-3-フルオロ-1-メチルプロピル]オキシ}-5-[4-(メチルスルホニル)フェノキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール (Example 15)
2- [5- (3-{[(1S) -3-Fluoro-1-methylpropyl] oxy} -5- [4- (methylsulfonyl) phenoxy] phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazole
(実施例14)で合成した化合物(72.5mg,0.154mmol)を塩化メチレン(5mL)に溶解し、0℃にてビス(2-メトキシエチル)アミノサルファー トリフルオリド(70μL,0.534mmol)を加えた。室温で4時間撹拌後、飽和炭酸水素ナトリウム水溶液を加え、塩化メチレン(10mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=70%~100%)を用いて精製することにより、白色固体の目的化合物(47.3mg,収率65%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, d, J=6.3Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 (2H, t, J=9.4Hz), 4.41 (2H, t, J=9.4Hz), 4.50-4.72 (3H, m), 6.51 (1H, d, J=3.9Hz), 6.53 (1H, t, J=2.0Hz), 6.76 (1H, d, J=3.9Hz), 6.83 (1H, brs), 6.96 (1H, brs), 7.13 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6Hz).
MS (ESI) m/z: 473.15464(M+H)+。 The compound synthesized in Example 14 (72.5 mg, 0.154 mmol) was dissolved in methylene chloride (5 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (70 μL, 0.534 mmol) at 0 ° C. Was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the desired compound (47.3 mg, Yield 65%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.37 (3H, d, J = 6.3 Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4Hz), 4.50-4.72 (3H, m), 6.51 (1H, d, J = 3.9Hz), 6.53 (1H, t, J = 2.0Hz), 6.76 ( 1H, d, J = 3.9Hz), 6.83 (1H, brs), 6.96 (1H, brs), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 473.15464 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, d, J=6.3Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 (2H, t, J=9.4Hz), 4.41 (2H, t, J=9.4Hz), 4.50-4.72 (3H, m), 6.51 (1H, d, J=3.9Hz), 6.53 (1H, t, J=2.0Hz), 6.76 (1H, d, J=3.9Hz), 6.83 (1H, brs), 6.96 (1H, brs), 7.13 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6Hz).
MS (ESI) m/z: 473.15464(M+H)+。 The compound synthesized in Example 14 (72.5 mg, 0.154 mmol) was dissolved in methylene chloride (5 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (70 μL, 0.534 mmol) at 0 ° C. Was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 70% to 100%) to give the desired compound (47.3 mg, Yield 65%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.37 (3H, d, J = 6.3 Hz), 2.00-2.13 (2H, m), 3.07 (3H, s), 3.98 (2H, t, J = 9.4 Hz), 4.41 (2H, t, J = 9.4Hz), 4.50-4.72 (3H, m), 6.51 (1H, d, J = 3.9Hz), 6.53 (1H, t, J = 2.0Hz), 6.76 ( 1H, d, J = 3.9Hz), 6.83 (1H, brs), 6.96 (1H, brs), 7.13 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 473.15464 (M + H) <+> .
(実施例16)
{(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 16)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 16)
{(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
(16a)5-クロロ-2-(メチルスルホニル)ピリジン
2,5-ジクロロピリジン(1.49g,10.1mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、窒素雰囲気下0℃にてナトリウムチオメトキシド(783mg,11.2mmol)を加え1時間撹拌した。水(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、無色油状の化合物(1.58g)を得た。 (16a) 5-Chloro-2- (methylsulfonyl) pyridine 2,5-dichloropyridine (1.49 g, 10.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and the resulting solution was at 0 ° C. under a nitrogen atmosphere. Sodium thiomethoxide (783 mg, 11.2 mmol) was added and stirred for 1 hour. Water (100 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily compound (1.58 g).
2,5-ジクロロピリジン(1.49g,10.1mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、窒素雰囲気下0℃にてナトリウムチオメトキシド(783mg,11.2mmol)を加え1時間撹拌した。水(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、無色油状の化合物(1.58g)を得た。 (16a) 5-Chloro-2- (methylsulfonyl) pyridine 2,5-dichloropyridine (1.49 g, 10.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and the resulting solution was at 0 ° C. under a nitrogen atmosphere. Sodium thiomethoxide (783 mg, 11.2 mmol) was added and stirred for 1 hour. Water (100 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily compound (1.58 g).
これを塩化メチレン(50mL)に溶解し、m-クロロ過安息香酸(約65%,5.25g,約20mmol)を0℃でゆっくり加え、窒素雰囲気下0℃で2時間撹拌した。飽和炭酸水素ナトリウム水溶液(200mL)を加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=25%~45%)を用いて精製することで白色固体の目的化合物(1.63g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.24 (3H, s), 7.95 (1H, dd, J = 8.2, 2.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.69 (1H, d, J = 2.3 Hz).
MS (ESI) m/z: 191.98866 (M+H)+.
(16b)3-メトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(1a)で合成した化合物(5.05g,24.9mmol)、ビス(ピナコレート)ジボロン(9.47g,37.3mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(634mg,0.776mmol)、酢酸カリウム(12.24g,125mmol)を用い、実施例(1d)と同様の方法で無色油状の目的化合物(4.49g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.34 (12H, s), 3.80 (3H, s), 4.91 (1H, s), 6.53 (1H, t, J = 2.3 Hz), 6.86 (1H, d, J= 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
MS (FAB) m/z: 251 (M+H)+.
(16c)t-ブチル 2,5-ジブロモ-1H-ピロール-1-カルボキシレート
t-ブチル 1-ピロールカルボキシレート(46.68g,279mmol)をテトラヒドロフラン(500mL)に溶解し-78℃に冷却した、これにN-ブロモスクシンイミド(100.48g,565mmol)を少しずつ1時間かけて加えた。反応液を自然に昇温させ室温で18時間撹拌した。反応液を0℃に冷却して亜硫酸ナトリウム(36.43g)を加えて30分撹拌した後、ヘキサン(200mL)を加えて生じた沈殿をセライト濾過により除去した。減圧下濾液の溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=1%~5%)を用いて精製することにより、無色油状の目的化合物(52.69g,収率58%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.65 (9H, s), 6.25 (2H, s).
MS (EI) m/z: 323(M+)。 This was dissolved in methylene chloride (50 mL), m-chloroperbenzoic acid (about 65%, 5.25 g, about 20 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 25% -45%) to give the target compound (1.63 g, yield) as a white solid. 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 7.95 (1H, dd, J = 8.2, 2.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.69 (1H, d , J = 2.3 Hz).
MS (ESI) m / z: 191.98866 (M + H) + .
(16b) 3-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (1a) (5.05 g, 24. 9 mmol), bis (pinacolato) diboron (9.47 g, 37.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (634 mg, 0.776 mmol), potassium acetate ( The target compound (4.49 g, yield 72%) as a colorless oil was obtained in the same manner as in Example (1d) using 12.24 g, 125 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (12H, s), 3.80 (3H, s), 4.91 (1H, s), 6.53 (1H, t, J = 2.3 Hz), 6.86 (1H, d , J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
MS (FAB) m / z: 251 (M + H) + .
(16c) t-butyl 2,5-dibromo-1H-pyrrole-1-carboxylate t-butyl 1-pyrrole carboxylate (46.68 g, 279 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to -78 ° C. To this was added N-bromosuccinimide (100.48 g, 565 mmol) in portions over 1 hour. The reaction was allowed to warm naturally and stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C., sodium sulfite (36.43 g) was added, and the mixture was stirred for 30 min. Hexane (200 mL) was added, and the resulting precipitate was removed by celite filtration. The solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 5%) to give the objective compound (52. 69 g, yield 58%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.65 (9H, s), 6.25 (2H, s).
MS (EI) m / z: 323 (M + ).
1H-NMR (CDCl3, 400MHz): δ 3.24 (3H, s), 7.95 (1H, dd, J = 8.2, 2.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.69 (1H, d, J = 2.3 Hz).
MS (ESI) m/z: 191.98866 (M+H)+.
(16b)3-メトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(1a)で合成した化合物(5.05g,24.9mmol)、ビス(ピナコレート)ジボロン(9.47g,37.3mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(634mg,0.776mmol)、酢酸カリウム(12.24g,125mmol)を用い、実施例(1d)と同様の方法で無色油状の目的化合物(4.49g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.34 (12H, s), 3.80 (3H, s), 4.91 (1H, s), 6.53 (1H, t, J = 2.3 Hz), 6.86 (1H, d, J= 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
MS (FAB) m/z: 251 (M+H)+.
(16c)t-ブチル 2,5-ジブロモ-1H-ピロール-1-カルボキシレート
t-ブチル 1-ピロールカルボキシレート(46.68g,279mmol)をテトラヒドロフラン(500mL)に溶解し-78℃に冷却した、これにN-ブロモスクシンイミド(100.48g,565mmol)を少しずつ1時間かけて加えた。反応液を自然に昇温させ室温で18時間撹拌した。反応液を0℃に冷却して亜硫酸ナトリウム(36.43g)を加えて30分撹拌した後、ヘキサン(200mL)を加えて生じた沈殿をセライト濾過により除去した。減圧下濾液の溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=1%~5%)を用いて精製することにより、無色油状の目的化合物(52.69g,収率58%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.65 (9H, s), 6.25 (2H, s).
MS (EI) m/z: 323(M+)。 This was dissolved in methylene chloride (50 mL), m-chloroperbenzoic acid (about 65%, 5.25 g, about 20 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 25% -45%) to give the target compound (1.63 g, yield) as a white solid. 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 7.95 (1H, dd, J = 8.2, 2.3 Hz), 8.06 (1H, d, J = 8.2 Hz), 8.69 (1H, d , J = 2.3 Hz).
MS (ESI) m / z: 191.98866 (M + H) + .
(16b) 3-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (1a) (5.05 g, 24. 9 mmol), bis (pinacolato) diboron (9.47 g, 37.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (634 mg, 0.776 mmol), potassium acetate ( The target compound (4.49 g, yield 72%) as a colorless oil was obtained in the same manner as in Example (1d) using 12.24 g, 125 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (12H, s), 3.80 (3H, s), 4.91 (1H, s), 6.53 (1H, t, J = 2.3 Hz), 6.86 (1H, d , J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
MS (FAB) m / z: 251 (M + H) + .
(16c) t-butyl 2,5-dibromo-1H-pyrrole-1-carboxylate t-butyl 1-pyrrole carboxylate (46.68 g, 279 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to -78 ° C. To this was added N-bromosuccinimide (100.48 g, 565 mmol) in portions over 1 hour. The reaction was allowed to warm naturally and stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C., sodium sulfite (36.43 g) was added, and the mixture was stirred for 30 min. Hexane (200 mL) was added, and the resulting precipitate was removed by celite filtration. The solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 5%) to give the objective compound (52. 69 g, yield 58%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.65 (9H, s), 6.25 (2H, s).
MS (EI) m / z: 323 (M + ).
(16d)2-ベンジル 1-t-ブチル 5-ブロモ-1H-ピロール-1,2-ジカルボキシレート
実施例(16c)で合成した化合物(10.98g,33.8mmol)をジエチルエーテル(135mL)に溶解し-78℃に冷却した。n-ブチルリチウム(2.77mol/Lヘキサン溶液,12.8mL,35.5mmol)をゆっくり滴下し、1時間撹拌した。反応液にベンジル クロロホルメート(6.25mL,44.0mmol)をゆっくり滴下し30分撹拌した。反応液を室温まで徐々に昇温しながら1時間撹拌した。反応液に飽和塩化アンモニウム水溶液(200mL)とジエチルエーテル(300mL)を加えて分液した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=1%~9%)を用いて精製することにより、赤茶色油状の目的化合物(8.80g,収率68%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.56 (9H, s), 5.26 (2H, s), 6.21 (1H, d, J = 3.9 Hz), 6.85 (1H, d, J = 3.9 Hz), 7.28-7.39 (5H, m).
MS (FAB) m/z: 380(M+H)+.
(16e)2-ベンジル 1-t-ブチル 5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-1,2-ジカルボキシレート
実施例(16d)で合成した化合物(7.78g,20.5mmol)と実施例(16b)で合成した化合物(4.26g,17.0mmol)を1,4-ジオキサン(80mL)と水(20mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(420mg,0.514mmol)及び炭酸カリウム(5.93g,42.9mmol)を加え、窒素雰囲気下55℃で6時間撹拌した。反応液を室温まで冷却後に水(200mL)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、赤茶色油状の目的化合物(5.20g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.41 (9H, s), 3.78 (3H, s), 5.05 (1H, s), 5.31 (2H, s), 6.19 (1H, d, J = 3.5 Hz), 6.41 (1H, t, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 1.4 Hz), 6.55 (1H, dd, J = 2.2, 1.4 Hz), 6.95 (1H, d, J = 3.5 Hz), 7.30-7.43 (5H, m).
MS (FAB) m/z: 424 (M+H)+.
(16f)ベンジル 5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(16e)で合成した化合物(2.96g,6.99mmol)と実施例(16a)で合成した化合物(1.39g,7.25mmol)をN,N-ジメチルホルムアミド(35mL)に溶解させ、炭酸セシウム(6.86g,21.1mmol)を加え窒素雰囲気下100℃で2時間半撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (16d) 2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (16c) (10.98 g, 33.8 mmol) was converted into diethyl ether (135 mL). And cooled to -78 ° C. n-Butyllithium (2.77 mol / L hexane solution, 12.8 mL, 35.5 mmol) was slowly added dropwise and stirred for 1 hour. To the reaction solution, benzyl chloroformate (6.25 mL, 44.0 mmol) was slowly added dropwise and stirred for 30 minutes. The reaction solution was stirred for 1 hour while gradually warming to room temperature. A saturated aqueous ammonium chloride solution (200 mL) and diethyl ether (300 mL) were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 9%) to give the desired compound (8.80 g) as a red-brown oil. Yield 68%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.56 (9H, s), 5.26 (2H, s), 6.21 (1H, d, J = 3.9 Hz), 6.85 (1H, d, J = 3.9 Hz), 7.28-7.39 (5H, m).
MS (FAB) m / z: 380 (M + H) + .
(16e) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound (7.78 g, 20) synthesized in Example (16d) 0.5 mmol) and the compound (4.26 g, 17.0 mmol) synthesized in Example (16b) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (20 mL), and [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (420 mg, 0.514 mmol) and potassium carbonate (5.93 g, 42.9 mmol) were added, and the mixture was stirred at 55 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.20 g) as a red-brown oil. Yield 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (9H, s), 3.78 (3H, s), 5.05 (1H, s), 5.31 (2H, s), 6.19 (1H, d, J = 3.5 Hz ), 6.41 (1H, t, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 1.4 Hz), 6.55 (1H, dd, J = 2.2, 1.4 Hz), 6.95 (1H, d, J = 3.5 Hz), 7.30-7.43 (5H, m).
MS (FAB) m / z: 424 (M + H) + .
(16f) Benzyl 5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (16e) ( 2.96 g, 6.99 mmol) and the compound synthesized in Example (16a) (1.39 g, 7.25 mmol) were dissolved in N, N-dimethylformamide (35 mL), and cesium carbonate (6.86 g, 21.20 mmol) was dissolved. 1 mmol) was added, and the mixture was stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(16c)で合成した化合物(10.98g,33.8mmol)をジエチルエーテル(135mL)に溶解し-78℃に冷却した。n-ブチルリチウム(2.77mol/Lヘキサン溶液,12.8mL,35.5mmol)をゆっくり滴下し、1時間撹拌した。反応液にベンジル クロロホルメート(6.25mL,44.0mmol)をゆっくり滴下し30分撹拌した。反応液を室温まで徐々に昇温しながら1時間撹拌した。反応液に飽和塩化アンモニウム水溶液(200mL)とジエチルエーテル(300mL)を加えて分液した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=1%~9%)を用いて精製することにより、赤茶色油状の目的化合物(8.80g,収率68%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.56 (9H, s), 5.26 (2H, s), 6.21 (1H, d, J = 3.9 Hz), 6.85 (1H, d, J = 3.9 Hz), 7.28-7.39 (5H, m).
MS (FAB) m/z: 380(M+H)+.
(16e)2-ベンジル 1-t-ブチル 5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-1,2-ジカルボキシレート
実施例(16d)で合成した化合物(7.78g,20.5mmol)と実施例(16b)で合成した化合物(4.26g,17.0mmol)を1,4-ジオキサン(80mL)と水(20mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(420mg,0.514mmol)及び炭酸カリウム(5.93g,42.9mmol)を加え、窒素雰囲気下55℃で6時間撹拌した。反応液を室温まで冷却後に水(200mL)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、赤茶色油状の目的化合物(5.20g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.41 (9H, s), 3.78 (3H, s), 5.05 (1H, s), 5.31 (2H, s), 6.19 (1H, d, J = 3.5 Hz), 6.41 (1H, t, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 1.4 Hz), 6.55 (1H, dd, J = 2.2, 1.4 Hz), 6.95 (1H, d, J = 3.5 Hz), 7.30-7.43 (5H, m).
MS (FAB) m/z: 424 (M+H)+.
(16f)ベンジル 5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(16e)で合成した化合物(2.96g,6.99mmol)と実施例(16a)で合成した化合物(1.39g,7.25mmol)をN,N-ジメチルホルムアミド(35mL)に溶解させ、炭酸セシウム(6.86g,21.1mmol)を加え窒素雰囲気下100℃で2時間半撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (16d) 2-Benzyl 1-t-butyl 5-bromo-1H-pyrrole-1,2-dicarboxylate The compound synthesized in Example (16c) (10.98 g, 33.8 mmol) was converted into diethyl ether (135 mL). And cooled to -78 ° C. n-Butyllithium (2.77 mol / L hexane solution, 12.8 mL, 35.5 mmol) was slowly added dropwise and stirred for 1 hour. To the reaction solution, benzyl chloroformate (6.25 mL, 44.0 mmol) was slowly added dropwise and stirred for 30 minutes. The reaction solution was stirred for 1 hour while gradually warming to room temperature. A saturated aqueous ammonium chloride solution (200 mL) and diethyl ether (300 mL) were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1% to 9%) to give the desired compound (8.80 g) as a red-brown oil. Yield 68%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.56 (9H, s), 5.26 (2H, s), 6.21 (1H, d, J = 3.9 Hz), 6.85 (1H, d, J = 3.9 Hz), 7.28-7.39 (5H, m).
MS (FAB) m / z: 380 (M + H) + .
(16e) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound (7.78 g, 20) synthesized in Example (16d) 0.5 mmol) and the compound (4.26 g, 17.0 mmol) synthesized in Example (16b) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (20 mL), and [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (420 mg, 0.514 mmol) and potassium carbonate (5.93 g, 42.9 mmol) were added, and the mixture was stirred at 55 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.20 g) as a red-brown oil. Yield 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (9H, s), 3.78 (3H, s), 5.05 (1H, s), 5.31 (2H, s), 6.19 (1H, d, J = 3.5 Hz ), 6.41 (1H, t, J = 2.2 Hz), 6.49 (1H, dd, J = 2.2, 1.4 Hz), 6.55 (1H, dd, J = 2.2, 1.4 Hz), 6.95 (1H, d, J = 3.5 Hz), 7.30-7.43 (5H, m).
MS (FAB) m / z: 424 (M + H) + .
(16f) Benzyl 5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (16e) ( 2.96 g, 6.99 mmol) and the compound synthesized in Example (16a) (1.39 g, 7.25 mmol) were dissolved in N, N-dimethylformamide (35 mL), and cesium carbonate (6.86 g, 21.20 mmol) was dissolved. 1 mmol) was added, and the mixture was stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣を塩化メチレン(20mL)に溶解し、トリフルオロ酢酸(10mL)を加え、室温で30分間撹拌した。反応液を濃縮後、飽和炭酸水素ナトリウム水溶液(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=25%~50%)を用いて精製することで、白色固体の目的化合物(1.23g,収率37%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.23 (3H, s), 3.85 (3H, s), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.56 (1H, t, J = 2.2 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.7, 2.5 Hz), 7.35-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s)。 The obtained residue was dissolved in methylene chloride (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 25% -50%) to give the desired compound (1.23 g, Yield 37%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 3.85 (3H, s), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.56 (1H , t, J = 2.2 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.7, 2.5 Hz), 7.35-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s).
1H-NMR (CDCl3, 400MHz): δ 3.23 (3H, s), 3.85 (3H, s), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.56 (1H, t, J = 2.2 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.7, 2.5 Hz), 7.35-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s)。 The obtained residue was dissolved in methylene chloride (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 25% -50%) to give the desired compound (1.23 g, Yield 37%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 3.85 (3H, s), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.56 (1H , t, J = 2.2 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.7, 2.5 Hz), 7.35-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.27 (1H, br s).
(16g)5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(16f)で合成した化合物(1.22g,2.55mmol)を酢酸エチル(50mL)に溶解し、10%パラジウム炭素触媒(872mg)を加え、水素雰囲気下室温で2時間半撹拌した。セライト濾過後、減圧下溶媒を留去し、白色固体の目的化合物(954mg,収率96%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.23 (3H, s), 3.87 (3H, s), 6.56-6.60 (2H, m), 6.89 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.07 (1H, dd, J = 3.7, 2.5 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
MS (FAB) m/z: 389 (M+H)+.
(16h)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(16g)で合成した化合物(946mg,2.44mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(574mg,6.30mmol)、DMT-MM(1.98g,6.32mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(949mg,84%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1H, m), 3.84 (3H, s), 6.46-6.51 (2H, m), 6.55 (1H, t, J = 2.2 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.88 (1H, br s).
MS (FAB) m/z: 462 (M+H)+.
(16i)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(16h)で合成した化合物(940mg,2.04mmol)を塩化メチレン(30mL)に溶解し、トリエチルアミン(0.85mL,6.13mmol)、トリイソプロピルシリルクロリド(525μL,2.45mmol)、4-ジメチルアミノピリジン(258mg,2.11mmmol)を加え、窒素雰囲気下で21時間攪拌した。反応液を塩化メチレン(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~75%)を用いて精製することで、白色固体の目的物(1.05g,83%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.43 (1H, m), 3.65-3.91 (4H, m), 3.85 (3H, s), 6.35 (1H, t, J = 5.7 Hz), 6.51 (1H, t, J = 3.3 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 3.7, 2.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.52 (1H, br s).
MS (FAB) m/z: 618 (M+H)+。 (16 g) 5- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (1) synthesized in Example (16f) .22 g, 2.55 mmol) was dissolved in ethyl acetate (50 mL), 10% palladium carbon catalyst (872 mg) was added, and the mixture was stirred at room temperature for 2 and a half hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure to obtain the target compound (954 mg, yield 96%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 3.87 (3H, s), 6.56-6.60 (2H, m), 6.89 (1H, t, J = 1.6 Hz), 7.01 (1H , t, J = 1.6 Hz), 7.07 (1H, dd, J = 3.7, 2.5 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
MS (FAB) m / z: 389 (M + H) + .
(16h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide Compound (946 mg, 2.44 mmol) synthesized in Example (16 g), (S)-(−)-3-amino-1,2-propanediol (574 mg, 6.30 mmol), DMT-MM ( Using 1.98 g, 6.32 mmol), the white solid target product (949 mg, 84%) was obtained in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1H, m), 3.84 (3H, s), 6.46-6.51 (2H, m), 6.55 (1H, t, J = 2.2 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.88 (1H, br s).
MS (FAB) m / z: 462 (M + H) + .
(16i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (16h) (940 mg, 2.04 mmol) was dissolved in methylene chloride (30 mL), triethylamine (0.85 mL, 6.13 mmol), Isopropylsilyl chloride (525 μL, 2.45 mmol) and 4-dimethylaminopyridine (258 mg, 2.11 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 21 hours. The reaction mixture was diluted with methylene chloride (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -75%) to give the desired product (1.05 g, 83%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.43 (1H, m), 3.65 -3.91 (4H, m), 3.85 (3H, s), 6.35 (1H, t, J = 5.7 Hz), 6.51 (1H, t, J = 3.3 Hz), 6.54 (1H, t, J = 2.0 Hz) , 6.61 (1H, dd, J = 3.7, 2.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.52 (1H, br s).
MS (FAB) m / z: 618 (M + H) <+> .
実施例(16f)で合成した化合物(1.22g,2.55mmol)を酢酸エチル(50mL)に溶解し、10%パラジウム炭素触媒(872mg)を加え、水素雰囲気下室温で2時間半撹拌した。セライト濾過後、減圧下溶媒を留去し、白色固体の目的化合物(954mg,収率96%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.23 (3H, s), 3.87 (3H, s), 6.56-6.60 (2H, m), 6.89 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.07 (1H, dd, J = 3.7, 2.5 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
MS (FAB) m/z: 389 (M+H)+.
(16h)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(16g)で合成した化合物(946mg,2.44mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(574mg,6.30mmol)、DMT-MM(1.98g,6.32mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(949mg,84%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1H, m), 3.84 (3H, s), 6.46-6.51 (2H, m), 6.55 (1H, t, J = 2.2 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.88 (1H, br s).
MS (FAB) m/z: 462 (M+H)+.
(16i)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(16h)で合成した化合物(940mg,2.04mmol)を塩化メチレン(30mL)に溶解し、トリエチルアミン(0.85mL,6.13mmol)、トリイソプロピルシリルクロリド(525μL,2.45mmol)、4-ジメチルアミノピリジン(258mg,2.11mmmol)を加え、窒素雰囲気下で21時間攪拌した。反応液を塩化メチレン(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~75%)を用いて精製することで、白色固体の目的物(1.05g,83%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.43 (1H, m), 3.65-3.91 (4H, m), 3.85 (3H, s), 6.35 (1H, t, J = 5.7 Hz), 6.51 (1H, t, J = 3.3 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 3.7, 2.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.52 (1H, br s).
MS (FAB) m/z: 618 (M+H)+。 (16 g) 5- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (1) synthesized in Example (16f) .22 g, 2.55 mmol) was dissolved in ethyl acetate (50 mL), 10% palladium carbon catalyst (872 mg) was added, and the mixture was stirred at room temperature for 2 and a half hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure to obtain the target compound (954 mg, yield 96%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 3.87 (3H, s), 6.56-6.60 (2H, m), 6.89 (1H, t, J = 1.6 Hz), 7.01 (1H , t, J = 1.6 Hz), 7.07 (1H, dd, J = 3.7, 2.5 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
MS (FAB) m / z: 389 (M + H) + .
(16h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide Compound (946 mg, 2.44 mmol) synthesized in Example (16 g), (S)-(−)-3-amino-1,2-propanediol (574 mg, 6.30 mmol), DMT-MM ( Using 1.98 g, 6.32 mmol), the white solid target product (949 mg, 84%) was obtained in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.16-3.24 (2H, m), 3.23 (3H, s), 3.48-3.60 (4H, m), 3.79-3.86 (1H, m), 3.84 (3H, s), 6.46-6.51 (2H, m), 6.55 (1H, t, J = 2.2 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.98 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.88 (1H, br s).
MS (FAB) m / z: 462 (M + H) + .
(16i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (16h) (940 mg, 2.04 mmol) was dissolved in methylene chloride (30 mL), triethylamine (0.85 mL, 6.13 mmol), Isopropylsilyl chloride (525 μL, 2.45 mmol) and 4-dimethylaminopyridine (258 mg, 2.11 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 21 hours. The reaction mixture was diluted with methylene chloride (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -75%) to give the desired product (1.05 g, 83%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.43 (1H, m), 3.65 -3.91 (4H, m), 3.85 (3H, s), 6.35 (1H, t, J = 5.7 Hz), 6.51 (1H, t, J = 3.3 Hz), 6.54 (1H, t, J = 2.0 Hz) , 6.61 (1H, dd, J = 3.7, 2.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.52 (1H, br s).
MS (FAB) m / z: 618 (M + H) <+> .
(16j)5-(3-メトキシ-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(16i)で合成した化合物(1.04g,1.68mmol)をテトラヒドロフラン(20mL)に溶解し、メタンスルホン酸無水物(594mg,3.41mmol)、トリエチルアミン(1.05mL,7.57mmol)を加え、窒素雰囲気下60℃で2時間撹拌した後、1時間加熱還流した。反応液に水(50mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~3%)を用いて精製することにより、淡黄色固体の目的化合物(955mg,収率94%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.02-1.14 (21H, m), 3.23 (3H, s), 3.83-3.91 (3H, m), 3.85 (3H, s), 4.00 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.79 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (FAB) m/z: 600 (M+H)+.
(16k){(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(16j)で合成した化合物(943mg,1.57mmol)をテトラヒドロフラン(10mL)に溶解し、テトラブチルアンモニウムフルオリド(1.0mol/Lテトラヒドロフラン溶液,1.70mL,1.70mmol)を加え、窒素雰囲気下室温で30分間撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~7%)を用いて精製することにより、白色固体の目的化合物(596mg,収率86%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.00 (1H, br s), 3.23 (3H, s), 3.68-3.83 (3H, m), 3.85 (3H, s), 4.03 (1H, dd, J = 14.3, 10.0 Hz), 4.75-4.82 (1H, m), 6.45 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.67 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 444.12012 (M+H)+。 (16j) 5- (3-Methoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (16i) (1.04 g, 1.68 mmol) was dissolved in tetrahydrofuran (20 mL) and methanesulfonic anhydride (594 mg, 3.41 mmol) and triethylamine (1.05 mL, 7.57 mmol) were added, and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere, and then heated to reflux for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 3%) to give the target compound (955 mg) as a pale yellow solid. 94% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.02-1.14 (21H, m), 3.23 (3H, s), 3.83-3.91 (3H, m), 3.85 (3H, s), 4.00 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.79 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 600 (M + H) + .
(16k) {(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol The compound (943 mg, 1.57 mmol) synthesized in Example (16j) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol / mol) was dissolved. L tetrahydrofuran solution, 1.70 mL, 1.70 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (596 mg, yield) as a white solid. 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.00 (1H, br s), 3.23 (3H, s), 3.68-3.83 (3H, m), 3.85 (3H, s), 4.03 (1H, dd, J = 14.3, 10.0 Hz), 4.75-4.82 (1H, m), 6.45 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.67 (1H, d, J = 3.9 Hz) ), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz) ), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 444.12012 (M + H) <+> .
実施例(16i)で合成した化合物(1.04g,1.68mmol)をテトラヒドロフラン(20mL)に溶解し、メタンスルホン酸無水物(594mg,3.41mmol)、トリエチルアミン(1.05mL,7.57mmol)を加え、窒素雰囲気下60℃で2時間撹拌した後、1時間加熱還流した。反応液に水(50mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~3%)を用いて精製することにより、淡黄色固体の目的化合物(955mg,収率94%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.02-1.14 (21H, m), 3.23 (3H, s), 3.83-3.91 (3H, m), 3.85 (3H, s), 4.00 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.79 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (FAB) m/z: 600 (M+H)+.
(16k){(5R)-2-[5-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(16j)で合成した化合物(943mg,1.57mmol)をテトラヒドロフラン(10mL)に溶解し、テトラブチルアンモニウムフルオリド(1.0mol/Lテトラヒドロフラン溶液,1.70mL,1.70mmol)を加え、窒素雰囲気下室温で30分間撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~7%)を用いて精製することにより、白色固体の目的化合物(596mg,収率86%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.00 (1H, br s), 3.23 (3H, s), 3.68-3.83 (3H, m), 3.85 (3H, s), 4.03 (1H, dd, J = 14.3, 10.0 Hz), 4.75-4.82 (1H, m), 6.45 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.67 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 444.12012 (M+H)+。 (16j) 5- (3-Methoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (16i) (1.04 g, 1.68 mmol) was dissolved in tetrahydrofuran (20 mL) and methanesulfonic anhydride (594 mg, 3.41 mmol) and triethylamine (1.05 mL, 7.57 mmol) were added, and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere, and then heated to reflux for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 3%) to give the target compound (955 mg) as a pale yellow solid. 94% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.02-1.14 (21H, m), 3.23 (3H, s), 3.83-3.91 (3H, m), 3.85 (3H, s), 4.00 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.79 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.53 (1H, t, J = 2.2 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 600 (M + H) + .
(16k) {(5R) -2- [5- (3-methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol The compound (943 mg, 1.57 mmol) synthesized in Example (16j) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol / mol) was dissolved. L tetrahydrofuran solution, 1.70 mL, 1.70 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (596 mg, yield) as a white solid. 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.00 (1H, br s), 3.23 (3H, s), 3.68-3.83 (3H, m), 3.85 (3H, s), 4.03 (1H, dd, J = 14.3, 10.0 Hz), 4.75-4.82 (1H, m), 6.45 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.67 (1H, d, J = 3.9 Hz) ), 6.83 (1H, t, J = 1.8 Hz), 6.95 (1H, t, J = 1.8 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz) ), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 444.12012 (M + H) <+> .
(実施例17)
{(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 17)
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 17)
{(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
(17a)1-ブロモ-3-エトキシ-5-メトキシベンゼン
実施例(1a)で合成した化合物(4.10g,20.2mmol)を,N,N-ジメチルホルムアミド(100mL)に溶解し、ヨードエタン(2.43mL,30.4mmol)、炭酸カリウム(7.00g,50.6mmol)を加え、窒素雰囲気下60℃で25時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(4.75g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 3.77 (3H, s), 3.99 (2H, q, J=7.0Hz), 6.38 (1H, m), 6.65 (1H, m), 6.66 (1H, m).
(17b)3-ブロモ-5-エトキシフェノール
実施例(17a)で合成した化合物(4.75g,20.6mmol)、ナトリウムチオメトキシド(1.56g,22.3mmol)を用い、実施例(1a)と同様の方法で白色固体の目的化合物(4.19g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 3.98 (1H, q, J=7.0Hz), 6.32 (1H, t, J=2.0Hz), 6.60 (1H, brs), 6.64 (1H, t, J=2.0Hz).
(17c)3-エトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(17b)で合成した化合物(4.19g,19.3mmol)、ビス(ピナコラート)ジボロン(7.35g,28.9mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(790mg,0.967mmol)、酢酸カリウム(9.47g,96.5mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(3.22g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (12H, s), 1.39 (3H, t, J=7.0Hz), 4.04 (2H, q, J=7.0Hz), 6.52 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.4Hz), 6.92 (1H, t, J=2.0Hz)。 (17a) 1-Bromo-3-ethoxy-5-methoxybenzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and iodoethane ( 2.43 mL, 30.4 mmol) and potassium carbonate (7.00 g, 50.6 mmol) were added, and the mixture was stirred at 60 ° C. for 25 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (4.75 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 3.77 (3H, s), 3.99 (2H, q, J = 7.0Hz), 6.38 (1H, m) , 6.65 (1H, m), 6.66 (1H, m).
(17b) 3-Bromo-5-ethoxyphenol Using the compound synthesized in Example (17a) (4.75 g, 20.6 mmol) and sodium thiomethoxide (1.56 g, 22.3 mmol), Example (1a ) To give the target compound (4.19 g, 94% yield) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ1.40 (3H, t, J = 7.0 Hz), 3.98 (1H, q, J = 7.0 Hz), 6.32 (1H, t, J = 2.0 Hz), 6.60 (1H, brs), 6.64 (1H, t, J = 2.0Hz).
(17c) 3-Ethoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (17b) (4.19 g, 19. 3 mmol), bis (pinacolato) diboron (7.35 g, 28.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (790 mg, 0.967 mmol), potassium acetate ( (9.47 g, 96.5 mmol) was used to obtain the target compound (3.22 g, yield 63%) as a white solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (12H, s), 1.39 (3H, t, J = 7.0 Hz), 4.04 (2H, q, J = 7.0 Hz), 6.52 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.4Hz), 6.92 (1H, t, J = 2.0Hz).
実施例(1a)で合成した化合物(4.10g,20.2mmol)を,N,N-ジメチルホルムアミド(100mL)に溶解し、ヨードエタン(2.43mL,30.4mmol)、炭酸カリウム(7.00g,50.6mmol)を加え、窒素雰囲気下60℃で25時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(4.75g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 3.77 (3H, s), 3.99 (2H, q, J=7.0Hz), 6.38 (1H, m), 6.65 (1H, m), 6.66 (1H, m).
(17b)3-ブロモ-5-エトキシフェノール
実施例(17a)で合成した化合物(4.75g,20.6mmol)、ナトリウムチオメトキシド(1.56g,22.3mmol)を用い、実施例(1a)と同様の方法で白色固体の目的化合物(4.19g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 3.98 (1H, q, J=7.0Hz), 6.32 (1H, t, J=2.0Hz), 6.60 (1H, brs), 6.64 (1H, t, J=2.0Hz).
(17c)3-エトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(17b)で合成した化合物(4.19g,19.3mmol)、ビス(ピナコラート)ジボロン(7.35g,28.9mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(790mg,0.967mmol)、酢酸カリウム(9.47g,96.5mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(3.22g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.33 (12H, s), 1.39 (3H, t, J=7.0Hz), 4.04 (2H, q, J=7.0Hz), 6.52 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.4Hz), 6.92 (1H, t, J=2.0Hz)。 (17a) 1-Bromo-3-ethoxy-5-methoxybenzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and iodoethane ( 2.43 mL, 30.4 mmol) and potassium carbonate (7.00 g, 50.6 mmol) were added, and the mixture was stirred at 60 ° C. for 25 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (4.75 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 3.77 (3H, s), 3.99 (2H, q, J = 7.0Hz), 6.38 (1H, m) , 6.65 (1H, m), 6.66 (1H, m).
(17b) 3-Bromo-5-ethoxyphenol Using the compound synthesized in Example (17a) (4.75 g, 20.6 mmol) and sodium thiomethoxide (1.56 g, 22.3 mmol), Example (1a ) To give the target compound (4.19 g, 94% yield) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ1.40 (3H, t, J = 7.0 Hz), 3.98 (1H, q, J = 7.0 Hz), 6.32 (1H, t, J = 2.0 Hz), 6.60 (1H, brs), 6.64 (1H, t, J = 2.0Hz).
(17c) 3-Ethoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (17b) (4.19 g, 19. 3 mmol), bis (pinacolato) diboron (7.35 g, 28.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (790 mg, 0.967 mmol), potassium acetate ( (9.47 g, 96.5 mmol) was used to obtain the target compound (3.22 g, yield 63%) as a white solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.33 (12H, s), 1.39 (3H, t, J = 7.0 Hz), 4.04 (2H, q, J = 7.0 Hz), 6.52 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.4Hz), 6.92 (1H, t, J = 2.0Hz).
(17d)エチル 5-(3-エトキシ-5-ヒドロキシフェニル)-1H-ピロール-2-カルボキシレート
実施例(17c)で合成した化合物(3.22g,12.2mmol)と、実施例(1g)で合成した化合物(4.66g,14.6mmol)を1,4-ジオキサン(45mL)と水(15mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(300mg,0.367mmol)、炭酸カリウム(3.40g,24.6mmol)を加え、窒素雰囲気下50℃で19時間撹拌した。反応液を室温まで冷却後、水(50mL)を加え、ジエチルエーテル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (17d) Ethyl 5- (3-ethoxy-5-hydroxyphenyl) -1H-pyrrole-2-carboxylate Compound (3.22 g, 12.2 mmol) synthesized in Example (17c) and Example (1 g) The compound synthesized in step (4.66 g, 14.6 mmol) was dissolved in a mixed solvent of 1,4-dioxane (45 mL) and water (15 mL), and [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (300 mg, 0.367 mmol) and potassium carbonate (3.40 g, 24.6 mmol) were added, and the mixture was stirred at 50 ° C. for 19 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with diethyl ether (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(17c)で合成した化合物(3.22g,12.2mmol)と、実施例(1g)で合成した化合物(4.66g,14.6mmol)を1,4-ジオキサン(45mL)と水(15mL)の混合溶媒に溶解し、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(300mg,0.367mmol)、炭酸カリウム(3.40g,24.6mmol)を加え、窒素雰囲気下50℃で19時間撹拌した。反応液を室温まで冷却後、水(50mL)を加え、ジエチルエーテル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (17d) Ethyl 5- (3-ethoxy-5-hydroxyphenyl) -1H-pyrrole-2-carboxylate Compound (3.22 g, 12.2 mmol) synthesized in Example (17c) and Example (1 g) The compound synthesized in step (4.66 g, 14.6 mmol) was dissolved in a mixed solvent of 1,4-dioxane (45 mL) and water (15 mL), and [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (300 mg, 0.367 mmol) and potassium carbonate (3.40 g, 24.6 mmol) were added, and the mixture was stirred at 50 ° C. for 19 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with diethyl ether (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣を塩化メチレン(30mL)に溶解し、トリフルオロ酢酸(30mL)を滴下した。窒素雰囲気下室温で1時間撹拌した後、減圧下溶媒を留去した。塩化メチレン(50mL)で希釈し、飽和炭酸水素ナトリウム水溶液(50mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、淡黄色固体の目的化合物(3.18g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.39 (3H, t, J=7.0Hz), 1.43 (3H, t, J=7.0Hz), 4.05 (2H, q, J=7.0Hz), 4.36 (2H, q, J=7.0Hz), 6.38 (1H, m), 6.50 (1H, t, J=2.7Hz), 6.69 (1H, brs), 6.77 (1H, m), 6.94 (1H, t, J=2.7Hz), 9.73 (1H, brs).
(17e)エチル 5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(17d)で合成した化合物(3.18g,11.6mmol)をN,N-ジメチルホルムアミド(80mL)に溶解した。実施例(16a)で合成した化合物(2.43g,12.7mmol)、炭酸セシウム(11.3g,34.7mmol)を加え、窒素雰囲気下100℃で17時間攪拌した。反応液を室温まで冷却後、水(100mL)を加え、ジエチルエーテル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的化合物(3.13g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, t, J=7.0Hz), 1.45 (3H, t, J=7.0Hz), 3.24 (3H, s), 4.07 (2H, q, J=7.0Hz), 4.35 (2H, q, J=7.0Hz), 6.53 (1H, m), 6.55 (1H, m), 6.86 (1H, brs), 6.94 (1H, m), 6.97 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.24 (1H, brs).
(17f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(17e)で合成した化合物(3.18g, 7.39mmol)をエタノール(50mL)に溶解し、5規定水酸化ナトリウム水溶液(20mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(50mL)を加え、酢酸エチル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 The obtained residue was dissolved in methylene chloride (30 mL), and trifluoroacetic acid (30 mL) was added dropwise. After stirring at room temperature for 1 hour in a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The mixture was diluted with methylene chloride (50 mL), and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (3.18 g) as a pale yellow solid. Yield 95%).
1 H-NMR (CDCl 3 , 400MHz): δ1.39 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 4.05 (2H, q, J = 7.0Hz), 4.36 (2H, q, J = 7.0Hz), 6.38 (1H, m), 6.50 (1H, t, J = 2.7Hz), 6.69 (1H, brs), 6.77 (1H, m), 6.94 (1H, t, J = 2.7Hz), 9.73 (1H, brs).
(17e) Ethyl 5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (17d) ( 3.18 g, 11.6 mmol) was dissolved in N, N-dimethylformamide (80 mL). The compound synthesized in Example (16a) (2.43 g, 12.7 mmol) and cesium carbonate (11.3 g, 34.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the target compound (3.13 g, Yield 63%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 1.45 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.07 (2H, q, J = 7.0Hz), 4.35 (2H, q, J = 7.0Hz), 6.53 (1H, m), 6.55 (1H, m), 6.86 (1H, brs), 6.94 (1H, m), 6.97 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.24 (1H, brs).
(17f) N-[(2S) -2,3-dihydroxypropyl] -5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide The compound synthesized in Example (17e) (3.18 g, 7.39 mmol) was dissolved in ethanol (50 mL), 5N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. . 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
1H-NMR (CDCl3, 400MHz):δ1.39 (3H, t, J=7.0Hz), 1.43 (3H, t, J=7.0Hz), 4.05 (2H, q, J=7.0Hz), 4.36 (2H, q, J=7.0Hz), 6.38 (1H, m), 6.50 (1H, t, J=2.7Hz), 6.69 (1H, brs), 6.77 (1H, m), 6.94 (1H, t, J=2.7Hz), 9.73 (1H, brs).
(17e)エチル 5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(17d)で合成した化合物(3.18g,11.6mmol)をN,N-ジメチルホルムアミド(80mL)に溶解した。実施例(16a)で合成した化合物(2.43g,12.7mmol)、炭酸セシウム(11.3g,34.7mmol)を加え、窒素雰囲気下100℃で17時間攪拌した。反応液を室温まで冷却後、水(100mL)を加え、ジエチルエーテル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的化合物(3.13g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, t, J=7.0Hz), 1.45 (3H, t, J=7.0Hz), 3.24 (3H, s), 4.07 (2H, q, J=7.0Hz), 4.35 (2H, q, J=7.0Hz), 6.53 (1H, m), 6.55 (1H, m), 6.86 (1H, brs), 6.94 (1H, m), 6.97 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.24 (1H, brs).
(17f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(17e)で合成した化合物(3.18g, 7.39mmol)をエタノール(50mL)に溶解し、5規定水酸化ナトリウム水溶液(20mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(50mL)を加え、酢酸エチル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 The obtained residue was dissolved in methylene chloride (30 mL), and trifluoroacetic acid (30 mL) was added dropwise. After stirring at room temperature for 1 hour in a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The mixture was diluted with methylene chloride (50 mL), and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (3.18 g) as a pale yellow solid. Yield 95%).
1 H-NMR (CDCl 3 , 400MHz): δ1.39 (3H, t, J = 7.0Hz), 1.43 (3H, t, J = 7.0Hz), 4.05 (2H, q, J = 7.0Hz), 4.36 (2H, q, J = 7.0Hz), 6.38 (1H, m), 6.50 (1H, t, J = 2.7Hz), 6.69 (1H, brs), 6.77 (1H, m), 6.94 (1H, t, J = 2.7Hz), 9.73 (1H, brs).
(17e) Ethyl 5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (17d) ( 3.18 g, 11.6 mmol) was dissolved in N, N-dimethylformamide (80 mL). The compound synthesized in Example (16a) (2.43 g, 12.7 mmol) and cesium carbonate (11.3 g, 34.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 60%) to give the target compound (3.13 g, Yield 63%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 1.45 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.07 (2H, q, J = 7.0Hz), 4.35 (2H, q, J = 7.0Hz), 6.53 (1H, m), 6.55 (1H, m), 6.86 (1H, brs), 6.94 (1H, m), 6.97 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.24 (1H, brs).
(17f) N-[(2S) -2,3-dihydroxypropyl] -5- (3-ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-Carboxamide The compound synthesized in Example (17e) (3.18 g, 7.39 mmol) was dissolved in ethanol (50 mL), 5N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. . 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣をメタノール(100mL)に溶解し、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.70g,18.7mmol)、DMT-MM(5.20g, 28.8mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(972mg,収率28%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.44 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.52-3.63 (4H, m), 3.84 (1H, m), 4.06 (2H, q, J=7.0Hz), 6.41 (1H, brs), 6.51 (1H, m), 6.54 (1H, brs), 6.64 (1H, m), 6.85 (1H, brs), 6.97 (1H, brs), 7.44 (1H, dd, J=2.4, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.4Hz), 9.72 (1H, brs)。 The obtained residue was dissolved in methanol (100 mL), (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 .8 mmol) was used to obtain the desired product (972 mg, yield 28%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400MHz): δ1.44 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.52-3.63 (4H, m), 3.84 (1H, m), 4.06 ( 2H, q, J = 7.0Hz), 6.41 (1H, brs), 6.51 (1H, m), 6.54 (1H, brs), 6.64 (1H, m), 6.85 (1H, brs), 6.97 (1H, brs ), 7.44 (1H, dd, J = 2.4, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.4Hz), 9.72 (1H, brs).
1H-NMR (CDCl3, 400MHz):δ1.44 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.52-3.63 (4H, m), 3.84 (1H, m), 4.06 (2H, q, J=7.0Hz), 6.41 (1H, brs), 6.51 (1H, m), 6.54 (1H, brs), 6.64 (1H, m), 6.85 (1H, brs), 6.97 (1H, brs), 7.44 (1H, dd, J=2.4, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.4Hz), 9.72 (1H, brs)。 The obtained residue was dissolved in methanol (100 mL), (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 .8 mmol) was used to obtain the desired product (972 mg, yield 28%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400MHz): δ1.44 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.52-3.63 (4H, m), 3.84 (1H, m), 4.06 ( 2H, q, J = 7.0Hz), 6.41 (1H, brs), 6.51 (1H, m), 6.54 (1H, brs), 6.64 (1H, m), 6.85 (1H, brs), 6.97 (1H, brs ), 7.44 (1H, dd, J = 2.4, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.4Hz), 9.72 (1H, brs).
(17g)5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(17f)で合成した化合物(972mg,2.05mmol)を塩化メチレン(40mL)に溶解し、トリイソプロピルシリルクロリド(483μL,2.26mmol)、トリエチルアミン(860μL, 6.17mol)、4-ジメチルアミノピリジン(250mg,2.05mmol)を加え、窒素雰囲気下室温で50時間撹拌した。水(40mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(975mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.01-1.14 (21H, m), 1.44 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60-3.78 (3H, m), 3.86 (1H, m), 4.05 (2H, q, J=7.0Hz), 6.43 (1H, brs), 6.48-6.53 (2H, m), 6.61 (1H, dd, J=2.4, 3.9Hz), 6.87 (1H, brs), 6.99 (1H, brs), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.48 (1H, d, J=2.7Hz), 9.90 (1H, brs).
(17h)5-(3-エトキシ-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(17g)で合成した化合物(975mg,1.55mmol)、メタンスルホン酸無水物(540mg,3.10mmol)、トリエチルアミン(1.08mL, 7.75mol)を用い、実施例(5e)と同様の方法で白色固体の目的物(856mg,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.95-1.12 (21H, m), 1.42 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.80-3.88 (3H, m), 3.94 (1H, m), 4.04 (2H, q, J=7.0Hz), 4.74 (1H, m), 6.49-6.51 (2H, m), 6.71 (1H, d, J=3.9Hz), 6.84 (1H, brs), 6.90 (1H, brs), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.7Hz).
(17i){(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(17h)で合成した化合物(856mg,1.39mmol)、テトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液,2.80mL,2.80mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(538mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.43 (3H, t, J=7.0Hz), 3.22 (3H, s), 3.67 (1H, dd, J=5.1, 12.5Hz), 3.72 (1H, dd, J=7.0, 14.1Hz), 3.79 (1H, dd, J=3.1, 12.5Hz), 3.98 (1H, dd, J=9.8, 14.1Hz), 4.05 (2H, q, J=7.0Hz), 4.74 (1H, m), 6.40 (1H, d, J=3.5Hz), 6.50 (1H, t, J=2.0Hz), 6.61 (1H, d, J=3.5Hz), 6.83 (1H, t, J=2.0Hz), 6.97 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 9.0Hz), 8.01 (1H, d, J=9.0Hz), 8.47 (1H, d, J=2.7Hz).
MS (ESI) m/z: 458.13858(M+H)+。 (17 g) 5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) Oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (17f) (972 mg, 2.05 mmol) was dissolved in methylene chloride (40 mL), triisopropylsilyl chloride (483 μL, 2.26 mmol), Triethylamine (860 μL, 6.17 mol) and 4-dimethylaminopyridine (250 mg, 2.05 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (40 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (975 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.01-1.14 (21H, m), 1.44 (3H, t, J = 7.0 Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60- 3.78 (3H, m), 3.86 (1H, m), 4.05 (2H, q, J = 7.0Hz), 6.43 (1H, brs), 6.48-6.53 (2H, m), 6.61 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, brs), 6.99 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz), 9.90 (1H, brs).
(17h) 5- (3-Ethoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (17 g) (975 mg, 1.55 mmol), methanesulfonic anhydride (540 mg, 3.10 mmol), triethylamine (1.08 mL, 7.75 mol) was used to obtain the white solid target product (856 mg, yield 90%) in the same manner as in Example (5e).
1 H-NMR (CDCl 3 , 400MHz): δ0.95-1.12 (21H, m), 1.42 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.80-3.88 (3H, m), 3.94 (1H, m), 4.04 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.49-6.51 (2H, m), 6.71 (1H, d, J = 3.9Hz), 6.84 (1H , brs), 6.90 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
(17i) {(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (856 mg, 1.39 mmol) synthesized in Example (17h), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.80 mL, 2.80 mmol) Was used to give the target compound (538 mg, yield 84%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ1.43 (3H, t, J = 7.0 Hz), 3.22 (3H, s), 3.67 (1H, dd, J = 5.1, 12.5 Hz), 3.72 (1H, dd, J = 7.0, 14.1Hz), 3.79 (1H, dd, J = 3.1, 12.5Hz), 3.98 (1H, dd, J = 9.8, 14.1Hz), 4.05 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.40 (1H, d, J = 3.5Hz), 6.50 (1H, t, J = 2.0Hz), 6.61 (1H, d, J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 9.0Hz), 8.01 (1H, d, J = 9.0Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 458.13858 (M + H) <+> .
実施例(17f)で合成した化合物(972mg,2.05mmol)を塩化メチレン(40mL)に溶解し、トリイソプロピルシリルクロリド(483μL,2.26mmol)、トリエチルアミン(860μL, 6.17mol)、4-ジメチルアミノピリジン(250mg,2.05mmol)を加え、窒素雰囲気下室温で50時間撹拌した。水(40mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(975mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.01-1.14 (21H, m), 1.44 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60-3.78 (3H, m), 3.86 (1H, m), 4.05 (2H, q, J=7.0Hz), 6.43 (1H, brs), 6.48-6.53 (2H, m), 6.61 (1H, dd, J=2.4, 3.9Hz), 6.87 (1H, brs), 6.99 (1H, brs), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.48 (1H, d, J=2.7Hz), 9.90 (1H, brs).
(17h)5-(3-エトキシ-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(17g)で合成した化合物(975mg,1.55mmol)、メタンスルホン酸無水物(540mg,3.10mmol)、トリエチルアミン(1.08mL, 7.75mol)を用い、実施例(5e)と同様の方法で白色固体の目的物(856mg,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.95-1.12 (21H, m), 1.42 (3H, t, J=7.0Hz), 3.23 (3H, s), 3.80-3.88 (3H, m), 3.94 (1H, m), 4.04 (2H, q, J=7.0Hz), 4.74 (1H, m), 6.49-6.51 (2H, m), 6.71 (1H, d, J=3.9Hz), 6.84 (1H, brs), 6.90 (1H, brs), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.7Hz).
(17i){(5R)-2-[5-(3-エトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(17h)で合成した化合物(856mg,1.39mmol)、テトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液,2.80mL,2.80mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(538mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.43 (3H, t, J=7.0Hz), 3.22 (3H, s), 3.67 (1H, dd, J=5.1, 12.5Hz), 3.72 (1H, dd, J=7.0, 14.1Hz), 3.79 (1H, dd, J=3.1, 12.5Hz), 3.98 (1H, dd, J=9.8, 14.1Hz), 4.05 (2H, q, J=7.0Hz), 4.74 (1H, m), 6.40 (1H, d, J=3.5Hz), 6.50 (1H, t, J=2.0Hz), 6.61 (1H, d, J=3.5Hz), 6.83 (1H, t, J=2.0Hz), 6.97 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 9.0Hz), 8.01 (1H, d, J=9.0Hz), 8.47 (1H, d, J=2.7Hz).
MS (ESI) m/z: 458.13858(M+H)+。 (17 g) 5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) Oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (17f) (972 mg, 2.05 mmol) was dissolved in methylene chloride (40 mL), triisopropylsilyl chloride (483 μL, 2.26 mmol), Triethylamine (860 μL, 6.17 mol) and 4-dimethylaminopyridine (250 mg, 2.05 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (40 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (975 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.01-1.14 (21H, m), 1.44 (3H, t, J = 7.0 Hz), 3.23 (3H, s), 3.38 (1H, m), 3.60- 3.78 (3H, m), 3.86 (1H, m), 4.05 (2H, q, J = 7.0Hz), 6.43 (1H, brs), 6.48-6.53 (2H, m), 6.61 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, brs), 6.99 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz), 9.90 (1H, brs).
(17h) 5- (3-Ethoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (17 g) (975 mg, 1.55 mmol), methanesulfonic anhydride (540 mg, 3.10 mmol), triethylamine (1.08 mL, 7.75 mol) was used to obtain the white solid target product (856 mg, yield 90%) in the same manner as in Example (5e).
1 H-NMR (CDCl 3 , 400MHz): δ0.95-1.12 (21H, m), 1.42 (3H, t, J = 7.0Hz), 3.23 (3H, s), 3.80-3.88 (3H, m), 3.94 (1H, m), 4.04 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.49-6.51 (2H, m), 6.71 (1H, d, J = 3.9Hz), 6.84 (1H , brs), 6.90 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
(17i) {(5R) -2- [5- (3-Ethoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4, 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (856 mg, 1.39 mmol) synthesized in Example (17h), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.80 mL, 2.80 mmol) Was used to give the target compound (538 mg, yield 84%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ1.43 (3H, t, J = 7.0 Hz), 3.22 (3H, s), 3.67 (1H, dd, J = 5.1, 12.5 Hz), 3.72 (1H, dd, J = 7.0, 14.1Hz), 3.79 (1H, dd, J = 3.1, 12.5Hz), 3.98 (1H, dd, J = 9.8, 14.1Hz), 4.05 (2H, q, J = 7.0Hz), 4.74 (1H, m), 6.40 (1H, d, J = 3.5Hz), 6.50 (1H, t, J = 2.0Hz), 6.61 (1H, d, J = 3.5Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 9.0Hz), 8.01 (1H, d, J = 9.0Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 458.13858 (M + H) <+> .
(実施例18)
[(5R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 18)
[(5R) -2- {5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol
[(5R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 18)
[(5R) -2- {5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol
(18a)1-ブロモ-3-メトキシ-5-(2,2,2-トリフルオロエトキシ)ベンゼン
実施例(1a)で合成した化合物(4.10g,20.2mmol)を,N,N-ジメチルホルムアミド(100mL)に溶解し、1,1,1-トリフルオロ-2-ヨードエタン(2.99mL,30.3mmol)、炭酸カリウム(7.00g,50.6mmol)を加え、窒素雰囲気下60℃で25時間撹拌した。更に1,1,1-トリフルオロ-2-ヨードエタン(2.99mL,30.3mmol)を加え、100℃で日間攪拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(5.84g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.79 (3H, s), 4.31 (2H, q, J=8.2Hz), 6.44 (1H, t, J=2.4Hz), 6.69 (1H, t, J=2.0Hz), 6.76 (1H, t, J=2.0Hz).
(18b)3-ブロモ-5-(2,2,2-トリフルオロエトキシ)フェノール
実施例(18a)で合成した化合物(5.76g,20.2mmol)、ナトリウムチオメトキシド(1.56g,22.3mmol)を用い、実施例(1a)と同様の方法で白色固体の目的化合物(3.57g,収率65%)を得た。
1H-NMR (CDCl3, 400MHz):δ4.31 (2H, q, J=8.2Hz), 6.40 (1H, t, J=2.0Hz), 6.69 (1H, t, J=2.0Hz), 6.72 (1H, t, J=2.0Hz).
(18c)3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-5-(2,2,2-トリフルオロエトキシ)フェノール
実施例(18b)で合成した化合物(3.57g,13.2mmol)、ビス(ピナコラート)ジボロン(5.02g,19.8mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(540mg,0.661mmol)、酢酸カリウム(6.48g,66.0mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(4.11g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (12H, s), 4.35 (2H, q, J=8.2Hz), 6.59 (1H, t, J=2.4Hz), 6.90 (1H, d, J=2.4Hz), 6.94 (1H, d, J=2.4Hz)。 (18a) 1-bromo-3-methoxy-5- (2,2,2-trifluoroethoxy) benzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was converted to N, N-dimethyl. Dissolve in formamide (100 mL), add 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) and potassium carbonate (7.00 g, 50.6 mmol) at 60 ° C. under nitrogen atmosphere. Stir for 25 hours. Further, 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) was added and stirred at 100 ° C. for a day. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.84 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.79 (3H, s), 4.31 (2H, q, J = 8.2 Hz), 6.44 (1H, t, J = 2.4 Hz), 6.69 (1H, t, J = 2.0Hz), 6.76 (1H, t, J = 2.0Hz).
(18b) 3-Bromo-5- (2,2,2-trifluoroethoxy) phenol The compound synthesized in Example (18a) (5.76 g, 20.2 mmol), sodium thiomethoxide (1.56 g, 22 .3 mmol) was used to obtain the target compound (3.57 g, yield 65%) as a white solid in the same manner as in Example (1a).
1 H-NMR (CDCl 3 , 400MHz): δ4.31 (2H, q, J = 8.2Hz), 6.40 (1H, t, J = 2.0Hz), 6.69 (1H, t, J = 2.0Hz), 6.72 (1H, t, J = 2.0Hz).
(18c) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5- (2,2,2-trifluoroethoxy) phenol In Example (18b) Synthesized compound (3.57 g, 13.2 mmol), bis (pinacolato) diboron (5.02 g, 19.8 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( 540 mg, 0.661 mmol) and potassium acetate (6.48 g, 66.0 mmol) were used to obtain the target compound (4.11 g, yield 98%) as a white solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (12H, s), 4.35 (2H, q, J = 8.2 Hz), 6.59 (1H, t, J = 2.4 Hz), 6.90 (1H, d, J = 2.4Hz), 6.94 (1H, d, J = 2.4Hz).
実施例(1a)で合成した化合物(4.10g,20.2mmol)を,N,N-ジメチルホルムアミド(100mL)に溶解し、1,1,1-トリフルオロ-2-ヨードエタン(2.99mL,30.3mmol)、炭酸カリウム(7.00g,50.6mmol)を加え、窒素雰囲気下60℃で25時間撹拌した。更に1,1,1-トリフルオロ-2-ヨードエタン(2.99mL,30.3mmol)を加え、100℃で日間攪拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~30%)を用いて精製することにより、白色固体の目的化合物(5.84g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.79 (3H, s), 4.31 (2H, q, J=8.2Hz), 6.44 (1H, t, J=2.4Hz), 6.69 (1H, t, J=2.0Hz), 6.76 (1H, t, J=2.0Hz).
(18b)3-ブロモ-5-(2,2,2-トリフルオロエトキシ)フェノール
実施例(18a)で合成した化合物(5.76g,20.2mmol)、ナトリウムチオメトキシド(1.56g,22.3mmol)を用い、実施例(1a)と同様の方法で白色固体の目的化合物(3.57g,収率65%)を得た。
1H-NMR (CDCl3, 400MHz):δ4.31 (2H, q, J=8.2Hz), 6.40 (1H, t, J=2.0Hz), 6.69 (1H, t, J=2.0Hz), 6.72 (1H, t, J=2.0Hz).
(18c)3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-5-(2,2,2-トリフルオロエトキシ)フェノール
実施例(18b)で合成した化合物(3.57g,13.2mmol)、ビス(ピナコラート)ジボロン(5.02g,19.8mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(540mg,0.661mmol)、酢酸カリウム(6.48g,66.0mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(4.11g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (12H, s), 4.35 (2H, q, J=8.2Hz), 6.59 (1H, t, J=2.4Hz), 6.90 (1H, d, J=2.4Hz), 6.94 (1H, d, J=2.4Hz)。 (18a) 1-bromo-3-methoxy-5- (2,2,2-trifluoroethoxy) benzene The compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was converted to N, N-dimethyl. Dissolve in formamide (100 mL), add 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) and potassium carbonate (7.00 g, 50.6 mmol) at 60 ° C. under nitrogen atmosphere. Stir for 25 hours. Further, 1,1,1-trifluoro-2-iodoethane (2.99 mL, 30.3 mmol) was added and stirred at 100 ° C. for a day. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -30%) to give the target compound (5.84 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.79 (3H, s), 4.31 (2H, q, J = 8.2 Hz), 6.44 (1H, t, J = 2.4 Hz), 6.69 (1H, t, J = 2.0Hz), 6.76 (1H, t, J = 2.0Hz).
(18b) 3-Bromo-5- (2,2,2-trifluoroethoxy) phenol The compound synthesized in Example (18a) (5.76 g, 20.2 mmol), sodium thiomethoxide (1.56 g, 22 .3 mmol) was used to obtain the target compound (3.57 g, yield 65%) as a white solid in the same manner as in Example (1a).
1 H-NMR (CDCl 3 , 400MHz): δ4.31 (2H, q, J = 8.2Hz), 6.40 (1H, t, J = 2.0Hz), 6.69 (1H, t, J = 2.0Hz), 6.72 (1H, t, J = 2.0Hz).
(18c) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5- (2,2,2-trifluoroethoxy) phenol In Example (18b) Synthesized compound (3.57 g, 13.2 mmol), bis (pinacolato) diboron (5.02 g, 19.8 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( 540 mg, 0.661 mmol) and potassium acetate (6.48 g, 66.0 mmol) were used to obtain the target compound (4.11 g, yield 98%) as a white solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (12H, s), 4.35 (2H, q, J = 8.2 Hz), 6.59 (1H, t, J = 2.4 Hz), 6.90 (1H, d, J = 2.4Hz), 6.94 (1H, d, J = 2.4Hz).
(18d)エチル 5-[3-ヒドロキシ-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(18c)で合成した化合物(4.11g,12.9mmol)、実施例(1g)で合成した化合物(4.93g,15.5mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(320mg,0.392mmol)、炭酸カリウム(3.60g,26.0mmol)トリフルオロ酢酸(30mL)を用い、実施例(17d)と同様の方法で淡黄色固体の目的化合物(3.38g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 4.38 (2H, q, J=7.0Hz), 4.38 (2H, q, J=7.8Hz), 6.43 (1H, t, J=2.4Hz), 6.52 (1H, dd, J=2.7, 3.9Hz), 6.73 (1H, t, J=2.0Hz), 6.90 (1H, brs), 6.95 (1H, dd, J=2.4, 3.9Hz), 9.84 (1H, brs).
(18e)エチル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(18d)で合成した化合物(3.38g,10.3mmol)をN,N-ジメチルホルムアミド(80mL)に溶解した。実施例(16a)で合成した化合物(2.16g,11.3mmol)、炭酸セシウム(10.0g,30.7mmol)を加え、窒素雰囲気下100℃で17時間攪拌した。反応液を室温まで冷却後、水(100mL)を加え、ジエチルエーテル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、淡褐色固体の目的化合物(3.53g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, t, J=7.0Hz), 3.24 (3H, s), 4.35 (2H, q, J=7.0Hz), 4.41 (2H, q, J=7.8Hz), 6.55 (1H, t, J=3.9Hz), 6.61 (1H, t, J=2.0Hz), 6.95 (1H, dd, J=2.4, 3.9Hz), 6.97 (1H, brs), 7.02 (1H, brs), 7.47 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.31 (1H, brs).
(18f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキサミド
実施例(18e)で合成した化合物(3.53g, 7.29mmol)をエタノール(50mL)に溶解し、5規定水酸化ナトリウム水溶液(20mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(50mL)を加え、酢酸エチル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (18d) Ethyl 5- [3-hydroxy-5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (4.11 g, 12) synthesized in Example (18c) 0.9 mmol), the compound synthesized in Example (1g) (4.93 g, 15.5 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (320 mg, 0.392 mmol) ), Potassium carbonate (3.60 g, 26.0 mmol), trifluoroacetic acid (30 mL), and the target compound (3.38 g, yield 80%) as a pale yellow solid was obtained in the same manner as in Example (17d) It was.
1 H-NMR (CDCl 3 , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 4.38 (2H, q, J = 7.0Hz), 4.38 (2H, q, J = 7.8Hz), 6.43 (1H, t, J = 2.4Hz), 6.52 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.90 (1H, brs), 6.95 (1H, dd, J = 2.4, 3.9Hz), 9.84 (1H, brs).
(18e) Ethyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate The compound (3.38 g, 10.3 mmol) synthesized in Example (18d) was dissolved in N, N-dimethylformamide (80 mL). The compound (2.16 g, 11.3 mmol) synthesized in Example (16a) and cesium carbonate (10.0 g, 30.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (3.53 g) as a pale brown solid. Yield 71%).
1 H-NMR (CDCl 3 , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.35 (2H, q, J = 7.0Hz), 4.41 (2H, q, J = 7.8Hz), 6.55 (1H, t, J = 3.9Hz), 6.61 (1H, t, J = 2.0Hz), 6.95 (1H, dd, J = 2.4, 3.9Hz), 6.97 (1H, brs) , 7.02 (1H, brs), 7.47 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.31 (1H, brs).
(18f) N-[(2S) -2,3-dihydroxypropyl] -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-tri Fluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (3.53 g, 7.29 mmol) synthesized in Example (18e) was dissolved in ethanol (50 mL), and 5N aqueous sodium hydroxide solution (20 mL) was added. In addition, the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(18c)で合成した化合物(4.11g,12.9mmol)、実施例(1g)で合成した化合物(4.93g,15.5mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(320mg,0.392mmol)、炭酸カリウム(3.60g,26.0mmol)トリフルオロ酢酸(30mL)を用い、実施例(17d)と同様の方法で淡黄色固体の目的化合物(3.38g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.40 (3H, t, J=7.0Hz), 4.38 (2H, q, J=7.0Hz), 4.38 (2H, q, J=7.8Hz), 6.43 (1H, t, J=2.4Hz), 6.52 (1H, dd, J=2.7, 3.9Hz), 6.73 (1H, t, J=2.0Hz), 6.90 (1H, brs), 6.95 (1H, dd, J=2.4, 3.9Hz), 9.84 (1H, brs).
(18e)エチル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(18d)で合成した化合物(3.38g,10.3mmol)をN,N-ジメチルホルムアミド(80mL)に溶解した。実施例(16a)で合成した化合物(2.16g,11.3mmol)、炭酸セシウム(10.0g,30.7mmol)を加え、窒素雰囲気下100℃で17時間攪拌した。反応液を室温まで冷却後、水(100mL)を加え、ジエチルエーテル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、淡褐色固体の目的化合物(3.53g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, t, J=7.0Hz), 3.24 (3H, s), 4.35 (2H, q, J=7.0Hz), 4.41 (2H, q, J=7.8Hz), 6.55 (1H, t, J=3.9Hz), 6.61 (1H, t, J=2.0Hz), 6.95 (1H, dd, J=2.4, 3.9Hz), 6.97 (1H, brs), 7.02 (1H, brs), 7.47 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.31 (1H, brs).
(18f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキサミド
実施例(18e)で合成した化合物(3.53g, 7.29mmol)をエタノール(50mL)に溶解し、5規定水酸化ナトリウム水溶液(20mL)を加え、窒素雰囲気下2時間加熱還流した。反応液に2規定塩酸(50mL)を加え、酢酸エチル(50mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (18d) Ethyl 5- [3-hydroxy-5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (4.11 g, 12) synthesized in Example (18c) 0.9 mmol), the compound synthesized in Example (1g) (4.93 g, 15.5 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (320 mg, 0.392 mmol) ), Potassium carbonate (3.60 g, 26.0 mmol), trifluoroacetic acid (30 mL), and the target compound (3.38 g, yield 80%) as a pale yellow solid was obtained in the same manner as in Example (17d) It was.
1 H-NMR (CDCl 3 , 400MHz): δ1.40 (3H, t, J = 7.0Hz), 4.38 (2H, q, J = 7.0Hz), 4.38 (2H, q, J = 7.8Hz), 6.43 (1H, t, J = 2.4Hz), 6.52 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.90 (1H, brs), 6.95 (1H, dd, J = 2.4, 3.9Hz), 9.84 (1H, brs).
(18e) Ethyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxylate The compound (3.38 g, 10.3 mmol) synthesized in Example (18d) was dissolved in N, N-dimethylformamide (80 mL). The compound (2.16 g, 11.3 mmol) synthesized in Example (16a) and cesium carbonate (10.0 g, 30.7 mmol) were added, and the mixture was stirred at 100 ° C. for 17 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (3.53 g) as a pale brown solid. Yield 71%).
1 H-NMR (CDCl 3 , 400MHz): δ1.38 (3H, t, J = 7.0Hz), 3.24 (3H, s), 4.35 (2H, q, J = 7.0Hz), 4.41 (2H, q, J = 7.8Hz), 6.55 (1H, t, J = 3.9Hz), 6.61 (1H, t, J = 2.0Hz), 6.95 (1H, dd, J = 2.4, 3.9Hz), 6.97 (1H, brs) , 7.02 (1H, brs), 7.47 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.31 (1H, brs).
(18f) N-[(2S) -2,3-dihydroxypropyl] -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-tri Fluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (3.53 g, 7.29 mmol) synthesized in Example (18e) was dissolved in ethanol (50 mL), and 5N aqueous sodium hydroxide solution (20 mL) was added. In addition, the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. 2N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣をメタノール(100mL)に溶解し、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.70g,18.7mmol)、DMT-MM(5.20g, 28.8mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(729mg,収率19%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.17 (3H, s), 3.29 (1H, m), 3.34-3.50 (3H, m), 3.37 (1H, m), 4.40 (2H, q, J=8.2Hz), 6.36 (1H, m), 6.50 (1H, brs), 6.64 (1H, m), 6.98 (1H, brs), 7.08 (1H, brs), 7.34 (1H, dd, J=2.7, 8.6Hz), 7.93 (1H, d, J=8.6Hz), 8.36 (1H, d, J=2.7Hz), 10.99 (1H, brs)。 The obtained residue was dissolved in methanol (100 mL), and (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 8 mmol) was used to obtain the desired product (729 mg, yield 19%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.17 (3H, s), 3.29 (1H, m), 3.34-3.50 (3H, m), 3.37 (1H, m), 4.40 (2H, q, J = 8.2Hz), 6.36 (1H, m), 6.50 (1H, brs), 6.64 (1H, m), 6.98 (1H, brs), 7.08 (1H, brs), 7.34 (1H, dd, J = 2.7, 8.6Hz), 7.93 (1H, d, J = 8.6Hz), 8.36 (1H, d, J = 2.7Hz), 10.99 (1H, brs).
1H-NMR (CDCl3, 400MHz):δ3.17 (3H, s), 3.29 (1H, m), 3.34-3.50 (3H, m), 3.37 (1H, m), 4.40 (2H, q, J=8.2Hz), 6.36 (1H, m), 6.50 (1H, brs), 6.64 (1H, m), 6.98 (1H, brs), 7.08 (1H, brs), 7.34 (1H, dd, J=2.7, 8.6Hz), 7.93 (1H, d, J=8.6Hz), 8.36 (1H, d, J=2.7Hz), 10.99 (1H, brs)。 The obtained residue was dissolved in methanol (100 mL), and (S)-(−)-3-amino-1,2-propanediol (1.70 g, 18.7 mmol), DMT-MM (5.20 g, 28 8 mmol) was used to obtain the desired product (729 mg, yield 19%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.17 (3H, s), 3.29 (1H, m), 3.34-3.50 (3H, m), 3.37 (1H, m), 4.40 (2H, q, J = 8.2Hz), 6.36 (1H, m), 6.50 (1H, brs), 6.64 (1H, m), 6.98 (1H, brs), 7.08 (1H, brs), 7.34 (1H, dd, J = 2.7, 8.6Hz), 7.93 (1H, d, J = 8.6Hz), 8.36 (1H, d, J = 2.7Hz), 10.99 (1H, brs).
(18g)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロエトキシ)フェニル]-1H-ピロール-2-カルボキサミド
実施例(18f)で合成した化合物(729mg,1.38mmol)を塩化メチレン(30mL)に溶解し、トリイソプロピルシリルクロリド(325μL,1.52mmol)、トリエチルアミン(578μL, 4.15mol)、4-ジメチルアミノピリジン(170mg,1.39mmol)を加え、窒素雰囲気下室温で50時間撹拌した。水(30mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(583mg,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1H, m), 3.60-3.76 (3H, m), 3.84 (1H, m), 4.38 (2H, q, J=8.2Hz), 6.50 (1H, m), 6.56 (1H, brs), 6.62 (1H, m), 7.01 (1H, brs), 7.07 (1H, brs), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz), 10.58 (1H, brs).
(18h)2-(メチルスルホニル)-5-[3-(2,2,2-トリフルオロエトキシ)-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ]ピリジン
実施例(18g)で合成した化合物(583mg,0.851mmol)、メタンスルホン酸無水物(300mg,1.72mmol)、トリエチルアミン(600μL, 4.30mol)を用い、実施例(5e)と同様の方法で白色固体の目的物(531mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.98-1.12 (21H, m), 3.23 (3H, s), 3.78-3.92 (4H, m), 4.37 (2H, q, J=8.2Hz), 4.72 (1H, m), 6.51 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.71 (1H, d, J=3.9Hz), 6.95 (1H, t, J=2.0Hz), 7.00 (1H, t, J=2.0Hz), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(18i)[(5R)-2-{5-[3{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(18h)で合成した化合物(531mg,0.795mmol)、テトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液,1.60mL,1.60mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(270mg,収率66%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.71 (1H, dd, J=5.1, 12.5Hz), 3.76 (1H, dd, J=7.4, 14.1Hz), 3.84 (1H, dd, J=3.1, 12.5Hz), 4.04 (1H, dd, J=9.4, 14.1Hz), 4.41 (2H, q, J=8.2Hz), 4.79 (1H, m), 6.45 (1H, d, J=3.9Hz), 6.58 (1H, brs), 6.66 (1H, d, J=3.9Hz), 6.94 (1H, brs), 7.02 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 512.11031(M+H)+。 (18 g) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5 -(2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (729 mg, 1.38 mmol) synthesized in Example (18f) was dissolved in methylene chloride (30 mL) and triisopropyl Silyl chloride (325 μL, 1.52 mmol), triethylamine (578 μL, 4.15 mol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (30 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (583 mg, yield) as a white solid. 62%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1H, m), 3.60-3.76 (3H, m), 3.84 (1H, m ), 4.38 (2H, q, J = 8.2Hz), 6.50 (1H, m), 6.56 (1H, brs), 6.62 (1H, m), 7.01 (1H, brs), 7.07 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz), 10.58 (1H, brs).
(18h) 2- (Methylsulfonyl) -5- [3- (2,2,2-trifluoroethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy] pyridine The compound synthesized in Example (18 g) (583 mg, 0.851 mmol), methanesulfonic anhydride Product (300 mg, 1.72 mmol) and triethylamine (600 μL, 4.30 mol) were used to obtain the desired product (531 mg, 93% yield) as a white solid in the same manner as in Example (5e).
1 H-NMR (CDCl 3 , 400 MHz): δ0.98-1.12 (21H, m), 3.23 (3H, s), 3.78-3.92 (4H, m), 4.37 (2H, q, J = 8.2Hz), 4.72 (1H, m), 6.51 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.71 (1H, d, J = 3.9Hz), 6.95 (1H, t, J = 2.0Hz), 7.00 (1H, t, J = 2.0Hz), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(18i) [(5R) -2- {5- [3 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoromethoxy) phenyl] -1H- Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (531 mg, 0.795 mmol) synthesized in Example (18h), tetrabutylammonium fluoride (1M tetrahydrofuran solution) , 1.60 mL, 1.60 mmol), and the target compound (270 mg, 66% yield) was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.71 (1H, dd, J = 5.1, 12.5 Hz), 3.76 (1H, dd, J = 7.4, 14.1 Hz), 3.84 ( 1H, dd, J = 3.1, 12.5Hz), 4.04 (1H, dd, J = 9.4, 14.1Hz), 4.41 (2H, q, J = 8.2Hz), 4.79 (1H, m), 6.45 (1H, d , J = 3.9Hz), 6.58 (1H, brs), 6.66 (1H, d, J = 3.9Hz), 6.94 (1H, brs), 7.02 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 512.11031 (M + H) <+> .
実施例(18f)で合成した化合物(729mg,1.38mmol)を塩化メチレン(30mL)に溶解し、トリイソプロピルシリルクロリド(325μL,1.52mmol)、トリエチルアミン(578μL, 4.15mol)、4-ジメチルアミノピリジン(170mg,1.39mmol)を加え、窒素雰囲気下室温で50時間撹拌した。水(30mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(583mg,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1H, m), 3.60-3.76 (3H, m), 3.84 (1H, m), 4.38 (2H, q, J=8.2Hz), 6.50 (1H, m), 6.56 (1H, brs), 6.62 (1H, m), 7.01 (1H, brs), 7.07 (1H, brs), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz), 10.58 (1H, brs).
(18h)2-(メチルスルホニル)-5-[3-(2,2,2-トリフルオロエトキシ)-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ]ピリジン
実施例(18g)で合成した化合物(583mg,0.851mmol)、メタンスルホン酸無水物(300mg,1.72mmol)、トリエチルアミン(600μL, 4.30mol)を用い、実施例(5e)と同様の方法で白色固体の目的物(531mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.98-1.12 (21H, m), 3.23 (3H, s), 3.78-3.92 (4H, m), 4.37 (2H, q, J=8.2Hz), 4.72 (1H, m), 6.51 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.71 (1H, d, J=3.9Hz), 6.95 (1H, t, J=2.0Hz), 7.00 (1H, t, J=2.0Hz), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(18i)[(5R)-2-{5-[3{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(2,2,2-トリフルオロメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(18h)で合成した化合物(531mg,0.795mmol)、テトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液,1.60mL,1.60mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(270mg,収率66%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.71 (1H, dd, J=5.1, 12.5Hz), 3.76 (1H, dd, J=7.4, 14.1Hz), 3.84 (1H, dd, J=3.1, 12.5Hz), 4.04 (1H, dd, J=9.4, 14.1Hz), 4.41 (2H, q, J=8.2Hz), 4.79 (1H, m), 6.45 (1H, d, J=3.9Hz), 6.58 (1H, brs), 6.66 (1H, d, J=3.9Hz), 6.94 (1H, brs), 7.02 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 512.11031(M+H)+。 (18 g) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5 -(2,2,2-trifluoroethoxy) phenyl] -1H-pyrrole-2-carboxamide The compound (729 mg, 1.38 mmol) synthesized in Example (18f) was dissolved in methylene chloride (30 mL) and triisopropyl Silyl chloride (325 μL, 1.52 mmol), triethylamine (578 μL, 4.15 mol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were added, and the mixture was stirred at room temperature for 50 hours under a nitrogen atmosphere. Water (30 mL) was added and extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (583 mg, yield) as a white solid. 62%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.00-1.14 (21H, m), 3.23 (3H, s), 3.34 (1H, m), 3.60-3.76 (3H, m), 3.84 (1H, m ), 4.38 (2H, q, J = 8.2Hz), 6.50 (1H, m), 6.56 (1H, brs), 6.62 (1H, m), 7.01 (1H, brs), 7.07 (1H, brs), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz), 10.58 (1H, brs).
(18h) 2- (Methylsulfonyl) -5- [3- (2,2,2-trifluoroethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy] pyridine The compound synthesized in Example (18 g) (583 mg, 0.851 mmol), methanesulfonic anhydride Product (300 mg, 1.72 mmol) and triethylamine (600 μL, 4.30 mol) were used to obtain the desired product (531 mg, 93% yield) as a white solid in the same manner as in Example (5e).
1 H-NMR (CDCl 3 , 400 MHz): δ0.98-1.12 (21H, m), 3.23 (3H, s), 3.78-3.92 (4H, m), 4.37 (2H, q, J = 8.2Hz), 4.72 (1H, m), 6.51 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.71 (1H, d, J = 3.9Hz), 6.95 (1H, t, J = 2.0Hz), 7.00 (1H, t, J = 2.0Hz), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(18i) [(5R) -2- {5- [3 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (2,2,2-trifluoromethoxy) phenyl] -1H- Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (531 mg, 0.795 mmol) synthesized in Example (18h), tetrabutylammonium fluoride (1M tetrahydrofuran solution) , 1.60 mL, 1.60 mmol), and the target compound (270 mg, 66% yield) was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.71 (1H, dd, J = 5.1, 12.5 Hz), 3.76 (1H, dd, J = 7.4, 14.1 Hz), 3.84 ( 1H, dd, J = 3.1, 12.5Hz), 4.04 (1H, dd, J = 9.4, 14.1Hz), 4.41 (2H, q, J = 8.2Hz), 4.79 (1H, m), 6.45 (1H, d , J = 3.9Hz), 6.58 (1H, brs), 6.66 (1H, d, J = 3.9Hz), 6.94 (1H, brs), 7.02 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 512.11031 (M + H) <+> .
(実施例19)
[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール Example 19
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol
[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール Example 19
[(5R) -2- {5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol
(19a)5-(3-ブロモ-5-メトキシフェノキシ)-2-(メチルスルホニル)ピリジン
実施例(1a)で合成した化合物(10.8g,53.2mmol)をN,N-ジメチルホルムアミド(300mL)に溶解した。実施例(16a)で合成した化合物(11.2g,58.4mmol)、炭酸セシウム(52.5g,161mmol)を加え、窒素雰囲気下100℃で3時間攪拌した。反応液を室温まで冷却後、水(300mL)を加え、ジエチルエーテル(200mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的化合物(17.9g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.4Hz), 6.96 (1H, t, J=2.4Hz), 7.44 (1H, dd, J=2.7, 8.6Hz), 8.07 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(19b)3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノール
実施例(19a)で合成した化合物(17.9g,50.0mmol)、三臭化ホウ素(1.0mol/L塩化メチレン溶液,100mL,100mmol)を用い、実施例(1c)と同様の方法で白色固体の目的物(17.2g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 6.53 (1H, t, J=2.0Hz), 6.81 (1H, t, J=2.0Hz), 6.92 (1H, t, J=2.0Hz), 7.46 (1H, dd, J=2.4, 8.6 Hz), 8.07 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.4Hz).
(19c)5-[3-ブロモ-5-(ジフルオロメトキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(3.77g,11.0mmol)を、N,N-ジメチルホルムアミド(100mL)に溶解し、メチル クロロ(ジフルオロ)アセテート(1.74mL,16.5mmol)、炭酸カリウム(2.28g,16.5mmol)を加え、窒素雰囲気下80℃で20時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、白色固体の目的化合物(2.32g,収率54%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 6.54 (1H, t, J=72.3Hz), 6.84 (1H, t, J=2.0Hz), 7.09 (1H, t, J=2.0Hz), 7.21 (1H, t, J=2.0Hz), 7.49 (1H, dd, J=2.7, 8.6 Hz), 8.11 (1H, d, J=8.6Hz), 8.48 (1H, d, J=2.7Hz)。 (19a) 5- (3-Bromo-5-methoxyphenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (1a) (10.8 g, 53.2 mmol) was converted to N, N-dimethylformamide (300 mL). ). The compound synthesized in Example (16a) (11.2 g, 58.4 mmol) and cesium carbonate (52.5 g, 161 mmol) were added, and the mixture was stirred at 100 ° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted 3 times with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (17.9 g, 17.9 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J = 2.4 Hz), 6.83 (1H, t, J = 2.4 Hz) , 6.96 (1H, t, J = 2.4Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz) .
(19b) 3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenol The compound synthesized in Example (19a) (17.9 g, 50.0 mmol), boron tribromide ( Using 1.0 mol / L methylene chloride solution, 100 mL, 100 mmol), a white solid target product (17.2 g, yield˜100%) was obtained in the same manner as in Example (1c).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 6.53 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.92 (1H, t, J = 2.0Hz), 7.46 (1H, dd, J = 2.4, 8.6 Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.4Hz).
(19c) 5- [3-Bromo-5- (difluoromethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (3.77 g, 11.0 mmol) was converted to N, N— It melt | dissolved in dimethylformamide (100 mL), methyl chloro (difluoro) acetate (1.74 mL, 16.5 mmol) and potassium carbonate (2.28 g, 16.5 mmol) were added, and it stirred at 80 degreeC by nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (2.32 g, 2.3%, Yield 54%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 6.54 (1H, t, J = 72.3 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.09 (1H, t, J = 2.0Hz), 7.21 (1H, t, J = 2.0Hz), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.11 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz).
実施例(1a)で合成した化合物(10.8g,53.2mmol)をN,N-ジメチルホルムアミド(300mL)に溶解した。実施例(16a)で合成した化合物(11.2g,58.4mmol)、炭酸セシウム(52.5g,161mmol)を加え、窒素雰囲気下100℃で3時間攪拌した。反応液を室温まで冷却後、水(300mL)を加え、ジエチルエーテル(200mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的化合物(17.9g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.4Hz), 6.96 (1H, t, J=2.4Hz), 7.44 (1H, dd, J=2.7, 8.6Hz), 8.07 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(19b)3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノール
実施例(19a)で合成した化合物(17.9g,50.0mmol)、三臭化ホウ素(1.0mol/L塩化メチレン溶液,100mL,100mmol)を用い、実施例(1c)と同様の方法で白色固体の目的物(17.2g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 6.53 (1H, t, J=2.0Hz), 6.81 (1H, t, J=2.0Hz), 6.92 (1H, t, J=2.0Hz), 7.46 (1H, dd, J=2.4, 8.6 Hz), 8.07 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.4Hz).
(19c)5-[3-ブロモ-5-(ジフルオロメトキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(3.77g,11.0mmol)を、N,N-ジメチルホルムアミド(100mL)に溶解し、メチル クロロ(ジフルオロ)アセテート(1.74mL,16.5mmol)、炭酸カリウム(2.28g,16.5mmol)を加え、窒素雰囲気下80℃で20時間撹拌した。反応液を室温まで冷却し、セライト濾過により炭酸カリウムを除去した後、1規定塩酸(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、白色固体の目的化合物(2.32g,収率54%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 6.54 (1H, t, J=72.3Hz), 6.84 (1H, t, J=2.0Hz), 7.09 (1H, t, J=2.0Hz), 7.21 (1H, t, J=2.0Hz), 7.49 (1H, dd, J=2.7, 8.6 Hz), 8.11 (1H, d, J=8.6Hz), 8.48 (1H, d, J=2.7Hz)。 (19a) 5- (3-Bromo-5-methoxyphenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (1a) (10.8 g, 53.2 mmol) was converted to N, N-dimethylformamide (300 mL). ). The compound synthesized in Example (16a) (11.2 g, 58.4 mmol) and cesium carbonate (52.5 g, 161 mmol) were added, and the mixture was stirred at 100 ° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted 3 times with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (17.9 g, 17.9 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.23 (3H, s), 3.81 (3H, s), 6.58 (1H, t, J = 2.4 Hz), 6.83 (1H, t, J = 2.4 Hz) , 6.96 (1H, t, J = 2.4Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz) .
(19b) 3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenol The compound synthesized in Example (19a) (17.9 g, 50.0 mmol), boron tribromide ( Using 1.0 mol / L methylene chloride solution, 100 mL, 100 mmol), a white solid target product (17.2 g, yield˜100%) was obtained in the same manner as in Example (1c).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 6.53 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.92 (1H, t, J = 2.0Hz), 7.46 (1H, dd, J = 2.4, 8.6 Hz), 8.07 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.4Hz).
(19c) 5- [3-Bromo-5- (difluoromethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (3.77 g, 11.0 mmol) was converted to N, N— It melt | dissolved in dimethylformamide (100 mL), methyl chloro (difluoro) acetate (1.74 mL, 16.5 mmol) and potassium carbonate (2.28 g, 16.5 mmol) were added, and it stirred at 80 degreeC by nitrogen atmosphere for 20 hours. The reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (2.32 g, 2.3%, Yield 54%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 6.54 (1H, t, J = 72.3 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.09 (1H, t, J = 2.0Hz), 7.21 (1H, t, J = 2.0Hz), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.11 (1H, d, J = 8.6Hz), 8.48 (1H, d, J = 2.7Hz).
(19d)ベンジル 1H-ピロール-2-カルボキシレート
ベンジルブロミド(20mL,168mmol)をN,N-ジメチルホルムアミド(200mL)に溶解し、炭酸カリウム(37.32g,270mmol)を加えた。窒素雰囲気下室温で撹拌しながら、ピロール-2-カルボン酸(5.03g,45.3mmol)を少しずつ加え、さらに16時間撹拌した。酢酸エチル(150mL)を加えて希釈し、セライトろ過により不溶物を除去した。水(400mL)とジエチルエーテル(200mL)を加えて分液し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣にジイソプロピルエーテル(25mL)とヘキサン(75mL)を加えて洗浄することで白色固体の目的物(22.70g,67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 6.28 (1H, q, J = 3.0 Hz), 6.95-6.99 (2H, m), 7.32-7.44 (5H, m), 9.14 (1H, br s).
(19e)ベンジル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート
実施例(19d)で合成した化合物(25.0g,124mmol)をヘキサン(370mL)にけん濁させ、ビス(ピナコラート)ジボロン(16.0g,63.0mmol)、4,4´-ジ-t-ブチル-2,2´-ジピリジル(500mg,1.86mmol)、メトキシ(シクロオクタジエン)イリジウム(I)ダイマー(617mg,0.931mmol)を加え、50℃で1時間撹拌した。反応液に酢酸エチル(300mL)を加え、水(150mL)で2回洗浄後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をジイソプロピルエーテル(200mL)で洗浄することで、淡桃色固体の目的物(32.71g,81%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.32 (12H, s), 5.32 (2H, s), 6.77 (1H, dd, J = 3.7, 2.3 Hz), 6.96 (1H, dd, J = 3.9, 2.3 Hz), 7.32-7.44 (5H, m), 9.45 (1H, br s).
MS (EI) m/z: 327 (M+).
(19f)ベンジル 5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(19c)で合成した化合物(2.32g,5.89mmol)、実施例(19e)で合成した化合物(2.50g,7.64mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(145mg,0.178mmol)、炭酸カリウム(2.44g,17.7mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(2.37g,収率78%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J=2.7, 3.9Hz), 6.58 (1H, t, J=72.7Hz), 6.80 (1H, t, J=2.4Hz), 7.00 (1H, dd, J=2.4, 3.9Hz), 7.11 (1H, t, J=2.4Hz), 7.20 (1H, t, J=1.6Hz), 7.35-7.45 (5H, m), 7.48 (1H, dd, J=2.7, 8.6 Hz), 8.09 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz)。 (19d) Benzyl 1H-pyrrole-2-carboxylate benzyl bromide (20 mL, 168 mmol) was dissolved in N, N-dimethylformamide (200 mL), and potassium carbonate (37.32 g, 270 mmol) was added. While stirring at room temperature under a nitrogen atmosphere, pyrrole-2-carboxylic acid (5.03 g, 45.3 mmol) was added little by little, and the mixture was further stirred for 16 hours. Ethyl acetate (150 mL) was added for dilution, and insolubles were removed by celite filtration. Water (400 mL) and diethyl ether (200 mL) were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether (25 mL) and hexane (75 mL) were added to the resulting residue and washed to obtain the desired product (22.70 g, 67%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 6.28 (1H, q, J = 3.0 Hz), 6.95-6.99 (2H, m), 7.32-7.44 (5H, m), 9.14 (1H, br s).
(19e) Benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate Compound (25) synthesized in Example (19d) 0.0 g, 124 mmol) in hexane (370 mL), bis (pinacolato) diboron (16.0 g, 63.0 mmol), 4,4′-di-t-butyl-2,2′-dipyridyl (500 mg, 1.86 mmol) and methoxy (cyclooctadiene) iridium (I) dimer (617 mg, 0.931 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hour. Ethyl acetate (300 mL) was added to the reaction solution, washed twice with water (150 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diisopropyl ether (200 mL) to obtain the desired product (32.71 g, 81%) as a pale pink solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (12H, s), 5.32 (2H, s), 6.77 (1H, dd, J = 3.7, 2.3 Hz), 6.96 (1H, dd, J = 3.9, 2.3 Hz), 7.32-7.44 (5H, m), 9.45 (1H, br s).
MS (EI) m / z: 327 (M + ).
(19f) Benzyl 5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (19c) Compound (2.32 g, 5.89 mmol), compound synthesized in Example (19e) (2.50 g, 7.64 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (145 mg, 0.178 mmol) and potassium carbonate (2.44 g, 17.7 mmol) in the same manner as in Example (16e), the target compound (2.37 g, yield 78%) was obtained as a pale yellow solid. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 2.7, 3.9Hz), 6.58 (1H, t, J = 72.7 Hz), 6.80 (1H, t, J = 2.4Hz), 7.00 (1H, dd, J = 2.4, 3.9Hz), 7.11 (1H, t, J = 2.4Hz), 7.20 (1H, t, J = 1.6 Hz), 7.35-7.45 (5H, m), 7.48 (1H, dd, J = 2.7, 8.6 Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).
ベンジルブロミド(20mL,168mmol)をN,N-ジメチルホルムアミド(200mL)に溶解し、炭酸カリウム(37.32g,270mmol)を加えた。窒素雰囲気下室温で撹拌しながら、ピロール-2-カルボン酸(5.03g,45.3mmol)を少しずつ加え、さらに16時間撹拌した。酢酸エチル(150mL)を加えて希釈し、セライトろ過により不溶物を除去した。水(400mL)とジエチルエーテル(200mL)を加えて分液し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣にジイソプロピルエーテル(25mL)とヘキサン(75mL)を加えて洗浄することで白色固体の目的物(22.70g,67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 6.28 (1H, q, J = 3.0 Hz), 6.95-6.99 (2H, m), 7.32-7.44 (5H, m), 9.14 (1H, br s).
(19e)ベンジル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート
実施例(19d)で合成した化合物(25.0g,124mmol)をヘキサン(370mL)にけん濁させ、ビス(ピナコラート)ジボロン(16.0g,63.0mmol)、4,4´-ジ-t-ブチル-2,2´-ジピリジル(500mg,1.86mmol)、メトキシ(シクロオクタジエン)イリジウム(I)ダイマー(617mg,0.931mmol)を加え、50℃で1時間撹拌した。反応液に酢酸エチル(300mL)を加え、水(150mL)で2回洗浄後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をジイソプロピルエーテル(200mL)で洗浄することで、淡桃色固体の目的物(32.71g,81%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.32 (12H, s), 5.32 (2H, s), 6.77 (1H, dd, J = 3.7, 2.3 Hz), 6.96 (1H, dd, J = 3.9, 2.3 Hz), 7.32-7.44 (5H, m), 9.45 (1H, br s).
MS (EI) m/z: 327 (M+).
(19f)ベンジル 5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(19c)で合成した化合物(2.32g,5.89mmol)、実施例(19e)で合成した化合物(2.50g,7.64mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(145mg,0.178mmol)、炭酸カリウム(2.44g,17.7mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(2.37g,収率78%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J=2.7, 3.9Hz), 6.58 (1H, t, J=72.7Hz), 6.80 (1H, t, J=2.4Hz), 7.00 (1H, dd, J=2.4, 3.9Hz), 7.11 (1H, t, J=2.4Hz), 7.20 (1H, t, J=1.6Hz), 7.35-7.45 (5H, m), 7.48 (1H, dd, J=2.7, 8.6 Hz), 8.09 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz)。 (19d) Benzyl 1H-pyrrole-2-carboxylate benzyl bromide (20 mL, 168 mmol) was dissolved in N, N-dimethylformamide (200 mL), and potassium carbonate (37.32 g, 270 mmol) was added. While stirring at room temperature under a nitrogen atmosphere, pyrrole-2-carboxylic acid (5.03 g, 45.3 mmol) was added little by little, and the mixture was further stirred for 16 hours. Ethyl acetate (150 mL) was added for dilution, and insolubles were removed by celite filtration. Water (400 mL) and diethyl ether (200 mL) were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether (25 mL) and hexane (75 mL) were added to the resulting residue and washed to obtain the desired product (22.70 g, 67%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 6.28 (1H, q, J = 3.0 Hz), 6.95-6.99 (2H, m), 7.32-7.44 (5H, m), 9.14 (1H, br s).
(19e) Benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate Compound (25) synthesized in Example (19d) 0.0 g, 124 mmol) in hexane (370 mL), bis (pinacolato) diboron (16.0 g, 63.0 mmol), 4,4′-di-t-butyl-2,2′-dipyridyl (500 mg, 1.86 mmol) and methoxy (cyclooctadiene) iridium (I) dimer (617 mg, 0.931 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hour. Ethyl acetate (300 mL) was added to the reaction solution, washed twice with water (150 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diisopropyl ether (200 mL) to obtain the desired product (32.71 g, 81%) as a pale pink solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (12H, s), 5.32 (2H, s), 6.77 (1H, dd, J = 3.7, 2.3 Hz), 6.96 (1H, dd, J = 3.9, 2.3 Hz), 7.32-7.44 (5H, m), 9.45 (1H, br s).
MS (EI) m / z: 327 (M + ).
(19f) Benzyl 5- [3- (difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (19c) Compound (2.32 g, 5.89 mmol), compound synthesized in Example (19e) (2.50 g, 7.64 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using a dichloromethane complex (145 mg, 0.178 mmol) and potassium carbonate (2.44 g, 17.7 mmol) in the same manner as in Example (16e), the target compound (2.37 g, yield 78%) was obtained as a pale yellow solid. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 2.7, 3.9Hz), 6.58 (1H, t, J = 72.7 Hz), 6.80 (1H, t, J = 2.4Hz), 7.00 (1H, dd, J = 2.4, 3.9Hz), 7.11 (1H, t, J = 2.4Hz), 7.20 (1H, t, J = 1.6 Hz), 7.35-7.45 (5H, m), 7.48 (1H, dd, J = 2.7, 8.6 Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).
(19g)5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-[(2S)-2,3-ジヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(19f)で合成した化合物(2.37g, 4.61mmol)をテトラヒドロフラン(50mL)に溶解し、10%パラジウム炭素触媒(1.00g)を加えて水素雰囲気下室温で1時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (19g) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.37 g, 4.61 mmol) synthesized in Example (19f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.00 g) was added, and room temperature was added under a hydrogen atmosphere. For 1 hour. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
実施例(19f)で合成した化合物(2.37g, 4.61mmol)をテトラヒドロフラン(50mL)に溶解し、10%パラジウム炭素触媒(1.00g)を加えて水素雰囲気下室温で1時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (19g) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.37 g, 4.61 mmol) synthesized in Example (19f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.00 g) was added, and room temperature was added under a hydrogen atmosphere. For 1 hour. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
得られた残渣をメタノール(50mL)に溶解し、(S)-(-)-3-アミノ-1,2-プロパンジオール(840mg,9.22mmol)、DMT-MM(3.20g, 11.6mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.93g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.25 (3H, s), 3.57-3.67 (4H, m), 3.87 (1H, m), 6.37 (1H, brs), 6.56 (1H, t, J=3.1Hz), 6.60 (1H, t, J=72.7Hz), 6.65 (1H, t, J=3.1Hz), 6.81 (1H, t, J=2.4Hz), 7.11 (1H, brs), 7.21 (1H, brs), 7.49 (1H, dd, J=2.7, 8.6 Hz), 8.10 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.66 (1H, brs).
(19h)5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(19g)で合成した化合物(1.93g,3.88mmol)を塩化メチレン(40mL)とN,N-ジメチルホルムアミド(2mL)の混合溶媒に溶解し、トリイソプロピルシリルクロリド(1.08mL,5.05mmol)、トリエチルアミン(1.62mL, 11.6mol)、4-ジメチルアミノピリジン(480mg,3.93mmol)を加え、窒素雰囲気下室温で21時間撹拌した。水(40mL)を加え、塩化メチレン(40mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.08g,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.16 (21H, m), 3.07 (1H, t, J=3.9Hz), 3.39 (1H, m), 3.67 (1H, dd, J=6.3, 9.8Hz), 3.72 (1H, m), 3.78 (1H, dd, J=9.8, 10.2Hz), 3.87 (1H, m), 6.42 (1H, m), 6.54 (1H, t, J=3.5Hz), 6.58 (1H, t, J=72.7Hz), 6.63 (1H, t, J=3.5Hz), 6.78 (1H, brs), 7.12 (1H, brs), 7.21 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.09 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.76 (1H, brs)。 The obtained residue was dissolved in methanol (50 mL), (S)-(−)-3-amino-1,2-propanediol (840 mg, 9.22 mmol), DMT-MM (3.20 g, 11.6 mmol). ) Was used to obtain the white solid target product (1.93 g, yield 84%) in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.25 (3H, s), 3.57-3.67 (4H, m), 3.87 (1H, m), 6.37 (1H, brs), 6.56 (1H, t, J = 3.1Hz), 6.60 (1H, t, J = 72.7Hz), 6.65 (1H, t, J = 3.1Hz), 6.81 (1H, t, J = 2.4Hz), 7.11 (1H, brs), 7.21 ( 1H, brs), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.10 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.66 (1H, brs).
(19h) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[(tri Isopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide Compound (1.93 g, 3.88 mmol) synthesized in Example (19 g) was dissolved in methylene chloride (40 mL) and N, N-dimethylformamide (2 mL). Dissolve in the mixed solvent, add triisopropylsilyl chloride (1.08 mL, 5.05 mmol), triethylamine (1.62 mL, 11.6 mol), 4-dimethylaminopyridine (480 mg, 3.93 mmol), and add nitrogen at room temperature. For 21 hours. Water (40 mL) was added and extracted three times with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product as a white solid (2.08 g, Yield 82%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.16 (21H, m), 3.07 (1H, t, J = 3.9 Hz), 3.39 (1H, m), 3.67 (1H, dd, J = 6.3 , 9.8Hz), 3.72 (1H, m), 3.78 (1H, dd, J = 9.8, 10.2Hz), 3.87 (1H, m), 6.42 (1H, m), 6.54 (1H, t, J = 3.5Hz ), 6.58 (1H, t, J = 72.7Hz), 6.63 (1H, t, J = 3.5Hz), 6.78 (1H, brs), 7.12 (1H, brs), 7.21 (1H, brs), 7.48 (1H , dd, J = 2.7, 8.6Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.76 (1H, brs).
1H-NMR (CDCl3, 400MHz):δ3.25 (3H, s), 3.57-3.67 (4H, m), 3.87 (1H, m), 6.37 (1H, brs), 6.56 (1H, t, J=3.1Hz), 6.60 (1H, t, J=72.7Hz), 6.65 (1H, t, J=3.1Hz), 6.81 (1H, t, J=2.4Hz), 7.11 (1H, brs), 7.21 (1H, brs), 7.49 (1H, dd, J=2.7, 8.6 Hz), 8.10 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.66 (1H, brs).
(19h)5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(19g)で合成した化合物(1.93g,3.88mmol)を塩化メチレン(40mL)とN,N-ジメチルホルムアミド(2mL)の混合溶媒に溶解し、トリイソプロピルシリルクロリド(1.08mL,5.05mmol)、トリエチルアミン(1.62mL, 11.6mol)、4-ジメチルアミノピリジン(480mg,3.93mmol)を加え、窒素雰囲気下室温で21時間撹拌した。水(40mL)を加え、塩化メチレン(40mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.08g,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.16 (21H, m), 3.07 (1H, t, J=3.9Hz), 3.39 (1H, m), 3.67 (1H, dd, J=6.3, 9.8Hz), 3.72 (1H, m), 3.78 (1H, dd, J=9.8, 10.2Hz), 3.87 (1H, m), 6.42 (1H, m), 6.54 (1H, t, J=3.5Hz), 6.58 (1H, t, J=72.7Hz), 6.63 (1H, t, J=3.5Hz), 6.78 (1H, brs), 7.12 (1H, brs), 7.21 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.09 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.76 (1H, brs)。 The obtained residue was dissolved in methanol (50 mL), (S)-(−)-3-amino-1,2-propanediol (840 mg, 9.22 mmol), DMT-MM (3.20 g, 11.6 mmol). ) Was used to obtain the white solid target product (1.93 g, yield 84%) in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.25 (3H, s), 3.57-3.67 (4H, m), 3.87 (1H, m), 6.37 (1H, brs), 6.56 (1H, t, J = 3.1Hz), 6.60 (1H, t, J = 72.7Hz), 6.65 (1H, t, J = 3.1Hz), 6.81 (1H, t, J = 2.4Hz), 7.11 (1H, brs), 7.21 ( 1H, brs), 7.49 (1H, dd, J = 2.7, 8.6 Hz), 8.10 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.66 (1H, brs).
(19h) 5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[(tri Isopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide Compound (1.93 g, 3.88 mmol) synthesized in Example (19 g) was dissolved in methylene chloride (40 mL) and N, N-dimethylformamide (2 mL). Dissolve in the mixed solvent, add triisopropylsilyl chloride (1.08 mL, 5.05 mmol), triethylamine (1.62 mL, 11.6 mol), 4-dimethylaminopyridine (480 mg, 3.93 mmol), and add nitrogen at room temperature. For 21 hours. Water (40 mL) was added and extracted three times with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product as a white solid (2.08 g, Yield 82%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.16 (21H, m), 3.07 (1H, t, J = 3.9 Hz), 3.39 (1H, m), 3.67 (1H, dd, J = 6.3 , 9.8Hz), 3.72 (1H, m), 3.78 (1H, dd, J = 9.8, 10.2Hz), 3.87 (1H, m), 6.42 (1H, m), 6.54 (1H, t, J = 3.5Hz ), 6.58 (1H, t, J = 72.7Hz), 6.63 (1H, t, J = 3.5Hz), 6.78 (1H, brs), 7.12 (1H, brs), 7.21 (1H, brs), 7.48 (1H , dd, J = 2.7, 8.6Hz), 8.09 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.76 (1H, brs).
(19i)5-[3-(ジフルオロメトキシ)-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(19h)で合成した化合物(2.08g,3.18mmol)、メタンスルホン酸無水物(1.17g,6.72mmol)、トリエチルアミン(2.22mL, 15.9mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(1.45g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.12 (21H, m), 3.24 (3H, s), 3.81-3.91 (3H, m), 4.00 (1H, dd, J=9.4, 14.5Hz), 4.76 (1H, m), 6.53 (1H, d, J=3.9Hz), 6.57 (1H, t, J=72.7Hz), 6.73 (1H, d, J=3.9Hz), 6.75 (1H, brs), 7.10 (1H, t, J=2.0Hz), 7.20 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz).
(19j)[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(19i)で合成した化合物(1.45g,2.28mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.74mL,2.74mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.00g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.68-3.80 (2H, m), 3.85 (1H, d, J=12.1Hz), 4.01 (1H, m), 4.80 (1H, m), 6.47 (1H, brs), 6.58 (1H, t, J=73.1Hz), 6.67 (1H, brs), 6.77 (1H, brs), 7.09 (1H, brs), 7.20 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz).
MS (ESI) m/z: 480.10409(M+H)+。 (19i) 5- [3- (Difluoromethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19h) (2.08 g, 3.18 mmol), methanesulfonic anhydride (1.17 g) , 6.72 mmol) and triethylamine (2.22 mL, 15.9 mol) were used to obtain the white solid target product (1.45 g, yield 72%) in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.12 (21H, m), 3.24 (3H, s), 3.81-3.91 (3H, m), 4.00 (1H, dd, J = 9.4, 14.5Hz ), 4.76 (1H, m), 6.53 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 72.7Hz), 6.73 (1H, d, J = 3.9Hz), 6.75 (1H, brs ), 7.10 (1H, t, J = 2.0Hz), 7.20 (1H, brs), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H , d, J = 2.7Hz).
(19j) [(5R) -2- {5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (1.45 g, 2.28 mmol) synthesized in Example (19i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 2 .74 mL, 2.74 mmol) was used to obtain the target compound (1.00 g, yield 91%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.68-3.80 (2H, m), 3.85 (1H, d, J = 12.1Hz), 4.01 (1H, m), 4.80 ( 1H, m), 6.47 (1H, brs), 6.58 (1H, t, J = 73.1Hz), 6.67 (1H, brs), 6.77 (1H, brs), 7.09 (1H, brs), 7.20 (1H, brs ), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 480.10409 (M + H) <+> .
実施例(19h)で合成した化合物(2.08g,3.18mmol)、メタンスルホン酸無水物(1.17g,6.72mmol)、トリエチルアミン(2.22mL, 15.9mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(1.45g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.12 (21H, m), 3.24 (3H, s), 3.81-3.91 (3H, m), 4.00 (1H, dd, J=9.4, 14.5Hz), 4.76 (1H, m), 6.53 (1H, d, J=3.9Hz), 6.57 (1H, t, J=72.7Hz), 6.73 (1H, d, J=3.9Hz), 6.75 (1H, brs), 7.10 (1H, t, J=2.0Hz), 7.20 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz).
(19j)[(5R)-2-{5-[3-(ジフルオロメトキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(19i)で合成した化合物(1.45g,2.28mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.74mL,2.74mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.00g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.68-3.80 (2H, m), 3.85 (1H, d, J=12.1Hz), 4.01 (1H, m), 4.80 (1H, m), 6.47 (1H, brs), 6.58 (1H, t, J=73.1Hz), 6.67 (1H, brs), 6.77 (1H, brs), 7.09 (1H, brs), 7.20 (1H, brs), 7.48 (1H, dd, J=2.7, 8.6Hz), 8.08 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz).
MS (ESI) m/z: 480.10409(M+H)+。 (19i) 5- [3- (Difluoromethoxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19h) (2.08 g, 3.18 mmol), methanesulfonic anhydride (1.17 g) , 6.72 mmol) and triethylamine (2.22 mL, 15.9 mol) were used to obtain the white solid target product (1.45 g, yield 72%) in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.12 (21H, m), 3.24 (3H, s), 3.81-3.91 (3H, m), 4.00 (1H, dd, J = 9.4, 14.5Hz ), 4.76 (1H, m), 6.53 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 72.7Hz), 6.73 (1H, d, J = 3.9Hz), 6.75 (1H, brs ), 7.10 (1H, t, J = 2.0Hz), 7.20 (1H, brs), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H , d, J = 2.7Hz).
(19j) [(5R) -2- {5- [3- (Difluoromethoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol Compound (1.45 g, 2.28 mmol) synthesized in Example (19i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 2 .74 mL, 2.74 mmol) was used to obtain the target compound (1.00 g, yield 91%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.68-3.80 (2H, m), 3.85 (1H, d, J = 12.1Hz), 4.01 (1H, m), 4.80 ( 1H, m), 6.47 (1H, brs), 6.58 (1H, t, J = 73.1Hz), 6.67 (1H, brs), 6.77 (1H, brs), 7.09 (1H, brs), 7.20 (1H, brs ), 7.48 (1H, dd, J = 2.7, 8.6Hz), 8.08 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 480.10409 (M + H) <+> .
(実施例20)
[(5R)-2-{5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 20)
[(5R) -2- {5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4 , 5-Dihydro-1,3-oxazol-5-yl] methanol
[(5R)-2-{5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 20)
[(5R) -2- {5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl} -4 , 5-Dihydro-1,3-oxazol-5-yl] methanol
(20a)1,3-ジブロモ-5-(2-クロロエトキシ)ベンゼン
3,5-ジブロモフェノール(7.00g,27.8mmol)をトルエン(200mL)に溶解し、2-クロロエタノール(2.23mL,33.4mmol)、トリフェニルホスフィン(8.02g,30.6mmol)を加えた。0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,15.2mL,33.4mmol)を滴下し、窒素雰囲気下室温で1時間攪拌した。減圧下溶媒を留去した残渣にジエチルエーテルを加え、生じた不溶物を濾過により除去した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的化合物(9.72g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.80 (2H, t, J=5.9Hz), 4.20 (2H, t, J=5.9Hz), 7.02 (2H, d, J=2.0Hz), 7.29 (1H, t, J=2.0Hz).
(20b)1,3-ジブロモ-5-(ビニルオキシ)ベンゼン
実施例(20a)で合成した化合物(8.74g,27.8mmol)をテトラヒドロフラン(200mL)に溶解し、0℃にてカリウム t-ブトキシド(4.10g,36.5mmol)を加えた。窒素雰囲気下室温で1時間攪拌した後、水(200mL)を加えジエチルエーテル(200mL)で抽出した。減圧下溶媒を留去し、生じた不溶物を濾過により除去し、ジエチルエーテルで洗浄した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的物(7.06g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ4.57 (1H, dd, J=2.0, 5.9Hz), 4.86 (1H, dd, J=2.0, 13.7Hz), 6.55 (1H, dd, J=5.9. 13.7Hz), 7.10 (2H, d, J=2.0Hz), 7.38 (1H, t, J=2.0Hz).
(20c)1,3-ジブロモ-5-(シクロプロピルオキシ)ベンゼン
実施例(20b)で合成した化合物(9.72g,33.3mmol)を1,2-ジクロロエタン(300mL)に溶解し、-78℃にてクロロ(ヨード)メタン(14.8mL,203mmol)、ジエチル亜鉛(1.09Mヘキサン溶液,100mL,109mmol)、トリフルオロ酢酸(800μL,10.4mmol)を加えた。窒素雰囲気下、室温まで徐々に昇温させながら1時間撹拌し、更に70℃で17時間攪拌した。反応駅を室温まで冷却後、1規定塩酸(200mL)を加え、ジエチルエーテル(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的物(5.62g,収率58%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.75-0.83 (4H, m), 3.71 (1H, m), 7.14 (2H, dd, J=0.8, 1.6Hz), 7.26 (1H, m)。 (20a) 1,3-dibromo-5- (2-chloroethoxy) benzene 3,5-dibromophenol (7.00 g, 27.8 mmol) was dissolved in toluene (200 mL), and 2-chloroethanol (2.23 mL) was dissolved. 33.4 mmol) and triphenylphosphine (8.02 g, 30.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 15.2 mL, 33.4 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the resulting insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to give the target compound (9.72 g, yield ˜100%) as a pale yellow oil. It was.
1 H-NMR (CDCl 3 , 400 MHz): δ3.80 (2H, t, J = 5.9 Hz), 4.20 (2H, t, J = 5.9 Hz), 7.02 (2H, d, J = 2.0 Hz), 7.29 (1H, t, J = 2.0Hz).
(20b) 1,3-dibromo-5- (vinyloxy) benzene The compound (8.74 g, 27.8 mmol) synthesized in Example (20a) was dissolved in tetrahydrofuran (200 mL), and potassium t-butoxide was dissolved at 0 ° C. (4.10 g, 36.5 mmol) was added. After stirring at room temperature for 1 hour under a nitrogen atmosphere, water (200 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The solvent was distilled off under reduced pressure, and the resulting insoluble material was removed by filtration and washed with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (7.06 g, yield 91%) as a pale yellow oil. .
1 H-NMR (CDCl 3 , 400 MHz): δ4.57 (1H, dd, J = 2.0, 5.9 Hz), 4.86 (1H, dd, J = 2.0, 13.7 Hz), 6.55 (1H, dd, J = 5.9 13.7Hz), 7.10 (2H, d, J = 2.0Hz), 7.38 (1H, t, J = 2.0Hz).
(20c) 1,3-Dibromo-5- (cyclopropyloxy) benzene The compound synthesized in Example (20b) (9.72 g, 33.3 mmol) was dissolved in 1,2-dichloroethane (300 mL), and -78 Chloro (iodo) methane (14.8 mL, 203 mmol), diethyl zinc (1.09 M hexane solution, 100 mL, 109 mmol), and trifluoroacetic acid (800 μL, 10.4 mmol) were added at ° C. The mixture was stirred for 1 hour while gradually warming to room temperature in a nitrogen atmosphere, and further stirred at 70 ° C. for 17 hours. The reaction station was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (5.62 g, yield 58%) as a pale yellow oil. .
1 H-NMR (CDCl 3 , 400 MHz): δ0.75-0.83 (4H, m), 3.71 (1H, m), 7.14 (2H, dd, J = 0.8, 1.6 Hz), 7.26 (1H, m).
3,5-ジブロモフェノール(7.00g,27.8mmol)をトルエン(200mL)に溶解し、2-クロロエタノール(2.23mL,33.4mmol)、トリフェニルホスフィン(8.02g,30.6mmol)を加えた。0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,15.2mL,33.4mmol)を滴下し、窒素雰囲気下室温で1時間攪拌した。減圧下溶媒を留去した残渣にジエチルエーテルを加え、生じた不溶物を濾過により除去した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的化合物(9.72g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.80 (2H, t, J=5.9Hz), 4.20 (2H, t, J=5.9Hz), 7.02 (2H, d, J=2.0Hz), 7.29 (1H, t, J=2.0Hz).
(20b)1,3-ジブロモ-5-(ビニルオキシ)ベンゼン
実施例(20a)で合成した化合物(8.74g,27.8mmol)をテトラヒドロフラン(200mL)に溶解し、0℃にてカリウム t-ブトキシド(4.10g,36.5mmol)を加えた。窒素雰囲気下室温で1時間攪拌した後、水(200mL)を加えジエチルエーテル(200mL)で抽出した。減圧下溶媒を留去し、生じた不溶物を濾過により除去し、ジエチルエーテルで洗浄した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的物(7.06g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ4.57 (1H, dd, J=2.0, 5.9Hz), 4.86 (1H, dd, J=2.0, 13.7Hz), 6.55 (1H, dd, J=5.9. 13.7Hz), 7.10 (2H, d, J=2.0Hz), 7.38 (1H, t, J=2.0Hz).
(20c)1,3-ジブロモ-5-(シクロプロピルオキシ)ベンゼン
実施例(20b)で合成した化合物(9.72g,33.3mmol)を1,2-ジクロロエタン(300mL)に溶解し、-78℃にてクロロ(ヨード)メタン(14.8mL,203mmol)、ジエチル亜鉛(1.09Mヘキサン溶液,100mL,109mmol)、トリフルオロ酢酸(800μL,10.4mmol)を加えた。窒素雰囲気下、室温まで徐々に昇温させながら1時間撹拌し、更に70℃で17時間攪拌した。反応駅を室温まで冷却後、1規定塩酸(200mL)を加え、ジエチルエーテル(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン)を用いて精製することにより、淡黄色油状の目的物(5.62g,収率58%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.75-0.83 (4H, m), 3.71 (1H, m), 7.14 (2H, dd, J=0.8, 1.6Hz), 7.26 (1H, m)。 (20a) 1,3-dibromo-5- (2-chloroethoxy) benzene 3,5-dibromophenol (7.00 g, 27.8 mmol) was dissolved in toluene (200 mL), and 2-chloroethanol (2.23 mL) was dissolved. 33.4 mmol) and triphenylphosphine (8.02 g, 30.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 15.2 mL, 33.4 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Diethyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the resulting insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to give the target compound (9.72 g, yield ˜100%) as a pale yellow oil. It was.
1 H-NMR (CDCl 3 , 400 MHz): δ3.80 (2H, t, J = 5.9 Hz), 4.20 (2H, t, J = 5.9 Hz), 7.02 (2H, d, J = 2.0 Hz), 7.29 (1H, t, J = 2.0Hz).
(20b) 1,3-dibromo-5- (vinyloxy) benzene The compound (8.74 g, 27.8 mmol) synthesized in Example (20a) was dissolved in tetrahydrofuran (200 mL), and potassium t-butoxide was dissolved at 0 ° C. (4.10 g, 36.5 mmol) was added. After stirring at room temperature for 1 hour under a nitrogen atmosphere, water (200 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The solvent was distilled off under reduced pressure, and the resulting insoluble material was removed by filtration and washed with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (7.06 g, yield 91%) as a pale yellow oil. .
1 H-NMR (CDCl 3 , 400 MHz): δ4.57 (1H, dd, J = 2.0, 5.9 Hz), 4.86 (1H, dd, J = 2.0, 13.7 Hz), 6.55 (1H, dd, J = 5.9 13.7Hz), 7.10 (2H, d, J = 2.0Hz), 7.38 (1H, t, J = 2.0Hz).
(20c) 1,3-Dibromo-5- (cyclopropyloxy) benzene The compound synthesized in Example (20b) (9.72 g, 33.3 mmol) was dissolved in 1,2-dichloroethane (300 mL), and -78 Chloro (iodo) methane (14.8 mL, 203 mmol), diethyl zinc (1.09 M hexane solution, 100 mL, 109 mmol), and trifluoroacetic acid (800 μL, 10.4 mmol) were added at ° C. The mixture was stirred for 1 hour while gradually warming to room temperature in a nitrogen atmosphere, and further stirred at 70 ° C. for 17 hours. The reaction station was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: hexane) to give the desired product (5.62 g, yield 58%) as a pale yellow oil. .
1 H-NMR (CDCl 3 , 400 MHz): δ0.75-0.83 (4H, m), 3.71 (1H, m), 7.14 (2H, dd, J = 0.8, 1.6 Hz), 7.26 (1H, m).
(20d)3-ブロモ-5-(シクロプロピルオキシ)フェノール
実施例(20c)で合成した化合物(5.62g,19.2mmol)をジエチルエーテル(150mL)に溶解し、-78℃にてブチルリチウム(1.65mol/Lヘキサン溶液,12.8mL,21.1mmol)を加えた。-78℃で1時間攪拌した後、トリメチル ボレート(3.64mL,32.6mmol)を加え、室温まで徐々に昇温させながら1.5時間撹拌した。反応液を0℃に冷却し、酢酸(3.63mL,63.4mmol)、30%過酸化水素水(7.40mL,65.3mmol)を順に滴下した。室温で21時間攪拌した後、水(100mL)を加えて分液した。有機層を飽和チオ硫酸ナトリウム水溶液、飽和食塩水で順に洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、白色固体の目的化合物(4.90g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.74-0.80 (4H, m), 3.69 (1H, m), 5.16 (1H, m), 6.47 (1H, t, J=2.4Hz), 6.63 (1H, t, J=2.4Hz), 6.81 (1H, t, J=2.4Hz).
(20e)5-[3-ブロモ-5-(シクロプロピルオキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(20d)で合成した化合物(4.41g,19.2mmol)をN,N-ジメチルホルムアミド(200mL)に溶解した。実施例(16a)で合成した化合物(4.00g,20.9mmol)、炭酸カリウム(8.00g,57.9mmol)を加え、窒素雰囲気下100℃で20時間攪拌した。反応液を室温まで冷却後、水(200mL)を加え、ジエチルエーテル(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、淡黄色油状の目的化合物(6.00g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.78-0.83 (4H, m), 3.23 (3H, s), 3.72 (1H, m), 6.70 (1H, t, J=2.4Hz), 6.84 (1H, t, J=2.4Hz), 7.26 (1H, m), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.07 (1H, d, J=8.6 Hz), 8.46 (1H, d, J=2.7Hz).
(20f)ベンジル 5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(20e)で合成した化合物(6.00g,15.6mmol)、実施例(19e)で合成した化合物(6.64g,20.3mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(390mg,0.478mmol)、炭酸カリウム(6.47g,46.8mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(6.23g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.78-0.85 (4H, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd, J=2.7, 3.9Hz), 6.73 (1H, t, J=2.0Hz), 6.87 (1H, t, J=2.0Hz), 6.99 (1H, dd, J=2.7, 3.9Hz), 7.10 (1H, t, J=2.0Hz), 7.34-7.47 (6H, m), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, brs), 9.35 (1H, brs)。 (20d) 3-Bromo-5- (cyclopropyloxy) phenol The compound (5.62 g, 19.2 mmol) synthesized in Example (20c) was dissolved in diethyl ether (150 mL), and butyllithium was dissolved at -78 ° C. (1.65 mol / L hexane solution, 12.8 mL, 21.1 mmol) was added. After stirring at −78 ° C. for 1 hour, trimethyl borate (3.64 mL, 32.6 mmol) was added, and the mixture was stirred for 1.5 hours while gradually warming to room temperature. The reaction mixture was cooled to 0 ° C., and acetic acid (3.63 mL, 63.4 mmol) and 30% aqueous hydrogen peroxide (7.40 mL, 65.3 mmol) were added dropwise in this order. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (4.90 g, 4.90 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.74-0.80 (4H, m), 3.69 (1H, m), 5.16 (1H, m), 6.47 (1H, t, J = 2.4Hz), 6.63 ( 1H, t, J = 2.4Hz), 6.81 (1H, t, J = 2.4Hz).
(20e) 5- [3-Bromo-5- (cyclopropyloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (4.41 g, 19.2 mmol) synthesized in Example (20d) was converted to N, N— Dissolved in dimethylformamide (200 mL). The compound synthesized in Example (16a) (4.00 g, 20.9 mmol) and potassium carbonate (8.00 g, 57.9 mmol) were added, and the mixture was stirred at 100 ° C. for 20 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the target compound (6.00 g) as a pale yellow oil. Yield 81%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.83 (4H, m), 3.23 (3H, s), 3.72 (1H, m), 6.70 (1H, t, J = 2.4 Hz), 6.84 ( 1H, t, J = 2.4Hz), 7.26 (1H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7Hz).
(20f) Benzyl 5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate in Example (20e) Synthesized compound (6.00 g, 15.6 mmol), compound synthesized in Example (19e) (6.64 g, 20.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (390 mg, 0.478 mmol) and potassium carbonate (6.47 g, 46.8 mmol) in the same manner as in Example (16e), the target compound (6.23 g, yield 79%) was obtained as a pale yellow solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.85 (4H, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.87 (1H, t, J = 2.0Hz), 6.99 (1H, dd, J = 2.7, 3.9Hz), 7.10 (1H, t , J = 2.0Hz), 7.34-7.47 (6H, m), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, brs), 9.35 (1H, brs).
実施例(20c)で合成した化合物(5.62g,19.2mmol)をジエチルエーテル(150mL)に溶解し、-78℃にてブチルリチウム(1.65mol/Lヘキサン溶液,12.8mL,21.1mmol)を加えた。-78℃で1時間攪拌した後、トリメチル ボレート(3.64mL,32.6mmol)を加え、室温まで徐々に昇温させながら1.5時間撹拌した。反応液を0℃に冷却し、酢酸(3.63mL,63.4mmol)、30%過酸化水素水(7.40mL,65.3mmol)を順に滴下した。室温で21時間攪拌した後、水(100mL)を加えて分液した。有機層を飽和チオ硫酸ナトリウム水溶液、飽和食塩水で順に洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、白色固体の目的化合物(4.90g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.74-0.80 (4H, m), 3.69 (1H, m), 5.16 (1H, m), 6.47 (1H, t, J=2.4Hz), 6.63 (1H, t, J=2.4Hz), 6.81 (1H, t, J=2.4Hz).
(20e)5-[3-ブロモ-5-(シクロプロピルオキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(20d)で合成した化合物(4.41g,19.2mmol)をN,N-ジメチルホルムアミド(200mL)に溶解した。実施例(16a)で合成した化合物(4.00g,20.9mmol)、炭酸カリウム(8.00g,57.9mmol)を加え、窒素雰囲気下100℃で20時間攪拌した。反応液を室温まで冷却後、水(200mL)を加え、ジエチルエーテル(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、淡黄色油状の目的化合物(6.00g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.78-0.83 (4H, m), 3.23 (3H, s), 3.72 (1H, m), 6.70 (1H, t, J=2.4Hz), 6.84 (1H, t, J=2.4Hz), 7.26 (1H, m), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.07 (1H, d, J=8.6 Hz), 8.46 (1H, d, J=2.7Hz).
(20f)ベンジル 5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(20e)で合成した化合物(6.00g,15.6mmol)、実施例(19e)で合成した化合物(6.64g,20.3mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(390mg,0.478mmol)、炭酸カリウム(6.47g,46.8mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(6.23g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.78-0.85 (4H, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd, J=2.7, 3.9Hz), 6.73 (1H, t, J=2.0Hz), 6.87 (1H, t, J=2.0Hz), 6.99 (1H, dd, J=2.7, 3.9Hz), 7.10 (1H, t, J=2.0Hz), 7.34-7.47 (6H, m), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, brs), 9.35 (1H, brs)。 (20d) 3-Bromo-5- (cyclopropyloxy) phenol The compound (5.62 g, 19.2 mmol) synthesized in Example (20c) was dissolved in diethyl ether (150 mL), and butyllithium was dissolved at -78 ° C. (1.65 mol / L hexane solution, 12.8 mL, 21.1 mmol) was added. After stirring at −78 ° C. for 1 hour, trimethyl borate (3.64 mL, 32.6 mmol) was added, and the mixture was stirred for 1.5 hours while gradually warming to room temperature. The reaction mixture was cooled to 0 ° C., and acetic acid (3.63 mL, 63.4 mmol) and 30% aqueous hydrogen peroxide (7.40 mL, 65.3 mmol) were added dropwise in this order. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (4.90 g, 4.90 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.74-0.80 (4H, m), 3.69 (1H, m), 5.16 (1H, m), 6.47 (1H, t, J = 2.4Hz), 6.63 ( 1H, t, J = 2.4Hz), 6.81 (1H, t, J = 2.4Hz).
(20e) 5- [3-Bromo-5- (cyclopropyloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (4.41 g, 19.2 mmol) synthesized in Example (20d) was converted to N, N— Dissolved in dimethylformamide (200 mL). The compound synthesized in Example (16a) (4.00 g, 20.9 mmol) and potassium carbonate (8.00 g, 57.9 mmol) were added, and the mixture was stirred at 100 ° C. for 20 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted twice with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the target compound (6.00 g) as a pale yellow oil. Yield 81%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.83 (4H, m), 3.23 (3H, s), 3.72 (1H, m), 6.70 (1H, t, J = 2.4 Hz), 6.84 ( 1H, t, J = 2.4Hz), 7.26 (1H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7Hz).
(20f) Benzyl 5- [3- (cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate in Example (20e) Synthesized compound (6.00 g, 15.6 mmol), compound synthesized in Example (19e) (6.64 g, 20.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (390 mg, 0.478 mmol) and potassium carbonate (6.47 g, 46.8 mmol) in the same manner as in Example (16e), the target compound (6.23 g, yield 79%) was obtained as a pale yellow solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.85 (4H, m), 3.23 (3H, s), 3.77 (1H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9Hz), 6.73 (1H, t, J = 2.0Hz), 6.87 (1H, t, J = 2.0Hz), 6.99 (1H, dd, J = 2.7, 3.9Hz), 7.10 (1H, t , J = 2.0Hz), 7.34-7.47 (6H, m), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, brs), 9.35 (1H, brs).
(20g)5-[3-(シクロプロポキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-[(2S)-2,3-ジヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(20f)で合成した化合物(2.62g, 5.19mmol)をテトラヒドロフラン(50mL)に溶解し、10%パラジウム炭素触媒(1.50g)を加えて水素雰囲気下室温で4.5時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (20 g) 5- [3- (Cyclopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.62 g, 5.19 mmol) synthesized in Example (20f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.50 g) was added, and room temperature was added under a hydrogen atmosphere. For 4.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
実施例(20f)で合成した化合物(2.62g, 5.19mmol)をテトラヒドロフラン(50mL)に溶解し、10%パラジウム炭素触媒(1.50g)を加えて水素雰囲気下室温で4.5時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (20 g) 5- [3- (Cyclopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-[(2S) -2,3-dihydroxypropyl] -1H -Pyrrole-2-carboxamide The compound (2.62 g, 5.19 mmol) synthesized in Example (20f) was dissolved in tetrahydrofuran (50 mL), 10% palladium carbon catalyst (1.50 g) was added, and room temperature was added under a hydrogen atmosphere. For 4.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
得られた残渣をメタノール(50mL)に溶解し、(S)-(-)-3-アミノ-1,2-プロパンジオール(710mg,7.79mmol)、DMT-MM(3.59g, 13.0mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(2.14g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.78-0.82 (4H, m), 3.22 (3H, s), 3.41-3.56 (5H, m), 3.76 (1H, m), 3.78 (1H, m), 6.46 (1H, dd, J=2.7, 3.9Hz), 6.65 (1H, dd, J=2.4, 3.9Hz), 6.59 (1H, t, J=2.0Hz), 6.70 (1H, m), 6.90 (1H, t, J=2.0Hz), 7.12 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.01 (1H, d, J=8.6Hz), 8.45 (1H, d, J=2.7Hz), 10.20 (1H, brs).
(20h)5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(20g)で合成した化合物(2.14g,4.39mmol)を塩化メチレン(50mL)に溶解し、トリイソプロピルシリルクロリド(1.22mL,5.70mmol)、トリエチルアミン(1.84mL, 13.2mol)、4-ジメチルアミノピリジン(540mg,4.42mmol)を加え、窒素雰囲気下室温で18時間撹拌した。水(50mL)を加え、塩化メチレン(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.00g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.80-0.85 (4H, m), 1.05-1.15 (21H, m), 3.11 (1H, d, J=4.3Hz), 3.24 (3H, s), 3.40 (1H, m), 3.68 (1H, dd, J=6.3, 10.2Hz), 3.71-3.80 (3H, m), 3.87 (1H, m), 6.38 (1H, t, J=3.9Hz), 6.51 (1H, t, J=3.1Hz), 6.62 (1H, dd, J=2.4, 3.9Hz), 6.70 (1H, t, J=2.4Hz), 6.87 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.58 (1H, brs)。 The obtained residue was dissolved in methanol (50 mL) and (S)-(−)-3-amino-1,2-propanediol (710 mg, 7.79 mmol), DMT-MM (3.59 g, 13.0 mmol) ) Was used to obtain the white solid target product (2.14 g, yield 85%) in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.82 (4H, m), 3.22 (3H, s), 3.41-3.56 (5H, m), 3.76 (1H, m), 3.78 (1H, m ), 6.46 (1H, dd, J = 2.7, 3.9Hz), 6.65 (1H, dd, J = 2.4, 3.9Hz), 6.59 (1H, t, J = 2.0Hz), 6.70 (1H, m), 6.90 (1H, t, J = 2.0Hz), 7.12 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.01 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz), 10.20 (1H, brs).
(20h) 5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[( Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (2.14 g, 4.39 mmol) synthesized in Example (20 g) was dissolved in methylene chloride (50 mL), and triisopropylsilyl chloride (1 .22 mL, 5.70 mmol), triethylamine (1.84 mL, 13.2 mol) and 4-dimethylaminopyridine (540 mg, 4.42 mmol) were added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (50 mL) was added and extracted twice with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (2.00 g, Yield 71%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.80-0.85 (4H, m), 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3Hz), 3.24 (3H, s), 3.40 (1H, m), 3.68 (1H, dd, J = 6.3, 10.2Hz), 3.71-3.80 (3H, m), 3.87 (1H, m), 6.38 (1H, t, J = 3.9Hz), 6.51 (1H, t, J = 3.1Hz), 6.62 (1H, dd, J = 2.4, 3.9Hz), 6.70 (1H, t, J = 2.4Hz), 6.87 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).
1H-NMR (CDCl3, 400MHz):δ0.78-0.82 (4H, m), 3.22 (3H, s), 3.41-3.56 (5H, m), 3.76 (1H, m), 3.78 (1H, m), 6.46 (1H, dd, J=2.7, 3.9Hz), 6.65 (1H, dd, J=2.4, 3.9Hz), 6.59 (1H, t, J=2.0Hz), 6.70 (1H, m), 6.90 (1H, t, J=2.0Hz), 7.12 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.01 (1H, d, J=8.6Hz), 8.45 (1H, d, J=2.7Hz), 10.20 (1H, brs).
(20h)5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(20g)で合成した化合物(2.14g,4.39mmol)を塩化メチレン(50mL)に溶解し、トリイソプロピルシリルクロリド(1.22mL,5.70mmol)、トリエチルアミン(1.84mL, 13.2mol)、4-ジメチルアミノピリジン(540mg,4.42mmol)を加え、窒素雰囲気下室温で18時間撹拌した。水(50mL)を加え、塩化メチレン(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.00g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.80-0.85 (4H, m), 1.05-1.15 (21H, m), 3.11 (1H, d, J=4.3Hz), 3.24 (3H, s), 3.40 (1H, m), 3.68 (1H, dd, J=6.3, 10.2Hz), 3.71-3.80 (3H, m), 3.87 (1H, m), 6.38 (1H, t, J=3.9Hz), 6.51 (1H, t, J=3.1Hz), 6.62 (1H, dd, J=2.4, 3.9Hz), 6.70 (1H, t, J=2.4Hz), 6.87 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.58 (1H, brs)。 The obtained residue was dissolved in methanol (50 mL) and (S)-(−)-3-amino-1,2-propanediol (710 mg, 7.79 mmol), DMT-MM (3.59 g, 13.0 mmol) ) Was used to obtain the white solid target product (2.14 g, yield 85%) in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ0.78-0.82 (4H, m), 3.22 (3H, s), 3.41-3.56 (5H, m), 3.76 (1H, m), 3.78 (1H, m ), 6.46 (1H, dd, J = 2.7, 3.9Hz), 6.65 (1H, dd, J = 2.4, 3.9Hz), 6.59 (1H, t, J = 2.0Hz), 6.70 (1H, m), 6.90 (1H, t, J = 2.0Hz), 7.12 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.01 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz), 10.20 (1H, brs).
(20h) 5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -N-{(2S) -2-hydroxy-3-[( Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (2.14 g, 4.39 mmol) synthesized in Example (20 g) was dissolved in methylene chloride (50 mL), and triisopropylsilyl chloride (1 .22 mL, 5.70 mmol), triethylamine (1.84 mL, 13.2 mol) and 4-dimethylaminopyridine (540 mg, 4.42 mmol) were added, and the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. Water (50 mL) was added and extracted twice with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (2.00 g, Yield 71%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.80-0.85 (4H, m), 1.05-1.15 (21H, m), 3.11 (1H, d, J = 4.3Hz), 3.24 (3H, s), 3.40 (1H, m), 3.68 (1H, dd, J = 6.3, 10.2Hz), 3.71-3.80 (3H, m), 3.87 (1H, m), 6.38 (1H, t, J = 3.9Hz), 6.51 (1H, t, J = 3.1Hz), 6.62 (1H, dd, J = 2.4, 3.9Hz), 6.70 (1H, t, J = 2.4Hz), 6.87 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).
(20i)5-[3-(シクロプロピルオキシ)-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(20h)で合成した化合物(2.00g,3.11mmol)、メタンスルホン酸無水物(1.14g,6.54mmol)、トリエチルアミン(2.17mL, 15.6mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(1.79g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.80-0.84 (4H, m), 1.02-1.12 (21H, m), 3.23 (3H, s), 3.77 (1H, m), 3.82-3.91 (3H, m), 4.00 (1H, dd, J=9.8, 14.1Hz), 4.76 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.67 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.87 (1H, t, J=1.6Hz), 7.14 (1H, t, J=1.6Hz), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
(20j)[(5R)-2-{5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(20i)で合成した化合物(1.79g,2.86mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.43mL,3.43mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.26g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.79-0.84 (4H, m), 3.23 (3H, s), 3.68-3.79 (3H, m), 3.85 (1H, dd, J=3.1, 12.5Hz), 4.03 (1H, dd, J=9.8, 14.1Hz), 4.79 (1H, m), 6.47 (1H, d, J=3.9Hz), 6.69 (1H, t, J=2.4Hz), 6.71 (1H, d, J=3.9Hz), 6.87 (1H, t, J=1.6Hz), 7.13 (1H, t, J=1.6Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 470.13858(M+H)+。 (20i) 5- [3- (cyclopropyloxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole- 2-yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (20h) (2.00 g, 3.11 mmol), methanesulfonic anhydride (1. 14 g, 6.54 mmol) and triethylamine (2.17 mL, 15.6 mol) were used to obtain the target product (1.79 g, yield 92%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ0.80-0.84 (4H, m), 1.02-1.12 (21H, m), 3.23 (3H, s), 3.77 (1H, m), 3.82-3.91 (3H , m), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.76 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.67 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.14 (1H, t, J = 1.6Hz), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(20j) [(5R) -2- {5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl } -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (20i) (1.79 g, 2.86 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, The target compound (1.26 g, 94% yield) was obtained in the same manner as in Example (16k) using 3.43 mL, 3.43 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ0.79-0.84 (4H, m), 3.23 (3H, s), 3.68-3.79 (3H, m), 3.85 (1H, dd, J = 3.1, 12.5 Hz ), 4.03 (1H, dd, J = 9.8, 14.1Hz), 4.79 (1H, m), 6.47 (1H, d, J = 3.9Hz), 6.69 (1H, t, J = 2.4Hz), 6.71 (1H , d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.13 (1H, t, J = 1.6Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H , d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 470.13858 (M + H) <+> .
実施例(20h)で合成した化合物(2.00g,3.11mmol)、メタンスルホン酸無水物(1.14g,6.54mmol)、トリエチルアミン(2.17mL, 15.6mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(1.79g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.80-0.84 (4H, m), 1.02-1.12 (21H, m), 3.23 (3H, s), 3.77 (1H, m), 3.82-3.91 (3H, m), 4.00 (1H, dd, J=9.8, 14.1Hz), 4.76 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.67 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.87 (1H, t, J=1.6Hz), 7.14 (1H, t, J=1.6Hz), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
(20j)[(5R)-2-{5-[3-(シクロプロピルオキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(20i)で合成した化合物(1.79g,2.86mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.43mL,3.43mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.26g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.79-0.84 (4H, m), 3.23 (3H, s), 3.68-3.79 (3H, m), 3.85 (1H, dd, J=3.1, 12.5Hz), 4.03 (1H, dd, J=9.8, 14.1Hz), 4.79 (1H, m), 6.47 (1H, d, J=3.9Hz), 6.69 (1H, t, J=2.4Hz), 6.71 (1H, d, J=3.9Hz), 6.87 (1H, t, J=1.6Hz), 7.13 (1H, t, J=1.6Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.04 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 470.13858(M+H)+。 (20i) 5- [3- (cyclopropyloxy) -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole- 2-yl] -1H-pyrrol-2-yl} phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (20h) (2.00 g, 3.11 mmol), methanesulfonic anhydride (1. 14 g, 6.54 mmol) and triethylamine (2.17 mL, 15.6 mol) were used to obtain the target product (1.79 g, yield 92%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ0.80-0.84 (4H, m), 1.02-1.12 (21H, m), 3.23 (3H, s), 3.77 (1H, m), 3.82-3.91 (3H , m), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.76 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.67 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.14 (1H, t, J = 1.6Hz), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(20j) [(5R) -2- {5- [3- (Cyclopropyloxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrol-2-yl } -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (20i) (1.79 g, 2.86 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, The target compound (1.26 g, 94% yield) was obtained in the same manner as in Example (16k) using 3.43 mL, 3.43 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ0.79-0.84 (4H, m), 3.23 (3H, s), 3.68-3.79 (3H, m), 3.85 (1H, dd, J = 3.1, 12.5 Hz ), 4.03 (1H, dd, J = 9.8, 14.1Hz), 4.79 (1H, m), 6.47 (1H, d, J = 3.9Hz), 6.69 (1H, t, J = 2.4Hz), 6.71 (1H , d, J = 3.9Hz), 6.87 (1H, t, J = 1.6Hz), 7.13 (1H, t, J = 1.6Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.04 (1H , d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 470.13858 (M + H) <+> .
(実施例21)
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-カルボン酸メチル (Example 21)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) Methyl pyridine-2-carboxylate
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-カルボン酸メチル (Example 21)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) Methyl pyridine-2-carboxylate
(21a)ベンジル 5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-2-カルボキシレート
実施例(1a)で合成した化合物(5.00g,24.6mmol)、実施例(19e)で合成した化合物(8.46g,25.9mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(600mg,0.74mmol)、炭酸カリウム(6.81g,49.3mmol)を用い、実施例(16e)と同様の方法で茶色固体の目的化合物(5.83g,収率73%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.83 (3H, s), 5.16 (1H, s), 5.34 (2H, s), 6.36 (1H, t, J = 2.3 Hz), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.66 (2H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.45-7.35 (5H, m), 9.32 (1H, s).
(21b)5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-2-カルボン酸
実施例(21a)で合成した化合物(2.00g,6.19mmol)を酢酸エチル(40mL)に溶解し、10%パラジウム炭素触媒(0.50g)を加えて水素雰囲気下室温で2時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、テトラヒドロフランで洗浄した。減圧下溶媒を留去することで白色固体の目的化合物(1.42g,99%)を得た。
1H-NMR (CD3OD, 400MHz): δ 3.87 (3H, dt, J = 91.6, 32.7 Hz), 6.44 (1H, t, J = 2.2 Hz), 6.56 (1H, d, J = 4.4 Hz), 6.91 (2H, d, J = 2.0 Hz), 6.93 (1H, d, J = 3.9 Hz).
(21c)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-2-カルボキサミド
実施例(21b)で合成した化合物(500mg,2.14mmol)、N-メチルモルホリン(0.47ml, 4.29mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、室温でWSCI・HCl(493mg, 2.57mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(215μL,2.36mmol)を加え、窒素雰囲気下14時間撹拌した。反応液を酢酸エチル(60mL)で希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~10%)を用いて精製することで白色固体の目的化合物(400mg,61%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.39 (2H, dd, J = 13.9, 6.6 Hz), 3.51-3.58 (3H, m), 3.79-3.82 (4H, m), 6.29 (1H, t, J = 2.2 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.69 (1H, t, J = 1.7 Hz), 6.75 (1H, t, J = 1.7 Hz), 6.84 (1H, d, J = 3.9 Hz)。 (21a) Benzyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylate Compound (5.00 g, 24.6 mmol) synthesized in Example (1a), Example (19e) Synthesized compound (8.46 g, 25.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (600 mg, 0.74 mmol), potassium carbonate (6.81 g, 49 3 mmol) was used to obtain the target compound (5.83 g, yield 73%) as a brown solid in the same manner as in Example (16e).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.83 (3H, s), 5.16 (1H, s), 5.34 (2H, s), 6.36 (1H, t, J = 2.3 Hz), 6.51 (1H, dd , J = 3.9, 2.7 Hz), 6.66 (2H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.45-7.35 (5H, m), 9.32 (1H, s) .
(21b) 5- (3-Hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (21a) (2.00 g, 6.19 mmol) was dissolved in ethyl acetate (40 mL). Then, 10% palladium carbon catalyst (0.50 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with tetrahydrofuran. The solvent was distilled off under reduced pressure to obtain the target compound (1.42 g, 99%) as a white solid.
1 H-NMR (CD 3 OD, 400 MHz): δ 3.87 (3H, dt, J = 91.6, 32.7 Hz), 6.44 (1H, t, J = 2.2 Hz), 6.56 (1H, d, J = 4.4 Hz) , 6.91 (2H, d, J = 2.0 Hz), 6.93 (1H, d, J = 3.9 Hz).
(21c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxamide Compound (500 mg, synthesized in Example (21b)) 2.14 mmol), N-methylmorpholine (0.47 ml, 4.29 mmol) was dissolved in N, N-dimethylformamide (10 mL), and WSCI · HCl (493 mg, 2.57 mmol), (S)-( −)-3-Amino-1,2-propanediol (215 μL, 2.36 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 10%) to give the target compound (400 mg, 61%) as a white solid. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.39 (2H, dd, J = 13.9, 6.6 Hz), 3.51-3.58 (3H, m), 3.79-3.82 (4H, m), 6.29 (1H, t, J = 2.2 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.69 (1H, t, J = 1.7 Hz), 6.75 (1H, t, J = 1.7 Hz), 6.84 (1H, d, J = 3.9 Hz).
実施例(1a)で合成した化合物(5.00g,24.6mmol)、実施例(19e)で合成した化合物(8.46g,25.9mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(600mg,0.74mmol)、炭酸カリウム(6.81g,49.3mmol)を用い、実施例(16e)と同様の方法で茶色固体の目的化合物(5.83g,収率73%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.83 (3H, s), 5.16 (1H, s), 5.34 (2H, s), 6.36 (1H, t, J = 2.3 Hz), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.66 (2H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.45-7.35 (5H, m), 9.32 (1H, s).
(21b)5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-2-カルボン酸
実施例(21a)で合成した化合物(2.00g,6.19mmol)を酢酸エチル(40mL)に溶解し、10%パラジウム炭素触媒(0.50g)を加えて水素雰囲気下室温で2時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、テトラヒドロフランで洗浄した。減圧下溶媒を留去することで白色固体の目的化合物(1.42g,99%)を得た。
1H-NMR (CD3OD, 400MHz): δ 3.87 (3H, dt, J = 91.6, 32.7 Hz), 6.44 (1H, t, J = 2.2 Hz), 6.56 (1H, d, J = 4.4 Hz), 6.91 (2H, d, J = 2.0 Hz), 6.93 (1H, d, J = 3.9 Hz).
(21c)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-ヒドロキシ-5-メトキシフェニル)-1H-ピロール-2-カルボキサミド
実施例(21b)で合成した化合物(500mg,2.14mmol)、N-メチルモルホリン(0.47ml, 4.29mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、室温でWSCI・HCl(493mg, 2.57mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(215μL,2.36mmol)を加え、窒素雰囲気下14時間撹拌した。反応液を酢酸エチル(60mL)で希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~10%)を用いて精製することで白色固体の目的化合物(400mg,61%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.39 (2H, dd, J = 13.9, 6.6 Hz), 3.51-3.58 (3H, m), 3.79-3.82 (4H, m), 6.29 (1H, t, J = 2.2 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.69 (1H, t, J = 1.7 Hz), 6.75 (1H, t, J = 1.7 Hz), 6.84 (1H, d, J = 3.9 Hz)。 (21a) Benzyl 5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylate Compound (5.00 g, 24.6 mmol) synthesized in Example (1a), Example (19e) Synthesized compound (8.46 g, 25.9 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (600 mg, 0.74 mmol), potassium carbonate (6.81 g, 49 3 mmol) was used to obtain the target compound (5.83 g, yield 73%) as a brown solid in the same manner as in Example (16e).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.83 (3H, s), 5.16 (1H, s), 5.34 (2H, s), 6.36 (1H, t, J = 2.3 Hz), 6.51 (1H, dd , J = 3.9, 2.7 Hz), 6.66 (2H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.45-7.35 (5H, m), 9.32 (1H, s) .
(21b) 5- (3-Hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (21a) (2.00 g, 6.19 mmol) was dissolved in ethyl acetate (40 mL). Then, 10% palladium carbon catalyst (0.50 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with tetrahydrofuran. The solvent was distilled off under reduced pressure to obtain the target compound (1.42 g, 99%) as a white solid.
1 H-NMR (CD 3 OD, 400 MHz): δ 3.87 (3H, dt, J = 91.6, 32.7 Hz), 6.44 (1H, t, J = 2.2 Hz), 6.56 (1H, d, J = 4.4 Hz) , 6.91 (2H, d, J = 2.0 Hz), 6.93 (1H, d, J = 3.9 Hz).
(21c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-hydroxy-5-methoxyphenyl) -1H-pyrrole-2-carboxamide Compound (500 mg, synthesized in Example (21b)) 2.14 mmol), N-methylmorpholine (0.47 ml, 4.29 mmol) was dissolved in N, N-dimethylformamide (10 mL), and WSCI · HCl (493 mg, 2.57 mmol), (S)-( −)-3-Amino-1,2-propanediol (215 μL, 2.36 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 10%) to give the target compound (400 mg, 61%) as a white solid. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.39 (2H, dd, J = 13.9, 6.6 Hz), 3.51-3.58 (3H, m), 3.79-3.82 (4H, m), 6.29 (1H, t, J = 2.2 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.69 (1H, t, J = 1.7 Hz), 6.75 (1H, t, J = 1.7 Hz), 6.84 (1H, d, J = 3.9 Hz).
(21d)N-{(2S)-2-ジヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(21c)で合成した化合物(400mg,1.31mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、トリエチルアミン(0.91mL,6.53mmol)、トリイソプロピルシリルクロリド(0.84mL,3.92mmol)、4-ジメチルアミノピリジン(239mg,1.96mmol)を加え、窒素雰囲気下で15時間攪拌した。反応液を酢酸エチル(50mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することで、白色固体の目的物(619mg,77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.07-1.13 (36H, m), 1.25-1.31 (6H, m), 3.42 (1H, ddd, J = 13.9, 7.1, 5.1 Hz), 3.69 (1H, dd, J = 10.0, 6.1 Hz), 3.74 (1H, td, J = 7.0, 3.3 Hz), 3.78 (1H, dd, J = 9.8, 4.9 Hz), 3.82 (3H, s), 3.89 (1H, br s), 6.33 (1H, t, J = 5.6 Hz), 6.38 (1H, t, J = 2.2 Hz), 6.47 (1H, t, J = 3.2 Hz), 6.61 (1H, dd, J = 3.7, 2.7 Hz), 6.68 (2H, dd, J = 4.2, 2.2 Hz), 9.42 (1H, br s).
(21e)(5R)-2-(5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール
実施例(21d)で合成した化合物(619mg,1.00mmol)、メタンスルホン酸無水物(348mg,2.00mmol)、トリエチルアミン(0.42mL,3.0mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(298mg,収率50%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.05 (18H, d, J = 5.5 Hz), 1.11 (19H, d, J = 6.6 Hz), 1.23-1.32 (6H, m), 3.81 (3H, s), 3.91-3.84 (3H, m), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.73-4.78 (1H, m), 6.36 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.70 (2H, d, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz).
(21f)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノール
実施例(21e)で合成した化合物(297mg,0.50mmol)、テトラブチルアンモニウムフルオリド(1.0mol/Lテトラヒドロフラン溶液,1.09mL,1.09mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(102mg,収率72%)を得た。
1H-NMR (CD3OD, 400MHz):δ 3.78 (1H, dd, J = 12.3, 5.3 Hz), 3.82 (3H, s), 3.93-3.99 (2H, m), 4.17 (1H, dd, J = 13.7, 9.8 Hz), 4.94-4.87 (1H, m), 6.31 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.68 (1H, t, J = 1.8 Hz), 6.80 (1H, d, J = 3.9 Hz), 7.06 (1H, t, J = 1.8 Hz), 10.98 (1H, s)。 (21d) N-{(2S) -2-dihydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole -2-Carboxamide The compound synthesized in Example (21c) (400 mg, 1.31 mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (0.91 mL, 6.53 mmol), triisopropylsilyl chloride ( 0.84 mL, 3.92 mmol) and 4-dimethylaminopyridine (239 mg, 1.96 mmol) were added, and the mixture was stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -50%) to give the desired product (619 mg, 77%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.07-1.13 (36H, m), 1.25-1.31 (6H, m), 3.42 (1H, ddd, J = 13.9, 7.1, 5.1 Hz), 3.69 (1H, dd, J = 10.0, 6.1 Hz), 3.74 (1H, td, J = 7.0, 3.3 Hz), 3.78 (1H, dd, J = 9.8, 4.9 Hz), 3.82 (3H, s), 3.89 (1H, br s), 6.33 (1H, t, J = 5.6 Hz), 6.38 (1H, t, J = 2.2 Hz), 6.47 (1H, t, J = 3.2 Hz), 6.61 (1H, dd, J = 3.7, 2.7 Hz), 6.68 (2H, dd, J = 4.2, 2.2 Hz), 9.42 (1H, br s).
(21e) (5R) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazole Compound (619 mg, 1.00 mmol) synthesized in Example (21d), methanesulfonic anhydride (348 mg, 2.00 mmol), triethylamine (0.42 mL, 3.0 mmol) and the white solid target compound (298 mg, yield 50%) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05 (18H, d, J = 5.5 Hz), 1.11 (19H, d, J = 6.6 Hz), 1.23-1.32 (6H, m), 3.81 (3H, s ), 3.91-3.84 (3H, m), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.73-4.78 (1H, m), 6.36 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.70 (2H, d, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz).
(21f) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenol Using the compound (297 mg, 0.50 mmol) synthesized in Example (21e) and tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.09 mL, 1.09 mmol), the same as in Example (16k) The target compound as a white solid (102 mg, yield 72%) was obtained by the method.
1 H-NMR (CD 3 OD, 400 MHz): δ 3.78 (1H, dd, J = 12.3, 5.3 Hz), 3.82 (3H, s), 3.93-3.99 (2H, m), 4.17 (1H, dd, J = 13.7, 9.8 Hz), 4.94-4.87 (1H, m), 6.31 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.68 (1H, t, J = 1.8 Hz ), 6.80 (1H, d, J = 3.9 Hz), 7.06 (1H, t, J = 1.8 Hz), 10.98 (1H, s).
実施例(21c)で合成した化合物(400mg,1.31mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、トリエチルアミン(0.91mL,6.53mmol)、トリイソプロピルシリルクロリド(0.84mL,3.92mmol)、4-ジメチルアミノピリジン(239mg,1.96mmol)を加え、窒素雰囲気下で15時間攪拌した。反応液を酢酸エチル(50mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することで、白色固体の目的物(619mg,77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.07-1.13 (36H, m), 1.25-1.31 (6H, m), 3.42 (1H, ddd, J = 13.9, 7.1, 5.1 Hz), 3.69 (1H, dd, J = 10.0, 6.1 Hz), 3.74 (1H, td, J = 7.0, 3.3 Hz), 3.78 (1H, dd, J = 9.8, 4.9 Hz), 3.82 (3H, s), 3.89 (1H, br s), 6.33 (1H, t, J = 5.6 Hz), 6.38 (1H, t, J = 2.2 Hz), 6.47 (1H, t, J = 3.2 Hz), 6.61 (1H, dd, J = 3.7, 2.7 Hz), 6.68 (2H, dd, J = 4.2, 2.2 Hz), 9.42 (1H, br s).
(21e)(5R)-2-(5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール
実施例(21d)で合成した化合物(619mg,1.00mmol)、メタンスルホン酸無水物(348mg,2.00mmol)、トリエチルアミン(0.42mL,3.0mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(298mg,収率50%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.05 (18H, d, J = 5.5 Hz), 1.11 (19H, d, J = 6.6 Hz), 1.23-1.32 (6H, m), 3.81 (3H, s), 3.91-3.84 (3H, m), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.73-4.78 (1H, m), 6.36 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.70 (2H, d, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz).
(21f)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノール
実施例(21e)で合成した化合物(297mg,0.50mmol)、テトラブチルアンモニウムフルオリド(1.0mol/Lテトラヒドロフラン溶液,1.09mL,1.09mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(102mg,収率72%)を得た。
1H-NMR (CD3OD, 400MHz):δ 3.78 (1H, dd, J = 12.3, 5.3 Hz), 3.82 (3H, s), 3.93-3.99 (2H, m), 4.17 (1H, dd, J = 13.7, 9.8 Hz), 4.94-4.87 (1H, m), 6.31 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.68 (1H, t, J = 1.8 Hz), 6.80 (1H, d, J = 3.9 Hz), 7.06 (1H, t, J = 1.8 Hz), 10.98 (1H, s)。 (21d) N-{(2S) -2-dihydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole -2-Carboxamide The compound synthesized in Example (21c) (400 mg, 1.31 mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (0.91 mL, 6.53 mmol), triisopropylsilyl chloride ( 0.84 mL, 3.92 mmol) and 4-dimethylaminopyridine (239 mg, 1.96 mmol) were added, and the mixture was stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -50%) to give the desired product (619 mg, 77%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.07-1.13 (36H, m), 1.25-1.31 (6H, m), 3.42 (1H, ddd, J = 13.9, 7.1, 5.1 Hz), 3.69 (1H, dd, J = 10.0, 6.1 Hz), 3.74 (1H, td, J = 7.0, 3.3 Hz), 3.78 (1H, dd, J = 9.8, 4.9 Hz), 3.82 (3H, s), 3.89 (1H, br s), 6.33 (1H, t, J = 5.6 Hz), 6.38 (1H, t, J = 2.2 Hz), 6.47 (1H, t, J = 3.2 Hz), 6.61 (1H, dd, J = 3.7, 2.7 Hz), 6.68 (2H, dd, J = 4.2, 2.2 Hz), 9.42 (1H, br s).
(21e) (5R) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazole Compound (619 mg, 1.00 mmol) synthesized in Example (21d), methanesulfonic anhydride (348 mg, 2.00 mmol), triethylamine (0.42 mL, 3.0 mmol) and the white solid target compound (298 mg, yield 50%) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05 (18H, d, J = 5.5 Hz), 1.11 (19H, d, J = 6.6 Hz), 1.23-1.32 (6H, m), 3.81 (3H, s ), 3.91-3.84 (3H, m), 4.02 (1H, dd, J = 14.1, 9.8 Hz), 4.73-4.78 (1H, m), 6.36 (1H, t, J = 2.2 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.70 (2H, d, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz).
(21f) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenol Using the compound (297 mg, 0.50 mmol) synthesized in Example (21e) and tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.09 mL, 1.09 mmol), the same as in Example (16k) The target compound as a white solid (102 mg, yield 72%) was obtained by the method.
1 H-NMR (CD 3 OD, 400 MHz): δ 3.78 (1H, dd, J = 12.3, 5.3 Hz), 3.82 (3H, s), 3.93-3.99 (2H, m), 4.17 (1H, dd, J = 13.7, 9.8 Hz), 4.94-4.87 (1H, m), 6.31 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.68 (1H, t, J = 1.8 Hz ), 6.80 (1H, d, J = 3.9 Hz), 7.06 (1H, t, J = 1.8 Hz), 10.98 (1H, s).
(21g)5-ヒドロキシピリジン-2-カルボン酸メチル
2-ブロモ-5-フルオロピリジン(3.80g,21.6mmol)をメタノール(50mL)およびN,N-ジメチルホルムアミド(50mL)に溶解し、酢酸パラジウム(484mg,2.16mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン(2.39g,4.32mmol)、トリエチルアミン(6.0mL,43.2mmol)を加え、一酸化炭素雰囲気下、室温で3日間撹拌後、反応溶液中の不溶物をろ過した。水(100mL)を加え、酢酸エチル(100mL)で抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することにより、淡黄色固体の目的化合物(2.87g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 4.01 (3H, s), 7.54 (1H, dt, J = 8.6, 3.9 Hz), 8.20 (1H, dd, J = 8.6, 4.7 Hz), 8.59 (1H, d, J = 2.7 Hz).
(21h)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-カルボン酸メチル
実施例(21f)で合成した化合物(420mg,1.45mmol)と、実施例(21g)で合成した化合物(224mg,1.44mmol)をN,N-ジメチルホルムアミド(5mL)に溶解させ、炭酸セシウム(723mg,2.22mmol)を加えて、窒素雰囲気下100℃にて1時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(330mg,収率54%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.73 (1H, dd, J = 12.2, 5.4 Hz), 3.80 (1H, dd, J = 14.4, 7.6 Hz), 3.85 (3H, s), 3.88 (1H, dd, J = 12.5, 3.2 Hz), 4.01 (3H, s), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.85-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.98 (1H, s), 7.37 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 424.15078 (M+H)+。 (21 g) Methyl 5-hydroxypyridine-2-carboxylate 2-Bromo-5-fluoropyridine (3.80 g, 21.6 mmol) was dissolved in methanol (50 mL) and N, N-dimethylformamide (50 mL). Palladium (484 mg, 2.16 mmol), 1,1′-bis (diphenylphosphino) ferrocene (2.39 g, 4.32 mmol), triethylamine (6.0 mL, 43.2 mmol) were added, and under a carbon monoxide atmosphere, After stirring at room temperature for 3 days, insoluble matters in the reaction solution were filtered. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% -50%) to give the target compound (2.87 g) as a pale yellow solid. Yield 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ 4.01 (3H, s), 7.54 (1H, dt, J = 8.6, 3.9 Hz), 8.20 (1H, dd, J = 8.6, 4.7 Hz), 8.59 (1H , d, J = 2.7 Hz).
(21h) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) methyl pyridine-2-carboxylate The compound synthesized in Example (21f) (420 mg, 1.45 mmol) and the compound synthesized in Example (21 g) (224 mg, 1.44 mmol) were combined with N, N- It was dissolved in dimethylformamide (5 mL), cesium carbonate (723 mg, 2.22 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (330 mg, yield) as a white solid. 54%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.73 (1H, dd, J = 12.2, 5.4 Hz), 3.80 (1H, dd, J = 14.4, 7.6 Hz), 3.85 (3H, s), 3.88 (1H , dd, J = 12.5, 3.2 Hz), 4.01 (3H, s), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.85-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.98 (1H, s), 7.37 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 424.15078 (M + H) <+> .
2-ブロモ-5-フルオロピリジン(3.80g,21.6mmol)をメタノール(50mL)およびN,N-ジメチルホルムアミド(50mL)に溶解し、酢酸パラジウム(484mg,2.16mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン(2.39g,4.32mmol)、トリエチルアミン(6.0mL,43.2mmol)を加え、一酸化炭素雰囲気下、室温で3日間撹拌後、反応溶液中の不溶物をろ過した。水(100mL)を加え、酢酸エチル(100mL)で抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することにより、淡黄色固体の目的化合物(2.87g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 4.01 (3H, s), 7.54 (1H, dt, J = 8.6, 3.9 Hz), 8.20 (1H, dd, J = 8.6, 4.7 Hz), 8.59 (1H, d, J = 2.7 Hz).
(21h)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-カルボン酸メチル
実施例(21f)で合成した化合物(420mg,1.45mmol)と、実施例(21g)で合成した化合物(224mg,1.44mmol)をN,N-ジメチルホルムアミド(5mL)に溶解させ、炭酸セシウム(723mg,2.22mmol)を加えて、窒素雰囲気下100℃にて1時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(330mg,収率54%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.73 (1H, dd, J = 12.2, 5.4 Hz), 3.80 (1H, dd, J = 14.4, 7.6 Hz), 3.85 (3H, s), 3.88 (1H, dd, J = 12.5, 3.2 Hz), 4.01 (3H, s), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.85-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.98 (1H, s), 7.37 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 424.15078 (M+H)+。 (21 g) Methyl 5-hydroxypyridine-2-carboxylate 2-Bromo-5-fluoropyridine (3.80 g, 21.6 mmol) was dissolved in methanol (50 mL) and N, N-dimethylformamide (50 mL). Palladium (484 mg, 2.16 mmol), 1,1′-bis (diphenylphosphino) ferrocene (2.39 g, 4.32 mmol), triethylamine (6.0 mL, 43.2 mmol) were added, and under a carbon monoxide atmosphere, After stirring at room temperature for 3 days, insoluble matters in the reaction solution were filtered. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% -50%) to give the target compound (2.87 g) as a pale yellow solid. Yield 86%).
1 H-NMR (CDCl 3 , 400 MHz): δ 4.01 (3H, s), 7.54 (1H, dt, J = 8.6, 3.9 Hz), 8.20 (1H, dd, J = 8.6, 4.7 Hz), 8.59 (1H , d, J = 2.7 Hz).
(21h) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) methyl pyridine-2-carboxylate The compound synthesized in Example (21f) (420 mg, 1.45 mmol) and the compound synthesized in Example (21 g) (224 mg, 1.44 mmol) were combined with N, N- It was dissolved in dimethylformamide (5 mL), cesium carbonate (723 mg, 2.22 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (330 mg, yield) as a white solid. 54%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.73 (1H, dd, J = 12.2, 5.4 Hz), 3.80 (1H, dd, J = 14.4, 7.6 Hz), 3.85 (3H, s), 3.88 (1H , dd, J = 12.5, 3.2 Hz), 4.01 (3H, s), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.85-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.98 (1H, s), 7.37 (1H, dd, J = 8.8, 2.9 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 424.15078 (M + H) <+> .
(実施例22)
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド (Example 22)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド (Example 22)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-carboxamide
(22a)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-カルボン酸
実施例(21h)で合成した化合物(300mg,0.71mmol)をテトラヒドロフラン(10mL)に溶解させ、メタノール(10mL)、水(4mL)、水酸化リチウム一水和物(89mg,2.13mmol)を加えた後、窒素雰囲気下60℃にて1.5時間撹拌した。反応液を室温まで冷却し、2N塩酸を加え酸性にした。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5%~10%)を用いて精製することで白色固体の目的化合物(290mg,収率100%)を得た。
1H-NMR (CD3OD, 400MHz): δ 3.81 (1H, dd, J = 13.2, 3.4 Hz), 3.89 (3H, s), 4.05-4.11 (2H, m), 4.23 (1H, t, J = 10.5 Hz), 5.51-5.47 (1H, m), 6.81 (1H, t, J = 2.2 Hz), 6.92 (1H, d, J = 3.9 Hz), 7.20 (1H, t, J = 1.7 Hz), 7.32 (1H, t, J = 1.7 Hz), 7.41 (1H, d, J = 4.4 Hz), 7.57 (1H, dd, J = 8.5, 2.7 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz).
(22b)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド
実施例(22a)で合成した化合物(70mg,0.17mmol)をN,N-ジメチルホルムアミド(1mL)に溶解し、HOBt・H2O(29mg, 0.19mmol)、メチルアミン塩酸塩(23mg,0.34mmol)、WSCI・HCl(39mg,0.21mmol)を加え、窒素雰囲気下14時間撹拌した。反応液を酢酸エチル(20mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~10%)を用いて精製することで白色固体の目的化合物(24mg,収率35%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.03 (3H, d, J = 5.4 Hz), 3.69 (1H, dd, J = 12.2, 5.4 Hz), 3.77 (1H, dd, J = 14.2, 7.3 Hz), 3.84-3.86 (4H, m), 4.02 (1H, dd, J = 13.9, 10.0 Hz), 4.75-4.80 (1H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.71 (1H, d, J = 3.4 Hz), 6.84 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 423.16652 (M+H)+。 (22a) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridine-2-carboxylic acid The compound (300 mg, 0.71 mmol) synthesized in Example (21h) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), water (4 mL), lithium hydroxide monohydrate A Japanese product (89 mg, 2.13 mmol) was added, followed by stirring at 60 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and acidified with 2N hydrochloric acid. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5% to 10%) to give the target compound (290 mg, yield 100) as a white solid. %).
1 H-NMR (CD 3 OD, 400 MHz): δ 3.81 (1H, dd, J = 13.2, 3.4 Hz), 3.89 (3H, s), 4.05-4.11 (2H, m), 4.23 (1H, t, J = 10.5 Hz), 5.51-5.47 (1H, m), 6.81 (1H, t, J = 2.2 Hz), 6.92 (1H, d, J = 3.9 Hz), 7.20 (1H, t, J = 1.7 Hz), 7.32 (1H, t, J = 1.7 Hz), 7.41 (1H, d, J = 4.4 Hz), 7.57 (1H, dd, J = 8.5, 2.7 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz).
(22b) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-carboxamide The compound synthesized in Example (22a) (70 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1 mL), and HOBt · H 2 O (29 mg) was dissolved. 0.19 mmol), methylamine hydrochloride (23 mg, 0.34 mmol) and WSCI.HCl (39 mg, 0.21 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 10%) to give the target compound (24 mg, yield 35) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.03 (3H, d, J = 5.4 Hz), 3.69 (1H, dd, J = 12.2, 5.4 Hz), 3.77 (1H, dd, J = 14.2, 7.3 Hz) ), 3.84-3.86 (4H, m), 4.02 (1H, dd, J = 13.9, 10.0 Hz), 4.75-4.80 (1H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.71 (1H, d, J = 3.4 Hz), 6.84 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 423.16652 (M + H) <+> .
実施例(21h)で合成した化合物(300mg,0.71mmol)をテトラヒドロフラン(10mL)に溶解させ、メタノール(10mL)、水(4mL)、水酸化リチウム一水和物(89mg,2.13mmol)を加えた後、窒素雰囲気下60℃にて1.5時間撹拌した。反応液を室温まで冷却し、2N塩酸を加え酸性にした。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5%~10%)を用いて精製することで白色固体の目的化合物(290mg,収率100%)を得た。
1H-NMR (CD3OD, 400MHz): δ 3.81 (1H, dd, J = 13.2, 3.4 Hz), 3.89 (3H, s), 4.05-4.11 (2H, m), 4.23 (1H, t, J = 10.5 Hz), 5.51-5.47 (1H, m), 6.81 (1H, t, J = 2.2 Hz), 6.92 (1H, d, J = 3.9 Hz), 7.20 (1H, t, J = 1.7 Hz), 7.32 (1H, t, J = 1.7 Hz), 7.41 (1H, d, J = 4.4 Hz), 7.57 (1H, dd, J = 8.5, 2.7 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz).
(22b)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-カルボキサミド
実施例(22a)で合成した化合物(70mg,0.17mmol)をN,N-ジメチルホルムアミド(1mL)に溶解し、HOBt・H2O(29mg, 0.19mmol)、メチルアミン塩酸塩(23mg,0.34mmol)、WSCI・HCl(39mg,0.21mmol)を加え、窒素雰囲気下14時間撹拌した。反応液を酢酸エチル(20mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~10%)を用いて精製することで白色固体の目的化合物(24mg,収率35%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.03 (3H, d, J = 5.4 Hz), 3.69 (1H, dd, J = 12.2, 5.4 Hz), 3.77 (1H, dd, J = 14.2, 7.3 Hz), 3.84-3.86 (4H, m), 4.02 (1H, dd, J = 13.9, 10.0 Hz), 4.75-4.80 (1H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.71 (1H, d, J = 3.4 Hz), 6.84 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 423.16652 (M+H)+。 (22a) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridine-2-carboxylic acid The compound (300 mg, 0.71 mmol) synthesized in Example (21h) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), water (4 mL), lithium hydroxide monohydrate A Japanese product (89 mg, 2.13 mmol) was added, followed by stirring at 60 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and acidified with 2N hydrochloric acid. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5% to 10%) to give the target compound (290 mg, yield 100) as a white solid. %).
1 H-NMR (CD 3 OD, 400 MHz): δ 3.81 (1H, dd, J = 13.2, 3.4 Hz), 3.89 (3H, s), 4.05-4.11 (2H, m), 4.23 (1H, t, J = 10.5 Hz), 5.51-5.47 (1H, m), 6.81 (1H, t, J = 2.2 Hz), 6.92 (1H, d, J = 3.9 Hz), 7.20 (1H, t, J = 1.7 Hz), 7.32 (1H, t, J = 1.7 Hz), 7.41 (1H, d, J = 4.4 Hz), 7.57 (1H, dd, J = 8.5, 2.7 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz).
(22b) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-carboxamide The compound synthesized in Example (22a) (70 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1 mL), and HOBt · H 2 O (29 mg) was dissolved. 0.19 mmol), methylamine hydrochloride (23 mg, 0.34 mmol) and WSCI.HCl (39 mg, 0.21 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 10%) to give the target compound (24 mg, yield 35) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.03 (3H, d, J = 5.4 Hz), 3.69 (1H, dd, J = 12.2, 5.4 Hz), 3.77 (1H, dd, J = 14.2, 7.3 Hz) ), 3.84-3.86 (4H, m), 4.02 (1H, dd, J = 13.9, 10.0 Hz), 4.75-4.80 (1H, m), 6.47 (1H, d, J = 3.4 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.71 (1H, d, J = 3.4 Hz), 6.84 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.87 (1H, d, J = 4.9 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.30 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 423.16652 (M + H) <+> .
(実施例23)
1-[5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-イル]エタノン (Example 23)
1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridin-2-yl] ethanone
1-[5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-イル]エタノン (Example 23)
1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) pyridin-2-yl] ethanone
(23a)5-フルオロ-N-メトキシ-N-メチルピリジン-2-カルボキサミド
5-フルオロ-2-ピリジンカルボン酸(200mg,1.42mmol)を塩化メチレン(10mL)に溶解し、HOBt・H2O(239mg, 1.56mmol)、N,O-ジメチルヒドロキシルアミン塩酸塩(277mg,2.83mmol)、WSCI・HCl(543mg,2.83mmol)、トリエチルアミン(0.98mL,7.09mmol)を加え、窒素雰囲気下15時間撹拌した。反応液を酢酸エチル(20mL)で希釈し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することで白色固体の目的化合物(214mg,収率82%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.44 (3H, s), 3.79 (3H, s), 7.52 (1H, td, J = 8.5, 2.9 Hz), 7.77 (1H, s), 8.50 (1H, d, J = 2.9 Hz).
(23b)1-(5-フルオロピリジン-2-イル)エタノン
実施例(23a)で合成した化合物(213mg,1.16mmol)をテトラヒドロフラン(5mL)に溶解し、-78℃に冷却した。窒素雰囲気下、メチルマグネシウムヨージド(3.0mol/Lテトラヒドロフラン溶液,0.58mL, 1.74mmol)を加え、室温に戻して2時間撹拌した。反応液を酢酸エチル(30mL)で希釈し、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~5%)を用いて精製することで無色油状液体の目的化合物(70mg,収率44%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.74 (3H, s), 7.54 (1H, td, J = 8.3, 2.0 Hz), 8.14 (1H, dd, J = 8.5, 4.6 Hz), 8.54 (1H, d, J = 2.4 Hz).
(23c)1-[5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-イル]エタノン
実施例(23b)で合成した化合物(63mg,0.46mmol)と、実施例(21f)で合成した化合物(125mg,0.43mmol)をN,N-ジメチルホルムアミド(2mL)に溶解させ、炭酸カリウム(120mg,0.87mmol)を加えて、窒素雰囲気下80℃にて3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(30mg,収率17%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.70 (3H, s), 3.72 (1H, dd, J = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (1H, dd, J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (1H, m), 6.49 (1H, d, J = 3.9 Hz), 6.53 (1H, s), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, s), 6.96 (1H, s), 7.35 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.43 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 408.15504 (M+H)+。 (23a) 5-Fluoro-N-methoxy-N-methylpyridine-2-carboxamide 5-Fluoro-2-pyridinecarboxylic acid (200 mg, 1.42 mmol) was dissolved in methylene chloride (10 mL), and HOBt · H 2 O was dissolved. (239 mg, 1.56 mmol), N, O-dimethylhydroxylamine hydrochloride (277 mg, 2.83 mmol), WSCI.HCl (543 mg, 2.83 mmol), triethylamine (0.98 mL, 7.09 mmol) were added, and nitrogen was added. Stir for 15 hours under atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 50%) to give the target compound (214 mg, yield 82) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.44 (3H, s), 3.79 (3H, s), 7.52 (1H, td, J = 8.5, 2.9 Hz), 7.77 (1H, s), 8.50 (1H , d, J = 2.9 Hz).
(23b) 1- (5-Fluoropyridin-2-yl) ethanone The compound (213 mg, 1.16 mmol) synthesized in Example (23a) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. Under a nitrogen atmosphere, methylmagnesium iodide (3.0 mol / L tetrahydrofuran solution, 0.58 mL, 1.74 mmol) was added, and the mixture was returned to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 5%) to give the target compound (70 mg, yield) as a colorless oily liquid. 44%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.74 (3H, s), 7.54 (1H, td, J = 8.3, 2.0 Hz), 8.14 (1H, dd, J = 8.5, 4.6 Hz), 8.54 (1H , d, J = 2.4 Hz).
(23c) 1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl } -5-methoxyphenoxy) pyridin-2-yl] ethanone The compound (63 mg, 0.46 mmol) synthesized in Example (23b) and the compound (125 mg, 0.43 mmol) synthesized in Example (21f) were mixed with N , N-dimethylformamide (2 mL), potassium carbonate (120 mg, 0.87 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (30 mg, yield) as a white solid. 17%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.70 (3H, s), 3.72 (1H, dd, J = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (1H , dd, J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (1H, m), 6.49 (1H, d, J = 3.9 Hz), 6.53 (1H, s), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, s), 6.96 (1H, s), 7.35 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.43 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 408.15504 (M + H) <+> .
5-フルオロ-2-ピリジンカルボン酸(200mg,1.42mmol)を塩化メチレン(10mL)に溶解し、HOBt・H2O(239mg, 1.56mmol)、N,O-ジメチルヒドロキシルアミン塩酸塩(277mg,2.83mmol)、WSCI・HCl(543mg,2.83mmol)、トリエチルアミン(0.98mL,7.09mmol)を加え、窒素雰囲気下15時間撹拌した。反応液を酢酸エチル(20mL)で希釈し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~50%)を用いて精製することで白色固体の目的化合物(214mg,収率82%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.44 (3H, s), 3.79 (3H, s), 7.52 (1H, td, J = 8.5, 2.9 Hz), 7.77 (1H, s), 8.50 (1H, d, J = 2.9 Hz).
(23b)1-(5-フルオロピリジン-2-イル)エタノン
実施例(23a)で合成した化合物(213mg,1.16mmol)をテトラヒドロフラン(5mL)に溶解し、-78℃に冷却した。窒素雰囲気下、メチルマグネシウムヨージド(3.0mol/Lテトラヒドロフラン溶液,0.58mL, 1.74mmol)を加え、室温に戻して2時間撹拌した。反応液を酢酸エチル(30mL)で希釈し、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~5%)を用いて精製することで無色油状液体の目的化合物(70mg,収率44%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.74 (3H, s), 7.54 (1H, td, J = 8.3, 2.0 Hz), 8.14 (1H, dd, J = 8.5, 4.6 Hz), 8.54 (1H, d, J = 2.4 Hz).
(23c)1-[5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)ピリジン-2-イル]エタノン
実施例(23b)で合成した化合物(63mg,0.46mmol)と、実施例(21f)で合成した化合物(125mg,0.43mmol)をN,N-ジメチルホルムアミド(2mL)に溶解させ、炭酸カリウム(120mg,0.87mmol)を加えて、窒素雰囲気下80℃にて3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(30mg,収率17%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.70 (3H, s), 3.72 (1H, dd, J = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (1H, dd, J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (1H, m), 6.49 (1H, d, J = 3.9 Hz), 6.53 (1H, s), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, s), 6.96 (1H, s), 7.35 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.43 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 408.15504 (M+H)+。 (23a) 5-Fluoro-N-methoxy-N-methylpyridine-2-carboxamide 5-Fluoro-2-pyridinecarboxylic acid (200 mg, 1.42 mmol) was dissolved in methylene chloride (10 mL), and HOBt · H 2 O was dissolved. (239 mg, 1.56 mmol), N, O-dimethylhydroxylamine hydrochloride (277 mg, 2.83 mmol), WSCI.HCl (543 mg, 2.83 mmol), triethylamine (0.98 mL, 7.09 mmol) were added, and nitrogen was added. Stir for 15 hours under atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 50%) to give the target compound (214 mg, yield 82) as a white solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.44 (3H, s), 3.79 (3H, s), 7.52 (1H, td, J = 8.5, 2.9 Hz), 7.77 (1H, s), 8.50 (1H , d, J = 2.9 Hz).
(23b) 1- (5-Fluoropyridin-2-yl) ethanone The compound (213 mg, 1.16 mmol) synthesized in Example (23a) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. Under a nitrogen atmosphere, methylmagnesium iodide (3.0 mol / L tetrahydrofuran solution, 0.58 mL, 1.74 mmol) was added, and the mixture was returned to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 5%) to give the target compound (70 mg, yield) as a colorless oily liquid. 44%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.74 (3H, s), 7.54 (1H, td, J = 8.3, 2.0 Hz), 8.14 (1H, dd, J = 8.5, 4.6 Hz), 8.54 (1H , d, J = 2.4 Hz).
(23c) 1- [5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl } -5-methoxyphenoxy) pyridin-2-yl] ethanone The compound (63 mg, 0.46 mmol) synthesized in Example (23b) and the compound (125 mg, 0.43 mmol) synthesized in Example (21f) were mixed with N , N-dimethylformamide (2 mL), potassium carbonate (120 mg, 0.87 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (30 mg, yield) as a white solid. 17%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.70 (3H, s), 3.72 (1H, dd, J = 12.1, 5.5 Hz), 3.82 (4H, td, J = 8.4, 5.3 Hz), 3.89 (1H , dd, J = 12.1, 3.1 Hz), 4.05 (1H, dd, J = 14.5, 9.8 Hz), 4.79-4.85 (1H, m), 6.49 (1H, d, J = 3.9 Hz), 6.53 (1H, s), 6.76 (1H, d, J = 3.9 Hz), 6.86 (1H, s), 6.96 (1H, s), 7.35 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.43 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 408.15504 (M + H) <+> .
(実施例24)
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-スルホンアミド (Example 24)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-sulfonamide
5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-スルホンアミド (Example 24)
5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-methoxyphenoxy ) -N-methylpyridine-2-sulfonamide
(24a)5-クロロピリジン-2-チオール
窒素雰囲気下、2,5-ジクロロピリジン(5.00g,33.8mmol)をジメチルスルホキシド(35mL)に溶解し、二硫化ナトリウム九水和物(9.00g,37.2mmol)を加えた後、120℃で2時間撹拌した。反応液を室温まで冷却し、水(50mL)を加え、5N塩酸で中和した。生じた沈殿をろ取し、水およびヘキサンで洗浄後、得られた固体をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~10%)を用いて精製することで、黄色固体の目的化合物(2.28g,収率46%)を得た
1H-NMR (CDCl3, 400MHz) δ 2.63 (1H, s), 7.34 (1H, dd, J = 9.0, 2.2 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.70 (1H, s).
(24b)5-クロロ-N-メチルピリジン-2-スルホンアミド
実施例(24a)で合成した化合物(1.00g,6.87mmol)を塩化メチレン(30mL)/1N塩酸(30mL)に溶解し、-5℃に冷却した。反応液を0℃以下に保ちながら、氷冷した5%過塩素酸ナトリウム水溶液(30mL)を滴下し、そのまま15分間攪拌した。予め氷冷した分液ロートで有機層を抽出し、-78℃に冷却して市販の40%メチルアミン/メタノール溶液(1.33mL,17.2mmol)の塩化メチレン溶液(10mL)を加え、0℃に昇温して2時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~80%)を用いて精製することで、白色固体の目的化合物(889mg,収率63%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.77 (3H, d, J = 4.9 Hz), 4.81 (1H, s), 7.90 (1H, dd, J = 8.3, 2.4 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.65 (1H, d, J = 2.4 Hz).
(24c)5-クロロ-N-(4-メトキシベンジル)-N-メチルピリジン-2-スルホンアミド
実施例(24b)で合成した化合物(889mg,4.30mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、水素化ナトリウム(172mg,4.30mmol)を加えた。氷冷した後、p-メトキシベンジルクロリド(0.70mL,5.16mmol)を加え、室温まで昇温して3時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(817mg,収率58%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.79 (3H, s), 3.81 (3H, s), 4.36 (2H, s), 6.87 (2H, dt, J = 9.4, 2.4 Hz), 7.25 (2H, d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.3, 2.4 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.66 (1H, d, J = 2.4 Hz)。 (24a) 5-Chloropyridine-2-thiol In a nitrogen atmosphere, 2,5-dichloropyridine (5.00 g, 33.8 mmol) was dissolved in dimethyl sulfoxide (35 mL), and sodium disulfide nonahydrate (9. (00 g, 37.2 mmol) was added, followed by stirring at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, and the obtained solid was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 10%) to give a yellow solid. The target compound (2.28 g, yield 46%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz) δ 2.63 (1H, s), 7.34 (1H, dd, J = 9.0, 2.2 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.70 (1H, s) .
(24b) 5-Chloro-N-methylpyridine-2-sulfonamide The compound synthesized in Example (24a) (1.00 g, 6.87 mmol) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). Cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, ice-cooled 5% aqueous sodium perchlorate solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercially available 40% methylamine / methanol solution (1.33 mL, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised to ° C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -80%) to give the target compound (889 mg, yield) as a white solid. 63%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.77 (3H, d, J = 4.9 Hz), 4.81 (1H, s), 7.90 (1H, dd, J = 8.3, 2.4 Hz), 7.97 (1H, d , J = 8.3 Hz), 8.65 (1H, d, J = 2.4 Hz).
(24c) 5-chloro-N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide The compound synthesized in Example (24b) (889 mg, 4.30 mmol) was converted to N, N-dimethylformamide (15 mL). ) And sodium hydride (172 mg, 4.30 mmol) was added. After cooling with ice, p-methoxybenzyl chloride (0.70 mL, 5.16 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the desired compound (817 mg, yield) as a colorless oily liquid. 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.79 (3H, s), 3.81 (3H, s), 4.36 (2H, s), 6.87 (2H, dt, J = 9.4, 2.4 Hz), 7.25 (2H , d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.3, 2.4 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.66 (1H, d, J = 2.4 Hz).
窒素雰囲気下、2,5-ジクロロピリジン(5.00g,33.8mmol)をジメチルスルホキシド(35mL)に溶解し、二硫化ナトリウム九水和物(9.00g,37.2mmol)を加えた後、120℃で2時間撹拌した。反応液を室温まで冷却し、水(50mL)を加え、5N塩酸で中和した。生じた沈殿をろ取し、水およびヘキサンで洗浄後、得られた固体をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~10%)を用いて精製することで、黄色固体の目的化合物(2.28g,収率46%)を得た
1H-NMR (CDCl3, 400MHz) δ 2.63 (1H, s), 7.34 (1H, dd, J = 9.0, 2.2 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.70 (1H, s).
(24b)5-クロロ-N-メチルピリジン-2-スルホンアミド
実施例(24a)で合成した化合物(1.00g,6.87mmol)を塩化メチレン(30mL)/1N塩酸(30mL)に溶解し、-5℃に冷却した。反応液を0℃以下に保ちながら、氷冷した5%過塩素酸ナトリウム水溶液(30mL)を滴下し、そのまま15分間攪拌した。予め氷冷した分液ロートで有機層を抽出し、-78℃に冷却して市販の40%メチルアミン/メタノール溶液(1.33mL,17.2mmol)の塩化メチレン溶液(10mL)を加え、0℃に昇温して2時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~80%)を用いて精製することで、白色固体の目的化合物(889mg,収率63%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.77 (3H, d, J = 4.9 Hz), 4.81 (1H, s), 7.90 (1H, dd, J = 8.3, 2.4 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.65 (1H, d, J = 2.4 Hz).
(24c)5-クロロ-N-(4-メトキシベンジル)-N-メチルピリジン-2-スルホンアミド
実施例(24b)で合成した化合物(889mg,4.30mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、水素化ナトリウム(172mg,4.30mmol)を加えた。氷冷した後、p-メトキシベンジルクロリド(0.70mL,5.16mmol)を加え、室温まで昇温して3時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(817mg,収率58%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.79 (3H, s), 3.81 (3H, s), 4.36 (2H, s), 6.87 (2H, dt, J = 9.4, 2.4 Hz), 7.25 (2H, d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.3, 2.4 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.66 (1H, d, J = 2.4 Hz)。 (24a) 5-Chloropyridine-2-thiol In a nitrogen atmosphere, 2,5-dichloropyridine (5.00 g, 33.8 mmol) was dissolved in dimethyl sulfoxide (35 mL), and sodium disulfide nonahydrate (9. (00 g, 37.2 mmol) was added, followed by stirring at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, and the obtained solid was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 10%) to give a yellow solid. The target compound (2.28 g, yield 46%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz) δ 2.63 (1H, s), 7.34 (1H, dd, J = 9.0, 2.2 Hz), 7.41 (1H, d, J = 9.3 Hz), 7.70 (1H, s) .
(24b) 5-Chloro-N-methylpyridine-2-sulfonamide The compound synthesized in Example (24a) (1.00 g, 6.87 mmol) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). Cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, ice-cooled 5% aqueous sodium perchlorate solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercially available 40% methylamine / methanol solution (1.33 mL, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised to ° C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -80%) to give the target compound (889 mg, yield) as a white solid. 63%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.77 (3H, d, J = 4.9 Hz), 4.81 (1H, s), 7.90 (1H, dd, J = 8.3, 2.4 Hz), 7.97 (1H, d , J = 8.3 Hz), 8.65 (1H, d, J = 2.4 Hz).
(24c) 5-chloro-N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide The compound synthesized in Example (24b) (889 mg, 4.30 mmol) was converted to N, N-dimethylformamide (15 mL). ) And sodium hydride (172 mg, 4.30 mmol) was added. After cooling with ice, p-methoxybenzyl chloride (0.70 mL, 5.16 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the desired compound (817 mg, yield) as a colorless oily liquid. 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.79 (3H, s), 3.81 (3H, s), 4.36 (2H, s), 6.87 (2H, dt, J = 9.4, 2.4 Hz), 7.25 (2H , d, J = 7.3 Hz), 7.88 (1H, dd, J = 8.3, 2.4 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.66 (1H, d, J = 2.4 Hz).
(24d)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-(4-メトキシベンジル)-N-メチルピリジン-2-スルホンアミド
実施例(24c)で合成した化合物(105mg,0.32mmol)と、実施例(21f)で合成した化合物(139mg,0.48mmol)をN,N-ジメチルホルムアミド(1.5mL)に溶解させ、炭酸セシウム(314mg,0.96mmol)を加え、窒素雰囲気下100℃で1.5時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~5%)を用いて精製することで、白色固体の目的化合物(90mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.79 (3H, s), 3.74 (2H, td, J = 12.1, 5.5 Hz), 3.80 (3H, s), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.3, 9.6 Hz), 4.37 (2H, s), 4.78-4.84 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86-6.88 (3H, m), 6.98 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 7.94 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(24e)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-スルホンアミド
窒素雰囲気下、実施例(24d)で合成した化合物(81mg,0.14mmol)をトリフルオロ酢酸(0.5mL)と塩化メチレン(5mL)に溶解し、16時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(43mg,収率67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.76 (3H, d, J = 3.4 Hz), 3.72 (1H, dd, J = 12.7, 4.9 Hz), 3.76-3.81 (1H, m), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.2, 9.8 Hz), 4.81 (1H, s), 5.05 (1H, br s), 6.51 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.4 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.99 (1H, s), 7.41 (1H, dd, J = 8.5, 2.7 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 459.13442 (M+H)+。 (24d) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound (105 mg, 0.32 mmol) synthesized in Example (24c) and compound synthesized in Example (21f) (139 mg, 0.48 mmol) was dissolved in N, N-dimethylformamide (1.5 mL), cesium carbonate (314 mg, 0.96 mmol) was added, and the mixture was stirred at 100 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (90 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.79 (3H, s), 3.74 (2H, td, J = 12.1, 5.5 Hz), 3.80 (3H, s), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.3, 9.6 Hz), 4.37 (2H, s), 4.78-4.84 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86-6.88 (3H, m), 6.98 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 7.94 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(24e) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-sulfonamide In a nitrogen atmosphere, the compound synthesized in Example (24d) (81 mg, 0.14 mmol) was added to trifluoroacetic acid (0.5 mL) and methylene chloride (5 mL). Dissolved and stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (43 mg, yield) as a white solid. 67%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.76 (3H, d, J = 3.4 Hz), 3.72 (1H, dd, J = 12.7, 4.9 Hz), 3.76-3.81 (1H, m), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.2, 9.8 Hz), 4.81 (1H, s), 5.05 (1H, br s), 6.51 (1H, d, J = 3.9 Hz), 6.54 (1H , t, J = 2.2 Hz), 6.76 (1H, d, J = 3.4 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.99 (1H, s), 7.41 (1H, dd, J = 8.5, 2.7 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 459.13442 (M + H) <+> .
実施例(24c)で合成した化合物(105mg,0.32mmol)と、実施例(21f)で合成した化合物(139mg,0.48mmol)をN,N-ジメチルホルムアミド(1.5mL)に溶解させ、炭酸セシウム(314mg,0.96mmol)を加え、窒素雰囲気下100℃で1.5時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~5%)を用いて精製することで、白色固体の目的化合物(90mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.79 (3H, s), 3.74 (2H, td, J = 12.1, 5.5 Hz), 3.80 (3H, s), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.3, 9.6 Hz), 4.37 (2H, s), 4.78-4.84 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86-6.88 (3H, m), 6.98 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 7.94 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(24e)5-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-メトキシフェノキシ)-N-メチルピリジン-2-スルホンアミド
窒素雰囲気下、実施例(24d)で合成した化合物(81mg,0.14mmol)をトリフルオロ酢酸(0.5mL)と塩化メチレン(5mL)に溶解し、16時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(43mg,収率67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.76 (3H, d, J = 3.4 Hz), 3.72 (1H, dd, J = 12.7, 4.9 Hz), 3.76-3.81 (1H, m), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.2, 9.8 Hz), 4.81 (1H, s), 5.05 (1H, br s), 6.51 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.4 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.99 (1H, s), 7.41 (1H, dd, J = 8.5, 2.7 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 459.13442 (M+H)+。 (24d) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound (105 mg, 0.32 mmol) synthesized in Example (24c) and compound synthesized in Example (21f) (139 mg, 0.48 mmol) was dissolved in N, N-dimethylformamide (1.5 mL), cesium carbonate (314 mg, 0.96 mmol) was added, and the mixture was stirred at 100 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (90 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.79 (3H, s), 3.74 (2H, td, J = 12.1, 5.5 Hz), 3.80 (3H, s), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.3, 9.6 Hz), 4.37 (2H, s), 4.78-4.84 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.86-6.88 (3H, m), 6.98 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 7.94 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(24e) 5- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Methoxyphenoxy) -N-methylpyridine-2-sulfonamide In a nitrogen atmosphere, the compound synthesized in Example (24d) (81 mg, 0.14 mmol) was added to trifluoroacetic acid (0.5 mL) and methylene chloride (5 mL). Dissolved and stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (43 mg, yield) as a white solid. 67%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.76 (3H, d, J = 3.4 Hz), 3.72 (1H, dd, J = 12.7, 4.9 Hz), 3.76-3.81 (1H, m), 3.86-3.89 (4H, m), 4.04 (1H, dd, J = 14.2, 9.8 Hz), 4.81 (1H, s), 5.05 (1H, br s), 6.51 (1H, d, J = 3.9 Hz), 6.54 (1H , t, J = 2.2 Hz), 6.76 (1H, d, J = 3.4 Hz), 6.87 (1H, t, J = 1.7 Hz), 6.99 (1H, s), 7.41 (1H, dd, J = 8.5, 2.7 Hz), 7.96 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 459.13442 (M + H) <+> .
(実施例25)
{(5R)-2-[5-(3-{[6-(アゼチジン-1-イルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 25)
{(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-{[6-(アゼチジン-1-イルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 25)
{(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol
(25a)2-(アゼチジン-1-イルスルホニル)-5-クロロピリジン
実施例(24a)で合成した化合物(1.00g,6.87mmol)を塩化メチレン(30mL)/1N塩酸(30mL)に溶解し、-5℃に冷却した。反応液を0℃以下に保ちながら、氷冷した7%過塩素酸ナトリウム水溶液(30mL)を滴下し、そのまま15分間攪拌した。予め氷冷した分液ロートで有機層を抽出し、-78℃に冷却して市販のアゼチジン塩酸塩(2.24mg,17.2mmol)の塩化メチレン懸濁液(10mL)を加え、0℃に昇温して30分間攪拌した。反応液に水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~60%)を用いて精製することで、白色固体の目的化合物(735mg,収率46%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.19-2.25 (2H, m), 4.10 (4H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 8.3, 2.0 Hz), 7.95 (1H, d, J = 7.8 Hz), 8.72 (1H, d, J = 2.0 Hz).
(25b){(5R)-2-[5-(3-{[6-(アゼチジン-1-イルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(25a)で合成した化合物(100mg,0.43mmol)と、実施例(21f)で合成した化合物(161mg,0.56mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸セシウム(280mg,0.86mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却し、水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~5%)を用いて精製することで、白色固体の目的化合物(111mg,収率53%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.18-2.24 (2H, m), 3.72 (1H, dd, J = 12.2, 5.4 Hz), 3.79 (1H, dd, J = 14.2, 7.8 Hz), 3.86-3.89 (4H, m), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.10 (4H, t, J = 7.8 Hz), 4.82 (1H, s), 6.51 (1H, d, J = 3.4 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.76 (1H, s), 6.88 (1H, d, J = 1.5 Hz), 6.99 (1H, s), 7.43 (1H, dd, J = 8.5, 2.7 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 485.14698 (M+H)+。 (25a) 2- (azetidin-1-ylsulfonyl) -5-chloropyridine The compound (1.00 g, 6.87 mmol) synthesized in Example (24a) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). And cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, an ice-cooled 7% sodium perchlorate aqueous solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercial maze of azetidine hydrochloride (2.24 mg, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised and the mixture was stirred for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 5% -60%) to give the target compound (735 mg, yield) as a white solid. 46%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.19-2.25 (2H, m), 4.10 (4H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 8.3, 2.0 Hz), 7.95 (1H , d, J = 7.8 Hz), 8.72 (1H, d, J = 2.0 Hz).
(25b) {(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazol-5-yl} methanol The compound synthesized in Example (25a) (100 mg, 0.43 mmol) and the compound synthesized in Example (21f) (161 mg, 0 .56 mmol) was dissolved in N, N-dimethylformamide (3 mL), cesium carbonate (280 mg, 0.86 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (111 mg, yield) as a white solid. 53%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.18-2.24 (2H, m), 3.72 (1H, dd, J = 12.2, 5.4 Hz), 3.79 (1H, dd, J = 14.2, 7.8 Hz), 3.86 -3.89 (4H, m), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.10 (4H, t, J = 7.8 Hz), 4.82 (1H, s), 6.51 (1H, d, J = 3.4 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.76 (1H, s), 6.88 (1H, d, J = 1.5 Hz), 6.99 (1H, s), 7.43 (1H, dd, J = 8.5 , 2.7 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 485.14698 (M + H) <+> .
実施例(24a)で合成した化合物(1.00g,6.87mmol)を塩化メチレン(30mL)/1N塩酸(30mL)に溶解し、-5℃に冷却した。反応液を0℃以下に保ちながら、氷冷した7%過塩素酸ナトリウム水溶液(30mL)を滴下し、そのまま15分間攪拌した。予め氷冷した分液ロートで有機層を抽出し、-78℃に冷却して市販のアゼチジン塩酸塩(2.24mg,17.2mmol)の塩化メチレン懸濁液(10mL)を加え、0℃に昇温して30分間攪拌した。反応液に水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~60%)を用いて精製することで、白色固体の目的化合物(735mg,収率46%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.19-2.25 (2H, m), 4.10 (4H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 8.3, 2.0 Hz), 7.95 (1H, d, J = 7.8 Hz), 8.72 (1H, d, J = 2.0 Hz).
(25b){(5R)-2-[5-(3-{[6-(アゼチジン-1-イルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(25a)で合成した化合物(100mg,0.43mmol)と、実施例(21f)で合成した化合物(161mg,0.56mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸セシウム(280mg,0.86mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却し、水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~5%)を用いて精製することで、白色固体の目的化合物(111mg,収率53%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.18-2.24 (2H, m), 3.72 (1H, dd, J = 12.2, 5.4 Hz), 3.79 (1H, dd, J = 14.2, 7.8 Hz), 3.86-3.89 (4H, m), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.10 (4H, t, J = 7.8 Hz), 4.82 (1H, s), 6.51 (1H, d, J = 3.4 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.76 (1H, s), 6.88 (1H, d, J = 1.5 Hz), 6.99 (1H, s), 7.43 (1H, dd, J = 8.5, 2.7 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 485.14698 (M+H)+。 (25a) 2- (azetidin-1-ylsulfonyl) -5-chloropyridine The compound (1.00 g, 6.87 mmol) synthesized in Example (24a) was dissolved in methylene chloride (30 mL) / 1N hydrochloric acid (30 mL). And cooled to -5 ° C. While maintaining the reaction solution at 0 ° C. or lower, an ice-cooled 7% sodium perchlorate aqueous solution (30 mL) was added dropwise, and the mixture was stirred as it was for 15 minutes. The organic layer was extracted with a separatory funnel previously cooled with ice, cooled to −78 ° C., and a commercial maze of azetidine hydrochloride (2.24 mg, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised and the mixture was stirred for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 5% -60%) to give the target compound (735 mg, yield) as a white solid. 46%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.19-2.25 (2H, m), 4.10 (4H, t, J = 7.8 Hz), 7.91 (1H, dd, J = 8.3, 2.0 Hz), 7.95 (1H , d, J = 7.8 Hz), 8.72 (1H, d, J = 2.0 Hz).
(25b) {(5R) -2- [5- (3-{[6- (azetidin-1-ylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl) -1H-pyrrol-2-yl ] -4,5-dihydro-1,3-oxazol-5-yl} methanol The compound synthesized in Example (25a) (100 mg, 0.43 mmol) and the compound synthesized in Example (21f) (161 mg, 0 .56 mmol) was dissolved in N, N-dimethylformamide (3 mL), cesium carbonate (280 mg, 0.86 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 5%) to give the desired compound (111 mg, yield) as a white solid. 53%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.18-2.24 (2H, m), 3.72 (1H, dd, J = 12.2, 5.4 Hz), 3.79 (1H, dd, J = 14.2, 7.8 Hz), 3.86 -3.89 (4H, m), 4.05 (1H, dd, J = 14.2, 9.8 Hz), 4.10 (4H, t, J = 7.8 Hz), 4.82 (1H, s), 6.51 (1H, d, J = 3.4 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.76 (1H, s), 6.88 (1H, d, J = 1.5 Hz), 6.99 (1H, s), 7.43 (1H, dd, J = 8.5 , 2.7 Hz), 7.95 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 485.14698 (M + H) <+> .
(実施例26)
[(5R)-2-{5-[3-メトキシ-5-({6-[(メトキシメチル)スルホニル]ピリジン-3-イル}オキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 26)
[(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol
[(5R)-2-{5-[3-メトキシ-5-({6-[(メトキシメチル)スルホニル]ピリジン-3-イル}オキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール (Example 26)
[(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4, 5-Dihydro-1,3-oxazol-5-yl] methanol
(26a)5-クロロ-2-[(メトキシメチル)チオ]ピリジン
実施例(24a)で合成した化合物(200mg,1.37mmol)をメタノール(5mL)に溶解させ、28%ナトリウムメトキシド/メタノール溶液(0.30mL,1.55mmol)、メトキシメチルクロリド(0.23mL,3.01mmol)を加え、窒素雰囲気下50℃にて3時間撹拌した。反応液を室温まで冷却し、水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(188mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz) δ 1.51 (3H, s), 3.37 (2H, s), 7.22 (1H, d, J = 10.2 Hz), 7.47 (1H, dd, J = 3.1, 8.6 Hz), 8.40 (1H, d, J = 2.7 Hz).
(26b)5-クロロ-2-[(メトキシメチル)スルホニル]ピリジン
実施例(26a)で合成した化合物(187mg,0.99mmol)を塩化メチレン(10mL)に溶解し、m-クロロ過安息香酸(524mg,1.97mmol)を加え、窒素雰囲気下、0℃で75分間攪拌した。反応液に水(30mL)を加え、塩化メチレン(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~35%)を用いて精製することで、白色固体の目的化合物(187mg,収率85%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.66 (3H, s), 4.88 (2H, s), 7.98 (1H, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.75 (1H, d, J = 2.0 Hz).
(26c)[(5R)-2-{5-[3-メトキシ-5-({6-[(メトキシメチル)スルホニル]ピリジン-3-イル}オキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(26b)で合成した化合物(185mg,0.83mmol)と、実施例(21f)で合成した化合物(360mg,1.25mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(231mg,1.67mmol)を加え、窒素雰囲気下100℃にて2時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~4%)を用いて精製することで、白色固体の目的化合物(229mg,収率58%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.67 (3H, s), 3.75 (1H, dd, J = 12.2, 5.4 Hz), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 3.86-3.91 (4H, m), 4.08 (1H, dd, J = 14.2, 9.8 Hz), 4.81-4.87 (3H, m), 6.53 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.01 (1H, s), 7.47 (1H, dd, J = 8.3, 2.9 Hz), 8.11 (1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.9 Hz).
MS (ESI) m/z: 474.13312 (M+H)+。 (26a) 5-Chloro-2-[(methoxymethyl) thio] pyridine The compound synthesized in Example (24a) (200 mg, 1.37 mmol) was dissolved in methanol (5 mL), and a 28% sodium methoxide / methanol solution was obtained. (0.30 mL, 1.55 mmol) and methoxymethyl chloride (0.23 mL, 3.01 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (188 mg, yield) as a colorless oily liquid. 74%).
1 H-NMR (CDCl 3 , 400 MHz) δ 1.51 (3H, s), 3.37 (2H, s), 7.22 (1H, d, J = 10.2 Hz), 7.47 (1H, dd, J = 3.1, 8.6 Hz) , 8.40 (1H, d, J = 2.7 Hz).
(26b) 5-chloro-2-[(methoxymethyl) sulfonyl] pyridine The compound synthesized in Example (26a) (187 mg, 0.99 mmol) was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic acid ( (524 mg, 1.97 mmol) was added, and the mixture was stirred at 0 ° C. for 75 minutes under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 35%) to give the target compound (187 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.66 (3H, s), 4.88 (2H, s), 7.98 (1H, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz ), 8.75 (1H, d, J = 2.0 Hz).
(26c) [(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (26b) (185 mg, 0.83 mmol) and the compound synthesized in Example (21f) (360 mg, 1. 25 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (231 mg, 1.67 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% -4%) to give the desired compound (229 mg, Yield 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.67 (3H, s), 3.75 (1H, dd, J = 12.2, 5.4 Hz), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 3.86-3.91 (4H, m), 4.08 (1H, dd, J = 14.2, 9.8 Hz), 4.81-4.87 (3H, m), 6.53 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.01 (1H, s), 7.47 (1H, dd, J = 8.3, 2.9 Hz), 8.11 ( 1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 474.13312 (M + H) <+> .
実施例(24a)で合成した化合物(200mg,1.37mmol)をメタノール(5mL)に溶解させ、28%ナトリウムメトキシド/メタノール溶液(0.30mL,1.55mmol)、メトキシメチルクロリド(0.23mL,3.01mmol)を加え、窒素雰囲気下50℃にて3時間撹拌した。反応液を室温まで冷却し、水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(188mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz) δ 1.51 (3H, s), 3.37 (2H, s), 7.22 (1H, d, J = 10.2 Hz), 7.47 (1H, dd, J = 3.1, 8.6 Hz), 8.40 (1H, d, J = 2.7 Hz).
(26b)5-クロロ-2-[(メトキシメチル)スルホニル]ピリジン
実施例(26a)で合成した化合物(187mg,0.99mmol)を塩化メチレン(10mL)に溶解し、m-クロロ過安息香酸(524mg,1.97mmol)を加え、窒素雰囲気下、0℃で75分間攪拌した。反応液に水(30mL)を加え、塩化メチレン(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~35%)を用いて精製することで、白色固体の目的化合物(187mg,収率85%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.66 (3H, s), 4.88 (2H, s), 7.98 (1H, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.75 (1H, d, J = 2.0 Hz).
(26c)[(5R)-2-{5-[3-メトキシ-5-({6-[(メトキシメチル)スルホニル]ピリジン-3-イル}オキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-5-イル]メタノール
実施例(26b)で合成した化合物(185mg,0.83mmol)と、実施例(21f)で合成した化合物(360mg,1.25mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(231mg,1.67mmol)を加え、窒素雰囲気下100℃にて2時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~4%)を用いて精製することで、白色固体の目的化合物(229mg,収率58%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.67 (3H, s), 3.75 (1H, dd, J = 12.2, 5.4 Hz), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 3.86-3.91 (4H, m), 4.08 (1H, dd, J = 14.2, 9.8 Hz), 4.81-4.87 (3H, m), 6.53 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.01 (1H, s), 7.47 (1H, dd, J = 8.3, 2.9 Hz), 8.11 (1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.9 Hz).
MS (ESI) m/z: 474.13312 (M+H)+。 (26a) 5-Chloro-2-[(methoxymethyl) thio] pyridine The compound synthesized in Example (24a) (200 mg, 1.37 mmol) was dissolved in methanol (5 mL), and a 28% sodium methoxide / methanol solution was obtained. (0.30 mL, 1.55 mmol) and methoxymethyl chloride (0.23 mL, 3.01 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (188 mg, yield) as a colorless oily liquid. 74%).
1 H-NMR (CDCl 3 , 400 MHz) δ 1.51 (3H, s), 3.37 (2H, s), 7.22 (1H, d, J = 10.2 Hz), 7.47 (1H, dd, J = 3.1, 8.6 Hz) , 8.40 (1H, d, J = 2.7 Hz).
(26b) 5-chloro-2-[(methoxymethyl) sulfonyl] pyridine The compound synthesized in Example (26a) (187 mg, 0.99 mmol) was dissolved in methylene chloride (10 mL), and m-chloroperbenzoic acid ( (524 mg, 1.97 mmol) was added, and the mixture was stirred at 0 ° C. for 75 minutes under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 35%) to give the target compound (187 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.66 (3H, s), 4.88 (2H, s), 7.98 (1H, dd, J = 8.3, 2.4 Hz), 8.12 (1H, d, J = 8.3 Hz ), 8.75 (1H, d, J = 2.0 Hz).
(26c) [(5R) -2- {5- [3-methoxy-5-({6-[(methoxymethyl) sulfonyl] pyridin-3-yl} oxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-5-yl] methanol The compound synthesized in Example (26b) (185 mg, 0.83 mmol) and the compound synthesized in Example (21f) (360 mg, 1. 25 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (231 mg, 1.67 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% -4%) to give the desired compound (229 mg, Yield 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.67 (3H, s), 3.75 (1H, dd, J = 12.2, 5.4 Hz), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 3.86-3.91 (4H, m), 4.08 (1H, dd, J = 14.2, 9.8 Hz), 4.81-4.87 (3H, m), 6.53 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.2 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.01 (1H, s), 7.47 (1H, dd, J = 8.3, 2.9 Hz), 8.11 ( 1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 474.13312 (M + H) <+> .
(実施例27)
{(5R)-2-[5-(3-{[6-(シクロプロピルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 27)
{(5R) -2- [5- (3-{[6- (Cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-{[6-(シクロプロピルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 27)
{(5R) -2- [5- (3-{[6- (Cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-5-yl} methanol
(27a)5-クロロ-2-[(3-クロロプロピル)チオ]ピリジン
実施例(24a)で合成した化合物(600mg,4.12mmol)をメタノール(15mL)に溶解し、28%ナトリウムメトキシド/メタノール溶液(0.95mL,4.94mmol)、1-ブロモ-3-クロロプロパン(0.61mL,6.18mmol)を加え、60℃で1.5時間攪拌した。反応液を室温まで冷却し、水(40mL)を加え、酢酸エチル(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、真空乾燥することで、無色油状液体の目的化合物(846mg,収率92%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.21-2.14 (2H, m), 3.30 (2H, t, J = 6.8 Hz), 3.67 (2H, t, J = 6.3 Hz), 7.13 (1H, dd, J = 8.6, 0.8 Hz), 7.45 (1H, dd, J = 8.6, 2.3 Hz), 8.37 (1H, dd, J = 5.1, 3.1 Hz).
(27b)5-クロロ-2-[(3-クロロプロピル)スルホニル]ピリジン
実施例(27a)で合成した化合物(846mg,3.80mmol)を塩化メチレン(20mL)に溶解し、氷冷後、m-クロロ過安息香酸(2.02g,7.62mmol)を加え、そのまま1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(40mL)を加え、塩化メチレン(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(733mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.26-2.31 (2H, m), 3.55-3.58 (2H, m), 3.67 (2H, t, J = 6.3 Hz), 7.96 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.70 (1H, d, J = 2.4 Hz)。 (27a) 5-Chloro-2-[(3-chloropropyl) thio] pyridine The compound synthesized in Example (24a) (600 mg, 4.12 mmol) was dissolved in methanol (15 mL), and 28% sodium methoxide / A methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying to obtain the target compound (846 mg, yield 92%) as a colorless oily liquid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.21-2.14 (2H, m), 3.30 (2H, t, J = 6.8 Hz), 3.67 (2H, t, J = 6.3 Hz), 7.13 (1H, dd , J = 8.6, 0.8 Hz), 7.45 (1H, dd, J = 8.6, 2.3 Hz), 8.37 (1H, dd, J = 5.1, 3.1 Hz).
(27b) 5-Chloro-2-[(3-chloropropyl) sulfonyl] pyridine The compound synthesized in Example (27a) (846 mg, 3.80 mmol) was dissolved in methylene chloride (20 mL). -Chloroperbenzoic acid (2.02 g, 7.62 mmol) was added and stirred as such for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (733 mg, yield) as a colorless oily liquid. 76%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.26-2.31 (2H, m), 3.55-3.58 (2H, m), 3.67 (2H, t, J = 6.3 Hz), 7.96 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.70 (1H, d, J = 2.4 Hz).
実施例(24a)で合成した化合物(600mg,4.12mmol)をメタノール(15mL)に溶解し、28%ナトリウムメトキシド/メタノール溶液(0.95mL,4.94mmol)、1-ブロモ-3-クロロプロパン(0.61mL,6.18mmol)を加え、60℃で1.5時間攪拌した。反応液を室温まで冷却し、水(40mL)を加え、酢酸エチル(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、真空乾燥することで、無色油状液体の目的化合物(846mg,収率92%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.21-2.14 (2H, m), 3.30 (2H, t, J = 6.8 Hz), 3.67 (2H, t, J = 6.3 Hz), 7.13 (1H, dd, J = 8.6, 0.8 Hz), 7.45 (1H, dd, J = 8.6, 2.3 Hz), 8.37 (1H, dd, J = 5.1, 3.1 Hz).
(27b)5-クロロ-2-[(3-クロロプロピル)スルホニル]ピリジン
実施例(27a)で合成した化合物(846mg,3.80mmol)を塩化メチレン(20mL)に溶解し、氷冷後、m-クロロ過安息香酸(2.02g,7.62mmol)を加え、そのまま1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(40mL)を加え、塩化メチレン(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、無色油状液体の目的化合物(733mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.26-2.31 (2H, m), 3.55-3.58 (2H, m), 3.67 (2H, t, J = 6.3 Hz), 7.96 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.70 (1H, d, J = 2.4 Hz)。 (27a) 5-Chloro-2-[(3-chloropropyl) thio] pyridine The compound synthesized in Example (24a) (600 mg, 4.12 mmol) was dissolved in methanol (15 mL), and 28% sodium methoxide / A methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying to obtain the target compound (846 mg, yield 92%) as a colorless oily liquid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.21-2.14 (2H, m), 3.30 (2H, t, J = 6.8 Hz), 3.67 (2H, t, J = 6.3 Hz), 7.13 (1H, dd , J = 8.6, 0.8 Hz), 7.45 (1H, dd, J = 8.6, 2.3 Hz), 8.37 (1H, dd, J = 5.1, 3.1 Hz).
(27b) 5-Chloro-2-[(3-chloropropyl) sulfonyl] pyridine The compound synthesized in Example (27a) (846 mg, 3.80 mmol) was dissolved in methylene chloride (20 mL). -Chloroperbenzoic acid (2.02 g, 7.62 mmol) was added and stirred as such for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 0% -20%) to give the target compound (733 mg, yield) as a colorless oily liquid. 76%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.26-2.31 (2H, m), 3.55-3.58 (2H, m), 3.67 (2H, t, J = 6.3 Hz), 7.96 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.70 (1H, d, J = 2.4 Hz).
(27c)5-クロロ-2-(シクロプロピルスルホニル)ピリジン
実施例(27b)で合成した化合物(732mg,3.05mmol)をテトラヒドロフラン(10mL)に溶解し、-30℃に冷却後、カリウム-t-ブトキシド(582mg,5.18mmol)を加え、そのまま30分間撹拌した。反応液に飽和塩化アンモニウム水溶液(40mL)を加え、塩化メチレン(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~25%)を用いて精製することで、白色固体の目的化合物(397mg,収率60%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.07-1.12 (2H, m), 1.37-1.41 (2H, m), 2.76-2.83 (1H, m), 7.91 (1H, dd, J = 8.2, 2.3 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.71 (1H, dd, J = 2.3, 0.8 Hz).
(27d){(5R)-2-[5-(3-{[6-(シクロプロピルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(27c)で合成した化合物(266mg,1.22mmol)と、実施例(21f)で合成した化合物(440mg,1.53mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(338mg,2.44mmol)を加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(96mg,収率17%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.06-1.11 (2H, m), 1.37-1.41 (2H, m), 2.80 (1H, tt, J = 8.2, 4.3 Hz), 3.70-3.89 (6H, m), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.85-4.78 (1H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 2.0 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 7.98 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 470.13790 (M+H)+。 (27c) 5-Chloro-2- (cyclopropylsulfonyl) pyridine The compound synthesized in Example (27b) (732 mg, 3.05 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −30 ° C., potassium-t -Butoxide (582 mg, 5.18 mmol) was added and stirred as such for 30 minutes. A saturated aqueous ammonium chloride solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 25%) to give the desired compound (397 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.07-1.12 (2H, m), 1.37-1.41 (2H, m), 2.76-2.83 (1H, m), 7.91 (1H, dd, J = 8.2, 2.3 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.71 (1H, dd, J = 2.3, 0.8 Hz).
(27d) {(5R) -2- [5- (3-{[6- (cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4, 5-dihydro-1,3-oxazol-5-yl} methanol Compound (266 mg, 1.22 mmol) synthesized in Example (27c) and compound (440 mg, 1.53 mmol) synthesized in Example (21f) It was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (338 mg, 2.44 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 3 hours at 100 ° C. The reaction mixture was cooled to room temperature and water (30 mL) was added. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) gave the target compound (96 mg, 17% yield) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.06-1.11 (2H, m), 1.37-1.41 (2H, m), 2.80 (1H, tt, J = 8.2, 4.3 Hz), 3.70-3.89 (6H, m), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.85-4.78 (1H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 2.0 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 7.98 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 470.13790 (M + H) <+> .
実施例(27b)で合成した化合物(732mg,3.05mmol)をテトラヒドロフラン(10mL)に溶解し、-30℃に冷却後、カリウム-t-ブトキシド(582mg,5.18mmol)を加え、そのまま30分間撹拌した。反応液に飽和塩化アンモニウム水溶液(40mL)を加え、塩化メチレン(40mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~25%)を用いて精製することで、白色固体の目的化合物(397mg,収率60%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.07-1.12 (2H, m), 1.37-1.41 (2H, m), 2.76-2.83 (1H, m), 7.91 (1H, dd, J = 8.2, 2.3 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.71 (1H, dd, J = 2.3, 0.8 Hz).
(27d){(5R)-2-[5-(3-{[6-(シクロプロピルスルホニル)ピリジン-3-イル]オキシ}-5-メトキシフェニル-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(27c)で合成した化合物(266mg,1.22mmol)と、実施例(21f)で合成した化合物(440mg,1.53mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(338mg,2.44mmol)を加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(96mg,収率17%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.06-1.11 (2H, m), 1.37-1.41 (2H, m), 2.80 (1H, tt, J = 8.2, 4.3 Hz), 3.70-3.89 (6H, m), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.85-4.78 (1H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 2.0 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 7.98 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 470.13790 (M+H)+。 (27c) 5-Chloro-2- (cyclopropylsulfonyl) pyridine The compound synthesized in Example (27b) (732 mg, 3.05 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −30 ° C., potassium-t -Butoxide (582 mg, 5.18 mmol) was added and stirred as such for 30 minutes. A saturated aqueous ammonium chloride solution (40 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 25%) to give the desired compound (397 mg, yield) as a white solid. 60%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.07-1.12 (2H, m), 1.37-1.41 (2H, m), 2.76-2.83 (1H, m), 7.91 (1H, dd, J = 8.2, 2.3 Hz), 7.98 (1H, d, J = 8.2 Hz), 8.71 (1H, dd, J = 2.3, 0.8 Hz).
(27d) {(5R) -2- [5- (3-{[6- (cyclopropylsulfonyl) pyridin-3-yl] oxy} -5-methoxyphenyl-1H-pyrrol-2-yl] -4, 5-dihydro-1,3-oxazol-5-yl} methanol Compound (266 mg, 1.22 mmol) synthesized in Example (27c) and compound (440 mg, 1.53 mmol) synthesized in Example (21f) It was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (338 mg, 2.44 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 3 hours at 100 ° C. The reaction mixture was cooled to room temperature and water (30 mL) was added. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) gave the target compound (96 mg, 17% yield) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.06-1.11 (2H, m), 1.37-1.41 (2H, m), 2.80 (1H, tt, J = 8.2, 4.3 Hz), 3.70-3.89 (6H, m), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.85-4.78 (1H, m), 6.51 (1H, d, J = 3.5 Hz), 6.54 (1H, t, J = 2.2 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.87 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 2.0 Hz), 7.42 (1H, dd, J = 8.6, 2.7 Hz), 7.98 (1H, d, J = 9.4 Hz), 8.52 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 470.13790 (M + H) <+> .
(実施例28)
{(5R)-2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 28)
{(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5- Dihydro-1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 28)
{(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5- Dihydro-1,3-oxazol-5-yl} methanol
(28a)1-ブロモ-3-イソプロポキシ-5-メトキシベンゼン
実施例(1a)で合成した化合物(31.62g,155.74mmol)をN,N-ジメチルホルムアミド(200mL)に溶解し、2-ブロモプロパン(29.25mL,311.48mmol)、炭酸カリウム(64.57g,467.22mmol)を加え、窒素雰囲気下60℃で3時間撹拌した。1規定塩酸(200mL)を加え、ジエチルエーテル(1.0L)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~10%)を用いて精製することにより、無色油状の目的化合物(33.95g,収率89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.29 (6H, d, J = 5.9 Hz), 3.73 (3H, s), 4.41-4.50 (1H, m), 6.33 (1H, t, J = 2.3 Hz), 6.59-6.62 (2H, m).
(28b)3-ブロモ-5-イソプロポキシフェノール
実施例(28a)で合成した化合物(33.95g,138.51mmol)、ナトリウムチオメトキシド(10.68g,152.36mmol)を用い、実施例(1a)と同様の方法で淡黄色油状の目的化合物(31.52g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (6H, d, J = 5.9 Hz), 4.43-4.52 (1H, m), 5.14 (1H, s), 6.31 (1H, t, J = 2.0 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.63 (1H, t, J = 2.0 Hz).
(28c)3-イソプロポキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(28b)で合成した化合物(31.52g,136.4mmol)、ビス(ピナコラート)ジボロン(51.96g,204.6mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(3.34g,4.09mmol)、酢酸カリウム(66.93g,682.0mmol)を用い、実施例(1d)と同様の方法で黄色油状の目的化合物(33.36g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.31 (6H, d, J = 6.3 Hz), 1.33 (12H, s), 4.51-4.60 (1H, m), 5.00 (1H, s), 6.51 (1H, t, J = 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz)。 (28a) 1-Bromo-3-isopropoxy-5-methoxybenzene The compound synthesized in Example (1a) (31.62 g, 155.74 mmol) was dissolved in N, N-dimethylformamide (200 mL), and 2- Bromopropane (29.25 mL, 311.48 mmol) and potassium carbonate (64.57 g, 467.22 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere. 1N Hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 10%) to give a colorless oily target compound (33.95 g, Yield 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.29 (6H, d, J = 5.9 Hz), 3.73 (3H, s), 4.41-4.50 (1H, m), 6.33 (1H, t, J = 2.3 Hz ), 6.59-6.62 (2H, m).
(28b) 3-Bromo-5-isopropoxyphenol The compound (33.95 g, 138.51 mmol) synthesized in Example (28a) and sodium thiomethoxide (10.68 g, 152.36 mmol) were used. A pale yellow oily target compound (31.52 g, yield 98%) was obtained in the same manner as in 1a).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (6H, d, J = 5.9 Hz), 4.43-4.52 (1H, m), 5.14 (1H, s), 6.31 (1H, t, J = 2.0 Hz ), 6.58 (1H, t, J = 2.0 Hz), 6.63 (1H, t, J = 2.0 Hz).
(28c) 3-Isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (28b) (31.52 g, 136 .4 mmol), bis (pinacolato) diboron (51.96 g, 204.6 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (3.34 g, 4.09 mmol), The target compound (33.36 g, yield 88%) as a yellow oil was obtained using potassium acetate (66.93 g, 682.0 mmol) in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.31 (6H, d, J = 6.3 Hz), 1.33 (12H, s), 4.51-4.60 (1H, m), 5.00 (1H, s), 6.51 (1H , t, J = 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
実施例(1a)で合成した化合物(31.62g,155.74mmol)をN,N-ジメチルホルムアミド(200mL)に溶解し、2-ブロモプロパン(29.25mL,311.48mmol)、炭酸カリウム(64.57g,467.22mmol)を加え、窒素雰囲気下60℃で3時間撹拌した。1規定塩酸(200mL)を加え、ジエチルエーテル(1.0L)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~10%)を用いて精製することにより、無色油状の目的化合物(33.95g,収率89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.29 (6H, d, J = 5.9 Hz), 3.73 (3H, s), 4.41-4.50 (1H, m), 6.33 (1H, t, J = 2.3 Hz), 6.59-6.62 (2H, m).
(28b)3-ブロモ-5-イソプロポキシフェノール
実施例(28a)で合成した化合物(33.95g,138.51mmol)、ナトリウムチオメトキシド(10.68g,152.36mmol)を用い、実施例(1a)と同様の方法で淡黄色油状の目的化合物(31.52g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (6H, d, J = 5.9 Hz), 4.43-4.52 (1H, m), 5.14 (1H, s), 6.31 (1H, t, J = 2.0 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.63 (1H, t, J = 2.0 Hz).
(28c)3-イソプロポキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノール
実施例(28b)で合成した化合物(31.52g,136.4mmol)、ビス(ピナコラート)ジボロン(51.96g,204.6mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(3.34g,4.09mmol)、酢酸カリウム(66.93g,682.0mmol)を用い、実施例(1d)と同様の方法で黄色油状の目的化合物(33.36g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.31 (6H, d, J = 6.3 Hz), 1.33 (12H, s), 4.51-4.60 (1H, m), 5.00 (1H, s), 6.51 (1H, t, J = 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz)。 (28a) 1-Bromo-3-isopropoxy-5-methoxybenzene The compound synthesized in Example (1a) (31.62 g, 155.74 mmol) was dissolved in N, N-dimethylformamide (200 mL), and 2- Bromopropane (29.25 mL, 311.48 mmol) and potassium carbonate (64.57 g, 467.22 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere. 1N Hydrochloric acid (200 mL) was added, and the mixture was extracted with diethyl ether (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 10%) to give a colorless oily target compound (33.95 g, Yield 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.29 (6H, d, J = 5.9 Hz), 3.73 (3H, s), 4.41-4.50 (1H, m), 6.33 (1H, t, J = 2.3 Hz ), 6.59-6.62 (2H, m).
(28b) 3-Bromo-5-isopropoxyphenol The compound (33.95 g, 138.51 mmol) synthesized in Example (28a) and sodium thiomethoxide (10.68 g, 152.36 mmol) were used. A pale yellow oily target compound (31.52 g, yield 98%) was obtained in the same manner as in 1a).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (6H, d, J = 5.9 Hz), 4.43-4.52 (1H, m), 5.14 (1H, s), 6.31 (1H, t, J = 2.0 Hz ), 6.58 (1H, t, J = 2.0 Hz), 6.63 (1H, t, J = 2.0 Hz).
(28c) 3-Isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol The compound synthesized in Example (28b) (31.52 g, 136 .4 mmol), bis (pinacolato) diboron (51.96 g, 204.6 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (3.34 g, 4.09 mmol), The target compound (33.36 g, yield 88%) as a yellow oil was obtained using potassium acetate (66.93 g, 682.0 mmol) in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.31 (6H, d, J = 6.3 Hz), 1.33 (12H, s), 4.51-4.60 (1H, m), 5.00 (1H, s), 6.51 (1H , t, J = 2.3 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.92 (1H, d, J = 2.3 Hz).
(28d)2-ベンジル 1-t-ブチル 5-(3-ヒドロキシ-5-イソプロポキシフェニル)-1H-ピロール-1,2-ジカルボキシレート
実施例(28c)で合成した化合物(20.17g,72.51mmol)、実施例(16d)で合成した化合物(28.95g,76.14mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(2.96g,3.63mmol)、炭酸カリウム(49.11g,355.32mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(27.53g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1H, m), 5.30 (2H, s), 5.58 (1H, s), 6.16 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz), 6.94 (1H, t, J = 3.9 Hz), 7.30-7.43 (5H, m).
(28e)ベンジル 5-(3-ヒドロキシ-5-イソプロポキシフェニル)-1H-ピロール-2-カルボキシレート
実施例(28d)で合成した化合物(9.97g,22.08mmol)を塩化メチレン(100mL)に溶解した。窒素雰囲気下室温で撹拌しながらトリフルオロ酢酸(40mL)を滴下した。30分撹拌後、減圧下溶媒を留去した。酢酸エチル(400mL)で希釈し、飽和炭酸水素ナトリウム水溶液(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~35%)を用いて精製することにより、淡茶色固体の目的化合物(6.20g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (6H, d, J = 5.9 Hz), 4.51-4.58 (1H, m), 5.35 (2H, s), 6.38 (1H, t, J = 2.3 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.69 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.86 (1H, brs), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m).
(28f)ベンジル 5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(28e)で合成した化合物(6.20g,17.64mmol)、実施例(16a)で合成した化合物(3.48g,18.17mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、炭酸セシウム(17.25g,52.93mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却後に水(100mL)を加え、ジエチルエーテル(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することにより、無色油状の目的化合物(6.21g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.52-4.61 (1H, m), 5.33 (2H, s), 6.51-6.54 (2H, m), 6.84 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.34-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.33 (1H, brs)。 (28d) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound synthesized in Example (28c) (20.17 g, 72.51 mmol), the compound synthesized in Example (16d) (28.95 g, 76.14 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (2.96 g, 3.63 mmol) and potassium carbonate (49.11 g, 355.32 mmol) were used to obtain the target compound (27.53 g, yield 84%) as a brown oil in the same manner as in Example (16e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1H, m), 5.30 (2H, s), 5.58 (1H , s), 6.16 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz) ), 6.94 (1H, t, J = 3.9 Hz), 7.30-7.43 (5H, m).
(28e) Benzyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-2-carboxylate Compound (9.97 g, 22.08 mmol) synthesized in Example (28d) was dissolved in methylene chloride (100 mL). Dissolved in. Trifluoroacetic acid (40 mL) was added dropwise with stirring at room temperature under a nitrogen atmosphere. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. The mixture was diluted with ethyl acetate (400 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -35%) to give the target compound (6.20 g) as a pale brown solid. , Yield 80%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (6H, d, J = 5.9 Hz), 4.51-4.58 (1H, m), 5.35 (2H, s), 6.38 (1H, t, J = 2.3 Hz ), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.69 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.86 (1H, brs), 6.99 (1H , dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m).
(28f) Benzyl 5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (28e) (6.20 g, 17.64 mmol), the compound synthesized in Example (16a) (3.48 g, 18.17 mmol) was dissolved in N, N-dimethylformamide (100 mL), and cesium carbonate (17.25 g, 52 .93 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the desired compound (6.21 g, 6.21 g, Yield 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.52-4.61 (1H, m), 5.33 (2H, s), 6.51-6.54 (2H, m), 6.84 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.34-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.33 (1H, brs).
実施例(28c)で合成した化合物(20.17g,72.51mmol)、実施例(16d)で合成した化合物(28.95g,76.14mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(2.96g,3.63mmol)、炭酸カリウム(49.11g,355.32mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(27.53g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1H, m), 5.30 (2H, s), 5.58 (1H, s), 6.16 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz), 6.94 (1H, t, J = 3.9 Hz), 7.30-7.43 (5H, m).
(28e)ベンジル 5-(3-ヒドロキシ-5-イソプロポキシフェニル)-1H-ピロール-2-カルボキシレート
実施例(28d)で合成した化合物(9.97g,22.08mmol)を塩化メチレン(100mL)に溶解した。窒素雰囲気下室温で撹拌しながらトリフルオロ酢酸(40mL)を滴下した。30分撹拌後、減圧下溶媒を留去した。酢酸エチル(400mL)で希釈し、飽和炭酸水素ナトリウム水溶液(200mL)を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~35%)を用いて精製することにより、淡茶色固体の目的化合物(6.20g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (6H, d, J = 5.9 Hz), 4.51-4.58 (1H, m), 5.35 (2H, s), 6.38 (1H, t, J = 2.3 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.69 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.86 (1H, brs), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m).
(28f)ベンジル 5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(28e)で合成した化合物(6.20g,17.64mmol)、実施例(16a)で合成した化合物(3.48g,18.17mmol)をN,N-ジメチルホルムアミド(100mL)に溶解し、炭酸セシウム(17.25g,52.93mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却後に水(100mL)を加え、ジエチルエーテル(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することにより、無色油状の目的化合物(6.21g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.52-4.61 (1H, m), 5.33 (2H, s), 6.51-6.54 (2H, m), 6.84 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.34-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.33 (1H, brs)。 (28d) 2-Benzyl 1-t-butyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-1,2-dicarboxylate Compound synthesized in Example (28c) (20.17 g, 72.51 mmol), the compound synthesized in Example (16d) (28.95 g, 76.14 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (2.96 g, 3.63 mmol) and potassium carbonate (49.11 g, 355.32 mmol) were used to obtain the target compound (27.53 g, yield 84%) as a brown oil in the same manner as in Example (16e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.31 (6H, d, J = 5.9 Hz), 1.40 (9H, s), 4.46-4.55 (1H, m), 5.30 (2H, s), 5.58 (1H , s), 6.16 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.0 Hz), 6.51 (1H, d, J = 2.0 Hz) ), 6.94 (1H, t, J = 3.9 Hz), 7.30-7.43 (5H, m).
(28e) Benzyl 5- (3-hydroxy-5-isopropoxyphenyl) -1H-pyrrole-2-carboxylate Compound (9.97 g, 22.08 mmol) synthesized in Example (28d) was dissolved in methylene chloride (100 mL). Dissolved in. Trifluoroacetic acid (40 mL) was added dropwise with stirring at room temperature under a nitrogen atmosphere. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. The mixture was diluted with ethyl acetate (400 mL), and a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -35%) to give the target compound (6.20 g) as a pale brown solid. , Yield 80%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (6H, d, J = 5.9 Hz), 4.51-4.58 (1H, m), 5.35 (2H, s), 6.38 (1H, t, J = 2.3 Hz ), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.69 (1H, t, J = 2.0 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.86 (1H, brs), 6.99 (1H , dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m).
(28f) Benzyl 5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (28e) (6.20 g, 17.64 mmol), the compound synthesized in Example (16a) (3.48 g, 18.17 mmol) was dissolved in N, N-dimethylformamide (100 mL), and cesium carbonate (17.25 g, 52 .93 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -50%) to give the desired compound (6.21 g, 6.21 g, Yield 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.52-4.61 (1H, m), 5.33 (2H, s), 6.51-6.54 (2H, m), 6.84 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.34-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.33 (1H, brs).
(28g)5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(28f)で合成した化合物(6.21g,12.26mmol)を酢酸エチル(70mL)とエタノール(20mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(1.17g)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで淡橙色固体の目的化合物(5.20g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.54-4.63 (1H, m), 6.54-6.57 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07 (1H, dd, J = 2.3, 3.9 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.49 (1H, brs).
(28h)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(28g)で合成した化合物(1.83g,4.39mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.00g,10.99mmol)、DMT-MM(2.09g,6.59mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(0.79g,37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.55-3.63 (4H, m), 3.82-3.86 (1H, m), 4.54-4.60 (1H, m), 6.39-6.43 (1H, br m), 6.48-6.52 (2H, m), 6.63 (1H, s), 6.84 (1H, s), 6.96 (1H, s), 7.43 (1H, dd, J = 2.9, 8.8 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.47 (1H, s).
(28i)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(28h)で合成した化合物(0.79g,1.61mmol)を塩化メチレン(20mL)に溶解し、トリイソプロピルシリルクロリド(0.52mL,2.42mmol)、トリエチルアミン(1.12mL, 8.07mol)、4-ジメチルアミノピリジン(0.30g,2.42mmol)を加え、窒素雰囲気下室温で22時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的物(779mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.16 (21H, m), 1.37 (6H, d, J = 5.9 Hz), 3.12 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.44 (1H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1H, m), 4.54-4.61 (1H, m), 6.33 (1H, t, J = 5.1 Hz), 6.49-6.52 (2H, m), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.41 (1H, brs)。 (28 g) 5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (28f) ( 6.21 g, 12.26 mmol) was dissolved in a mixed solvent of ethyl acetate (70 mL) and ethanol (20 mL), 10% palladium carbon catalyst (1.17 g) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.20 g, yield ˜100%) as a pale orange solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.54-4.63 (1H, m), 6.54-6.57 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07 (1H, dd, J = 2.3, 3.9 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.49 (1H, brs).
(28h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole -2-Carboxamide Compound (1.83 g, 4.39 mmol) synthesized in Example (28 g), (S)-(−)-3-amino-1,2-propanediol (1.00 g, 10.99 mmol) , DMT-MM (2.09 g, 6.59 mmol) was used to give the target compound (0.79 g, 37%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.55-3.63 (4H, m), 3.82-3.86 (1H, m), 4.54 -4.60 (1H, m), 6.39-6.43 (1H, br m), 6.48-6.52 (2H, m), 6.63 (1H, s), 6.84 (1H, s), 6.96 (1H, s), 7.43 ( 1H, dd, J = 2.9, 8.8 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.47 (1H, s).
(28i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl ] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (0.79 g, 1.61 mmol) synthesized in Example (28h) was dissolved in methylene chloride (20 mL), and triisopropylsilyl chloride (0.52 mL, 2.42 mmol), triethylamine (1.12 mL, 8.07 mol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol) were added, and the mixture was stirred at room temperature for 22 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the desired product (779 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.16 (21H, m), 1.37 (6H, d, J = 5.9 Hz), 3.12 (1H, d, J = 4.3 Hz), 3.23 (3H, s ), 3.36-3.44 (1H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1H, m), 4.54-4.61 (1H, m), 6.33 (1H, t, J = 5.1 Hz), 6.49-6.52 (2H, m), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.44 (1H , dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.41 (1H, brs).
実施例(28f)で合成した化合物(6.21g,12.26mmol)を酢酸エチル(70mL)とエタノール(20mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(1.17g)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで淡橙色固体の目的化合物(5.20g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.54-4.63 (1H, m), 6.54-6.57 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07 (1H, dd, J = 2.3, 3.9 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.49 (1H, brs).
(28h)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(28g)で合成した化合物(1.83g,4.39mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.00g,10.99mmol)、DMT-MM(2.09g,6.59mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(0.79g,37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.55-3.63 (4H, m), 3.82-3.86 (1H, m), 4.54-4.60 (1H, m), 6.39-6.43 (1H, br m), 6.48-6.52 (2H, m), 6.63 (1H, s), 6.84 (1H, s), 6.96 (1H, s), 7.43 (1H, dd, J = 2.9, 8.8 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.47 (1H, s).
(28i)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(28h)で合成した化合物(0.79g,1.61mmol)を塩化メチレン(20mL)に溶解し、トリイソプロピルシリルクロリド(0.52mL,2.42mmol)、トリエチルアミン(1.12mL, 8.07mol)、4-ジメチルアミノピリジン(0.30g,2.42mmol)を加え、窒素雰囲気下室温で22時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的物(779mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.16 (21H, m), 1.37 (6H, d, J = 5.9 Hz), 3.12 (1H, d, J = 4.3 Hz), 3.23 (3H, s), 3.36-3.44 (1H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1H, m), 4.54-4.61 (1H, m), 6.33 (1H, t, J = 5.1 Hz), 6.49-6.52 (2H, m), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.41 (1H, brs)。 (28 g) 5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound synthesized in Example (28f) ( 6.21 g, 12.26 mmol) was dissolved in a mixed solvent of ethyl acetate (70 mL) and ethanol (20 mL), 10% palladium carbon catalyst (1.17 g) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.20 g, yield ˜100%) as a pale orange solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.54-4.63 (1H, m), 6.54-6.57 (2H, m), 6.87 (1H, s), 7.00 (1H, s), 7.07 (1H, dd, J = 2.3, 3.9 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.49 (1H, brs).
(28h) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole -2-Carboxamide Compound (1.83 g, 4.39 mmol) synthesized in Example (28 g), (S)-(−)-3-amino-1,2-propanediol (1.00 g, 10.99 mmol) , DMT-MM (2.09 g, 6.59 mmol) was used to give the target compound (0.79 g, 37%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.55-3.63 (4H, m), 3.82-3.86 (1H, m), 4.54 -4.60 (1H, m), 6.39-6.43 (1H, br m), 6.48-6.52 (2H, m), 6.63 (1H, s), 6.84 (1H, s), 6.96 (1H, s), 7.43 ( 1H, dd, J = 2.9, 8.8 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.47 (1H, s).
(28i) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl ] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (0.79 g, 1.61 mmol) synthesized in Example (28h) was dissolved in methylene chloride (20 mL), and triisopropylsilyl chloride (0.52 mL, 2.42 mmol), triethylamine (1.12 mL, 8.07 mol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol) were added, and the mixture was stirred at room temperature for 22 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 30% -60%) to give the desired product (779 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.16 (21H, m), 1.37 (6H, d, J = 5.9 Hz), 3.12 (1H, d, J = 4.3 Hz), 3.23 (3H, s ), 3.36-3.44 (1H, m), 3.65-3.79 (3H, m), 3.84-3.90 (1H, m), 4.54-4.61 (1H, m), 6.33 (1H, t, J = 5.1 Hz), 6.49-6.52 (2H, m), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.44 (1H , dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.41 (1H, brs).
(28j)5-(3-イソプロポキシ-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(28i)で合成した化合物(779mg,1.21mmol)、メタンスルホン酸無水物(420mg,2.41mmol)、トリエチルアミン(0.67mL,4.82mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(695mg,収率92%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.03-1.12 (21H, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54-4.59 (1H, m), 4.73-4.78 (1H, m), 6.49-6.51 (2H, m), 6.73 (1H, d, J = 3.4 Hz), 6.80 (1H, t, J = 1.5 Hz), 6.93 (1H, t, J = 1.5 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 2.9 Hz).
(28k){(5R)-2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(28j)で合成した化合物(921mg,1.47mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,1.61mL,1.61mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(538mg,収率78%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.69-3.79 (2H, m), 3.84 (1H, dd, J = 3.4, 12.7 Hz), 4.03 (1H, dd, J = 9.8, 14.2 Hz), 4.53-4.61 (1H, m), 4.76-4.82 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.4 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz).
MS (ESI) m/z: 472.15594 (M+H)+。 (28j) 5- (3-Isopropoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl ] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (28i) (779 mg, 1.21 mmol), methanesulfonic anhydride (420 mg, 2.41 mmol), Using triethylamine (0.67 mL, 4.82 mmol), the target product (695 mg, yield 92%) was obtained as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.03-1.12 (21H, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54 -4.59 (1H, m), 4.73-4.78 (1H, m), 6.49-6.51 (2H, m), 6.73 (1H, d, J = 3.4 Hz), 6.80 (1H, t, J = 1.5 Hz), 6.93 (1H, t, J = 1.5 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 2.9 Hz).
(28k) {(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (921 mg, 1.47 mmol) synthesized in Example (28j), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 1.61 mL, 1 .61 mmol) was used to obtain the target compound (538 mg, yield 78%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.69-3.79 (2H, m), 3.84 (1H, dd, J = 3.4, 12.7 Hz), 4.03 (1H, dd, J = 9.8, 14.2 Hz), 4.53-4.61 (1H, m), 4.76-4.82 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.51 ( 1H, t, J = 2.4 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 472.15594 (M + H) <+> .
実施例(28i)で合成した化合物(779mg,1.21mmol)、メタンスルホン酸無水物(420mg,2.41mmol)、トリエチルアミン(0.67mL,4.82mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(695mg,収率92%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.03-1.12 (21H, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54-4.59 (1H, m), 4.73-4.78 (1H, m), 6.49-6.51 (2H, m), 6.73 (1H, d, J = 3.4 Hz), 6.80 (1H, t, J = 1.5 Hz), 6.93 (1H, t, J = 1.5 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 2.9 Hz).
(28k){(5R)-2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(28j)で合成した化合物(921mg,1.47mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,1.61mL,1.61mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(538mg,収率78%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.69-3.79 (2H, m), 3.84 (1H, dd, J = 3.4, 12.7 Hz), 4.03 (1H, dd, J = 9.8, 14.2 Hz), 4.53-4.61 (1H, m), 4.76-4.82 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.4 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz).
MS (ESI) m/z: 472.15594 (M+H)+。 (28j) 5- (3-Isopropoxy-5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazol-2-yl ] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (28i) (779 mg, 1.21 mmol), methanesulfonic anhydride (420 mg, 2.41 mmol), Using triethylamine (0.67 mL, 4.82 mmol), the target product (695 mg, yield 92%) was obtained as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.03-1.12 (21H, m), 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.83-3.91 (4H, m), 4.54 -4.59 (1H, m), 4.73-4.78 (1H, m), 6.49-6.51 (2H, m), 6.73 (1H, d, J = 3.4 Hz), 6.80 (1H, t, J = 1.5 Hz), 6.93 (1H, t, J = 1.5 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 2.9 Hz).
(28k) {(5R) -2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4 , 5-Dihydro-1,3-oxazol-5-yl} methanol Compound (921 mg, 1.47 mmol) synthesized in Example (28j), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 1.61 mL, 1 .61 mmol) was used to obtain the target compound (538 mg, yield 78%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 3.69-3.79 (2H, m), 3.84 (1H, dd, J = 3.4, 12.7 Hz), 4.03 (1H, dd, J = 9.8, 14.2 Hz), 4.53-4.61 (1H, m), 4.76-4.82 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.51 ( 1H, t, J = 2.4 Hz), 6.69 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 2.0 Hz), 6.95 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 2.9, 8.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz).
MS (ESI) m / z: 472.15594 (M + H) <+> .
(実施例29)
5-(3-イソプロポキシ-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン (Example 29)
5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy)- 2- (Methylsulfonyl) pyridine
5-(3-イソプロポキシ-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン (Example 29)
5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy)- 2- (Methylsulfonyl) pyridine
(29a)N-[(1R)-2-ヒドロキシ-1-メチルエチル]-5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(28g)で合成した化合物(530mg,1.27mmol)、D-アラニノール(0.15mL,1.91mmol)、HOBT・H2O(206mg,1.53mmol)、N-メチルモルホリン(0.28mL,2.55mmol)をN,N-ジメチルホルムアミド(12mL)に溶解し、室温でWSCI・HCl(268mg,1.40mmol)を加え、窒素雰囲気下20時間攪拌した。反応液を酢酸エチル(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~100%)を用いて精製することにより、白色固体の目的化合物(538mg,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1H, m), 3.23 (3H, s), 3.59-3.65 (1H, m), 3.73-3.78 (1H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1H, m), 6.09 (1H, d, J = 7.4 Hz), 6.49 (1H, t, J = 3.1 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.69 (1H, br s).
(29b)5-(3-イソプロポキシ-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(29a)で合成した化合物(538mg,1.14mmol)、メタンスルホン酸無水物(408mg,2.27mmol)、トリエチルアミン(0.63mL, 4.54mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(395mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (3H, d, J = 6.6 Hz), 1.36 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.92 (1H, t, J = 7.8 Hz), 4.27-4.37 (1H, m), 4.49 (1H, dd, J = 8.2, 9.0 Hz), 4.57 (1H, q, J = 5.9 Hz), 6.50-6.52 (2H, m), 6.75 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (EI) m/z: 455.1517 (M+)。 (29a) N-[(1R) -2-hydroxy-1-methylethyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxamide Compound (530 mg, 1.27 mmol) synthesized in Example (28 g), D-alaninol (0.15 mL, 1.91 mmol), HOBT.H 2 O (206 mg, 1.53 mmol), N -Methylmorpholine (0.28 mL, 2.55 mmol) was dissolved in N, N-dimethylformamide (12 mL), WSCI · HCl (268 mg, 1.40 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 20 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% to 100%) to give the target compound (538 mg, 89%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1H, m), 3.23 (3H, s ), 3.59-3.65 (1H, m), 3.73-3.78 (1H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1H, m), 6.09 (1H, d, J = 7.4 Hz) , 6.49 (1H, t, J = 3.1 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.83 (1H, t, J = 2.0 Hz) , 6.95 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) , 9.69 (1H, br s).
(29b) 5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} Phenoxy) -2- (methylsulfonyl) pyridine Compound (538 mg, 1.14 mmol) synthesized in Example (29a), methanesulfonic anhydride (408 mg, 2.27 mmol), triethylamine (0.63 mL, 4.54 mmol) Was used to give the target compound (395 mg, yield 76%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 1.36 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.92 (1H, t, J = 7.8 Hz), 4.27-4.37 (1H, m), 4.49 (1H, dd, J = 8.2, 9.0 Hz), 4.57 (1H, q, J = 5.9 Hz), 6.50-6.52 (2H, m), 6.75 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (EI) m / z: 455.1517 (M <+> ).
実施例(28g)で合成した化合物(530mg,1.27mmol)、D-アラニノール(0.15mL,1.91mmol)、HOBT・H2O(206mg,1.53mmol)、N-メチルモルホリン(0.28mL,2.55mmol)をN,N-ジメチルホルムアミド(12mL)に溶解し、室温でWSCI・HCl(268mg,1.40mmol)を加え、窒素雰囲気下20時間攪拌した。反応液を酢酸エチル(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~100%)を用いて精製することにより、白色固体の目的化合物(538mg,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1H, m), 3.23 (3H, s), 3.59-3.65 (1H, m), 3.73-3.78 (1H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1H, m), 6.09 (1H, d, J = 7.4 Hz), 6.49 (1H, t, J = 3.1 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.69 (1H, br s).
(29b)5-(3-イソプロポキシ-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(29a)で合成した化合物(538mg,1.14mmol)、メタンスルホン酸無水物(408mg,2.27mmol)、トリエチルアミン(0.63mL, 4.54mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(395mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.32 (3H, d, J = 6.6 Hz), 1.36 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.92 (1H, t, J = 7.8 Hz), 4.27-4.37 (1H, m), 4.49 (1H, dd, J = 8.2, 9.0 Hz), 4.57 (1H, q, J = 5.9 Hz), 6.50-6.52 (2H, m), 6.75 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (EI) m/z: 455.1517 (M+)。 (29a) N-[(1R) -2-hydroxy-1-methylethyl] -5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxamide Compound (530 mg, 1.27 mmol) synthesized in Example (28 g), D-alaninol (0.15 mL, 1.91 mmol), HOBT.H 2 O (206 mg, 1.53 mmol), N -Methylmorpholine (0.28 mL, 2.55 mmol) was dissolved in N, N-dimethylformamide (12 mL), WSCI · HCl (268 mg, 1.40 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 20 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% to 100%) to give the target compound (538 mg, 89%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 1.36 (6H, d, J = 6.3 Hz), 2.83-2.87 (1H, m), 3.23 (3H, s ), 3.59-3.65 (1H, m), 3.73-3.78 (1H, m), 4.21-4.28 (1H, br m), 4.52-4.60 (1H, m), 6.09 (1H, d, J = 7.4 Hz) , 6.49 (1H, t, J = 3.1 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.83 (1H, t, J = 2.0 Hz) , 6.95 (1H, d, J = 2.0 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) , 9.69 (1H, br s).
(29b) 5- (3-Isopropoxy-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} Phenoxy) -2- (methylsulfonyl) pyridine Compound (538 mg, 1.14 mmol) synthesized in Example (29a), methanesulfonic anhydride (408 mg, 2.27 mmol), triethylamine (0.63 mL, 4.54 mmol) Was used to give the target compound (395 mg, yield 76%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 1.36 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.92 (1H, t, J = 7.8 Hz), 4.27-4.37 (1H, m), 4.49 (1H, dd, J = 8.2, 9.0 Hz), 4.57 (1H, q, J = 5.9 Hz), 6.50-6.52 (2H, m), 6.75 (1H, d, J = 3.9 Hz), 6.81 (1H, t, J = 1.8 Hz), 6.96 (1H, t, J = 1.8 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (EI) m / z: 455.1517 (M <+> ).
(実施例30)
{2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 30)
{2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1, 3-oxazol-4-yl} methanol
{2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 30)
{2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1, 3-oxazol-4-yl} methanol
(30a)メチル N-{[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]カルボニル}セリネート
実施例(28g)で合成した化合物(2.00g,4.80mmol)、DL-セリン メチルエステル 塩酸塩(0.82g,5.28mmol)、HOBT・H2O(0.71g,5.28mmol)、N-メチルモルホリン(1.06mL,9.60mmol)、WSCI・HCl(1.10g,5.76mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(2.36g,95%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 2.84 (1H, t, J = 6.1 Hz), 3.24 (3H, s), 3.80 (3H, s), 3.98-4.09 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.80-4.84 (1H, m), 6.50-6.52 (2H, m), 6.74 (1H, dd, J = 2.7, 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.77 (1H, br s).
(30b)メチル 2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(30a)で合成した化合物(2.36g,4.41mmol)、メタンスルホン酸無水物(1.58g,8.81mmol)、トリエチルアミン(2.46mL, 17.63mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(1.52g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 6.3 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.55-4.61 (2H, m), 4.66 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.51-6.53 (2H, m), 6.80-6.82 (2H, m), 6.95 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
(30c){2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(30b)で合成した化合物(498mg,1.00mmol)をテトラヒドロフラン(10mL)に溶解し、0℃で水素化リチウムアルミニウム(114mg,2.99mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.12mL)、5規定水酸化ナトリウム水溶液(0.12mL)、水(0.36mL)の順に加え、10分間攪拌した。酢酸エチル(40mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、白色固体の目的化合物(295mg,63%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.62 (1H, dd, J = 4.3, 11.7 Hz), 3.90 (1H, dd, J = 2.7, 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.33-4.39 (1H, m), 4.39-4.43 (1H, m), 4.57 (1H, q, J = 5.9 Hz), 6.43 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 472.15279 (M+H)+。 (30a) Methyl N-{[5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] carbonyl} selinate Examples Compound (2.00 g, 4.80 mmol) synthesized in (28 g), DL-serine methyl ester hydrochloride (0.82 g, 5.28 mmol), HOBT.H 2 O (0.71 g, 5.28 mmol), N -The target compound (2.36 g, 95%) of white solid was prepared in the same manner as in Example (29a) using methylmorpholine (1.06 mL, 9.60 mmol) and WSCI.HCl (1.10 g, 5.76 mmol). )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.84 (1H, t, J = 6.1 Hz), 3.24 (3H, s), 3.80 (3H, s), 3.98-4.09 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.80-4.84 (1H, m), 6.50-6.52 (2H, m), 6.74 (1H, dd, J = 2.7, 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.77 (1H, br s).
(30b) Methyl 2- [5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazole-4-carboxylate Compound (2.36 g, 4.41 mmol) synthesized in Example (30a), methanesulfonic anhydride (1.58 g, 8.81 mmol), triethylamine (2.46 mL) , 17.63 mmol) and the white solid target compound (1.52 g, yield 69%) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.55-4.61 (2H, m), 4.66 (1H , t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.51-6.53 (2H, m), 6.80-6.82 (2H, m), 6.95 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
(30c) {2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-4-yl} methanol The compound synthesized in Example (30b) (498 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (114 mg, 2.99 mmol) was added at 0 ° C. ) Was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.12 mL), 5N aqueous sodium hydroxide solution (0.12 mL), and water (0.36 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (40 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the desired compound (295 mg, 63%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.62 (1H, dd, J = 4.3, 11.7 Hz), 3.90 (1H, dd , J = 2.7, 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.33-4.39 (1H, m), 4.39-4.43 (1H, m), 4.57 (1H, q, J = 5.9 Hz) , 6.43 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 472.15279 (M + H) <+> .
実施例(28g)で合成した化合物(2.00g,4.80mmol)、DL-セリン メチルエステル 塩酸塩(0.82g,5.28mmol)、HOBT・H2O(0.71g,5.28mmol)、N-メチルモルホリン(1.06mL,9.60mmol)、WSCI・HCl(1.10g,5.76mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(2.36g,95%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 2.84 (1H, t, J = 6.1 Hz), 3.24 (3H, s), 3.80 (3H, s), 3.98-4.09 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.80-4.84 (1H, m), 6.50-6.52 (2H, m), 6.74 (1H, dd, J = 2.7, 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.77 (1H, br s).
(30b)メチル 2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(30a)で合成した化合物(2.36g,4.41mmol)、メタンスルホン酸無水物(1.58g,8.81mmol)、トリエチルアミン(2.46mL, 17.63mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(1.52g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 6.3 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.55-4.61 (2H, m), 4.66 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.51-6.53 (2H, m), 6.80-6.82 (2H, m), 6.95 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
(30c){2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(30b)で合成した化合物(498mg,1.00mmol)をテトラヒドロフラン(10mL)に溶解し、0℃で水素化リチウムアルミニウム(114mg,2.99mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.12mL)、5規定水酸化ナトリウム水溶液(0.12mL)、水(0.36mL)の順に加え、10分間攪拌した。酢酸エチル(40mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、白色固体の目的化合物(295mg,63%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.62 (1H, dd, J = 4.3, 11.7 Hz), 3.90 (1H, dd, J = 2.7, 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.33-4.39 (1H, m), 4.39-4.43 (1H, m), 4.57 (1H, q, J = 5.9 Hz), 6.43 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 472.15279 (M+H)+。 (30a) Methyl N-{[5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] carbonyl} selinate Examples Compound (2.00 g, 4.80 mmol) synthesized in (28 g), DL-serine methyl ester hydrochloride (0.82 g, 5.28 mmol), HOBT.H 2 O (0.71 g, 5.28 mmol), N -The target compound (2.36 g, 95%) of white solid was prepared in the same manner as in Example (29a) using methylmorpholine (1.06 mL, 9.60 mmol) and WSCI.HCl (1.10 g, 5.76 mmol). )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.84 (1H, t, J = 6.1 Hz), 3.24 (3H, s), 3.80 (3H, s), 3.98-4.09 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.80-4.84 (1H, m), 6.50-6.52 (2H, m), 6.74 (1H, dd, J = 2.7, 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.77 (1H, br s).
(30b) Methyl 2- [5- (3-isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazole-4-carboxylate Compound (2.36 g, 4.41 mmol) synthesized in Example (30a), methanesulfonic anhydride (1.58 g, 8.81 mmol), triethylamine (2.46 mL) , 17.63 mmol) and the white solid target compound (1.52 g, yield 69%) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.55-4.61 (2H, m), 4.66 (1H , t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.51-6.53 (2H, m), 6.80-6.82 (2H, m), 6.95 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.44 (1H, br s).
(30c) {2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro -1,3-oxazol-4-yl} methanol The compound synthesized in Example (30b) (498 mg, 1.00 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (114 mg, 2.99 mmol) was added at 0 ° C. ) Was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.12 mL), 5N aqueous sodium hydroxide solution (0.12 mL), and water (0.36 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (40 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the desired compound (295 mg, 63%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (6H, d, J = 6.3 Hz), 3.23 (3H, s), 3.62 (1H, dd, J = 4.3, 11.7 Hz), 3.90 (1H, dd , J = 2.7, 11.7 Hz), 4.13 (1H, t, J = 7.0 Hz), 4.33-4.39 (1H, m), 4.39-4.43 (1H, m), 4.57 (1H, q, J = 5.9 Hz) , 6.43 (1H, d, J = 3.9 Hz), 6.51 (1H, t, J = 2.0 Hz), 6.60 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 472.15279 (M + H) <+> .
(実施例31)
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボン酸 (Example 31)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxylic acid
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボン酸 (Example 31)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxylic acid
実施例(30b)で合成した化合物(620mg,1.24mmol)をエタノール(12mL)に溶解し、2規定水酸化ナトリウム水溶液(6.21mL)を加え、窒素雰囲気下1時間加熱還流した。
反応液を2規定塩酸で中和し、減圧下溶媒を留去した。水(50ml)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、白色固体の目的化合物(600mg,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 6.3 Hz), 3.21 (3H, s), 4.63 (1H, q, J = 5.9 Hz), 4.88-4.98 (2H, m), 5.01-5.07 (1H, m), 6.58 (1H, s), 6.62 (1H, s), 7.14 (1H, s), 7.26 (1H, s), 7.36 (1H, s), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz), 13.72 (1H, br s).
MS (ESI) m/z: 486.13511 (M+H)+。 The compound synthesized in Example (30b) (620 mg, 1.24 mmol) was dissolved in ethanol (12 mL), 2N aqueous sodium hydroxide solution (6.21 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere.
The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was distilled off under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (600 mg, yield 100%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 6.3 Hz), 3.21 (3H, s), 4.63 (1H, q, J = 5.9 Hz), 4.88-4.98 (2H, m ), 5.01-5.07 (1H, m), 6.58 (1H, s), 6.62 (1H, s), 7.14 (1H, s), 7.26 (1H, s), 7.36 (1H, s), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz), 13.72 (1H, br s).
MS (ESI) m / z: 486.13511 (M + H) <+> .
反応液を2規定塩酸で中和し、減圧下溶媒を留去した。水(50ml)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、白色固体の目的化合物(600mg,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 6.3 Hz), 3.21 (3H, s), 4.63 (1H, q, J = 5.9 Hz), 4.88-4.98 (2H, m), 5.01-5.07 (1H, m), 6.58 (1H, s), 6.62 (1H, s), 7.14 (1H, s), 7.26 (1H, s), 7.36 (1H, s), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz), 13.72 (1H, br s).
MS (ESI) m/z: 486.13511 (M+H)+。 The compound synthesized in Example (30b) (620 mg, 1.24 mmol) was dissolved in ethanol (12 mL), 2N aqueous sodium hydroxide solution (6.21 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere.
The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was distilled off under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (600 mg, yield 100%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 6.3 Hz), 3.21 (3H, s), 4.63 (1H, q, J = 5.9 Hz), 4.88-4.98 (2H, m ), 5.01-5.07 (1H, m), 6.58 (1H, s), 6.62 (1H, s), 7.14 (1H, s), 7.26 (1H, s), 7.36 (1H, s), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz), 13.72 (1H, br s).
MS (ESI) m / z: 486.13511 (M + H) <+> .
(実施例32)
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-N,N-ジメチル-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキサミド (Example 32)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -N, N-dimethyl-4,5 -Dihydro-1,3-oxazole-4-carboxamide
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-N,N-ジメチル-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキサミド (Example 32)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -N, N-dimethyl-4,5 -Dihydro-1,3-oxazole-4-carboxamide
(実施例31)で合成した化合物(156mg,0.32mmol)、ジメチルアミン塩酸塩(78mg,0.96mmol)、WSCI・HCl(123mg, 0.64mmol)、4-ジメチルアミノピリジン(118mg,0.96mmol)を用い、実施例(1k)と同様の方法で白色固体の目的化合物(111mg,収率67%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1H, m), 4.55 (1H, q, J = 5.9 Hz), 5.00-5.07 (2H, m), 6.49-6.51 (2H, m), 6.77 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.70 (1H, br s).
MS (ESI) m/z: 513.18300 (M+H)+。 Compound synthesized in Example 31 (156 mg, 0.32 mmol), dimethylamine hydrochloride (78 mg, 0.96 mmol), WSCI · HCl (123 mg, 0.64 mmol), 4-dimethylaminopyridine (118 mg, 0. 96 mmol) was used to obtain the target compound (111 mg, yield 67%) as a white solid in the same manner as in Example (1k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1H , m), 4.55 (1H, q, J = 5.9 Hz), 5.00-5.07 (2H, m), 6.49-6.51 (2H, m), 6.77 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.70 (1H, br s).
MS (ESI) m / z: 513.18300 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.36 (6H, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1H, m), 4.55 (1H, q, J = 5.9 Hz), 5.00-5.07 (2H, m), 6.49-6.51 (2H, m), 6.77 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.70 (1H, br s).
MS (ESI) m/z: 513.18300 (M+H)+。 Compound synthesized in Example 31 (156 mg, 0.32 mmol), dimethylamine hydrochloride (78 mg, 0.96 mmol), WSCI · HCl (123 mg, 0.64 mmol), 4-dimethylaminopyridine (118 mg, 0. 96 mmol) was used to obtain the target compound (111 mg, yield 67%) as a white solid in the same manner as in Example (1k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (6H, d, J = 5.9 Hz), 2.97 (3H, s), 3.23 (3H, s), 3.25 (3H, s), 4.40-4.47 (1H , m), 4.55 (1H, q, J = 5.9 Hz), 5.00-5.07 (2H, m), 6.49-6.51 (2H, m), 6.77 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.70 (1H, br s).
MS (ESI) m / z: 513.18300 (M + H) <+> .
(実施例33)
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキサミド (Example 33)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxamide
2-[5-(3-イソプロポキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキサミド (Example 33)
2- [5- (3-Isopropoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3 -Oxazole-4-carboxamide
(実施例31)で合成した化合物(200mg,0.41mmol)を塩化メチレン(10mL)に溶解し、アンモニア水溶液(28%,0.13mL,2.06mmol)、WSCI・HCl(95mg, 0.49mmol)、HOBT・H2O(61mg, 0.45mmol)を加え、窒素雰囲気下室温で5時間撹拌した。反応液を塩化メチレン(30mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、白色固体の目的化合物(145mg,収率73%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.55-4.66 (3H, m), 4.78 (1H, dd, J = 8.3, 10.3 Hz), 5.59 (1H, br s), 6.54 (2H, s), 6.60 (1H, br s), 6.83-6.85 (2H, m), 6.98 (1H, s), 7.45 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.49 (1H, br s).
MS (ESI) m/z: 485.14881 (M+H)+。 The compound synthesized in (Example 31) (200 mg, 0.41 mmol) was dissolved in methylene chloride (10 mL), an aqueous ammonia solution (28%, 0.13 mL, 2.06 mmol), WSCI · HCl (95 mg, 0.49 mmol). ), HOBT.H 2 O (61 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (30 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (145 mg, yield) as a white solid. 73%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.55-4.66 (3H, m), 4.78 (1H, dd, J = 8.3, 10.3 Hz), 5.59 (1H, br s), 6.54 (2H, s), 6.60 (1H, br s), 6.83-6.85 (2H, m), 6.98 (1H, s), 7.45 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.49 (1H, br s).
MS (ESI) m / z: 485.14881 (M + H) <+> .
1H-NMR (CDCl3, 500MHz):δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.55-4.66 (3H, m), 4.78 (1H, dd, J = 8.3, 10.3 Hz), 5.59 (1H, br s), 6.54 (2H, s), 6.60 (1H, br s), 6.83-6.85 (2H, m), 6.98 (1H, s), 7.45 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.49 (1H, br s).
MS (ESI) m/z: 485.14881 (M+H)+。 The compound synthesized in (Example 31) (200 mg, 0.41 mmol) was dissolved in methylene chloride (10 mL), an aqueous ammonia solution (28%, 0.13 mL, 2.06 mmol), WSCI · HCl (95 mg, 0.49 mmol). ), HOBT.H 2 O (61 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (30 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (145 mg, yield) as a white solid. 73%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.37 (6H, d, J = 5.9 Hz), 3.23 (3H, s), 4.55-4.66 (3H, m), 4.78 (1H, dd, J = 8.3, 10.3 Hz), 5.59 (1H, br s), 6.54 (2H, s), 6.60 (1H, br s), 6.83-6.85 (2H, m), 6.98 (1H, s), 7.45 (1H, dd, J = 2.9, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.49 (1H, br s).
MS (ESI) m / z: 485.14881 (M + H) <+> .
(実施例34)
2-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン (Example 34)
2- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine
2-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン (Example 34)
2- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine
(34a)2-クロロ-5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン
5-ヒドロキシピラジン-2-カルボン酸(5.00g,39.0mmol)を塩化チオニル(64mL)に溶解し、N,N-ジメチルホルムアミドを数滴加えた後、窒素雰囲気下5時間加熱還流した。減圧下溶媒を留去し、得られた残渣を塩化メチレン(50mL)で希釈した。氷浴にて冷却しながらジイソプロピルエチルアミン(18.7mL,107mmol)、1-メチルピペラジン(4.37mL,39.2mmol)を加え、窒素雰囲気下室温で3日間撹拌した。反応液に水(100mL)を加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~5%)を用いて精製することにより、茶色固体の目的化合物(5.32g,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.34 (3H, s), 2.44 (2H, t, J = 5.1 Hz), 2.53 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.1 Hz), 3.84 (2H, t, J = 4.9 Hz), 8.55 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz).
(34b)(2R)-1-{[t-ブチル(ジメチル)シリル]オキシ}プロパン-2-オール
(R)-(-)-1,2-プロパンジオール(21.23g,279.01mmol)を塩化メチレン(300ml)に溶解し、トリエチルアミン(58.33mL,418.52mmol)、4-ジメチルアミノピリジン(3.41g,27.90mmol)、t-ブチルジメチルクロロシラン(42.05g,279.01mmol)を加え、室温で終夜攪拌した。塩化メチレン(200mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することにより、無色油状の目的化合物(43.75g,82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.08 (6H, s), 0.91 (9H, s), 1.12 (3H, d, J = 6.3 Hz), 2.46 (1H, br s), 3.35 (1H, dd, J = 7.8, 10.2 Hz), 3.59 (1H, dd, J = 3.5, 10.2 Hz), 3.78-3.86 (1H, m).
(34c){[(2S)-2-(3-ブロモ-5-メトキシフェノキシ)プロピル]オキシ}(t-ブチル)ジメチルシラン
実施例(1a)で合成した化合物(33.47g,164.9mmol)、実施例(34b)で合成した化合物(37.7g,197.82mmol)、トリフェニルホスフィン(47.74g,181.3mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,79.00mL,181.34mmol)を用い、実施例(20a)と同様の方法で無色油状の目的化合物(57.19g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd, J = 5.1, 10.6 Hz), 3.74-3.78 (1H, m), 3.76 (3H, s), 4.34-4.41 (1H, m), 6.39 (1H, t, J = 2.3 Hz), 6.64 (1H, t, J = 1.6 Hz), 6.69 (1H, t, J = 1.6 Hz)。 (34a) 2-Chloro-5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine 5-hydroxypyrazine-2-carboxylic acid (5.00 g, 39.0 mmol) was dissolved in thionyl chloride (64 mL). After adding a few drops of N, N-dimethylformamide, the mixture was heated to reflux for 5 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with methylene chloride (50 mL). Diisopropylethylamine (18.7 mL, 107 mmol) and 1-methylpiperazine (4.37 mL, 39.2 mmol) were added while cooling in an ice bath, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 5%) to give the target compound (5.32 g, 5.3%, Yield 62%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.34 (3H, s), 2.44 (2H, t, J = 5.1 Hz), 2.53 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.1 Hz), 3.84 (2H, t, J = 4.9 Hz), 8.55 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz).
(34b) (2R) -1-{[t-Butyl (dimethyl) silyl] oxy} propan-2-ol (R)-(−)-1,2-propanediol (21.23 g, 279.01 mmol) Dissolve in methylene chloride (300 ml) and add triethylamine (58.33 mL, 418.52 mmol), 4-dimethylaminopyridine (3.41 g, 27.90 mmol), t-butyldimethylchlorosilane (42.05 g, 279.01 mmol). In addition, the mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride (200 mL), and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oil. The target compound (43.75 g, 82%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.08 (6H, s), 0.91 (9H, s), 1.12 (3H, d, J = 6.3 Hz), 2.46 (1H, br s), 3.35 (1H, dd, J = 7.8, 10.2 Hz), 3.59 (1H, dd, J = 3.5, 10.2 Hz), 3.78-3.86 (1H, m).
(34c) {[(2S) -2- (3-Bromo-5-methoxyphenoxy) propyl] oxy} (t-butyl) dimethylsilane Compound synthesized in Example (1a) (33.47 g, 164.9 mmol) The compound synthesized in Example (34b) (37.7 g, 197.82 mmol), triphenylphosphine (47.74 g, 181.3 mmol), diethyl azodicarboxylate (40% toluene solution, 79.00 mL, 181.34 mmol) ) To give a colorless oily target compound (57.19 g, yield 92%) in the same manner as in Example (20a).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.74-3.78 (1H, m), 3.76 (3H, s), 4.34-4.41 (1H, m), 6.39 (1H, t, J = 2.3 Hz), 6.64 (1H, t, J = 1.6 Hz), 6.69 (1H, t, J = 1.6 Hz).
5-ヒドロキシピラジン-2-カルボン酸(5.00g,39.0mmol)を塩化チオニル(64mL)に溶解し、N,N-ジメチルホルムアミドを数滴加えた後、窒素雰囲気下5時間加熱還流した。減圧下溶媒を留去し、得られた残渣を塩化メチレン(50mL)で希釈した。氷浴にて冷却しながらジイソプロピルエチルアミン(18.7mL,107mmol)、1-メチルピペラジン(4.37mL,39.2mmol)を加え、窒素雰囲気下室温で3日間撹拌した。反応液に水(100mL)を加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=3%~5%)を用いて精製することにより、茶色固体の目的化合物(5.32g,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.34 (3H, s), 2.44 (2H, t, J = 5.1 Hz), 2.53 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.1 Hz), 3.84 (2H, t, J = 4.9 Hz), 8.55 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz).
(34b)(2R)-1-{[t-ブチル(ジメチル)シリル]オキシ}プロパン-2-オール
(R)-(-)-1,2-プロパンジオール(21.23g,279.01mmol)を塩化メチレン(300ml)に溶解し、トリエチルアミン(58.33mL,418.52mmol)、4-ジメチルアミノピリジン(3.41g,27.90mmol)、t-ブチルジメチルクロロシラン(42.05g,279.01mmol)を加え、室温で終夜攪拌した。塩化メチレン(200mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することにより、無色油状の目的化合物(43.75g,82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.08 (6H, s), 0.91 (9H, s), 1.12 (3H, d, J = 6.3 Hz), 2.46 (1H, br s), 3.35 (1H, dd, J = 7.8, 10.2 Hz), 3.59 (1H, dd, J = 3.5, 10.2 Hz), 3.78-3.86 (1H, m).
(34c){[(2S)-2-(3-ブロモ-5-メトキシフェノキシ)プロピル]オキシ}(t-ブチル)ジメチルシラン
実施例(1a)で合成した化合物(33.47g,164.9mmol)、実施例(34b)で合成した化合物(37.7g,197.82mmol)、トリフェニルホスフィン(47.74g,181.3mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,79.00mL,181.34mmol)を用い、実施例(20a)と同様の方法で無色油状の目的化合物(57.19g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd, J = 5.1, 10.6 Hz), 3.74-3.78 (1H, m), 3.76 (3H, s), 4.34-4.41 (1H, m), 6.39 (1H, t, J = 2.3 Hz), 6.64 (1H, t, J = 1.6 Hz), 6.69 (1H, t, J = 1.6 Hz)。 (34a) 2-Chloro-5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine 5-hydroxypyrazine-2-carboxylic acid (5.00 g, 39.0 mmol) was dissolved in thionyl chloride (64 mL). After adding a few drops of N, N-dimethylformamide, the mixture was heated to reflux for 5 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with methylene chloride (50 mL). Diisopropylethylamine (18.7 mL, 107 mmol) and 1-methylpiperazine (4.37 mL, 39.2 mmol) were added while cooling in an ice bath, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 3% to 5%) to give the target compound (5.32 g, 5.3%, Yield 62%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.34 (3H, s), 2.44 (2H, t, J = 5.1 Hz), 2.53 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.1 Hz), 3.84 (2H, t, J = 4.9 Hz), 8.55 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.6 Hz).
(34b) (2R) -1-{[t-Butyl (dimethyl) silyl] oxy} propan-2-ol (R)-(−)-1,2-propanediol (21.23 g, 279.01 mmol) Dissolve in methylene chloride (300 ml) and add triethylamine (58.33 mL, 418.52 mmol), 4-dimethylaminopyridine (3.41 g, 27.90 mmol), t-butyldimethylchlorosilane (42.05 g, 279.01 mmol). In addition, the mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride (200 mL), and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to give a colorless oil. The target compound (43.75 g, 82%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.08 (6H, s), 0.91 (9H, s), 1.12 (3H, d, J = 6.3 Hz), 2.46 (1H, br s), 3.35 (1H, dd, J = 7.8, 10.2 Hz), 3.59 (1H, dd, J = 3.5, 10.2 Hz), 3.78-3.86 (1H, m).
(34c) {[(2S) -2- (3-Bromo-5-methoxyphenoxy) propyl] oxy} (t-butyl) dimethylsilane Compound synthesized in Example (1a) (33.47 g, 164.9 mmol) The compound synthesized in Example (34b) (37.7 g, 197.82 mmol), triphenylphosphine (47.74 g, 181.3 mmol), diethyl azodicarboxylate (40% toluene solution, 79.00 mL, 181.34 mmol) ) To give a colorless oily target compound (57.19 g, yield 92%) in the same manner as in Example (20a).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.74-3.78 (1H, m), 3.76 (3H, s), 4.34-4.41 (1H, m), 6.39 (1H, t, J = 2.3 Hz), 6.64 (1H, t, J = 1.6 Hz), 6.69 (1H, t, J = 1.6 Hz).
(34d)3-ブロモ-5-[(1S)-2-{[t-ブチル(ジメチル)シリル]オキシ}-1-メチルエトキシ]フェノール
実施例(34c)で合成した化合物(57.19g,152mmol)、ナトリウムチオメトキシド(11.56g,160mmol)を用い、実施例(1a)と同様の方法で淡黄色油状の目的化合物(45.50g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd, J = 5.1, 10.6 Hz), 3.75 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.33 (1H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s), 6.66 (1H, s).
(34e)ベンジル 5-{3-[(1S)-2-{[t-ブチル(ジメチル)シリル]オキシ}-1-メチルエトキシ]-5-ヒドロキシフェニル}-1H-ピロール-2-カルボキシレート
実施例(34d)で合成した化合物(45.50g,126mmol)、実施例(19e)で合成した化合物(43.26g,132mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(5.14g,6.30mmol)、炭酸カリウム(87.01g,630mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(56.70g,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.30 (3H, d, J = 6.3 Hz), 3.64 (1H, dd, J = 5.5, 10.6 Hz), 3.80 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.48 (1H, m), 5.35 (2H, s), 6.41 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.66 (1H, br s), 6.71 (1H, t, J = 1.6 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.32-7.46 (5H, m), 9.92 (1H, s).
(34f)ベンジル 5-{3-ヒドロキシ-5-[(1S)-2-ヒドロキシ-1-メチルエトキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(34e)で合成した化合物(34.12g,70.84mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,79.00mL,79.00mmol)を用い、実施例(16k)と同様の方法で淡黄色油状の目的化合物(22.00g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.3 Hz), 3.70-3.79 (2H, m), 4.47-4.54 (1H, m), 5.34 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, dd, J = 2.7, 3.9 Hz), 6.53 (1H, br s), 6.70 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.83 (1H, br s)。 (34d) 3-Bromo-5-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] phenol Compound (57.19 g, 152 mmol) synthesized in Example (34c) ) And sodium thiomethoxide (11.56 g, 160 mmol), and the target compound (45.50 g, yield 83%) was obtained as a pale yellow oil in the same manner as in Example (1a).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.75 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.33 (1H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s) , 6.66 (1H, s).
(34e) Benzyl 5- {3-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (45.50 g, 126 mmol) synthesized in Example (34d), compound (43.26 g, 132 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (5.14 g, 6.30 mmol) and potassium carbonate (87.01 g, 630 mmol) were used in the same manner as in Example (16e), and the target compound (56.70 g, yield: 93%) was obtained. )
1 H-NMR (CDCl 3 , 400 MHz): δ 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.30 (3H, d, J = 6.3 Hz), 3.64 (1H, dd , J = 5.5, 10.6 Hz), 3.80 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.48 (1H, m), 5.35 (2H, s), 6.41 (1H, t, J = 2.0 Hz) , 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.66 (1H, br s), 6.71 (1H, t, J = 1.6 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.99 (1H , dd, J = 2.7, 3.9 Hz), 7.32-7.46 (5H, m), 9.92 (1H, s).
(34f) Benzyl 5- {3-hydroxy-5-[(1S) -2-hydroxy-1-methylethoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (34.) synthesized in Example (34e). 12 g, 70.84 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 79.00 mL, 79.00 mmol), and the target compound (22.00 g) as a pale yellow oil in the same manner as in Example (16k). Yield 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 3.70-3.79 (2H, m), 4.47-4.54 (1H, m), 5.34 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, dd, J = 2.7, 3.9 Hz), 6.53 (1H, br s), 6.70 (1H, t, J = 1.6 Hz), 6.76 (1H, t , J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.83 (1H, br s).
実施例(34c)で合成した化合物(57.19g,152mmol)、ナトリウムチオメトキシド(11.56g,160mmol)を用い、実施例(1a)と同様の方法で淡黄色油状の目的化合物(45.50g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd, J = 5.1, 10.6 Hz), 3.75 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.33 (1H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s), 6.66 (1H, s).
(34e)ベンジル 5-{3-[(1S)-2-{[t-ブチル(ジメチル)シリル]オキシ}-1-メチルエトキシ]-5-ヒドロキシフェニル}-1H-ピロール-2-カルボキシレート
実施例(34d)で合成した化合物(45.50g,126mmol)、実施例(19e)で合成した化合物(43.26g,132mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(5.14g,6.30mmol)、炭酸カリウム(87.01g,630mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(56.70g,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.30 (3H, d, J = 6.3 Hz), 3.64 (1H, dd, J = 5.5, 10.6 Hz), 3.80 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.48 (1H, m), 5.35 (2H, s), 6.41 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.66 (1H, br s), 6.71 (1H, t, J = 1.6 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.32-7.46 (5H, m), 9.92 (1H, s).
(34f)ベンジル 5-{3-ヒドロキシ-5-[(1S)-2-ヒドロキシ-1-メチルエトキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(34e)で合成した化合物(34.12g,70.84mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,79.00mL,79.00mmol)を用い、実施例(16k)と同様の方法で淡黄色油状の目的化合物(22.00g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.3 Hz), 3.70-3.79 (2H, m), 4.47-4.54 (1H, m), 5.34 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, dd, J = 2.7, 3.9 Hz), 6.53 (1H, br s), 6.70 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.83 (1H, br s)。 (34d) 3-Bromo-5-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] phenol Compound (57.19 g, 152 mmol) synthesized in Example (34c) ) And sodium thiomethoxide (11.56 g, 160 mmol), and the target compound (45.50 g, yield 83%) was obtained as a pale yellow oil in the same manner as in Example (1a).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.04 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.27 (3H, d, J = 6.3 Hz), 3.63 (1H, dd , J = 5.1, 10.6 Hz), 3.75 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.33 (1H, m), 6.34 (1H, t, J = 2.0 Hz), 6.58 (1H, s) , 6.66 (1H, s).
(34e) Benzyl 5- {3-[(1S) -2-{[t-butyl (dimethyl) silyl] oxy} -1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (45.50 g, 126 mmol) synthesized in Example (34d), compound (43.26 g, 132 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (5.14 g, 6.30 mmol) and potassium carbonate (87.01 g, 630 mmol) were used in the same manner as in Example (16e), and the target compound (56.70 g, yield: 93%) was obtained. )
1 H-NMR (CDCl 3 , 400 MHz): δ 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.30 (3H, d, J = 6.3 Hz), 3.64 (1H, dd , J = 5.5, 10.6 Hz), 3.80 (1H, dd, J = 5.9, 10.6 Hz), 4.40-4.48 (1H, m), 5.35 (2H, s), 6.41 (1H, t, J = 2.0 Hz) , 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.66 (1H, br s), 6.71 (1H, t, J = 1.6 Hz), 6.80 (1H, t, J = 1.6 Hz), 6.99 (1H , dd, J = 2.7, 3.9 Hz), 7.32-7.46 (5H, m), 9.92 (1H, s).
(34f) Benzyl 5- {3-hydroxy-5-[(1S) -2-hydroxy-1-methylethoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (34.) synthesized in Example (34e). 12 g, 70.84 mmol), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 79.00 mL, 79.00 mmol), and the target compound (22.00 g) as a pale yellow oil in the same manner as in Example (16k). Yield 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.3 Hz), 3.70-3.79 (2H, m), 4.47-4.54 (1H, m), 5.34 (2H, s), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, dd, J = 2.7, 3.9 Hz), 6.53 (1H, br s), 6.70 (1H, t, J = 1.6 Hz), 6.76 (1H, t , J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.83 (1H, br s).
(34g)ベンジル 5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-ヒドロキシフェニル}-1H-ピロール-2-カルボキシレート
実施例(34f)で合成した化合物(4.81g,13.09mmol)を1,2-ジメトキシエタン(100mL)に溶解し、-78℃でビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.14mL,17.02mmol)を滴下した。窒素雰囲気下30分攪拌後、自然に昇温させ0℃で再びビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.00mL,16.27mmol)を加え30分攪拌した。自然に昇温させ室温で2時間攪拌後、さらにビス(2-メトキシエチル)アミノサルファー トリフルオリド(4.80mL,26.03mmol)を加え、終夜攪拌した。エタノール(10mL)を加え10分攪拌後、水(40mL)を加えた。酢酸エチル(200mL)で抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、黄色固体の目的化合物(4.00g,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.69 (3H, m), 5.35 (2H, s), 6.32 (1H, br s), 6.41 (1H, t, J = 2.0 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.73 (1H, t, J = 1.6 Hz), 6.81 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.33-7.46 (5H, m), 9.81 (1H, s).
(34h)ベンジル 5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-({5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン-2-イル}オキシ)フェニル}-1H-ピロール-2-カルボキシレート
実施例(34g)で合成した化合物(1.50g,4.06mmol)、(34a)で合成した化合物(0.96g,3.98mmol)をアセトニトリル(40mL)に溶解し、炭酸カリウム(1.68g,12.18mmol)を加え、窒素雰囲気下80℃で18時間攪拌した。反応液を室温まで冷却後に水(30mL)を加え、酢酸エチル(80mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~5%)を用いて精製することにより、白色固体の目的化合物(2.20g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 2.34 (3H, s), 2.43-2.46 (2H, br m), 2.51-2.54 (2H, br m), 3.69-3.73 (2H, br m), 3.81-3.85 (2H, br m), 4.43-4.72 (3H, m), 5.32 (2H, s), 6.52 (1H, dd, J = 2.7, 4.3 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 4.3 Hz), 7.03 (1H, t, J = 1.6 Hz), 7.32-7.44 (5H, m), 8.35 (1H, d, J = 1.6 Hz), 8.53 (1H, d, J = 1.2 Hz), 9.31 (1H, br s)。 (34 g) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (4.) synthesized in Example (34f). 81 g, 13.09 mmol) was dissolved in 1,2-dimethoxyethane (100 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (3.14 mL, 17.02 mmol) was added dropwise at -78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, the temperature was naturally raised, and bis (2-methoxyethyl) aminosulfur trifluoride (3.00 mL, 16.27 mmol) was added again at 0 ° C., followed by stirring for 30 minutes. The mixture was naturally warmed up and stirred at room temperature for 2 hours. Further, bis (2-methoxyethyl) aminosulfur trifluoride (4.80 mL, 26.03 mmol) was added, and the mixture was stirred overnight. Ethanol (10 mL) was added and the mixture was stirred for 10 min, and water (40 mL) was added. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -40%) to give the target compound (4.00 g, 4.00 g, 83%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.69 (3H, m), 5.35 (2H, s), 6.32 (1H, br s), 6.41 (1H, t, J = 2.0 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.73 (1H, t, J = 1.6 Hz), 6.81 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.33-7.46 (5H, m), 9.81 (1H, s).
(34h) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy ) Phenyl} -1H-pyrrole-2-carboxylate Compound (1.50 g, 4.06 mmol) synthesized in Example (34 g) and compound (0.96 g, 3.98 mmol) synthesized in (34a) were mixed with acetonitrile ( 40 mL), potassium carbonate (1.68 g, 12.18 mmol) was added, and the mixture was stirred at 80 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give the target compound (2.20 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 2.34 (3H, s), 2.43-2.46 (2H, br m), 2.51-2.54 (2H, br m), 3.69-3.73 (2H, br m), 3.81-3.85 (2H, br m), 4.43-4.72 (3H, m), 5.32 (2H, s), 6.52 (1H, dd, J = 2.7, 4.3 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 4.3 Hz), 7.03 (1H, t, J = 1.6 Hz), 7.32-7.44 (5H, m), 8.35 (1H, d, J = 1.6 Hz), 8.53 (1H, d, J = 1.2 Hz), 9.31 (1H, br s).
実施例(34f)で合成した化合物(4.81g,13.09mmol)を1,2-ジメトキシエタン(100mL)に溶解し、-78℃でビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.14mL,17.02mmol)を滴下した。窒素雰囲気下30分攪拌後、自然に昇温させ0℃で再びビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.00mL,16.27mmol)を加え30分攪拌した。自然に昇温させ室温で2時間攪拌後、さらにビス(2-メトキシエチル)アミノサルファー トリフルオリド(4.80mL,26.03mmol)を加え、終夜攪拌した。エタノール(10mL)を加え10分攪拌後、水(40mL)を加えた。酢酸エチル(200mL)で抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、黄色固体の目的化合物(4.00g,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.69 (3H, m), 5.35 (2H, s), 6.32 (1H, br s), 6.41 (1H, t, J = 2.0 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.73 (1H, t, J = 1.6 Hz), 6.81 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.33-7.46 (5H, m), 9.81 (1H, s).
(34h)ベンジル 5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-({5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン-2-イル}オキシ)フェニル}-1H-ピロール-2-カルボキシレート
実施例(34g)で合成した化合物(1.50g,4.06mmol)、(34a)で合成した化合物(0.96g,3.98mmol)をアセトニトリル(40mL)に溶解し、炭酸カリウム(1.68g,12.18mmol)を加え、窒素雰囲気下80℃で18時間攪拌した。反応液を室温まで冷却後に水(30mL)を加え、酢酸エチル(80mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~5%)を用いて精製することにより、白色固体の目的化合物(2.20g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 2.34 (3H, s), 2.43-2.46 (2H, br m), 2.51-2.54 (2H, br m), 3.69-3.73 (2H, br m), 3.81-3.85 (2H, br m), 4.43-4.72 (3H, m), 5.32 (2H, s), 6.52 (1H, dd, J = 2.7, 4.3 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 4.3 Hz), 7.03 (1H, t, J = 1.6 Hz), 7.32-7.44 (5H, m), 8.35 (1H, d, J = 1.6 Hz), 8.53 (1H, d, J = 1.2 Hz), 9.31 (1H, br s)。 (34 g) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-hydroxyphenyl} -1H-pyrrole-2-carboxylate Compound (4.) synthesized in Example (34f). 81 g, 13.09 mmol) was dissolved in 1,2-dimethoxyethane (100 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (3.14 mL, 17.02 mmol) was added dropwise at -78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, the temperature was naturally raised, and bis (2-methoxyethyl) aminosulfur trifluoride (3.00 mL, 16.27 mmol) was added again at 0 ° C., followed by stirring for 30 minutes. The mixture was naturally warmed up and stirred at room temperature for 2 hours. Further, bis (2-methoxyethyl) aminosulfur trifluoride (4.80 mL, 26.03 mmol) was added, and the mixture was stirred overnight. Ethanol (10 mL) was added and the mixture was stirred for 10 min, and water (40 mL) was added. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -40%) to give the target compound (4.00 g, 4.00 g, 83%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.69 (3H, m), 5.35 (2H, s), 6.32 (1H, br s), 6.41 (1H, t, J = 2.0 Hz), 6.49 (1H, dd, J = 2.7, 3.9 Hz), 6.73 (1H, t, J = 1.6 Hz), 6.81 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.33-7.46 (5H, m), 9.81 (1H, s).
(34h) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy ) Phenyl} -1H-pyrrole-2-carboxylate Compound (1.50 g, 4.06 mmol) synthesized in Example (34 g) and compound (0.96 g, 3.98 mmol) synthesized in (34a) were mixed with acetonitrile ( 40 mL), potassium carbonate (1.68 g, 12.18 mmol) was added, and the mixture was stirred at 80 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give the target compound (2.20 g, Yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 2.34 (3H, s), 2.43-2.46 (2H, br m), 2.51-2.54 (2H, br m), 3.69-3.73 (2H, br m), 3.81-3.85 (2H, br m), 4.43-4.72 (3H, m), 5.32 (2H, s), 6.52 (1H, dd, J = 2.7, 4.3 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 4.3 Hz), 7.03 (1H, t, J = 1.6 Hz), 7.32-7.44 (5H, m), 8.35 (1H, d, J = 1.6 Hz), 8.53 (1H, d, J = 1.2 Hz), 9.31 (1H, br s).
(34i)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-({5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン-2-イル}オキシ)フェニル}-1H-ピロール-2-カルボン酸
実施例(34h)で合成した化合物(2.20g,3.84mmol)をメタノール(35mL)に溶解し、10%パラジウム炭素触媒(2.4g)を加えて水素雰囲気下に6時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで淡黄色固体の目的化合物(1.54g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.30 (3H, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.88 (4H, br m), 4.37-4.70 (3H, m), 6.43 (1H, s), 6.60 (1H, s), 6.79 (1H, s), 7.00-7.11 (2H, m), 8.24 (1H, s), 8.47 (1H, s), 10.41 (1H, br s).
(34j)2-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン
実施例(34i)で合成した化合物(500mg,1.03mmol)、(R)-1-アミノ-2-プロパノール(194mg,2.59mmol)、4-ジメチルアミノピリジン(505mg, 4.14mmol)を塩化メチレン(20mL)に溶解し、室温でWSCI・HCl(496mg, 2.59mmol)を加え、窒素雰囲気下15時間撹拌した。反応液を塩化メチレン(60mL)で希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5%)を用いて精製した。 (34i) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy) Phenyl} -1H-pyrrole-2-carboxylic acid The compound (2.20 g, 3.84 mmol) synthesized in Example (34h) was dissolved in methanol (35 mL), and 10% palladium carbon catalyst (2.4 g) was added. And stirred for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.54 g, yield 83%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.30 (3H, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.88 (4H, br m), 4.37-4.70 ( 3H, m), 6.43 (1H, s), 6.60 (1H, s), 6.79 (1H, s), 7.00-7.11 (2H, m), 8.24 (1H, s), 8.47 (1H, s), 10.41 (1H, br s).
(34j) 2- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine The compound synthesized in Example (34i) (500 mg, 1.03 mmol), (R ) -1-amino-2-propanol (194 mg, 2.59 mmol) and 4-dimethylaminopyridine (505 mg, 4.14 mmol) were dissolved in methylene chloride (20 mL), and WSCI.HCl (496 mg, 2.59 mmol) was dissolved at room temperature. And stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5%).
実施例(34h)で合成した化合物(2.20g,3.84mmol)をメタノール(35mL)に溶解し、10%パラジウム炭素触媒(2.4g)を加えて水素雰囲気下に6時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで淡黄色固体の目的化合物(1.54g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.30 (3H, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.88 (4H, br m), 4.37-4.70 (3H, m), 6.43 (1H, s), 6.60 (1H, s), 6.79 (1H, s), 7.00-7.11 (2H, m), 8.24 (1H, s), 8.47 (1H, s), 10.41 (1H, br s).
(34j)2-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-[(4-メチルピペラジン-1-イル)カルボニル]ピラジン
実施例(34i)で合成した化合物(500mg,1.03mmol)、(R)-1-アミノ-2-プロパノール(194mg,2.59mmol)、4-ジメチルアミノピリジン(505mg, 4.14mmol)を塩化メチレン(20mL)に溶解し、室温でWSCI・HCl(496mg, 2.59mmol)を加え、窒素雰囲気下15時間撹拌した。反応液を塩化メチレン(60mL)で希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5%)を用いて精製した。 (34i) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy) Phenyl} -1H-pyrrole-2-carboxylic acid The compound (2.20 g, 3.84 mmol) synthesized in Example (34h) was dissolved in methanol (35 mL), and 10% palladium carbon catalyst (2.4 g) was added. And stirred for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.54 g, yield 83%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.30 (3H, s), 2.38 (3H, s), 2.53-2.67 (4H, br m), 3.68-3.88 (4H, br m), 4.37-4.70 ( 3H, m), 6.43 (1H, s), 6.60 (1H, s), 6.79 (1H, s), 7.00-7.11 (2H, m), 8.24 (1H, s), 8.47 (1H, s), 10.41 (1H, br s).
(34j) 2- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine The compound synthesized in Example (34i) (500 mg, 1.03 mmol), (R ) -1-amino-2-propanol (194 mg, 2.59 mmol) and 4-dimethylaminopyridine (505 mg, 4.14 mmol) were dissolved in methylene chloride (20 mL), and WSCI.HCl (496 mg, 2.59 mmol) was dissolved at room temperature. And stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 5%).
得られた白色固体の化合物(360mg)、メタンスルホン酸無水物(185mg,1.02mmol)、トリエチルアミン(285μL,2.03mmol)を用い、実施例(16j)と同様の方法で、白色固体の目的化合物(242mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 2.34 (3H, s), 2.44-2.48 (2H, br m), 2.51-2.55 (2H, br m), 3.55 (1H, dd, J = 7.4, 14.1 Hz), 3.70-3.74 (2H, br m), 3.81-3.86 (2H, br m), 4.09 (1H, dd, J = 9.4, 14.1 Hz), 4.44-4.72 (3H, m), 4.80-4.88 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.65 (1H, t, J = 2.3 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.95 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz), 8.54 (1H, d, J = 1.2 Hz).
MS (ESI) m/z: 523.24603 (M+H)+。 Using the obtained white solid compound (360 mg), methanesulfonic anhydride (185 mg, 1.02 mmol) and triethylamine (285 μL, 2.03 mmol), in the same manner as in Example (16j), the purpose of the white solid was The compound (242 mg, yield 49%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 2.34 (3H, s), 2.44-2.48 (2H , br m), 2.51-2.55 (2H, br m), 3.55 (1H, dd, J = 7.4, 14.1 Hz), 3.70-3.74 (2H, br m), 3.81-3.86 (2H, br m), 4.09 (1H, dd, J = 9.4, 14.1 Hz), 4.44-4.72 (3H, m), 4.80-4.88 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.65 (1H, t, J = 2.3 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.95 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz), 8.54 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 523.24603 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 2.34 (3H, s), 2.44-2.48 (2H, br m), 2.51-2.55 (2H, br m), 3.55 (1H, dd, J = 7.4, 14.1 Hz), 3.70-3.74 (2H, br m), 3.81-3.86 (2H, br m), 4.09 (1H, dd, J = 9.4, 14.1 Hz), 4.44-4.72 (3H, m), 4.80-4.88 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.65 (1H, t, J = 2.3 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.95 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz), 8.54 (1H, d, J = 1.2 Hz).
MS (ESI) m/z: 523.24603 (M+H)+。 Using the obtained white solid compound (360 mg), methanesulfonic anhydride (185 mg, 1.02 mmol) and triethylamine (285 μL, 2.03 mmol), in the same manner as in Example (16j), the purpose of the white solid was The compound (242 mg, yield 49%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.43 (3H, d, J = 6.3 Hz), 2.34 (3H, s), 2.44-2.48 (2H , br m), 2.51-2.55 (2H, br m), 3.55 (1H, dd, J = 7.4, 14.1 Hz), 3.70-3.74 (2H, br m), 3.81-3.86 (2H, br m), 4.09 (1H, dd, J = 9.4, 14.1 Hz), 4.44-4.72 (3H, m), 4.80-4.88 (1H, m), 6.52 (1H, d, J = 3.9 Hz), 6.65 (1H, t, J = 2.3 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.95 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 8.35 (1H, d, J = 1.6 Hz), 8.54 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 523.24603 (M + H) <+> .
(実施例35)
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 35)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 35)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol
(35a)ベンジル 5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(34g)で合成した化合物(924mg,2.50mmol)と実施例(16a)で合成した化合物(503mg,2.63mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(2.44g,7.50mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却後に水(50mL)を加え、ジエチルエーテル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色固体の目的化合物(1.67g,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 3.1, 3.9 Hz), 6.59 (1H, t, J = 2.3 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).
(35b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(35a)で合成した化合物(1.67g,3.18mmol)を酢酸エチル(30mL)とエタノール(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(820mg)を加えて水素雰囲気下に5時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(1.31g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, d, J = 6.3 Hz), 3.21 (3H, s), 4.43-4.74 (3H, m), 6.51 (1H, s), 6.60 (1H, s), 6.91 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.67 (1H, br s).
(35c)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.31g,3.02mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(0.69g,7.54mmol)、DMT-MM(2.39g,7.54mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(1.27g,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.47-3.60 (4H, m), 3.79-3.83 (1H, br m), 4.44-4.73 (3H, m), 6.48 (1H, dd, J = 2.3, 3.9 Hz), 6.54 (1H, t, J = 6.3 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.64 (1H, dd, J = 2.0, 3.9 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 10.03 (1H, br s)。 (35a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (924 mg, 2.50 mmol) synthesized in Example (34 g) and compound (503 mg, 2.63 mmol) synthesized in Example (16a) were dissolved in N, N-dimethylformamide (20 mL). Cesium carbonate (2.44 g, 7.50 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (1.67 g) as a pale yellow solid. Yield 62%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 3.1, 3.9 Hz), 6.59 (1H, t, J = 2.3 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz) , 7.01 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).
(35b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.67 g, 3.18 mmol) synthesized in Example (35a) was dissolved in a mixed solvent of ethyl acetate (30 mL) and ethanol (5 mL), 10% palladium carbon catalyst (820 mg) was added, and hydrogen was added. Stir for 5 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.31 g, yield 95%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, d, J = 6.3 Hz), 3.21 (3H, s), 4.43-4.74 (3H, m), 6.51 (1H, s), 6.60 (1H , s), 6.91 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.67 (1H, br s).
(35c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine- 3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.31 g, 3.02 mmol) synthesized in Example (35b), (S)-(−)-3-amino-1,2 Using propanediol (0.69 g, 7.54 mmol) and DMT-MM (2.39 g, 7.54 mmol) in the same manner as in Example (5d), the target compound (1.27 g, 83% )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.47-3.60 (4H, m), 3.79-3.83 (1H, br m ), 4.44-4.73 (3H, m), 6.48 (1H, dd, J = 2.3, 3.9 Hz), 6.54 (1H, t, J = 6.3 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.64 (1H, dd, J = 2.0, 3.9 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz) , 8.03 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 10.03 (1H, br s).
実施例(34g)で合成した化合物(924mg,2.50mmol)と実施例(16a)で合成した化合物(503mg,2.63mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(2.44g,7.50mmol)を加え、窒素雰囲気下100℃で2時間撹拌した。反応液を室温まで冷却後に水(50mL)を加え、ジエチルエーテル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、淡黄色固体の目的化合物(1.67g,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 3.1, 3.9 Hz), 6.59 (1H, t, J = 2.3 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).
(35b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(35a)で合成した化合物(1.67g,3.18mmol)を酢酸エチル(30mL)とエタノール(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(820mg)を加えて水素雰囲気下に5時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(1.31g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, d, J = 6.3 Hz), 3.21 (3H, s), 4.43-4.74 (3H, m), 6.51 (1H, s), 6.60 (1H, s), 6.91 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.67 (1H, br s).
(35c)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.31g,3.02mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(0.69g,7.54mmol)、DMT-MM(2.39g,7.54mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(1.27g,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.47-3.60 (4H, m), 3.79-3.83 (1H, br m), 4.44-4.73 (3H, m), 6.48 (1H, dd, J = 2.3, 3.9 Hz), 6.54 (1H, t, J = 6.3 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.64 (1H, dd, J = 2.0, 3.9 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 10.03 (1H, br s)。 (35a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (924 mg, 2.50 mmol) synthesized in Example (34 g) and compound (503 mg, 2.63 mmol) synthesized in Example (16a) were dissolved in N, N-dimethylformamide (20 mL). Cesium carbonate (2.44 g, 7.50 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with diethyl ether (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the target compound (1.67 g) as a pale yellow solid. Yield 62%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 4.45-4.70 (3H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 3.1, 3.9 Hz), 6.59 (1H, t, J = 2.3 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz) , 7.01 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.33 (1H, br s).
(35b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.67 g, 3.18 mmol) synthesized in Example (35a) was dissolved in a mixed solvent of ethyl acetate (30 mL) and ethanol (5 mL), 10% palladium carbon catalyst (820 mg) was added, and hydrogen was added. Stir for 5 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.31 g, yield 95%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, d, J = 6.3 Hz), 3.21 (3H, s), 4.43-4.74 (3H, m), 6.51 (1H, s), 6.60 (1H , s), 6.91 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.44 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.67 (1H, br s).
(35c) N-[(2S) -2,3-dihydroxypropyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine- 3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.31 g, 3.02 mmol) synthesized in Example (35b), (S)-(−)-3-amino-1,2 Using propanediol (0.69 g, 7.54 mmol) and DMT-MM (2.39 g, 7.54 mmol) in the same manner as in Example (5d), the target compound (1.27 g, 83% )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.47-3.60 (4H, m), 3.79-3.83 (1H, br m ), 4.44-4.73 (3H, m), 6.48 (1H, dd, J = 2.3, 3.9 Hz), 6.54 (1H, t, J = 6.3 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.64 (1H, dd, J = 2.0, 3.9 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz) , 8.03 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 10.03 (1H, br s).
(35d)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(35c)で合成した化合物(1.27g,2.50mmol)を塩化メチレン(25mL)に溶解し、トリイソプロピルシリルクロリド(0.80mL,3.75mmol)、トリエチルアミン(1.74mL, 12.51mol)、4-ジメチルアミノピリジン(0.46g,3.75mmol)を加え、窒素雰囲気下室温で22時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的物(1.46g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.13 (21H, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H, s), 3.34-3.42 (1H, m), 3.64-3.78 (3H, m), 3.83-3.90 (1H, br m), 4.44-4.73 (3H, m), 6.38 (1H, t, J = 5.9 Hz), 6.50 (1H, dd, J = 2.7, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.01 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.72 (1H, s).
(35e)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(35d)で合成した化合物(1.46g,2.20mmol)、メタンスルホン酸無水物(790mg,4.40mmol)、トリエチルアミン(1.23mL,8.80mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(1.25g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.03-1.14 (21H, m), 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.82-3.94 (4H, m), 4.44-4.71 (3H, m), 4.72-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(35f){(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(35e)で合成した化合物(1.25g,1.94mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.32mL,2.32mmol)を用い、実施例(16k)と同様の方法で淡黄色固体の目的化合物(830mg,収率88%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.34 (1H, br s), 3.67-3.77 (2H, m), 3.82 (1H, dd, J = 3.1, 12.1 Hz), 4.01 (1H, dd, J = 9.8, 13.7 Hz), 4.44-4.72 (3H, m), 4.74-4.81 (1H, m), 6.43 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 7.00 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 490.14446 (M+H)+。 (35d) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-Hydroxy-3-[(triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (1.27 g, 2.50 mmol) synthesized in Example (35c) was added to methylene chloride (25 mL). Dissolve, add triisopropylsilyl chloride (0.80 mL, 3.75 mmol), triethylamine (1.74 mL, 12.51 mol), 4-dimethylaminopyridine (0.46 g, 3.75 mmol), and add nitrogen at room temperature. Stir for 22 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the desired product (1.46 g, Yield 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.13 (21H, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H , s), 3.34-3.42 (1H, m), 3.64-3.78 (3H, m), 3.83-3.90 (1H, br m), 4.44-4.73 (3H, m), 6.38 (1H, t, J = 5.9 Hz), 6.50 (1H, dd, J = 2.7, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.01 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.72 (1H, s).
(35e) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (35d) (1.46 g, 2.20 mmol) , Methanesulfonic anhydride (790 mg, 4.40 mmol) and triethylamine (1.23 mL, 8.80 mmol) in the same manner as in Example (16j), the target compound (1.25 g, yield) 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.03-1.14 (21H, m), 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.82-3.94 (4H, m), 4.44-4.71 (3H, m), 4.72-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.85 ( 1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 ( (1H, d, J = 2.7 Hz).
(35f) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (1.25 g, 1.94 mmol) synthesized in Example (35e), tetrabutylammonium The target compound (830 mg, yield 88%) was obtained as a pale yellow solid in the same manner as in Example (16k) using fluoride (1 mol / L tetrahydrofuran solution, 2.32 mL, 2.32 mmol).
1 H-NMR (CDCl 3 , 500 MHz): δ1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.34 (1H, br s), 3.67-3.77 (2H, m) , 3.82 (1H, dd, J = 3.1, 12.1 Hz), 4.01 (1H, dd, J = 9.8, 13.7 Hz), 4.44-4.72 (3H, m), 4.74-4.81 (1H, m), 6.43 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 7.00 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14446 (M + H) <+> .
実施例(35c)で合成した化合物(1.27g,2.50mmol)を塩化メチレン(25mL)に溶解し、トリイソプロピルシリルクロリド(0.80mL,3.75mmol)、トリエチルアミン(1.74mL, 12.51mol)、4-ジメチルアミノピリジン(0.46g,3.75mmol)を加え、窒素雰囲気下室温で22時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的物(1.46g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.13 (21H, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H, s), 3.34-3.42 (1H, m), 3.64-3.78 (3H, m), 3.83-3.90 (1H, br m), 4.44-4.73 (3H, m), 6.38 (1H, t, J = 5.9 Hz), 6.50 (1H, dd, J = 2.7, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.01 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.72 (1H, s).
(35e)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(35d)で合成した化合物(1.46g,2.20mmol)、メタンスルホン酸無水物(790mg,4.40mmol)、トリエチルアミン(1.23mL,8.80mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(1.25g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.03-1.14 (21H, m), 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.82-3.94 (4H, m), 4.44-4.71 (3H, m), 4.72-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(35f){(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(35e)で合成した化合物(1.25g,1.94mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.32mL,2.32mmol)を用い、実施例(16k)と同様の方法で淡黄色固体の目的化合物(830mg,収率88%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.34 (1H, br s), 3.67-3.77 (2H, m), 3.82 (1H, dd, J = 3.1, 12.1 Hz), 4.01 (1H, dd, J = 9.8, 13.7 Hz), 4.44-4.72 (3H, m), 4.74-4.81 (1H, m), 6.43 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 7.00 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 490.14446 (M+H)+。 (35d) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2S) -2-Hydroxy-3-[(triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound (1.27 g, 2.50 mmol) synthesized in Example (35c) was added to methylene chloride (25 mL). Dissolve, add triisopropylsilyl chloride (0.80 mL, 3.75 mmol), triethylamine (1.74 mL, 12.51 mol), 4-dimethylaminopyridine (0.46 g, 3.75 mmol), and add nitrogen at room temperature. Stir for 22 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the desired product (1.46 g, Yield 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.13 (21H, m), 1.36 (3H, dd, J = 6.3, 1.6 Hz), 3.13 (1H, d, J = 4.7 Hz), 3.23 (3H , s), 3.34-3.42 (1H, m), 3.64-3.78 (3H, m), 3.83-3.90 (1H, br m), 4.44-4.73 (3H, m), 6.38 (1H, t, J = 5.9 Hz), 6.50 (1H, dd, J = 2.7, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.61 (1H, dd, J = 2.3, 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.01 (1H, d, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.72 (1H, s).
(35e) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine Compound synthesized in Example (35d) (1.46 g, 2.20 mmol) , Methanesulfonic anhydride (790 mg, 4.40 mmol) and triethylamine (1.23 mL, 8.80 mmol) in the same manner as in Example (16j), the target compound (1.25 g, yield) 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.03-1.14 (21H, m), 1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.82-3.94 (4H, m), 4.44-4.71 (3H, m), 4.72-4.79 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.73 (1H, d, J = 3.9 Hz), 6.85 ( 1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 ( (1H, d, J = 2.7 Hz).
(35f) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (1.25 g, 1.94 mmol) synthesized in Example (35e), tetrabutylammonium The target compound (830 mg, yield 88%) was obtained as a pale yellow solid in the same manner as in Example (16k) using fluoride (1 mol / L tetrahydrofuran solution, 2.32 mL, 2.32 mmol).
1 H-NMR (CDCl 3 , 500 MHz): δ1.36 (3H, dd, J = 1.6, 6.3 Hz), 3.23 (3H, s), 3.34 (1H, br s), 3.67-3.77 (2H, m) , 3.82 (1H, dd, J = 3.1, 12.1 Hz), 4.01 (1H, dd, J = 9.8, 13.7 Hz), 4.44-4.72 (3H, m), 4.74-4.81 (1H, m), 6.43 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.3 Hz), 6.65 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 7.00 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14446 (M + H) <+> .
(実施例36)
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン (Example 36)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン (Example 36)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine
(36a)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-[(1R)-2-ヒドロキシ-1-メチルエチル]-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(150mg,0.35mmol)、D-アラニノール(80μL,1.04mmol)、DMT-MM(273mg,0.86mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(124mg,73%)を得た。
1H -NMR (CDCl3, 400MHz):δ 1.26 (3H, d, J = 7.0 Hz), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 2.92 (1H, t, J = 5.5 Hz), 3.23 (3H, s), 3.57-3.63 (1H, m), 3.72-3.78 (1H, m), 4.20-4.27 (1H, br m), 4.45-4.72 (3H, m), 6.11 (1H, d, J = 7.4 Hz), 6.48 (1H, t, J = 3.5 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.87 (1H, br s).
(36b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(36a)で合成した化合物(124mg,0.25mmol)、メタンスルホン酸無水物(91mg,0.50mmol)、トリエチルアミン(0.14mL,1.01mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(84mg,70%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 1.36 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.45-4.72 (4H, m), 6.52 (1H, d, J = 3.5 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 474.14763(M+H)+。 (36a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -2-Hydroxy-1-methylethyl] -1H-pyrrole-2-carboxamide Compound (150 mg, 0.35 mmol) synthesized in Example (35b), D-alaninol (80 μL, 1.04 mmol), DMT-MM ( 273 mg, 0.86 mmol) was used to give the target compound (124 mg, 73%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.26 (3H, d, J = 7.0 Hz), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 2.92 (1H, t, J = 5.5 Hz), 3.23 (3H, s), 3.57-3.63 (1H, m), 3.72-3.78 (1H, m), 4.20-4.27 (1H, br m), 4.45-4.72 (3H, m), 6.11 (1H, d, J = 7.4 Hz), 6.48 (1H, t, J = 3.5 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.87 (1H, br s).
(36b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (36a) (124 mg, 0.25 mmol), methanesulfonic anhydride (91 mg, 0.50 mmol) ) And triethylamine (0.14 mL, 1.01 mmol) were used to obtain the target compound (84 mg, 70%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 1.36 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.45-4.72 (4H, m), 6.52 (1H, d, J = 3.5 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.76 (1H , d, J = 3.5 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 474.14763 (M + H) <+> .
実施例(35b)で合成した化合物(150mg,0.35mmol)、D-アラニノール(80μL,1.04mmol)、DMT-MM(273mg,0.86mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(124mg,73%)を得た。
1H -NMR (CDCl3, 400MHz):δ 1.26 (3H, d, J = 7.0 Hz), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 2.92 (1H, t, J = 5.5 Hz), 3.23 (3H, s), 3.57-3.63 (1H, m), 3.72-3.78 (1H, m), 4.20-4.27 (1H, br m), 4.45-4.72 (3H, m), 6.11 (1H, d, J = 7.4 Hz), 6.48 (1H, t, J = 3.5 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.87 (1H, br s).
(36b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(36a)で合成した化合物(124mg,0.25mmol)、メタンスルホン酸無水物(91mg,0.50mmol)、トリエチルアミン(0.14mL,1.01mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(84mg,70%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 1.36 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.45-4.72 (4H, m), 6.52 (1H, d, J = 3.5 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.76 (1H, d, J = 3.5 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 474.14763(M+H)+。 (36a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -2-Hydroxy-1-methylethyl] -1H-pyrrole-2-carboxamide Compound (150 mg, 0.35 mmol) synthesized in Example (35b), D-alaninol (80 μL, 1.04 mmol), DMT-MM ( 273 mg, 0.86 mmol) was used to give the target compound (124 mg, 73%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.26 (3H, d, J = 7.0 Hz), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 2.92 (1H, t, J = 5.5 Hz), 3.23 (3H, s), 3.57-3.63 (1H, m), 3.72-3.78 (1H, m), 4.20-4.27 (1H, br m), 4.45-4.72 (3H, m), 6.11 (1H, d, J = 7.4 Hz), 6.48 (1H, t, J = 3.5 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.01 (1H, t, J = 1.6 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.87 (1H, br s).
(36b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (36a) (124 mg, 0.25 mmol), methanesulfonic anhydride (91 mg, 0.50 mmol) ) And triethylamine (0.14 mL, 1.01 mmol) were used to obtain the target compound (84 mg, 70%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 1.36 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.45-4.72 (4H, m), 6.52 (1H, d, J = 3.5 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.76 (1H , d, J = 3.5 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 474.14763 (M + H) <+> .
(実施例37)
5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-(5-{[(4R)-4-[2-(メチルチオ)エチル]-4,5-ジヒドロ-1,3-オキサゾール-2-イル}-1H-ピロール-2-イル)フェノキシ}-2-(メチルスルホニル)ピリジン (Example 37)
5- {3-[(1S) -2-fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro-1, 3-Oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine
5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-(5-{[(4R)-4-[2-(メチルチオ)エチル]-4,5-ジヒドロ-1,3-オキサゾール-2-イル}-1H-ピロール-2-イル)フェノキシ}-2-(メチルスルホニル)ピリジン (Example 37)
5- {3-[(1S) -2-fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro-1, 3-Oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine
(37a)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-[(1R)-1-(ヒドロキシメチル)-3-(メチルチオ)プロピル]-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(150mg,0.35mmol)、D-メチオニノール(51mg,0.38mmol)、HOBT・H2O(51mg,0.38mmol)、N-メチルモルホリン(76μL,0.69mmol)、WSCI・HCl(79mg,0.41mmol)を用い、実施例(29a)と同様の方法で無色油状の目的化合物(174mg,91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.90-2.00 (2H, m), 2.14 (3H, s), 2.62 (2H, t, J = 6.6 Hz), 3.24 (3H, s), 3.72-3.82 (2H, m), 4.21-4.29 (1H, br m), 4.45-4.74 (3H, m), 6.41 (1H, d, J = 8.2 Hz), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.64 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, t, J = 1.8 Hz), 7.00 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) 9.49 (1H, br s).
(37b)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-(5-{[(4R)-4-[2-(メチルチオ)エチル]-4,5-ジヒドロ-1,3-オキサゾール-2-イル}-1H-ピロール-2-イル)フェノキシ}-2-(メチルスルホニル)ピリジン
実施例(37a)で合成した化合物(178mg,0.32mmol)、メタンスルホン酸無水物(116mg,0.65mmol)、トリエチルアミン(0.22mL,1.61mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(88mg,51%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, dd, J = 1.6, 6.3 Hz), 1.75-1.90 (2H, m), 2.03 (3H, s), 2.49-2.63 (2H, m), 3.23 (3H, s), 4.03 (1H, t, J = 7.8 Hz), 4.24-4.32 (1H, m), 4.42-4.68 (4H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (FAB+) m/z: 534.1534 (M+H)+。 (37a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -1- (Hydroxymethyl) -3- (methylthio) propyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (35b) (150 mg, 0.35 mmol), D-methioninol (51 mg, 0.38 mmol) , HOBT · H 2 O (51 mg, 0.38 mmol), N-methylmorpholine (76 μL, 0.69 mmol), WSCI · HCl (79 mg, 0.41 mmol) and colorless in the same manner as in Example (29a) An oily target compound (174 mg, 91%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.90-2.00 (2H, m), 2.14 (3H, s), 2.62 (2H, t, J = 6.6 Hz), 3.24 (3H, s), 3.72-3.82 (2H, m), 4.21-4.29 (1H, br m), 4.45-4.74 (3H, m), 6.41 (1H, d, J = 8.2 Hz) , 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.64 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, t, J = 1.8 Hz), 7.00 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) 9.49 (1H, br s).
(37b) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro -1,3-oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine Compound (178 mg, 0.32 mmol) synthesized in Example (37a), methanesulfonic acid The target compound (88 mg, 51%) was obtained as a white solid in the same manner as in Example (16j) using anhydride (116 mg, 0.65 mmol) and triethylamine (0.22 mL, 1.61 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, dd, J = 1.6, 6.3 Hz), 1.75-1.90 (2H, m), 2.03 (3H, s), 2.49-2.63 (2H, m) , 3.23 (3H, s), 4.03 (1H, t, J = 7.8 Hz), 4.24-4.32 (1H, m), 4.42-4.68 (4H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.42 ( 1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (FAB <+> ) m / z: 534.1534 (M + H) <+> .
実施例(35b)で合成した化合物(150mg,0.35mmol)、D-メチオニノール(51mg,0.38mmol)、HOBT・H2O(51mg,0.38mmol)、N-メチルモルホリン(76μL,0.69mmol)、WSCI・HCl(79mg,0.41mmol)を用い、実施例(29a)と同様の方法で無色油状の目的化合物(174mg,91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.90-2.00 (2H, m), 2.14 (3H, s), 2.62 (2H, t, J = 6.6 Hz), 3.24 (3H, s), 3.72-3.82 (2H, m), 4.21-4.29 (1H, br m), 4.45-4.74 (3H, m), 6.41 (1H, d, J = 8.2 Hz), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.64 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, t, J = 1.8 Hz), 7.00 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) 9.49 (1H, br s).
(37b)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-(5-{[(4R)-4-[2-(メチルチオ)エチル]-4,5-ジヒドロ-1,3-オキサゾール-2-イル}-1H-ピロール-2-イル)フェノキシ}-2-(メチルスルホニル)ピリジン
実施例(37a)で合成した化合物(178mg,0.32mmol)、メタンスルホン酸無水物(116mg,0.65mmol)、トリエチルアミン(0.22mL,1.61mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(88mg,51%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, dd, J = 1.6, 6.3 Hz), 1.75-1.90 (2H, m), 2.03 (3H, s), 2.49-2.63 (2H, m), 3.23 (3H, s), 4.03 (1H, t, J = 7.8 Hz), 4.24-4.32 (1H, m), 4.42-4.68 (4H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.42 (1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (FAB+) m/z: 534.1534 (M+H)+。 (37a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-[(1R) -1- (Hydroxymethyl) -3- (methylthio) propyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (35b) (150 mg, 0.35 mmol), D-methioninol (51 mg, 0.38 mmol) , HOBT · H 2 O (51 mg, 0.38 mmol), N-methylmorpholine (76 μL, 0.69 mmol), WSCI · HCl (79 mg, 0.41 mmol) and colorless in the same manner as in Example (29a) An oily target compound (174 mg, 91%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.3 Hz), 1.90-2.00 (2H, m), 2.14 (3H, s), 2.62 (2H, t, J = 6.6 Hz), 3.24 (3H, s), 3.72-3.82 (2H, m), 4.21-4.29 (1H, br m), 4.45-4.74 (3H, m), 6.41 (1H, d, J = 8.2 Hz) , 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, d, J = 2.0 Hz), 6.64 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, t, J = 1.8 Hz), 7.00 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) 9.49 (1H, br s).
(37b) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5- (5-{[(4R) -4- [2- (methylthio) ethyl] -4,5-dihydro -1,3-oxazol-2-yl} -1H-pyrrol-2-yl) phenoxy} -2- (methylsulfonyl) pyridine Compound (178 mg, 0.32 mmol) synthesized in Example (37a), methanesulfonic acid The target compound (88 mg, 51%) was obtained as a white solid in the same manner as in Example (16j) using anhydride (116 mg, 0.65 mmol) and triethylamine (0.22 mL, 1.61 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, dd, J = 1.6, 6.3 Hz), 1.75-1.90 (2H, m), 2.03 (3H, s), 2.49-2.63 (2H, m) , 3.23 (3H, s), 4.03 (1H, t, J = 7.8 Hz), 4.24-4.32 (1H, m), 4.42-4.68 (4H, m), 6.51 (1H, d, J = 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.42 ( 1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (FAB <+> ) m / z: 534.1534 (M + H) <+> .
(実施例38)
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 38)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 38)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
(38a)メチル N-{[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]カルボニル}-L-セリネート
実施例(35b)で合成した化合物(1.10g,2.53mmol)、L-セリン メチルエステル塩酸塩(0.43g,2.79mmol)、HOBT・H2O(0.38g,2.79mmol)、N-メチルモルホリン(0.56mL,5.06mmol)を塩化メチレン(20mL)とN,N-ジメチルホルムアミド(8mL)の混合溶媒に溶解し、室温でWSCI・HCl(0.58g,3.04mmol)を加え、窒素雰囲気下20時間攪拌した。反応液を塩化メチレン(200mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製することにより、白色固体の目的化合物(1.21g,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.81 (3H, s), 3.99-4.09 (2H, m), 4.44-4.72 (3H, m), 4.80-4.85 (1H, m), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, br s), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(38b)メチル (4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(38a)で合成した化合物(910mg,1.70mmol)を塩化メチレン(20mL)に溶解し、-78℃でビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.39mL,2.12mmol)を滴下した。窒素雰囲気下30分攪拌後、炭酸カリウム(0.35g,2.55mmol)を加え0℃で10分攪拌し、自然に昇温させ室温で3時間攪拌した。飽和炭酸水素ナトリウム水溶液(10mL)を加え、塩化メチレン(50mL)で抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的化合物(811mg,92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.6 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.45-4.73 (5H, m), 4.91 (1H, dd, J = 7.8, 10.9 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.82 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.03 (1H, s), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(38c){(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(38b)で合成した化合物(950mg,1.84mmol)をテトラヒドロフラン(20mL)に溶解し、0℃でリチウムアルミニウムヒドリド(140mg,3.67mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.14mL)、5規定水酸化ナトリウム水溶液(0.14mL)、水(0.45mL)の順に加え、10分間攪拌した。酢酸エチル(70mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(602mg,67%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.38 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.61 (1H, dd, J = 3.1, 12.5 Hz), 3.98 (1H, dd, J = 2.0, 12.5 Hz), 4.11-4.16 (1H, m), 4.31-4.41 (2H, m), 4.45-4.72 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 490.14356 (M+H)+。 (38a) Methyl N-{[5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-yl] carbonyl} -L-serineate Compound (1.10 g, 2.53 mmol) synthesized in Example (35b), L-serine methyl ester hydrochloride (0.43 g, 2.79 mmol), HOBT H 2 O (0.38 g, 2.79 mmol), N-methylmorpholine (0.56 mL, 5.06 mmol) was dissolved in a mixed solvent of methylene chloride (20 mL) and N, N-dimethylformamide (8 mL), WSCI · HCl (0.58 g, 3.04 mmol) was added at room temperature, and the mixture was stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (200 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired compound (1.21 g, 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.81 (3H, s), 3.99-4.09 (2H, m), 4.44 -4.72 (3H, m), 4.80-4.85 (1H, m), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, br s), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(38b) Methyl (4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate The compound synthesized in Example (38a) (910 mg, 1.70 mmol) was added to methylene chloride (20 mL). After dissolution, bis (2-methoxyethyl) aminosulfur trifluoride (0.39 mL, 2.12 mmol) was added dropwise at −78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, potassium carbonate (0.35 g, 2.55 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes, allowed to warm naturally and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -70%) to give the target compound (811 mg, 92%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.6 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.45-4.73 (5H, m), 4.91 (1H, dd, J = 7.8, 10.9 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.82 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.03 (1H, s), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(38c) {(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (950 mg, 1.84 mmol) synthesized in Example (38b) was added to tetrahydrofuran (20 mL). Dissolved and lithium aluminum hydride (140 mg, 3.67 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.14 mL), 5N aqueous sodium hydroxide solution (0.14 mL) and water (0.45 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (602 mg, 67%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.61 (1H, dd, J = 3.1, 12.5 Hz), 3.98 (1H , dd, J = 2.0, 12.5 Hz), 4.11-4.16 (1H, m), 4.31-4.41 (2H, m), 4.45-4.72 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.46 ( 1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14356 (M + H) <+> .
実施例(35b)で合成した化合物(1.10g,2.53mmol)、L-セリン メチルエステル塩酸塩(0.43g,2.79mmol)、HOBT・H2O(0.38g,2.79mmol)、N-メチルモルホリン(0.56mL,5.06mmol)を塩化メチレン(20mL)とN,N-ジメチルホルムアミド(8mL)の混合溶媒に溶解し、室温でWSCI・HCl(0.58g,3.04mmol)を加え、窒素雰囲気下20時間攪拌した。反応液を塩化メチレン(200mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製することにより、白色固体の目的化合物(1.21g,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.81 (3H, s), 3.99-4.09 (2H, m), 4.44-4.72 (3H, m), 4.80-4.85 (1H, m), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, br s), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(38b)メチル (4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(38a)で合成した化合物(910mg,1.70mmol)を塩化メチレン(20mL)に溶解し、-78℃でビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.39mL,2.12mmol)を滴下した。窒素雰囲気下30分攪拌後、炭酸カリウム(0.35g,2.55mmol)を加え0℃で10分攪拌し、自然に昇温させ室温で3時間攪拌した。飽和炭酸水素ナトリウム水溶液(10mL)を加え、塩化メチレン(50mL)で抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的化合物(811mg,92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, dd, J = 1.6, 6.6 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.45-4.73 (5H, m), 4.91 (1H, dd, J = 7.8, 10.9 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.82 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.03 (1H, s), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(38c){(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(38b)で合成した化合物(950mg,1.84mmol)をテトラヒドロフラン(20mL)に溶解し、0℃でリチウムアルミニウムヒドリド(140mg,3.67mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.14mL)、5規定水酸化ナトリウム水溶液(0.14mL)、水(0.45mL)の順に加え、10分間攪拌した。酢酸エチル(70mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(602mg,67%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.38 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.61 (1H, dd, J = 3.1, 12.5 Hz), 3.98 (1H, dd, J = 2.0, 12.5 Hz), 4.11-4.16 (1H, m), 4.31-4.41 (2H, m), 4.45-4.72 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 490.14356 (M+H)+。 (38a) Methyl N-{[5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-yl] carbonyl} -L-serineate Compound (1.10 g, 2.53 mmol) synthesized in Example (35b), L-serine methyl ester hydrochloride (0.43 g, 2.79 mmol), HOBT H 2 O (0.38 g, 2.79 mmol), N-methylmorpholine (0.56 mL, 5.06 mmol) was dissolved in a mixed solvent of methylene chloride (20 mL) and N, N-dimethylformamide (8 mL), WSCI · HCl (0.58 g, 3.04 mmol) was added at room temperature, and the mixture was stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (200 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired compound (1.21 g, 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.81 (3H, s), 3.99-4.09 (2H, m), 4.44 -4.72 (3H, m), 4.80-4.85 (1H, m), 6.51 (1H, dd, J = 2.7, 3.9 Hz), 6.58 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86 (1H, br s), 6.88 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(38b) Methyl (4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate The compound synthesized in Example (38a) (910 mg, 1.70 mmol) was added to methylene chloride (20 mL). After dissolution, bis (2-methoxyethyl) aminosulfur trifluoride (0.39 mL, 2.12 mmol) was added dropwise at −78 ° C. After stirring for 30 minutes under a nitrogen atmosphere, potassium carbonate (0.35 g, 2.55 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes, allowed to warm naturally and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -70%) to give the target compound (811 mg, 92%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, dd, J = 1.6, 6.6 Hz), 3.24 (3H, s), 3.82 (3H, s), 4.45-4.73 (5H, m), 4.91 (1H, dd, J = 7.8, 10.9 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.59 (1H, t, J = 2.0 Hz), 6.82 (1H, d, J = 3.9 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.03 (1H, s), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
(38c) {(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (950 mg, 1.84 mmol) synthesized in Example (38b) was added to tetrahydrofuran (20 mL). Dissolved and lithium aluminum hydride (140 mg, 3.67 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.14 mL), 5N aqueous sodium hydroxide solution (0.14 mL) and water (0.45 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (602 mg, 67%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 1.6, 6.6 Hz), 3.23 (3H, s), 3.61 (1H, dd, J = 3.1, 12.5 Hz), 3.98 (1H , dd, J = 2.0, 12.5 Hz), 4.11-4.16 (1H, m), 4.31-4.41 (2H, m), 4.45-4.72 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.46 ( 1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 490.14356 (M + H) <+> .
(実施例39)
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール (Example 39)
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール (Example 39)
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol
(39a)N-{(2R)-2-(ベンジルオキシ)-4-[(トリイソプロピルシリル)オキシ]ブチル}-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(2.50g,5.75mmol)、公知{J.Org.Chem.(ジャーナル オブ オーガニック ケミストリー)60巻、12号、3910-3915項(1995年)}の(2R)-2-(ベンジルオキシ)-4-[(トリイソプロピルシリル)オキシ]ブタン-1-アミン(2.04g,5.80mmol)、DMT-MM(3.98g, 14.4mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(4.23g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.13 (21H, m), 1.37 (3H, dd, J=1.6, 6.3Hz), 1.77 (1H, m), 1.89 (1H, m), 3.24 (3H, s), 3.49 (1H, td, J=5.9, 14.1Hz), 3.72 (1H, ddd, 4.3, 5.9, 14.1Hz), 3.84 (2H, t, J=5.9Hz), 3.85 (1H, m), 4.47 (1H, d, J=5.1Hz), 4.56 (1H, d, J=11.7Hz), 4.59 (1H, d, J=5.1Hz), 4.65 (1H, d, J=11.7Hz), 4.67 (1H, m), 6.22 (1H, t, J=5.9Hz), 6.44 (1H, dd, J=2.7, 3.9Hz), 6.48 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.86 (1H, t, J=2.4Hz), 7.01 (1H, t, J=2.0Hz), 7.28-7.37 (5H, m), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.60 (1H, brs).
(39b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-{(2R)-2-ヒドロキシ-4-[(トリイソプロピルシリル)オキシ]ブチル}-1H-ピロール-2-カルボキサミド
実施例(39a)で合成した化合物(4.23g,5.51mmol)を酢酸(80mL)に溶解し、10%パラジウム炭素触媒(1.70g)を加えて水素雰囲気下室温で7時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.28g,収率61%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.17 (21H, m), 1.37 (3H, dd, J=1.6, 6.3Hz), 1.62-1.84 (2H, m), 3.23 (3H, s), 3.34 (1H, m), 3.68 (1H, ddd, J=3.9, 6.3, 14.1Hz), 3.93-4.09 (3H, m), 4.46 (1H, d, =4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.48 (1H, m), 6.50 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.64 (1H, dd, J=2.7, 3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.03 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.76 (1H, brs)。 (39a) N-{(2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy]- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.50 g, 5.75 mmol) synthesized in Example (35b), known {J . Org. Chem. (Journal of Organic Chemistry) Vol. 60, No. 12, 3910-3915 (1995)} (2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butan-1-amine (2 0.04 g, 5.80 mmol) and DMT-MM (3.98 g, 14.4 mmol) were used to obtain the target product (4.23 g, yield 96%) as a white solid in the same manner as in Example (5d). It was.
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.13 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.77 (1H, m), 1.89 (1H, m), 3.24 (3H, s), 3.49 (1H, td, J = 5.9, 14.1Hz), 3.72 (1H, ddd, 4.3, 5.9, 14.1Hz), 3.84 (2H, t, J = 5.9Hz), 3.85 (1H , m), 4.47 (1H, d, J = 5.1Hz), 4.56 (1H, d, J = 11.7Hz), 4.59 (1H, d, J = 5.1Hz), 4.65 (1H, d, J = 11.7Hz) ), 4.67 (1H, m), 6.22 (1H, t, J = 5.9Hz), 6.44 (1H, dd, J = 2.7, 3.9Hz), 6.48 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.86 (1H, t, J = 2.4Hz), 7.01 (1H, t, J = 2.0Hz), 7.28-7.37 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.60 (1H, brs).
(39b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2R) -2-Hydroxy-4-[(triisopropylsilyl) oxy] butyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (39a) (4.23 g, 5.51 mmol) was dissolved in acetic acid (80 mL). Then, 10% palladium carbon catalyst (1.70 g) was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -60%) to give the desired product (2.28 g, Yield 61%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.17 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.62-1.84 (2H, m), 3.23 (3H, s ), 3.34 (1H, m), 3.68 (1H, ddd, J = 3.9, 6.3, 14.1Hz), 3.93-4.09 (3H, m), 4.46 (1H, d, = 4.7Hz), 4.58 (1H, d , J = 4.7Hz), 4.68 (1H, m), 6.48 (1H, m), 6.50 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.64 (1H , dd, J = 2.7, 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.76 (1H, brs).
実施例(35b)で合成した化合物(2.50g,5.75mmol)、公知{J.Org.Chem.(ジャーナル オブ オーガニック ケミストリー)60巻、12号、3910-3915項(1995年)}の(2R)-2-(ベンジルオキシ)-4-[(トリイソプロピルシリル)オキシ]ブタン-1-アミン(2.04g,5.80mmol)、DMT-MM(3.98g, 14.4mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(4.23g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.13 (21H, m), 1.37 (3H, dd, J=1.6, 6.3Hz), 1.77 (1H, m), 1.89 (1H, m), 3.24 (3H, s), 3.49 (1H, td, J=5.9, 14.1Hz), 3.72 (1H, ddd, 4.3, 5.9, 14.1Hz), 3.84 (2H, t, J=5.9Hz), 3.85 (1H, m), 4.47 (1H, d, J=5.1Hz), 4.56 (1H, d, J=11.7Hz), 4.59 (1H, d, J=5.1Hz), 4.65 (1H, d, J=11.7Hz), 4.67 (1H, m), 6.22 (1H, t, J=5.9Hz), 6.44 (1H, dd, J=2.7, 3.9Hz), 6.48 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.86 (1H, t, J=2.4Hz), 7.01 (1H, t, J=2.0Hz), 7.28-7.37 (5H, m), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.7Hz), 9.60 (1H, brs).
(39b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-{(2R)-2-ヒドロキシ-4-[(トリイソプロピルシリル)オキシ]ブチル}-1H-ピロール-2-カルボキサミド
実施例(39a)で合成した化合物(4.23g,5.51mmol)を酢酸(80mL)に溶解し、10%パラジウム炭素触媒(1.70g)を加えて水素雰囲気下室温で7時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することにより、白色固体の目的物(2.28g,収率61%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.04-1.17 (21H, m), 1.37 (3H, dd, J=1.6, 6.3Hz), 1.62-1.84 (2H, m), 3.23 (3H, s), 3.34 (1H, m), 3.68 (1H, ddd, J=3.9, 6.3, 14.1Hz), 3.93-4.09 (3H, m), 4.46 (1H, d, =4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.48 (1H, m), 6.50 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.64 (1H, dd, J=2.7, 3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.03 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.76 (1H, brs)。 (39a) N-{(2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy]- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.50 g, 5.75 mmol) synthesized in Example (35b), known {J . Org. Chem. (Journal of Organic Chemistry) Vol. 60, No. 12, 3910-3915 (1995)} (2R) -2- (benzyloxy) -4-[(triisopropylsilyl) oxy] butan-1-amine (2 0.04 g, 5.80 mmol) and DMT-MM (3.98 g, 14.4 mmol) were used to obtain the target product (4.23 g, yield 96%) as a white solid in the same manner as in Example (5d). It was.
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.13 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.77 (1H, m), 1.89 (1H, m), 3.24 (3H, s), 3.49 (1H, td, J = 5.9, 14.1Hz), 3.72 (1H, ddd, 4.3, 5.9, 14.1Hz), 3.84 (2H, t, J = 5.9Hz), 3.85 (1H , m), 4.47 (1H, d, J = 5.1Hz), 4.56 (1H, d, J = 11.7Hz), 4.59 (1H, d, J = 5.1Hz), 4.65 (1H, d, J = 11.7Hz) ), 4.67 (1H, m), 6.22 (1H, t, J = 5.9Hz), 6.44 (1H, dd, J = 2.7, 3.9Hz), 6.48 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.86 (1H, t, J = 2.4Hz), 7.01 (1H, t, J = 2.0Hz), 7.28-7.37 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.7Hz), 9.60 (1H, brs).
(39b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N-{(2R) -2-Hydroxy-4-[(triisopropylsilyl) oxy] butyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (39a) (4.23 g, 5.51 mmol) was dissolved in acetic acid (80 mL). Then, 10% palladium carbon catalyst (1.70 g) was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -60%) to give the desired product (2.28 g, Yield 61%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.04-1.17 (21H, m), 1.37 (3H, dd, J = 1.6, 6.3Hz), 1.62-1.84 (2H, m), 3.23 (3H, s ), 3.34 (1H, m), 3.68 (1H, ddd, J = 3.9, 6.3, 14.1Hz), 3.93-4.09 (3H, m), 4.46 (1H, d, = 4.7Hz), 4.58 (1H, d , J = 4.7Hz), 4.68 (1H, m), 6.48 (1H, m), 6.50 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.64 (1H , dd, J = 2.7, 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.76 (1H, brs).
(39c)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5S)-5-{2-[(トリイソプロピルシリル)オキシ]エチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-2-(メチルスルホニル)ピリジン
実施例(39b)で合成した化合物(2.28g,3.36mmol)、メタンスルホン酸無水物(1.46g,8.38mmol)、トリエチルアミン(2.81mL, 20.2mol)を用い、実施例(16j)と同様の方法で、白色固体の目的物(2.10g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02-1.15 (21H, m), 1.37 (3H, dd, J=0.8, 6.3Hz), 1.86 (1H, m), 1.96 (1H, m), 3.23 (3H, s), 3.66 (1H, dd, J=7.8, 14.1Hz), 3.87 (1H, m), 3.89 (1H, m), 4.08 (1H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.67 (1H, m), 4.91 (1H, m), 6.50 (1H, d, J=3.5Hz), 6.56 (1H, t, J=2.0Hz), 6.73 (1H, d, J=3.5Hz), 6.88 (1H, brs), 7.03 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
(39d)2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール
実施例(39c)で合成した化合物(2.10g,3.18mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.82mL,3.82mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.15g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, d, J=6.3Hz), 1.90 (1H, m), 1.98 (1H, m), 3.22 (3H, s), 3.61 (1H, dd, J=7.4, 14.1Hz), 3.85 (2H, t, J=6.3Hz), 4.05 (1H, dd, J=9.4, 14.1Hz), 4.44 (1H, d, J=4.7Hz), 4.56 (1H, d, J=4.7Hz), 4.66 (1H, m), 4.86 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.55 (1H, t, J=2.0Hz), 6.73 (1H, d, J=3.9Hz), 6.90 (1H, brs), 7.05 (1H, brs), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.7Hz).
MS (ESI) m/z: 504.16046(M+H)+。 (39c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5- {2-[(triisopropylsilyl) oxy] ethyl} -4 , 5-Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (39b) (2.28 g, 3. 36 mmol), methanesulfonic anhydride (1.46 g, 8.38 mmol), and triethylamine (2.81 mL, 20.2 mol) in the same manner as in Example (16j), and the target product (2. 10 g, yield 95%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.15 (21H, m), 1.37 (3H, dd, J = 0.8, 6.3Hz), 1.86 (1H, m), 1.96 (1H, m), 3.23 (3H, s), 3.66 (1H, dd, J = 7.8, 14.1Hz), 3.87 (1H, m), 3.89 (1H, m), 4.08 (1H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.91 (1H, m), 6.50 (1H, d, J = 3.5Hz), 6.56 (1H, t, J = 2.0Hz), 6.73 (1H, d, J = 3.5Hz), 6.88 (1H, brs), 7.03 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(39d) 2-{(5S) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol Compound (2.10 g, 3.18 mmol) synthesized in Example (39c), tetra Using butylammonium fluoride (1 mol / L tetrahydrofuran solution, 3.82 mL, 3.82 mmol), the target compound (1.15 g, yield 72%) as a white solid was obtained in the same manner as in Example (16k). .
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz), 1.90 (1H, m), 1.98 (1H, m), 3.22 (3H, s), 3.61 (1H, dd, J = 7.4, 14.1Hz), 3.85 (2H, t, J = 6.3Hz), 4.05 (1H, dd, J = 9.4, 14.1Hz), 4.44 (1H, d, J = 4.7Hz), 4.56 ( 1H, d, J = 4.7Hz), 4.66 (1H, m), 4.86 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.55 (1H, t, J = 2.0Hz), 6.73 ( 1H, d, J = 3.9Hz), 6.90 (1H, brs), 7.05 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) <+> .
実施例(39b)で合成した化合物(2.28g,3.36mmol)、メタンスルホン酸無水物(1.46g,8.38mmol)、トリエチルアミン(2.81mL, 20.2mol)を用い、実施例(16j)と同様の方法で、白色固体の目的物(2.10g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02-1.15 (21H, m), 1.37 (3H, dd, J=0.8, 6.3Hz), 1.86 (1H, m), 1.96 (1H, m), 3.23 (3H, s), 3.66 (1H, dd, J=7.8, 14.1Hz), 3.87 (1H, m), 3.89 (1H, m), 4.08 (1H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.67 (1H, m), 4.91 (1H, m), 6.50 (1H, d, J=3.5Hz), 6.56 (1H, t, J=2.0Hz), 6.73 (1H, d, J=3.5Hz), 6.88 (1H, brs), 7.03 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
(39d)2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール
実施例(39c)で合成した化合物(2.10g,3.18mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.82mL,3.82mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.15g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, d, J=6.3Hz), 1.90 (1H, m), 1.98 (1H, m), 3.22 (3H, s), 3.61 (1H, dd, J=7.4, 14.1Hz), 3.85 (2H, t, J=6.3Hz), 4.05 (1H, dd, J=9.4, 14.1Hz), 4.44 (1H, d, J=4.7Hz), 4.56 (1H, d, J=4.7Hz), 4.66 (1H, m), 4.86 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.55 (1H, t, J=2.0Hz), 6.73 (1H, d, J=3.9Hz), 6.90 (1H, brs), 7.05 (1H, brs), 7.43 (1H, dd, J=2.7, 8.6Hz), 8.03 (1H, d, J=8.6Hz), 8.47 (1H, d, J=2.7Hz).
MS (ESI) m/z: 504.16046(M+H)+。 (39c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5S) -5- {2-[(triisopropylsilyl) oxy] ethyl} -4 , 5-Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -2- (methylsulfonyl) pyridine The compound synthesized in Example (39b) (2.28 g, 3. 36 mmol), methanesulfonic anhydride (1.46 g, 8.38 mmol), and triethylamine (2.81 mL, 20.2 mol) in the same manner as in Example (16j), and the target product (2. 10 g, yield 95%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.15 (21H, m), 1.37 (3H, dd, J = 0.8, 6.3Hz), 1.86 (1H, m), 1.96 (1H, m), 3.23 (3H, s), 3.66 (1H, dd, J = 7.8, 14.1Hz), 3.87 (1H, m), 3.89 (1H, m), 4.08 (1H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.91 (1H, m), 6.50 (1H, d, J = 3.5Hz), 6.56 (1H, t, J = 2.0Hz), 6.73 (1H, d, J = 3.5Hz), 6.88 (1H, brs), 7.03 (1H, brs), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
(39d) 2-{(5S) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol Compound (2.10 g, 3.18 mmol) synthesized in Example (39c), tetra Using butylammonium fluoride (1 mol / L tetrahydrofuran solution, 3.82 mL, 3.82 mmol), the target compound (1.15 g, yield 72%) as a white solid was obtained in the same manner as in Example (16k). .
1 H-NMR (CDCl 3 , 400 MHz): δ1.34 (3H, d, J = 6.3 Hz), 1.90 (1H, m), 1.98 (1H, m), 3.22 (3H, s), 3.61 (1H, dd, J = 7.4, 14.1Hz), 3.85 (2H, t, J = 6.3Hz), 4.05 (1H, dd, J = 9.4, 14.1Hz), 4.44 (1H, d, J = 4.7Hz), 4.56 ( 1H, d, J = 4.7Hz), 4.66 (1H, m), 4.86 (1H, m), 6.50 (1H, d, J = 3.9Hz), 6.55 (1H, t, J = 2.0Hz), 6.73 ( 1H, d, J = 3.9Hz), 6.90 (1H, brs), 7.05 (1H, brs), 7.43 (1H, dd, J = 2.7, 8.6Hz), 8.03 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) <+> .
(実施例40)
(Example 40)
2-{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール
2-{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol
(40a)(2S)-4-(ベンジルオキシ)-1-[(トリイソプロピルシリル)オキシ]ブタン-2-オール
(2S)-4-(ベンジルオキシ)ブタン-1,2-ジオール(3.00g,15.3mmol)を塩化メチレン(150mL)に溶解し、トリイソプロピルシリルクロリド(3.60mL,16.8mmol)、トリエチルアミン(6.40mL, 45.9mol)、4-ジメチルアミノピリジン(1.87g,15.3mmol)を加え、窒素雰囲気下室温で24時間撹拌した。水(150mL)を加え、塩化メチレン(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(5.64g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02-1.12 (21H, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J=3.1Hz), 3.58 (1H, dd, J=6.7, 9.8Hz), 3.62-3.72 (3H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H,m).
(40b)2-[(1R)-3-(ベンジルオキシ)-1-{[(トリイソプロピルシリル)オキシ]メチル}プロピル]-1H-イソインドール-1,3(2H)-ジオン
実施例(40a)で合成した化合物(5.64g,16.0mmol)をテトラヒドロフラン(150mL)に溶解し、フタルイミド(2.59g,17.6mmol)、トリフェニルホスフィン(4.62g,17.6mmol)を加えた。0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,8.00mL,17.6mmol)を滴下し、窒素雰囲気下室温で3時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、淡黄色油状の目的化合物(4.87g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.92-1.08 (21H, m), 2.06 (1H, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, dd, J=6.3, 9.8Hz), 4.14 (1H, t, J=9.8Hz), 4.39 (2H, s), 4.59 (1H, m), 7.18-7.27 (5H, m), 7.65-7.70 (2H,m), 7.76-7.80 (2H, m).
(40c)(2R)-4-(ベンジルオキシ)-1-[(トリイソプロピルシリル)オキシ]ブタン-2-アミン
実施例(40b)で合成した化合物(4.87g,10.1mmol)をエタノール(100mL)に溶解した。ヒドラジン一水和物(4.90mL,101mmol)を加え、窒素雰囲気下3時間加熱還流した。不溶物を濾過により除去した後、飽和炭酸水素ナトリウム水溶液(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、無色油状の目的物(3.34g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.12 (21H, m), 1.72-1.80 (2H, m), 3.03 (1H, m), 3.47 (1H, dd, J=7.0, 9.8Hz), 3.58-3.68 (2H, m), 3.67 (1H, dd, J=4.3, 9.4Hz), 4.51 (2H, s), 7.27-7.35 (5H, m)。 (40a) (2S) -4- (benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-ol (2S) -4- (benzyloxy) butane-1,2-diol (3.00 g , 15.3 mmol) in methylene chloride (150 mL), triisopropylsilyl chloride (3.60 mL, 16.8 mmol), triethylamine (6.40 mL, 45.9 mol), 4-dimethylaminopyridine (1.87 g, 15.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (150 mL) was added and extracted twice with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (5.64 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.12 (21H, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J = 3.1Hz), 3.58 (1H, dd, J = 6.7, 9.8Hz), 3.62-3.72 (3H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H, m).
(40b) 2-[(1R) -3- (Benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -1H-isoindole-1,3 (2H) -dione Example (40a) ) Compound (5.64 g, 16.0 mmol) was dissolved in tetrahydrofuran (150 mL), and phthalimide (2.59 g, 17.6 mmol) and triphenylphosphine (4.62 g, 17.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 8.00 mL, 17.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -30%) to give the target compound (4.87 g) as a pale yellow oil. Yield 63%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.92-1.08 (21H, m), 2.06 (1H, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, dd , J = 6.3, 9.8Hz), 4.14 (1H, t, J = 9.8Hz), 4.39 (2H, s), 4.59 (1H, m), 7.18-7.27 (5H, m), 7.65-7.70 (2H, m), 7.76-7.80 (2H, m).
(40c) (2R) -4- (Benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-amine The compound (4.87 g, 10.1 mmol) synthesized in Example (40b) was added to ethanol ( 100 mL). Hydrazine monohydrate (4.90 mL, 101 mmol) was added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily target product (3.34 g, yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.12 (21H, m), 1.72-1.80 (2H, m), 3.03 (1H, m), 3.47 (1H, dd, J = 7.0, 9.8Hz ), 3.58-3.68 (2H, m), 3.67 (1H, dd, J = 4.3, 9.4Hz), 4.51 (2H, s), 7.27-7.35 (5H, m).
(2S)-4-(ベンジルオキシ)ブタン-1,2-ジオール(3.00g,15.3mmol)を塩化メチレン(150mL)に溶解し、トリイソプロピルシリルクロリド(3.60mL,16.8mmol)、トリエチルアミン(6.40mL, 45.9mol)、4-ジメチルアミノピリジン(1.87g,15.3mmol)を加え、窒素雰囲気下室温で24時間撹拌した。水(150mL)を加え、塩化メチレン(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(5.64g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02-1.12 (21H, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J=3.1Hz), 3.58 (1H, dd, J=6.7, 9.8Hz), 3.62-3.72 (3H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H,m).
(40b)2-[(1R)-3-(ベンジルオキシ)-1-{[(トリイソプロピルシリル)オキシ]メチル}プロピル]-1H-イソインドール-1,3(2H)-ジオン
実施例(40a)で合成した化合物(5.64g,16.0mmol)をテトラヒドロフラン(150mL)に溶解し、フタルイミド(2.59g,17.6mmol)、トリフェニルホスフィン(4.62g,17.6mmol)を加えた。0℃にてアゾジカルボン酸ジエチル(40%トルエン溶液,8.00mL,17.6mmol)を滴下し、窒素雰囲気下室温で3時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、淡黄色油状の目的化合物(4.87g,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ0.92-1.08 (21H, m), 2.06 (1H, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, dd, J=6.3, 9.8Hz), 4.14 (1H, t, J=9.8Hz), 4.39 (2H, s), 4.59 (1H, m), 7.18-7.27 (5H, m), 7.65-7.70 (2H,m), 7.76-7.80 (2H, m).
(40c)(2R)-4-(ベンジルオキシ)-1-[(トリイソプロピルシリル)オキシ]ブタン-2-アミン
実施例(40b)で合成した化合物(4.87g,10.1mmol)をエタノール(100mL)に溶解した。ヒドラジン一水和物(4.90mL,101mmol)を加え、窒素雰囲気下3時間加熱還流した。不溶物を濾過により除去した後、飽和炭酸水素ナトリウム水溶液(100mL)を加え、ジエチルエーテル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、無色油状の目的物(3.34g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.12 (21H, m), 1.72-1.80 (2H, m), 3.03 (1H, m), 3.47 (1H, dd, J=7.0, 9.8Hz), 3.58-3.68 (2H, m), 3.67 (1H, dd, J=4.3, 9.4Hz), 4.51 (2H, s), 7.27-7.35 (5H, m)。 (40a) (2S) -4- (benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-ol (2S) -4- (benzyloxy) butane-1,2-diol (3.00 g , 15.3 mmol) in methylene chloride (150 mL), triisopropylsilyl chloride (3.60 mL, 16.8 mmol), triethylamine (6.40 mL, 45.9 mol), 4-dimethylaminopyridine (1.87 g, 15.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water (150 mL) was added and extracted twice with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (5.64 g, Yield ˜100%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.12 (21H, m), 1.72-1.84 (2H, m), 2.86 (1H, d, J = 3.1Hz), 3.58 (1H, dd, J = 6.7, 9.8Hz), 3.62-3.72 (3H, m), 3.86 (1H, m), 4.52 (2H, s), 7.28-7.35 (5H, m).
(40b) 2-[(1R) -3- (Benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -1H-isoindole-1,3 (2H) -dione Example (40a) ) Compound (5.64 g, 16.0 mmol) was dissolved in tetrahydrofuran (150 mL), and phthalimide (2.59 g, 17.6 mmol) and triphenylphosphine (4.62 g, 17.6 mmol) were added. Diethyl azodicarboxylate (40% toluene solution, 8.00 mL, 17.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -30%) to give the target compound (4.87 g) as a pale yellow oil. Yield 63%).
1 H-NMR (CDCl 3 , 400 MHz): δ0.92-1.08 (21H, m), 2.06 (1H, m), 2.37 (1H, m), 3.46-3.58 (2H, m), 3.94 (1H, dd , J = 6.3, 9.8Hz), 4.14 (1H, t, J = 9.8Hz), 4.39 (2H, s), 4.59 (1H, m), 7.18-7.27 (5H, m), 7.65-7.70 (2H, m), 7.76-7.80 (2H, m).
(40c) (2R) -4- (Benzyloxy) -1-[(triisopropylsilyl) oxy] butan-2-amine The compound (4.87 g, 10.1 mmol) synthesized in Example (40b) was added to ethanol ( 100 mL). Hydrazine monohydrate (4.90 mL, 101 mmol) was added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless oily target product (3.34 g, yield 94%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.12 (21H, m), 1.72-1.80 (2H, m), 3.03 (1H, m), 3.47 (1H, dd, J = 7.0, 9.8Hz ), 3.58-3.68 (2H, m), 3.67 (1H, dd, J = 4.3, 9.4Hz), 4.51 (2H, s), 7.27-7.35 (5H, m).
(40d)N-{(1R)-3-(ベンジルオキシ)-1-{[(トリイソプロピルシリル)オキシ]メチル}プロピル]-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.90g,4.37mmol)、実施例(40c)で合成した化合物(1.75g,4.98mmol)、DMT-MM(3.63g, 13.1mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(2.33g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.13 (21H, m), 1.37 (3H, d, J=6.3Hz), 2.00-2.06 (2H, m), 3.24 (3H, s), 3.64 (1H, m), 3.71-3.77 (2H, m), 3.88 (1H, dd, J=2.7, 9.7Hz), 4.29 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.51 (2H, s), 4.58 (1H, d, J=5.1Hz), 4.67 (1H, m), 6.23 (1H, t, J=3.5Hz), 6.40 (1H, t, J=3.5Hz), 6.57 (1H, brs), 6.73 (1H, brd, J=8.2Hz), 6.85 (1H, brs), 6.99 (1H, brs), 7.27-7.37 (5H, m), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.54 (1H, brs).
(40e)N-{(1R)-3-(ベンジルオキシ)-1-(ヒドロキシメチル)プロピル]-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(40d)で合成した化合物(2.32g,3.02mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,6.35mL,6.35mmol)を用い、実施例(16k)と同様の方法で白色固体の目的物(1.43g,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, dd, J=1.6, 6.7Hz), 1.93-2.07 (2H, m), 3.23 (3H, s), 3.61 (1H, dd, J=4.3, 7.4Hz), 3.68-3.80 (4H, m), 4.22 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.54 (2H, s), 4.58 (1H, d, J=5.1Hz), 4.68 (1H, m), 6.23 (1H, dd, J=2.4, 3.9Hz), 6.37 (1H, dd, J=3.1, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.85(1H, t, J=2.0Hz), 6.99 (1H, t, J=2.0Hz), 7.05 (1H, brd, J=6.7Hz), 7.32-7.40 (5H, m), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.54 (1H, brs)。 (40d) N-{(1R) -3- (benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -5- (3-[(1S) -2-fluoro-1-methyl Ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.90 g, 4.37 mmol) synthesized in Example (35b), Using the compound (1.75 g, 4.98 mmol) synthesized in Example (40c) and DMT-MM (3.63 g, 13.1 mmol), the target product (white solid) was obtained in the same manner as in Example (5d). 2.33 g, 69% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.13 (21H, m), 1.37 (3H, d, J = 6.3 Hz), 2.00-2.06 (2H, m), 3.24 (3H, s), 3.64 (1H, m), 3.71-3.77 (2H, m), 3.88 (1H, dd, J = 2.7, 9.7Hz), 4.29 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.51 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.67 (1H, m), 6.23 (1H, t, J = 3.5Hz), 6.40 (1H, t, J = 3.5Hz), 6.57 (1H, brs), 6.73 (1H, brd, J = 8.2Hz), 6.85 (1H, brs), 6.99 (1H, brs), 7.27-7.37 (5H, m), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).
(40e) N-{(1R) -3- (benzyloxy) -1- (hydroxymethyl) propyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.32 g, 3.02 mmol) synthesized in Example (40d), tetrabutylammonium fluoride (1 mol) / L tetrahydrofuran solution, 6.35 mL, 6.35 mmol) was used to obtain the desired product (1.43 g, yield 77%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ1.37 (3H, dd, J = 1.6, 6.7 Hz), 1.93-2.07 (2H, m), 3.23 (3H, s), 3.61 (1H, dd, J = 4.3, 7.4Hz), 3.68-3.80 (4H, m), 4.22 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.54 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.68 (1H, m), 6.23 (1H, dd, J = 2.4, 3.9Hz), 6.37 (1H, dd, J = 3.1, 3.9Hz), 6.57 (1H, t, J = 2.4Hz) , 6.85 (1H, t, J = 2.0Hz), 6.99 (1H, t, J = 2.0Hz), 7.05 (1H, brd, J = 6.7Hz), 7.32-7.40 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).
実施例(35b)で合成した化合物(1.90g,4.37mmol)、実施例(40c)で合成した化合物(1.75g,4.98mmol)、DMT-MM(3.63g, 13.1mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(2.33g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.13 (21H, m), 1.37 (3H, d, J=6.3Hz), 2.00-2.06 (2H, m), 3.24 (3H, s), 3.64 (1H, m), 3.71-3.77 (2H, m), 3.88 (1H, dd, J=2.7, 9.7Hz), 4.29 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.51 (2H, s), 4.58 (1H, d, J=5.1Hz), 4.67 (1H, m), 6.23 (1H, t, J=3.5Hz), 6.40 (1H, t, J=3.5Hz), 6.57 (1H, brs), 6.73 (1H, brd, J=8.2Hz), 6.85 (1H, brs), 6.99 (1H, brs), 7.27-7.37 (5H, m), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.54 (1H, brs).
(40e)N-{(1R)-3-(ベンジルオキシ)-1-(ヒドロキシメチル)プロピル]-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(40d)で合成した化合物(2.32g,3.02mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,6.35mL,6.35mmol)を用い、実施例(16k)と同様の方法で白色固体の目的物(1.43g,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, dd, J=1.6, 6.7Hz), 1.93-2.07 (2H, m), 3.23 (3H, s), 3.61 (1H, dd, J=4.3, 7.4Hz), 3.68-3.80 (4H, m), 4.22 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.54 (2H, s), 4.58 (1H, d, J=5.1Hz), 4.68 (1H, m), 6.23 (1H, dd, J=2.4, 3.9Hz), 6.37 (1H, dd, J=3.1, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.85(1H, t, J=2.0Hz), 6.99 (1H, t, J=2.0Hz), 7.05 (1H, brd, J=6.7Hz), 7.32-7.40 (5H, m), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.54 (1H, brs)。 (40d) N-{(1R) -3- (benzyloxy) -1-{[(triisopropylsilyl) oxy] methyl} propyl] -5- (3-[(1S) -2-fluoro-1-methyl Ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.90 g, 4.37 mmol) synthesized in Example (35b), Using the compound (1.75 g, 4.98 mmol) synthesized in Example (40c) and DMT-MM (3.63 g, 13.1 mmol), the target product (white solid) was obtained in the same manner as in Example (5d). 2.33 g, 69% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.13 (21H, m), 1.37 (3H, d, J = 6.3 Hz), 2.00-2.06 (2H, m), 3.24 (3H, s), 3.64 (1H, m), 3.71-3.77 (2H, m), 3.88 (1H, dd, J = 2.7, 9.7Hz), 4.29 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.51 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.67 (1H, m), 6.23 (1H, t, J = 3.5Hz), 6.40 (1H, t, J = 3.5Hz), 6.57 (1H, brs), 6.73 (1H, brd, J = 8.2Hz), 6.85 (1H, brs), 6.99 (1H, brs), 7.27-7.37 (5H, m), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).
(40e) N-{(1R) -3- (benzyloxy) -1- (hydroxymethyl) propyl] -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (2.32 g, 3.02 mmol) synthesized in Example (40d), tetrabutylammonium fluoride (1 mol) / L tetrahydrofuran solution, 6.35 mL, 6.35 mmol) was used to obtain the desired product (1.43 g, yield 77%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ1.37 (3H, dd, J = 1.6, 6.7 Hz), 1.93-2.07 (2H, m), 3.23 (3H, s), 3.61 (1H, dd, J = 4.3, 7.4Hz), 3.68-3.80 (4H, m), 4.22 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.54 (2H, s), 4.58 (1H, d, J = 5.1Hz), 4.68 (1H, m), 6.23 (1H, dd, J = 2.4, 3.9Hz), 6.37 (1H, dd, J = 3.1, 3.9Hz), 6.57 (1H, t, J = 2.4Hz) , 6.85 (1H, t, J = 2.0Hz), 6.99 (1H, t, J = 2.0Hz), 7.05 (1H, brd, J = 6.7Hz), 7.32-7.40 (5H, m), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.54 (1H, brs).
(40f)5-{3-(5-{(4R)-4-[2-(ベンジルオキシ)エチル]-4,5-ジヒドロ-1,3-オキサゾール-2-イル}-1H-ピロール-2-イル)-5-[(1S)-2-フルオロ-1-メチルエトキシ]フェノキシ}-2-(メチルスルホニル)ピリジン
実施例(40e)で合成した化合物(1.43g,2.34mmol)、メタンスルホン酸無水物(1.02g,5.86mmol)、トリエチルアミン(1.96mL,14.1mol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(1.29g,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, dd, J=1.2, 6.3Hz), 1.82-1.92 (2H, m), 3.22 (3H, s), 3.55-3.61 (2H, m), 4.07 (1H, t, J=7.8), 4.33 (1H, m), 4.38-4.49 (4H, m), 4.55 (1H, d, J=4.7Hz), 4.63 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.03 (1H, t, J=2.0Hz), 7.24-7.34 (5H, m), 7.41 (1H, dd, J=2.7, 8.6Hz), 8.02 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(40g)2-{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール
実施例(40f)で合成した化合物(1.29g,2.17mmol)を塩化メチレン(30mL)に溶解し、-78℃にて三臭化ホウ素 (1.0mol/L塩化メチレン溶液,2.61mL,2.61mmol)を加え、窒素雰囲気下室温で1.5時間撹拌した。飽和炭酸水素ナトリウム水溶液(30mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的物(984mg,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, dd, J=1.6, 6.3Hz), 1.73-1.96 (2H, m), 3.23 (3H, s), 3.82-3.95 (2H, m), 4.04 (1H, t, J=7.8Hz), 4.41 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.56 (1H, m), 4.58 (1H, d, J=5.1Hz), 4.70 (1H, m), 6.52 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.0Hz), 6.78 (1H, d, J=3.9Hz), 6.91 (1H, brs), 7.08 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 504.16046(M+H)+。 (40f) 5- {3- (5-{(4R) -4- [2- (benzyloxy) ethyl] -4,5-dihydro-1,3-oxazol-2-yl} -1H-pyrrole-2 -Yl) -5-[(1S) -2-fluoro-1-methylethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (40e) (1.43 g, 2.34 mmol), methane Using sulfonic anhydride (1.02 g, 5.86 mmol) and triethylamine (1.96 mL, 14.1 mol), the target product (1.29 g, yield) was obtained in the same manner as in Example (16j). 93%).
1 H-NMR (CDCl 3 , 400MHz): δ1.34 (3H, dd, J = 1.2, 6.3Hz), 1.82-1.92 (2H, m), 3.22 (3H, s), 3.55-3.61 (2H, m ), 4.07 (1H, t, J = 7.8), 4.33 (1H, m), 4.38-4.49 (4H, m), 4.55 (1H, d, J = 4.7Hz), 4.63 (1H, m), 6.50 ( 1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.24-7.34 (5H, m), 7.41 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(40 g) 2-{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol The compound (1.29 g, 2.17 mmol) synthesized in Example (40f) was chlorinated. After dissolving in methylene (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 2.61 mL, 2.61 mmol) was added at −78 ° C., and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired product (984 mg, yield) as a white solid. 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.38 (3H, dd, J = 1.6, 6.3 Hz), 1.73-1.96 (2H, m), 3.23 (3H, s), 3.82-3.95 (2H, m ), 4.04 (1H, t, J = 7.8Hz), 4.41 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.56 (1H, m), 4.58 (1H, d, J = 5.1Hz) ), 4.70 (1H, m), 6.52 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.0Hz), 6.78 (1H, d, J = 3.9Hz), 6.91 (1H, brs ), 7.08 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) <+> .
実施例(40e)で合成した化合物(1.43g,2.34mmol)、メタンスルホン酸無水物(1.02g,5.86mmol)、トリエチルアミン(1.96mL,14.1mol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(1.29g,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.34 (3H, dd, J=1.2, 6.3Hz), 1.82-1.92 (2H, m), 3.22 (3H, s), 3.55-3.61 (2H, m), 4.07 (1H, t, J=7.8), 4.33 (1H, m), 4.38-4.49 (4H, m), 4.55 (1H, d, J=4.7Hz), 4.63 (1H, m), 6.50 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.03 (1H, t, J=2.0Hz), 7.24-7.34 (5H, m), 7.41 (1H, dd, J=2.7, 8.6Hz), 8.02 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(40g)2-{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール
実施例(40f)で合成した化合物(1.29g,2.17mmol)を塩化メチレン(30mL)に溶解し、-78℃にて三臭化ホウ素 (1.0mol/L塩化メチレン溶液,2.61mL,2.61mmol)を加え、窒素雰囲気下室温で1.5時間撹拌した。飽和炭酸水素ナトリウム水溶液(30mL)を加え、塩化メチレン(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的物(984mg,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.38 (3H, dd, J=1.6, 6.3Hz), 1.73-1.96 (2H, m), 3.23 (3H, s), 3.82-3.95 (2H, m), 4.04 (1H, t, J=7.8Hz), 4.41 (1H, m), 4.46 (1H, d, J=5.1Hz), 4.56 (1H, m), 4.58 (1H, d, J=5.1Hz), 4.70 (1H, m), 6.52 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.0Hz), 6.78 (1H, d, J=3.9Hz), 6.91 (1H, brs), 7.08 (1H, brs), 7.46 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 504.16046(M+H)+。 (40f) 5- {3- (5-{(4R) -4- [2- (benzyloxy) ethyl] -4,5-dihydro-1,3-oxazol-2-yl} -1H-pyrrole-2 -Yl) -5-[(1S) -2-fluoro-1-methylethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (40e) (1.43 g, 2.34 mmol), methane Using sulfonic anhydride (1.02 g, 5.86 mmol) and triethylamine (1.96 mL, 14.1 mol), the target product (1.29 g, yield) was obtained in the same manner as in Example (16j). 93%).
1 H-NMR (CDCl 3 , 400MHz): δ1.34 (3H, dd, J = 1.2, 6.3Hz), 1.82-1.92 (2H, m), 3.22 (3H, s), 3.55-3.61 (2H, m ), 4.07 (1H, t, J = 7.8), 4.33 (1H, m), 4.38-4.49 (4H, m), 4.55 (1H, d, J = 4.7Hz), 4.63 (1H, m), 6.50 ( 1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.03 (1H, t, J = 2.0Hz), 7.24-7.34 (5H, m), 7.41 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(40 g) 2-{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy } Phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol The compound (1.29 g, 2.17 mmol) synthesized in Example (40f) was chlorinated. After dissolving in methylene (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 2.61 mL, 2.61 mmol) was added at −78 ° C., and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired product (984 mg, yield) as a white solid. 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.38 (3H, dd, J = 1.6, 6.3 Hz), 1.73-1.96 (2H, m), 3.23 (3H, s), 3.82-3.95 (2H, m ), 4.04 (1H, t, J = 7.8Hz), 4.41 (1H, m), 4.46 (1H, d, J = 5.1Hz), 4.56 (1H, m), 4.58 (1H, d, J = 5.1Hz) ), 4.70 (1H, m), 6.52 (1H, d, J = 3.9Hz), 6.57 (1H, t, J = 2.0Hz), 6.78 (1H, d, J = 3.9Hz), 6.91 (1H, brs ), 7.08 (1H, brs), 7.46 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 504.16046 (M + H) <+> .
(実施例41)
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール (Example 41)
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール (Example 41)
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol
(41a)N-{(2S)-2-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]-2-ヒドロキシエチル}-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.54g,3.54mmol)、公知{Chem.Res.Toxicol.(ケミカル リサーチ イン トキシコロジー)14巻、4号、379-388項(2001年)}の(1S)-2-アミノ-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール(690mg,4.28mmol)、DMT-MM(2.45g, 8.85mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.65g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, d, J=6.3Hz), 1.38 (3H, s), 1.46 (3H, s), 2.72 (1H, brd, J=5.1Hz), 3.24 (3H, s), 3.43 (1H, ddd, J=5.1, 6.3, 14.1Hz), 3.68 (1H, m), 3.90 (1H, m), 3.95 (1H, d, J=12.1Hz), 4.05-4.15 (2H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.44 (1H, brt, J=5.1Hz), 6.50 (1H, t, J=3.1Hz), 6.58 (1H, t, J=2.4Hz), 6.61 (1H, t, J=3.1Hz), 6.87 (1H, brs), 7.01 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.65 (1H, brs).
(41b)(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール
実施例(41a)で合成した化合物(1.64g,2.84mmol)をテトラヒドロフラン(40mL)に溶解し、メタンスルホン酸無水物(1.24g,7.12mmol)、トリエチルアミン(2.38mL, 17.1mol)を加え、窒素雰囲気下50℃で22時間撹拌した。水(40mL)を加え、酢酸エチル(40mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (41a) N-{(2S) -2-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.1) synthesized in Example (35b). 54 g, 3.54 mmol), known {Chem. Res. Toxicol. (Chemical Research Intoxicology) Vol. 14, No. 4, 379-388 (2001)}, (1S) -2-amino-1-[(4S) -2,2-dimethyl-1,3-dioxolane-4 -Il] ethanol (690 mg, 4.28 mmol) and DMT-MM (2.45 g, 8.85 mmol) were used in the same manner as in Example (5d) to give the desired product (1.65 g, yield 80) %).
1 H-NMR (CDCl 3 , 400MHz): δ1.37 (3H, d, J = 6.3Hz), 1.38 (3H, s), 1.46 (3H, s), 2.72 (1H, brd, J = 5.1Hz) , 3.24 (3H, s), 3.43 (1H, ddd, J = 5.1, 6.3, 14.1Hz), 3.68 (1H, m), 3.90 (1H, m), 3.95 (1H, d, J = 12.1Hz), 4.05-4.15 (2H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.44 (1H, brt, J = 5.1Hz ), 6.50 (1H, t, J = 3.1Hz), 6.58 (1H, t, J = 2.4Hz), 6.61 (1H, t, J = 3.1Hz), 6.87 (1H, brs), 7.01 (1H, brs) ), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.65 (1H, brs).
(41b) (1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol The compound synthesized in Example (41a) ( 1.64 g, 2.84 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.24 g, 7.12 mmol) and triethylamine (2.38 mL, 17.1 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 22 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(35b)で合成した化合物(1.54g,3.54mmol)、公知{Chem.Res.Toxicol.(ケミカル リサーチ イン トキシコロジー)14巻、4号、379-388項(2001年)}の(1S)-2-アミノ-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール(690mg,4.28mmol)、DMT-MM(2.45g, 8.85mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.65g,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.37 (3H, d, J=6.3Hz), 1.38 (3H, s), 1.46 (3H, s), 2.72 (1H, brd, J=5.1Hz), 3.24 (3H, s), 3.43 (1H, ddd, J=5.1, 6.3, 14.1Hz), 3.68 (1H, m), 3.90 (1H, m), 3.95 (1H, d, J=12.1Hz), 4.05-4.15 (2H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.44 (1H, brt, J=5.1Hz), 6.50 (1H, t, J=3.1Hz), 6.58 (1H, t, J=2.4Hz), 6.61 (1H, t, J=3.1Hz), 6.87 (1H, brs), 7.01 (1H, brs), 7.45 (1H, dd, J=2.7, 8.6 Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.65 (1H, brs).
(41b)(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール
実施例(41a)で合成した化合物(1.64g,2.84mmol)をテトラヒドロフラン(40mL)に溶解し、メタンスルホン酸無水物(1.24g,7.12mmol)、トリエチルアミン(2.38mL, 17.1mol)を加え、窒素雰囲気下50℃で22時間撹拌した。水(40mL)を加え、酢酸エチル(40mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (41a) N-{(2S) -2-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide Compound (1.1) synthesized in Example (35b). 54 g, 3.54 mmol), known {Chem. Res. Toxicol. (Chemical Research Intoxicology) Vol. 14, No. 4, 379-388 (2001)}, (1S) -2-amino-1-[(4S) -2,2-dimethyl-1,3-dioxolane-4 -Il] ethanol (690 mg, 4.28 mmol) and DMT-MM (2.45 g, 8.85 mmol) were used in the same manner as in Example (5d) to give the desired product (1.65 g, yield 80) %).
1 H-NMR (CDCl 3 , 400MHz): δ1.37 (3H, d, J = 6.3Hz), 1.38 (3H, s), 1.46 (3H, s), 2.72 (1H, brd, J = 5.1Hz) , 3.24 (3H, s), 3.43 (1H, ddd, J = 5.1, 6.3, 14.1Hz), 3.68 (1H, m), 3.90 (1H, m), 3.95 (1H, d, J = 12.1Hz), 4.05-4.15 (2H, m), 4.46 (1H, d, J = 4.7Hz), 4.58 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.44 (1H, brt, J = 5.1Hz ), 6.50 (1H, t, J = 3.1Hz), 6.58 (1H, t, J = 2.4Hz), 6.61 (1H, t, J = 3.1Hz), 6.87 (1H, brs), 7.01 (1H, brs) ), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.65 (1H, brs).
(41b) (1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol The compound synthesized in Example (41a) ( 1.64 g, 2.84 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.24 g, 7.12 mmol) and triethylamine (2.38 mL, 17.1 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 22 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣を酢酸(30mL)と水(10mL)の混合溶媒に溶解し、窒素雰囲気下50℃で16時間撹拌した。減圧下溶媒を留去し、飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~8%)を用いて精製することにより、白色固体の目的化合物(854mg,収率58%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, dd, J=1.6, 6.7Hz), 3.13 (1H, brd, J=1.2Hz), 3.23 (3H, s), 3.69 (1H, dd, J=5.9, 11.3Hz), 3.81 (1H, dd, J=3.5, 11.3Hz), 3.88 (1H, m), 3.93-4.01 (2H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.67 (1H, m), 4.68 (1H, d, J=5.5Hz), 6.49 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.04 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 520.15537(M+H)+。 The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 16 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the desired compound (854 mg, yield) as a white solid. 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.36 (3H, dd, J = 1.6, 6.7 Hz), 3.13 (1H, brd, J = 1.2 Hz), 3.23 (3H, s), 3.69 (1H, dd, J = 5.9, 11.3Hz), 3.81 (1H, dd, J = 3.5, 11.3Hz), 3.88 (1H, m), 3.93-4.01 (2H, m), 4.46 (1H, d, J = 4.7Hz ), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.68 (1H, d, J = 5.5Hz), 6.49 (1H, d, J = 3.9Hz), 6.57 (1H, t , J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.04 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 520.15537 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, dd, J=1.6, 6.7Hz), 3.13 (1H, brd, J=1.2Hz), 3.23 (3H, s), 3.69 (1H, dd, J=5.9, 11.3Hz), 3.81 (1H, dd, J=3.5, 11.3Hz), 3.88 (1H, m), 3.93-4.01 (2H, m), 4.46 (1H, d, J=4.7Hz), 4.58 (1H, d, J=4.7Hz), 4.67 (1H, m), 4.68 (1H, d, J=5.5Hz), 6.49 (1H, d, J=3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.73 (1H, d, J=3.9Hz), 6.88 (1H, t, J=2.0Hz), 7.04 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.05 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz).
MS (ESI) m/z: 520.15537(M+H)+。 The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 16 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the desired compound (854 mg, yield) as a white solid. 58%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.36 (3H, dd, J = 1.6, 6.7 Hz), 3.13 (1H, brd, J = 1.2 Hz), 3.23 (3H, s), 3.69 (1H, dd, J = 5.9, 11.3Hz), 3.81 (1H, dd, J = 3.5, 11.3Hz), 3.88 (1H, m), 3.93-4.01 (2H, m), 4.46 (1H, d, J = 4.7Hz ), 4.58 (1H, d, J = 4.7Hz), 4.67 (1H, m), 4.68 (1H, d, J = 5.5Hz), 6.49 (1H, d, J = 3.9Hz), 6.57 (1H, t , J = 2.4Hz), 6.73 (1H, d, J = 3.9Hz), 6.88 (1H, t, J = 2.0Hz), 7.04 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.05 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz).
MS (ESI) m / z: 520.15537 (M + H) <+> .
(実施例42)
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタン-1,2-ジオール (Example 42)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタン-1,2-ジオール (Example 42)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol
(42a)(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール
公知{J.Am.Chem.Soc.(ジャーナル オブ アメリカン ケミカル ソサイエティー)123巻、24号、5695-5702項(2001年)}の(1S)-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタン-1,2-ジオール(7.34g,45.3mmol)を塩化メチレン(300mL)に溶解し、t-ブチルジフェニルシリルクロリド(14.2mL,54.6mmol)、トリエチルアミン(15.8mL,113mmol)、4-ジメチルアミノピリジン(560mg,4.58mmol) を加え、窒素雰囲気下室温で23時間撹拌した。水(300mL)を加え、塩化メチレン(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(17.2g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 2.43 (1H, d, J=5.5Hz), 3.63-3.72 (3H, m), 3.81 (1H, dd, J=7.0, 8.2Hz), 4.00 (1H, dd, J=6.3, 8.6Hz), 4.21 (1H, m), 7.37-7.47 (6H, m), 7.64-7.68 (4H, m).
(42b)(1R)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エチル 4-ニトロベンゾエート
実施例(42a)で合成した化合物(8.65g,21.6mmol)、4-ニトロ安息香酸(5.42g,32.4mmol)、トリフェニルホスフィン(7.93g,30.2mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,14.7mL,32.3mmol)を用い、実施例(20a)と同様の方法で淡黄色油状の目的化合物(10.7g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02 (9H, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J=3.5Hz), 4.05 (1H, dd, J=7.0, 8.6Hz), 4.13 (1H, m), 4.48 (1H, m), 5.34 (1H, m), 7.23-7.44 (6H, m), 7.60 (4H, t, J=7.8Hz), 8.20 (2H, d, J=8.2Hz), 8.31 (2H, d, J=8.2Hz).
(42c)(1R)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール
実施例(42b)で合成した化合物(10.7g,19.4mmol)を塩化メチレン(200mL)に溶解し、-78℃にて水素化ジイソプロピルアルミニウム(1.02mol/Lトルエン溶液,48.0mL,50.0mmol)を滴下した。窒素雰囲気下-20℃で1.5時間攪拌した後、1規定水酸化ナトリウム水溶液(100mL)を加え、塩化メチレン(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(6.87g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 2.50 (1H, d, J=4.7Hz), 3.68 (1H, m), 3.75 (1H, dd, J=5.5, 10.2Hz), 3.82 (1H, dd, J=3.9, 10.2Hz), 3.98 (1H, m), 4.04-4.10 (2H, m), 7.36-7.46 (6H, m), 7.64-7.68 (4H, m)。 (42a) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Known {J. Am. Chem. Soc. (Journal of American Chemical Society) 123, 24, 5695-5702 (2001)}, (1S) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] Ethane-1,2-diol (7.34 g, 45.3 mmol) was dissolved in methylene chloride (300 mL), t-butyldiphenylsilyl chloride (14.2 mL, 54.6 mmol), triethylamine (15.8 mL, 113 mmol). 4-dimethylaminopyridine (560 mg, 4.58 mmol) was added, and the mixture was stirred at room temperature for 23 hours under a nitrogen atmosphere. Water (300 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (17.2 g, Yield 95%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 2.43 (1H, d, J = 5.5 Hz), 3.63-3.72 ( 3H, m), 3.81 (1H, dd, J = 7.0, 8.2Hz), 4.00 (1H, dd, J = 6.3, 8.6Hz), 4.21 (1H, m), 7.37-7.47 (6H, m), 7.64 -7.68 (4H, m).
(42b) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl 4-nitrobenzoate Compound (8.65 g, 21.6 mmol) synthesized in Example (42a), 4-nitrobenzoic acid (5.42 g, 32.4 mmol), triphenylphosphine (7.93 g, 30.2 mmol), azodicarboxylic acid Using diethyl (40% toluene solution, 14.7 mL, 32.3 mmol) in the same manner as in Example (20a), the target compound (10.7 g, yield 90%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.02 (9H, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J = 3.5 Hz), 4.05 (1H, dd, J = 7.0, 8.6Hz), 4.13 (1H, m), 4.48 (1H, m), 5.34 (1H, m), 7.23-7.44 (6H, m), 7.60 (4H, t, J = 7.8Hz ), 8.20 (2H, d, J = 8.2Hz), 8.31 (2H, d, J = 8.2Hz).
(42c) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Example (42b) ) (10.7 g, 19.4 mmol) was dissolved in methylene chloride (200 mL), and diisopropylaluminum hydride (1.02 mol / L toluene solution, 48.0 mL, 50.0 mmol) was dissolved at −78 ° C. Was dripped. The mixture was stirred at −20 ° C. for 1.5 hours under a nitrogen atmosphere, 1N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (6.87 g, Yield 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 2.50 (1H, d, J = 4.7 Hz), 3.68 (1H, m), 3.75 (1H, dd, J = 5.5, 10.2Hz), 3.82 (1H, dd, J = 3.9, 10.2Hz), 3.98 (1H, m), 4.04-4.10 (2H, m), 7.36-7.46 (6H, m), 7.64-7.68 (4H, m).
公知{J.Am.Chem.Soc.(ジャーナル オブ アメリカン ケミカル ソサイエティー)123巻、24号、5695-5702項(2001年)}の(1S)-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタン-1,2-ジオール(7.34g,45.3mmol)を塩化メチレン(300mL)に溶解し、t-ブチルジフェニルシリルクロリド(14.2mL,54.6mmol)、トリエチルアミン(15.8mL,113mmol)、4-ジメチルアミノピリジン(560mg,4.58mmol) を加え、窒素雰囲気下室温で23時間撹拌した。水(300mL)を加え、塩化メチレン(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(17.2g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 2.43 (1H, d, J=5.5Hz), 3.63-3.72 (3H, m), 3.81 (1H, dd, J=7.0, 8.2Hz), 4.00 (1H, dd, J=6.3, 8.6Hz), 4.21 (1H, m), 7.37-7.47 (6H, m), 7.64-7.68 (4H, m).
(42b)(1R)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エチル 4-ニトロベンゾエート
実施例(42a)で合成した化合物(8.65g,21.6mmol)、4-ニトロ安息香酸(5.42g,32.4mmol)、トリフェニルホスフィン(7.93g,30.2mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,14.7mL,32.3mmol)を用い、実施例(20a)と同様の方法で淡黄色油状の目的化合物(10.7g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02 (9H, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J=3.5Hz), 4.05 (1H, dd, J=7.0, 8.6Hz), 4.13 (1H, m), 4.48 (1H, m), 5.34 (1H, m), 7.23-7.44 (6H, m), 7.60 (4H, t, J=7.8Hz), 8.20 (2H, d, J=8.2Hz), 8.31 (2H, d, J=8.2Hz).
(42c)(1R)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタノール
実施例(42b)で合成した化合物(10.7g,19.4mmol)を塩化メチレン(200mL)に溶解し、-78℃にて水素化ジイソプロピルアルミニウム(1.02mol/Lトルエン溶液,48.0mL,50.0mmol)を滴下した。窒素雰囲気下-20℃で1.5時間攪拌した後、1規定水酸化ナトリウム水溶液(100mL)を加え、塩化メチレン(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~30%)を用いて精製することにより、無色油状の目的物(6.87g,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 2.50 (1H, d, J=4.7Hz), 3.68 (1H, m), 3.75 (1H, dd, J=5.5, 10.2Hz), 3.82 (1H, dd, J=3.9, 10.2Hz), 3.98 (1H, m), 4.04-4.10 (2H, m), 7.36-7.46 (6H, m), 7.64-7.68 (4H, m)。 (42a) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Known {J. Am. Chem. Soc. (Journal of American Chemical Society) 123, 24, 5695-5702 (2001)}, (1S) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] Ethane-1,2-diol (7.34 g, 45.3 mmol) was dissolved in methylene chloride (300 mL), t-butyldiphenylsilyl chloride (14.2 mL, 54.6 mmol), triethylamine (15.8 mL, 113 mmol). 4-dimethylaminopyridine (560 mg, 4.58 mmol) was added, and the mixture was stirred at room temperature for 23 hours under a nitrogen atmosphere. Water (300 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (17.2 g, Yield 95%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.37 (3H, s), 1.41 (3H, s), 2.43 (1H, d, J = 5.5 Hz), 3.63-3.72 ( 3H, m), 3.81 (1H, dd, J = 7.0, 8.2Hz), 4.00 (1H, dd, J = 6.3, 8.6Hz), 4.21 (1H, m), 7.37-7.47 (6H, m), 7.64 -7.68 (4H, m).
(42b) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl 4-nitrobenzoate Compound (8.65 g, 21.6 mmol) synthesized in Example (42a), 4-nitrobenzoic acid (5.42 g, 32.4 mmol), triphenylphosphine (7.93 g, 30.2 mmol), azodicarboxylic acid Using diethyl (40% toluene solution, 14.7 mL, 32.3 mmol) in the same manner as in Example (20a), the target compound (10.7 g, yield 90%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.02 (9H, s), 1.31 (3H, s), 1.36 (3H, s), 3.97 (2H, d, J = 3.5 Hz), 4.05 (1H, dd, J = 7.0, 8.6Hz), 4.13 (1H, m), 4.48 (1H, m), 5.34 (1H, m), 7.23-7.44 (6H, m), 7.60 (4H, t, J = 7.8Hz ), 8.20 (2H, d, J = 8.2Hz), 8.31 (2H, d, J = 8.2Hz).
(42c) (1R) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol Example (42b) ) (10.7 g, 19.4 mmol) was dissolved in methylene chloride (200 mL), and diisopropylaluminum hydride (1.02 mol / L toluene solution, 48.0 mL, 50.0 mmol) was dissolved at −78 ° C. Was dripped. The mixture was stirred at −20 ° C. for 1.5 hours under a nitrogen atmosphere, 1N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -30%) to give the desired product as a colorless oil (6.87 g, Yield 88%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 2.50 (1H, d, J = 4.7 Hz), 3.68 (1H, m), 3.75 (1H, dd, J = 5.5, 10.2Hz), 3.82 (1H, dd, J = 3.9, 10.2Hz), 3.98 (1H, m), 4.04-4.10 (2H, m), 7.36-7.46 (6H, m), 7.64-7.68 (4H, m).
(42d)2-{(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エチル}-1H-イソインドール-1,3(2H)-ジオン
実施例(42c)で合成した化合物(6.87g,17.2mmol)、フタルイミド(2.78g,18.9mmol)、トリフェニルホスフィン(4.96g,18.9mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,8.60mL,18.9mmol)を用い、実施例(20a)と同様の方法で淡黄色油状の目的化合物(8.65g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, J=6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m), 7.59-7.78 (8H, m).
(42e)(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタンアミン
実施例(42d)で合成した化合物(8.65g,16.3mmol)をエタノール(150mL)に溶解した。ヒドラジン一水和物(7.92mL,163mmol)を加え、窒素雰囲気下1.5時間加熱還流した。不溶物を濾過により除去した後、飽和炭酸水素ナトリウム水溶液(150mL)を加え、ジエチルエーテル(150mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色油状の目的化合物(5.85g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.27 (3H, s), 1.31 (3H, s), 2.76 (1H, dd, J=2.7, 3.9Hz), 3.64 (1H, m), 3.66 (1H, dd, J=6.7, 8.2Hz), 3.99 (1H, dd, J=6.3, 8.2Hz), 4.18 (1H, m), 7.36-7.47 (6H, m), 7.64-7.70 (4H, m).
(42f)N-{(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エチル}-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.55g,3.57mmol)、実施例(42e)で合成した化合物(1.71g,4.28mmol)、DMT-MM(2.47g, 8.93mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(2.67g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.33 (6H, s), 1.37 (3H, dd, J=1.6, 6.3Hz), 3.24 (3H, s), 3.46 (1H, td, J=5.9, 14.1Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, J=6.3, 8.2Hz), 4.11 (1H, m), 4.47 (1H, d, J=4.7Hz), 4.59 (1H, d, J=4.7Hz), 4.67 (1H, m), 5.86 (1H, dd, J=2.4, 3.9Hz), 6.14 (1H, brt, J=5.9Hz), 6.39 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.0Hz), 6.97 (1H, t, J=2.4Hz), 7.30-7.50 (7H, m), 7.63-7.71 (4H, m), 8.07 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.38 (1H, brs)。 (42d) 2-{(1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione The compound synthesized in Example (42c) (6.87 g, 17.2 mmol), phthalimide (2.78 g, 18.9 mmol), triphenylphosphine (4. 96 g, 18.9 mmol) and diethyl azodicarboxylate (40% toluene solution, 8.60 mL, 18.9 mmol) were used in the same manner as in Example (20a) to obtain the target compound (8.65 g, yield) as a pale yellow oil. 95%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, J = 6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m), 7.59-7.78 (8H, m).
(42e) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanamine Example (42d) ) (8.65 g, 16.3 mmol) was dissolved in ethanol (150 mL). Hydrazine monohydrate (7.92 mL, 163 mmol) was added, and the mixture was heated to reflux for 1.5 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (150 mL) was added, and the mixture was extracted twice with diethyl ether (150 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (5.85 g) as a pale yellow oil. Yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.27 (3H, s), 1.31 (3H, s), 2.76 (1H, dd, J = 2.7, 3.9Hz), 3.64 ( 1H, m), 3.66 (1H, dd, J = 6.7, 8.2Hz), 3.99 (1H, dd, J = 6.3, 8.2Hz), 4.18 (1H, m), 7.36-7.47 (6H, m), 7.64 -7.70 (4H, m).
(42f) N-{(1S) -2-{[t-butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (1.55 g, 3.57 mmol) synthesized in Example (35b), the compound (1.71 g, 4.28 mmol) synthesized in Example (42e), and DMT-MM (2.47 g, 8.93 mmol) were used. In the same manner as in Example (5d), the white solid target product (2.67 g, yield 92%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.33 (6H, s), 1.37 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.46 ( 1H, td, J = 5.9, 14.1Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, J = 6.3, 8.2Hz), 4.11 (1H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.67 (1H, m), 5.86 (1H, dd, J = 2.4, 3.9Hz), 6.14 (1H, brt, J = 5.9Hz), 6.39 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.4Hz), 7.30-7.50 (7H, m), 7.63-7.71 (4H, m), 8.07 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.38 ( 1H, brs).
実施例(42c)で合成した化合物(6.87g,17.2mmol)、フタルイミド(2.78g,18.9mmol)、トリフェニルホスフィン(4.96g,18.9mmol)、アゾジカルボン酸ジエチル(40%トルエン溶液,8.60mL,18.9mmol)を用い、実施例(20a)と同様の方法で淡黄色油状の目的化合物(8.65g,収率95%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, J=6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m), 7.59-7.78 (8H, m).
(42e)(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エタンアミン
実施例(42d)で合成した化合物(8.65g,16.3mmol)をエタノール(150mL)に溶解した。ヒドラジン一水和物(7.92mL,163mmol)を加え、窒素雰囲気下1.5時間加熱還流した。不溶物を濾過により除去した後、飽和炭酸水素ナトリウム水溶液(150mL)を加え、ジエチルエーテル(150mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色油状の目的化合物(5.85g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.27 (3H, s), 1.31 (3H, s), 2.76 (1H, dd, J=2.7, 3.9Hz), 3.64 (1H, m), 3.66 (1H, dd, J=6.7, 8.2Hz), 3.99 (1H, dd, J=6.3, 8.2Hz), 4.18 (1H, m), 7.36-7.47 (6H, m), 7.64-7.70 (4H, m).
(42f)N-{(1S)-2-{[t-ブチル(ジフェニル)シリル]オキシ}-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]エチル}-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(35b)で合成した化合物(1.55g,3.57mmol)、実施例(42e)で合成した化合物(1.71g,4.28mmol)、DMT-MM(2.47g, 8.93mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(2.67g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.06 (9H, s), 1.33 (6H, s), 1.37 (3H, dd, J=1.6, 6.3Hz), 3.24 (3H, s), 3.46 (1H, td, J=5.9, 14.1Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, J=6.3, 8.2Hz), 4.11 (1H, m), 4.47 (1H, d, J=4.7Hz), 4.59 (1H, d, J=4.7Hz), 4.67 (1H, m), 5.86 (1H, dd, J=2.4, 3.9Hz), 6.14 (1H, brt, J=5.9Hz), 6.39 (1H, dd, J=2.7, 3.9Hz), 6.57 (1H, t, J=2.4Hz), 6.83 (1H, t, J=2.0Hz), 6.97 (1H, t, J=2.4Hz), 7.30-7.50 (7H, m), 7.63-7.71 (4H, m), 8.07 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.38 (1H, brs)。 (42d) 2-{(1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione The compound synthesized in Example (42c) (6.87 g, 17.2 mmol), phthalimide (2.78 g, 18.9 mmol), triphenylphosphine (4. 96 g, 18.9 mmol) and diethyl azodicarboxylate (40% toluene solution, 8.60 mL, 18.9 mmol) were used in the same manner as in Example (20a) to obtain the target compound (8.65 g, yield) as a pale yellow oil. 95%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 3.67-3.81 (3H, m), 3.94 (1H, dd, J = 6.3, 8.6Hz), 4.08 (1H, m), 4.24 (1H, m), 7.27-7.44 (6H, m), 7.59-7.78 (8H, m).
(42e) (1S) -2-{[t-Butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanamine Example (42d) ) (8.65 g, 16.3 mmol) was dissolved in ethanol (150 mL). Hydrazine monohydrate (7.92 mL, 163 mmol) was added, and the mixture was heated to reflux for 1.5 hours under a nitrogen atmosphere. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution (150 mL) was added, and the mixture was extracted twice with diethyl ether (150 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -50%) to give the target compound (5.85 g) as a pale yellow oil. Yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.27 (3H, s), 1.31 (3H, s), 2.76 (1H, dd, J = 2.7, 3.9Hz), 3.64 ( 1H, m), 3.66 (1H, dd, J = 6.7, 8.2Hz), 3.99 (1H, dd, J = 6.3, 8.2Hz), 4.18 (1H, m), 7.36-7.47 (6H, m), 7.64 -7.70 (4H, m).
(42f) N-{(1S) -2-{[t-butyl (diphenyl) silyl] oxy} -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethyl} -5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (1.55 g, 3.57 mmol) synthesized in Example (35b), the compound (1.71 g, 4.28 mmol) synthesized in Example (42e), and DMT-MM (2.47 g, 8.93 mmol) were used. In the same manner as in Example (5d), the white solid target product (2.67 g, yield 92%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ1.06 (9H, s), 1.33 (6H, s), 1.37 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.46 ( 1H, td, J = 5.9, 14.1Hz), 3.65 (1H, m), 3.71-3.81 (2H, m), 4.01 (1H, dd, J = 6.3, 8.2Hz), 4.11 (1H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.67 (1H, m), 5.86 (1H, dd, J = 2.4, 3.9Hz), 6.14 (1H, brt, J = 5.9Hz), 6.39 (1H, dd, J = 2.7, 3.9Hz), 6.57 (1H, t, J = 2.4Hz), 6.83 (1H, t, J = 2.0Hz), 6.97 (1H, t, J = 2.4Hz), 7.30-7.50 (7H, m), 7.63-7.71 (4H, m), 8.07 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.38 ( 1H, brs).
(42g)N-{(1S)-1-[(4R)-2,2-ジメチル-1,3-ジオキソラン-4-イル]-2-ヒドロキシエチル}-5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(42f)で合成した化合物(2.67g,3.27mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,4.43mL,4.43mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.56g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, s), 1.37 (3H, dd, J=1.7, 6.3Hz), 1.43 (3H, s), 3.23 (3H, s), 3.48 (1H, td, J=5.9, 14.1Hz), 3.72-3.82 (2H, m), 3.88 (1H, brs), 3.98-4.15 (3H, m), 4.47 (1H, d, J=4.7Hz), 4.59 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.42 (1H, brt, J=5.5Hz), 6.51 (1H, dd, J=2.7, 3.9Hz), 6.59 (1H, t, J=2.4Hz), 6.64 (1H, dd, J=2.4, 3.9Hz), 6.87 (1H, t, J=2.0Hz), 7.01 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.58 (1H, brs).
(42h)(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタン-1,2-ジオール
実施例(42g)で合成した化合物(1.56g,2.70mmol)をテトラヒドロフラン(40mL)に溶解し、メタンスルホン酸無水物(1.18g,6.77mmol)、トリエチルアミン(2.26mL, 16.2mol)を加え、窒素雰囲気下50℃で16時間撹拌した。水(40mL)を加え、酢酸エチル(40mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (42g) N-{(1S) -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (42f) (2. 67 g, 3.27 mmol) and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 4.43 mL, 4.43 mmol) were used in the same manner as in Example (16k) to obtain the target compound (1.56 g, Yield 83%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.36 (3H, s), 1.37 (3H, dd, J = 1.7, 6.3Hz), 1.43 (3H, s), 3.23 (3H, s), 3.48 ( 1H, td, J = 5.9, 14.1Hz), 3.72-3.82 (2H, m), 3.88 (1H, brs), 3.98-4.15 (3H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.42 (1H, brt, J = 5.5Hz), 6.51 (1H, dd, J = 2.7, 3.9Hz), 6.59 (1H, t, J = 2.4Hz), 6.64 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).
(42h) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol Compound synthesized in Example (42g) ( 1.56 g, 2.70 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.18 g, 6.77 mmol) and triethylamine (2.26 mL, 16.2 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 16 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(42f)で合成した化合物(2.67g,3.27mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,4.43mL,4.43mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.56g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.36 (3H, s), 1.37 (3H, dd, J=1.7, 6.3Hz), 1.43 (3H, s), 3.23 (3H, s), 3.48 (1H, td, J=5.9, 14.1Hz), 3.72-3.82 (2H, m), 3.88 (1H, brs), 3.98-4.15 (3H, m), 4.47 (1H, d, J=4.7Hz), 4.59 (1H, d, J=4.7Hz), 4.68 (1H, m), 6.42 (1H, brt, J=5.5Hz), 6.51 (1H, dd, J=2.7, 3.9Hz), 6.59 (1H, t, J=2.4Hz), 6.64 (1H, dd, J=2.4, 3.9Hz), 6.87 (1H, t, J=2.0Hz), 7.01 (1H, t, J=2.0Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.49 (1H, d, J=2.7Hz), 9.58 (1H, brs).
(42h)(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタン-1,2-ジオール
実施例(42g)で合成した化合物(1.56g,2.70mmol)をテトラヒドロフラン(40mL)に溶解し、メタンスルホン酸無水物(1.18g,6.77mmol)、トリエチルアミン(2.26mL, 16.2mol)を加え、窒素雰囲気下50℃で16時間撹拌した。水(40mL)を加え、酢酸エチル(40mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (42g) N-{(1S) -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} -5- (3-[(1S)- 2-Fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound synthesized in Example (42f) (2. 67 g, 3.27 mmol) and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 4.43 mL, 4.43 mmol) were used in the same manner as in Example (16k) to obtain the target compound (1.56 g, Yield 83%) was obtained.
1 H-NMR (CDCl 3 , 400MHz): δ1.36 (3H, s), 1.37 (3H, dd, J = 1.7, 6.3Hz), 1.43 (3H, s), 3.23 (3H, s), 3.48 ( 1H, td, J = 5.9, 14.1Hz), 3.72-3.82 (2H, m), 3.88 (1H, brs), 3.98-4.15 (3H, m), 4.47 (1H, d, J = 4.7Hz), 4.59 (1H, d, J = 4.7Hz), 4.68 (1H, m), 6.42 (1H, brt, J = 5.5Hz), 6.51 (1H, dd, J = 2.7, 3.9Hz), 6.59 (1H, t, J = 2.4Hz), 6.64 (1H, dd, J = 2.4, 3.9Hz), 6.87 (1H, t, J = 2.0Hz), 7.01 (1H, t, J = 2.0Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.49 (1H, d, J = 2.7Hz), 9.58 (1H, brs).
(42h) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridine-3 -Yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethane-1,2-diol Compound synthesized in Example (42g) ( 1.56 g, 2.70 mmol) was dissolved in tetrahydrofuran (40 mL), methanesulfonic anhydride (1.18 g, 6.77 mmol) and triethylamine (2.26 mL, 16.2 mol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. For 16 hours. Water (40 mL) was added and extracted twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣を酢酸(30mL)と水(10mL)の混合溶媒に溶解し、窒素雰囲気下50℃で17時間撹拌した。減圧下溶媒を留去し、飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~8%)を用いて精製することにより、白色固体の目的化合物(710mg,収率54%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.35 (3H, dd, J=1.6, 6.3Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J=7.4, 14.1Hz), 3.98 (1H, dd, J=10.2, 14.1Hz), 4.45 (1H, d, J=4.7Hz), 4.57 (1H, d, J=4.7Hz), 4.62-4.70 (2H, m), 6.38 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.61 (1H, d, J=3.9Hz), 6.86 (1H, t, J=2.0Hz), 7.02 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.02 (1H, d, J=8.6Hz), 8.45 (1H, d, J=2.7Hz).
MS (ESI) m/z: 520.15537(M+H)+。 The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 17 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the target compound (710 mg, yield) as a white solid. 54%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J = 7.4, 14.1Hz), 3.98 (1H, dd, J = 10.2, 14.1Hz), 4.45 (1H, d, J = 4.7Hz), 4.57 (1H, d, J = 4.7Hz), 4.62-4.70 (2H , m), 6.38 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.9Hz), 6.86 (1H, t, J = 2.0Hz) ), 7.02 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz) ).
MS (ESI) m / z: 520.15537 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.35 (3H, dd, J=1.6, 6.3Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J=7.4, 14.1Hz), 3.98 (1H, dd, J=10.2, 14.1Hz), 4.45 (1H, d, J=4.7Hz), 4.57 (1H, d, J=4.7Hz), 4.62-4.70 (2H, m), 6.38 (1H, d, J=3.9Hz), 6.54 (1H, t, J=2.4Hz), 6.61 (1H, d, J=3.9Hz), 6.86 (1H, t, J=2.0Hz), 7.02 (1H, t, J=2.0Hz), 7.42 (1H, dd, J=2.7, 8.6Hz), 8.02 (1H, d, J=8.6Hz), 8.45 (1H, d, J=2.7Hz).
MS (ESI) m/z: 520.15537(M+H)+。 The obtained residue was dissolved in a mixed solvent of acetic acid (30 mL) and water (10 mL), and stirred at 50 ° C. for 17 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 8%) to give the target compound (710 mg, yield) as a white solid. 54%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.22 (3H, s), 3.68-3.71 (3H, m), 3.80 (1H, dd, J = 7.4, 14.1Hz), 3.98 (1H, dd, J = 10.2, 14.1Hz), 4.45 (1H, d, J = 4.7Hz), 4.57 (1H, d, J = 4.7Hz), 4.62-4.70 (2H , m), 6.38 (1H, d, J = 3.9Hz), 6.54 (1H, t, J = 2.4Hz), 6.61 (1H, d, J = 3.9Hz), 6.86 (1H, t, J = 2.0Hz) ), 7.02 (1H, t, J = 2.0Hz), 7.42 (1H, dd, J = 2.7, 8.6Hz), 8.02 (1H, d, J = 8.6Hz), 8.45 (1H, d, J = 2.7Hz) ).
MS (ESI) m / z: 520.15537 (M + H) <+> .
(実施例43)
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 43)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール (Example 43)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol
(43a)5-(メチルスルファニル)ピラジン-2-アミン
2-アミノピラジン(50.8g,0.53mmol)を塩化メチレン(1.0L)に溶解し、N-ブロモコハク酸イミド(97.9g,0.55mol)を0℃で30分かけて加え、窒素雰囲気下0℃で2時間半撹拌した。反応液を室温まで戻し、析出物を濾別した。濾別した析出物は酢酸エチルを用いて洗浄した。母液を集めて減圧下溶媒を留去した。この操作を2回繰り返し得られた母液を減圧下溶媒留去することで黄色油状の化合物が得られた。 (43a) 5- (Methylsulfanyl) pyrazin-2-amine 2-Aminopyrazine (50.8 g, 0.53 mmol) was dissolved in methylene chloride (1.0 L), and N-bromosuccinimide (97.9 g, 0 .55 mol) was added at 0 ° C. over 30 minutes, and the mixture was stirred at 0 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, and the precipitate was filtered off. The precipitate separated by filtration was washed with ethyl acetate. The mother liquor was collected and the solvent was distilled off under reduced pressure. The mother liquor obtained by repeating this operation twice was evaporated under reduced pressure to give a yellow oily compound.
2-アミノピラジン(50.8g,0.53mmol)を塩化メチレン(1.0L)に溶解し、N-ブロモコハク酸イミド(97.9g,0.55mol)を0℃で30分かけて加え、窒素雰囲気下0℃で2時間半撹拌した。反応液を室温まで戻し、析出物を濾別した。濾別した析出物は酢酸エチルを用いて洗浄した。母液を集めて減圧下溶媒を留去した。この操作を2回繰り返し得られた母液を減圧下溶媒留去することで黄色油状の化合物が得られた。 (43a) 5- (Methylsulfanyl) pyrazin-2-amine 2-Aminopyrazine (50.8 g, 0.53 mmol) was dissolved in methylene chloride (1.0 L), and N-bromosuccinimide (97.9 g, 0 .55 mol) was added at 0 ° C. over 30 minutes, and the mixture was stirred at 0 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, and the precipitate was filtered off. The precipitate separated by filtration was washed with ethyl acetate. The mother liquor was collected and the solvent was distilled off under reduced pressure. The mother liquor obtained by repeating this operation twice was evaporated under reduced pressure to give a yellow oily compound.
これをN,N-ジメチルホルムアミド(300mL)に溶解し、ナトリウムチオメトキシド(75.0g,1.07mol)を加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで戻し、水(1.5L)を加え、酢酸エチル(1.0L)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~30%)を用いて精製することにより、橙色固体の目的化合物(42.5g,収率56%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.52 (3H, s), 4.41 (2H, br s), 7.92 (1H, d, J = 1.6 Hz), 7.98 (1H, d, J = 1.6 Hz).
(43b)2-クロロ-5-(メチルスルファニル)ピラジン
亜硝酸ナトリウム(50.9g,0.74mol)を水(150mL)に溶解し、
5N塩酸(1.0L)中に0℃で一時間かけて滴下した。その後、実施例(43a)で合成した化合物(40.4g,0.28mol)を0℃で40分かけて加え、0℃で一時間撹拌した。反応液を室温まで戻し、水(500mL)を加え、酢酸エチル(1.0mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~20%)を用いて精製することにより、白色固体の目的化合物(11.9g,収率26%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.57 (3H, s), 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz).
(43c)2-クロロ-5-(メチルスルホニル)ピラジン
実施例(43b)で合成した化合物(10.82g,67.4mmol)を塩化メチレン(200mL)に溶解し、m-クロロ過安息香酸(約65%,37.4g,約140mmol)を0℃でゆっくり加え、窒素雰囲気下0℃で一時間半撹拌した。飽和炭酸水素ナトリウム水溶液(300mL)を加え、塩化メチレン(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することで白色固体の目的化合物(10.1g,収率78%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.27 (3H, s), 8.70 (1H, d, J = 1.2 Hz), 9.09 (1H, d, J = 1.2 Hz)。 This was dissolved in N, N-dimethylformamide (300 mL), sodium thiomethoxide (75.0 g, 1.07 mol) was added, and the mixture was stirred at 100 ° C. for 3 hours under nitrogen atmosphere. The reaction solution was returned to room temperature, water (1.5 L) was added, and the mixture was extracted with ethyl acetate (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -30%) to give the target compound (42.5 g, Yield 56%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.52 (3H, s), 4.41 (2H, br s), 7.92 (1H, d, J = 1.6 Hz), 7.98 (1H, d, J = 1.6 Hz) .
(43b) 2-chloro-5- (methylsulfanyl) pyrazine sodium nitrite (50.9 g, 0.74 mol) is dissolved in water (150 mL),
The mixture was added dropwise to 5N hydrochloric acid (1.0 L) at 0 ° C. over 1 hour. Thereafter, the compound (40.4 g, 0.28 mol) synthesized in Example (43a) was added at 0 ° C. over 40 minutes, and the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was returned to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (1.0 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 20%) to give the target compound (11.9 g, Yield 26%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.57 (3H, s), 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz).
(43c) 2-Chloro-5- (methylsulfonyl) pyrazine The compound (10.82 g, 67.4 mmol) synthesized in Example (43b) was dissolved in methylene chloride (200 mL), and m-chloroperbenzoic acid (about 65%, 37.4 g, about 140 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with methylene chloride (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -50%) to give the target compound (10.1 g, yield) as a white solid. 78%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.27 (3H, s), 8.70 (1H, d, J = 1.2 Hz), 9.09 (1H, d, J = 1.2 Hz).
1H-NMR (CDCl3, 400MHz):δ 2.52 (3H, s), 4.41 (2H, br s), 7.92 (1H, d, J = 1.6 Hz), 7.98 (1H, d, J = 1.6 Hz).
(43b)2-クロロ-5-(メチルスルファニル)ピラジン
亜硝酸ナトリウム(50.9g,0.74mol)を水(150mL)に溶解し、
5N塩酸(1.0L)中に0℃で一時間かけて滴下した。その後、実施例(43a)で合成した化合物(40.4g,0.28mol)を0℃で40分かけて加え、0℃で一時間撹拌した。反応液を室温まで戻し、水(500mL)を加え、酢酸エチル(1.0mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~20%)を用いて精製することにより、白色固体の目的化合物(11.9g,収率26%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.57 (3H, s), 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz).
(43c)2-クロロ-5-(メチルスルホニル)ピラジン
実施例(43b)で合成した化合物(10.82g,67.4mmol)を塩化メチレン(200mL)に溶解し、m-クロロ過安息香酸(約65%,37.4g,約140mmol)を0℃でゆっくり加え、窒素雰囲気下0℃で一時間半撹拌した。飽和炭酸水素ナトリウム水溶液(300mL)を加え、塩化メチレン(400mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~50%)を用いて精製することで白色固体の目的化合物(10.1g,収率78%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.27 (3H, s), 8.70 (1H, d, J = 1.2 Hz), 9.09 (1H, d, J = 1.2 Hz)。 This was dissolved in N, N-dimethylformamide (300 mL), sodium thiomethoxide (75.0 g, 1.07 mol) was added, and the mixture was stirred at 100 ° C. for 3 hours under nitrogen atmosphere. The reaction solution was returned to room temperature, water (1.5 L) was added, and the mixture was extracted with ethyl acetate (1.0 L). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% -30%) to give the target compound (42.5 g, Yield 56%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.52 (3H, s), 4.41 (2H, br s), 7.92 (1H, d, J = 1.6 Hz), 7.98 (1H, d, J = 1.6 Hz) .
(43b) 2-chloro-5- (methylsulfanyl) pyrazine sodium nitrite (50.9 g, 0.74 mol) is dissolved in water (150 mL),
The mixture was added dropwise to 5N hydrochloric acid (1.0 L) at 0 ° C. over 1 hour. Thereafter, the compound (40.4 g, 0.28 mol) synthesized in Example (43a) was added at 0 ° C. over 40 minutes, and the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was returned to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (1.0 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 20%) to give the target compound (11.9 g, Yield 26%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.57 (3H, s), 8.24 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 1.2 Hz).
(43c) 2-Chloro-5- (methylsulfonyl) pyrazine The compound (10.82 g, 67.4 mmol) synthesized in Example (43b) was dissolved in methylene chloride (200 mL), and m-chloroperbenzoic acid (about 65%, 37.4 g, about 140 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with methylene chloride (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -50%) to give the target compound (10.1 g, yield) as a white solid. 78%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.27 (3H, s), 8.70 (1H, d, J = 1.2 Hz), 9.09 (1H, d, J = 1.2 Hz).
(43d)ベンジル 5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(34g)で合成した化合物(9.72g,26.31mmol)、トリエチルアミン(11.00mL,78.94mmol)、4-ジメチルアミノピリジン(4.82g,39.47mmol)を塩化メチレン(250mL)に溶解し、室温でトリイソプロピルシリルクロリド(8.45mL,39.47mmol)を加え、窒素雰囲気下5時間攪拌した。反応液を塩化メチレン(300mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~15%)を用いて精製し、無色油状の目的物(13.32g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.10-1.13 (18H, m), 1.22-1.30 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.66 (3H, m), 5.33 (2H, s), 6.42 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 1.6 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.17 (1H, br s).
(43e)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(43d)で合成した化合物(13.65g,25.96mmol)をエタノール(400mL)に溶解し、10%パラジウム炭素触媒(2.00g)を加えて水素雰囲気下に40分撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(10.37g,収率92%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.11-1.14 (18H, m), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 4.43-4.67 (3H, m), 6.44 (1H, t, J = 2.0 Hz), 6.51 (1H, t, J = 2.9 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.07 (1H, t, J = 2.4 Hz), 9.32 (1H, br s).
(43f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(43e)で合成した化合物(3.52g,8.08mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.84g,20.20mmol)、DMT-MM(6.40g,20.20mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(3.83g,94%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.10-1.13 (18H, m), 1.23-1.29 (3H, m), 1.34 (3H, dd, J = 1.6, 6.3 Hz), 3.51-3.66 (4H, m), 3.84-3.89 (1H, m), 4.41-4.67 (3H, m), 6.40 (1H, t, J = 2.0 Hz), 6.45 (1H, t, J = 3.5 Hz), 6.54 (1H, t, J = 5.9 Hz), 6.65 (1H, dd, J = 2.7, 3.9 Hz), 6.71 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 9.81 (1H, br s)。 (43d) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylate Example (34g) (9.72 g, 26.31 mmol), triethylamine (11.00 mL, 78.94 mmol) and 4-dimethylaminopyridine (4.82 g, 39.47 mmol) were dissolved in methylene chloride (250 mL) at room temperature. Added triisopropylsilyl chloride (8.45 mL, 39.47 mmol) and stirred for 5 hours under nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (300 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 15%) to give the desired product (13.32 g, 96%) as a colorless oil. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.10-1.13 (18H, m), 1.22-1.30 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.66 (3H, m), 5.33 (2H, s), 6.42 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 1.6 Hz), 6.70 ( 1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.17 (1H, br s).
(43e) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylic acid In Example (43d) The synthesized compound (13.65 g, 25.96 mmol) was dissolved in ethanol (400 mL), 10% palladium carbon catalyst (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (10.37 g, yield 92%) as a white solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.11-1.14 (18H, m), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 4.43-4.67 (3H, m), 6.44 (1H, t, J = 2.0 Hz), 6.51 (1H, t, J = 2.9 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.07 (1H, t, J = 2.4 Hz), 9.32 (1H, br s).
(43f) N-[(2S) -2,3-dihydroxypropyl] -5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide Compound (3.52 g, 8.08 mmol) synthesized in Example (43e), (S)-(−)-3-amino-1,2-propanediol (1.84 g, 20.20 mmol) and DMT-MM (6.40 g, 20.20 mmol) were used to give the target compound (3.83 g, 94%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.10-1.13 (18H, m), 1.23-1.29 (3H, m), 1.34 (3H, dd, J = 1.6, 6.3 Hz), 3.51-3.66 (4H, m), 3.84-3.89 (1H, m), 4.41-4.67 (3H, m), 6.40 (1H, t, J = 2.0 Hz), 6.45 (1H, t, J = 3.5 Hz), 6.54 (1H, t , J = 5.9 Hz), 6.65 (1H, dd, J = 2.7, 3.9 Hz), 6.71 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 9.81 (1H, br s).
実施例(34g)で合成した化合物(9.72g,26.31mmol)、トリエチルアミン(11.00mL,78.94mmol)、4-ジメチルアミノピリジン(4.82g,39.47mmol)を塩化メチレン(250mL)に溶解し、室温でトリイソプロピルシリルクロリド(8.45mL,39.47mmol)を加え、窒素雰囲気下5時間攪拌した。反応液を塩化メチレン(300mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~15%)を用いて精製し、無色油状の目的物(13.32g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.10-1.13 (18H, m), 1.22-1.30 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.66 (3H, m), 5.33 (2H, s), 6.42 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 1.6 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.17 (1H, br s).
(43e)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(43d)で合成した化合物(13.65g,25.96mmol)をエタノール(400mL)に溶解し、10%パラジウム炭素触媒(2.00g)を加えて水素雰囲気下に40分撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(10.37g,収率92%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.11-1.14 (18H, m), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 4.43-4.67 (3H, m), 6.44 (1H, t, J = 2.0 Hz), 6.51 (1H, t, J = 2.9 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.07 (1H, t, J = 2.4 Hz), 9.32 (1H, br s).
(43f)N-[(2S)-2,3-ジヒドロキシプロピル]-5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(43e)で合成した化合物(3.52g,8.08mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(1.84g,20.20mmol)、DMT-MM(6.40g,20.20mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(3.83g,94%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.10-1.13 (18H, m), 1.23-1.29 (3H, m), 1.34 (3H, dd, J = 1.6, 6.3 Hz), 3.51-3.66 (4H, m), 3.84-3.89 (1H, m), 4.41-4.67 (3H, m), 6.40 (1H, t, J = 2.0 Hz), 6.45 (1H, t, J = 3.5 Hz), 6.54 (1H, t, J = 5.9 Hz), 6.65 (1H, dd, J = 2.7, 3.9 Hz), 6.71 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 9.81 (1H, br s)。 (43d) Benzyl 5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylate Example (34g) (9.72 g, 26.31 mmol), triethylamine (11.00 mL, 78.94 mmol) and 4-dimethylaminopyridine (4.82 g, 39.47 mmol) were dissolved in methylene chloride (250 mL) at room temperature. Added triisopropylsilyl chloride (8.45 mL, 39.47 mmol) and stirred for 5 hours under nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (300 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 15%) to give the desired product (13.32 g, 96%) as a colorless oil. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.10-1.13 (18H, m), 1.22-1.30 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 4.41-4.66 (3H, m), 5.33 (2H, s), 6.42 (1H, t, J = 2.0 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 1.6 Hz), 6.70 ( 1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 2.3, 3.9 Hz), 7.32-7.46 (5H, m), 9.17 (1H, br s).
(43e) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxylic acid In Example (43d) The synthesized compound (13.65 g, 25.96 mmol) was dissolved in ethanol (400 mL), 10% palladium carbon catalyst (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (10.37 g, yield 92%) as a white solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.11-1.14 (18H, m), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 4.43-4.67 (3H, m), 6.44 (1H, t, J = 2.0 Hz), 6.51 (1H, t, J = 2.9 Hz), 6.71 (1H, s), 6.74 (1H, s), 7.07 (1H, t, J = 2.4 Hz), 9.32 (1H, br s).
(43f) N-[(2S) -2,3-dihydroxypropyl] -5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide Compound (3.52 g, 8.08 mmol) synthesized in Example (43e), (S)-(−)-3-amino-1,2-propanediol (1.84 g, 20.20 mmol) and DMT-MM (6.40 g, 20.20 mmol) were used to give the target compound (3.83 g, 94%) as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.10-1.13 (18H, m), 1.23-1.29 (3H, m), 1.34 (3H, dd, J = 1.6, 6.3 Hz), 3.51-3.66 (4H, m), 3.84-3.89 (1H, m), 4.41-4.67 (3H, m), 6.40 (1H, t, J = 2.0 Hz), 6.45 (1H, t, J = 3.5 Hz), 6.54 (1H, t , J = 5.9 Hz), 6.65 (1H, dd, J = 2.7, 3.9 Hz), 6.71 (1H, t, J = 1.6 Hz), 6.76 (1H, t, J = 1.6 Hz), 9.81 (1H, br s).
(43g)5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-1H-ピロール-2-カルボキサミド
実施例(43f)で合成した化合物(3.83g,7.53mmol)を塩化メチレン(70mL)に溶解し、トリイソプロピルシリルクロリド(2.42mL,11.29mmol)、トリエチルアミン(5.25mL, 37.64mol)、4-ジメチルアミノピリジン(1.38g,11.29mmol)を加え、窒素雰囲気下室温で8時間撹拌した。反応液を塩化メチレン(100mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、無色油状の目的化合物(5.01g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.05-1.14 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.38-3.45 (1H, m), 3.66-3.79 (3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.30-6.35 (1H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.69 (1H, t, J = 1.6 Hz), 6.71 (1H, t, J = 1.6 Hz), 9.38 (1H, br s).
(43h)(5R)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール
実施例(43g)で合成した化合物(5.01g,7.52mmol)、メタンスルホン酸無水物(2.70g,15.04mmol)、トリエチルアミン(4.19mL, 30.07mmol)を用い、実施例(16j)と同様の方法で橙色油状の目的物(4.15g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.03-1.15 (39H, m), 1.24-1.29 (3H, m), 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.84-3.90 (3H, m), 4.01 (1H, dd, J = 9.4, 14.1 Hz), 4.40-4.65 (3H, m), 4.71-4.78 (1H, m), 6.39 (1H, t, J = 3.5 Hz), 6.46 (1H, d, J = 3.9 Hz), 6.72-6.68 (2H, m), 6.74 (1H, d, J = 3.9 Hz)。 (43 g) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -N-{(2S) -2-hydroxy-3- [ (Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (43f) (3.83 g, 7.53 mmol) was dissolved in methylene chloride (70 mL), and triisopropylsilyl chloride ( 2.42 mL, 11.29 mmol), triethylamine (5.25 mL, 37.64 mol) and 4-dimethylaminopyridine (1.38 g, 11.29 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the desired compound (5.01 g, Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.14 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.38-3.45 (1H, m), 3.66-3.79 (3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.30-6.35 (1H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.69 (1H, t, J = 1.6 Hz), 6.71 (1H, t, J = 1.6 Hz), 9.38 (1H, br s ).
(43h) (5R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl ) -5-{[(Triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole Compound (5.01 g, 7.52 mmol) synthesized in Example (43 g), methanesulfonic anhydride Product (2.70 g, 15.04 mmol) and triethylamine (4.19 mL, 30.07 mmol) were used in the same manner as in Example (16j) to give the target product (4.15 g, yield 85%) as an orange oil. Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.03-1.15 (39H, m), 1.24-1.29 (3H, m), 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.84-3.90 (3H, m), 4.01 (1H, dd, J = 9.4, 14.1 Hz), 4.40-4.65 (3H, m), 4.71-4.78 (1H, m), 6.39 (1H, t, J = 3.5 Hz), 6.46 (1H , d, J = 3.9 Hz), 6.72-6.68 (2H, m), 6.74 (1H, d, J = 3.9 Hz).
実施例(43f)で合成した化合物(3.83g,7.53mmol)を塩化メチレン(70mL)に溶解し、トリイソプロピルシリルクロリド(2.42mL,11.29mmol)、トリエチルアミン(5.25mL, 37.64mol)、4-ジメチルアミノピリジン(1.38g,11.29mmol)を加え、窒素雰囲気下室温で8時間撹拌した。反応液を塩化メチレン(100mL)で希釈し、1規定塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、無色油状の目的化合物(5.01g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.05-1.14 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.38-3.45 (1H, m), 3.66-3.79 (3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.30-6.35 (1H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.69 (1H, t, J = 1.6 Hz), 6.71 (1H, t, J = 1.6 Hz), 9.38 (1H, br s).
(43h)(5R)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール
実施例(43g)で合成した化合物(5.01g,7.52mmol)、メタンスルホン酸無水物(2.70g,15.04mmol)、トリエチルアミン(4.19mL, 30.07mmol)を用い、実施例(16j)と同様の方法で橙色油状の目的物(4.15g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.03-1.15 (39H, m), 1.24-1.29 (3H, m), 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.84-3.90 (3H, m), 4.01 (1H, dd, J = 9.4, 14.1 Hz), 4.40-4.65 (3H, m), 4.71-4.78 (1H, m), 6.39 (1H, t, J = 3.5 Hz), 6.46 (1H, d, J = 3.9 Hz), 6.72-6.68 (2H, m), 6.74 (1H, d, J = 3.9 Hz)。 (43 g) 5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -N-{(2S) -2-hydroxy-3- [ (Triisopropylsilyl) oxy] propyl} -1H-pyrrole-2-carboxamide The compound synthesized in Example (43f) (3.83 g, 7.53 mmol) was dissolved in methylene chloride (70 mL), and triisopropylsilyl chloride ( 2.42 mL, 11.29 mmol), triethylamine (5.25 mL, 37.64 mol) and 4-dimethylaminopyridine (1.38 g, 11.29 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the desired compound (5.01 g, Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.14 (42H, m), 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.38-3.45 (1H, m), 3.66-3.79 (3H, m), 3.85-3.91 (1H, br m), 4.42-4.66 (3H, m), 6.30-6.35 (1H, br m), 6.40 (1H, t, J = 2.0 Hz), 6.46 (1H, t, J = 2.7 Hz), 6.60 (1H, dd, J = 2.3, 3.9 Hz), 6.69 (1H, t, J = 1.6 Hz), 6.71 (1H, t, J = 1.6 Hz), 9.38 (1H, br s ).
(43h) (5R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl ) -5-{[(Triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole Compound (5.01 g, 7.52 mmol) synthesized in Example (43 g), methanesulfonic anhydride Product (2.70 g, 15.04 mmol) and triethylamine (4.19 mL, 30.07 mmol) were used in the same manner as in Example (16j) to give the target product (4.15 g, yield 85%) as an orange oil. Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.03-1.15 (39H, m), 1.24-1.29 (3H, m), 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.84-3.90 (3H, m), 4.01 (1H, dd, J = 9.4, 14.1 Hz), 4.40-4.65 (3H, m), 4.71-4.78 (1H, m), 6.39 (1H, t, J = 3.5 Hz), 6.46 (1H , d, J = 3.9 Hz), 6.72-6.68 (2H, m), 6.74 (1H, d, J = 3.9 Hz).
(43i)3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノール
実施例(43h)で合成した化合物(4.15g,6.41mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,13.50mL,13.50mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(2.02g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.78 (1H, dd, J = 5.5, 12.1 Hz), 3.93-3.99 (2H, m), 4.18 (1H, dd, J = 9.8, 13.3 Hz), 4.42-4.69 (3H, m), 4.87-4.94 (1H, m), 6.34 (1H, t, J = 2.3 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.08 (1H, t, J = 1.6 Hz), 10.99 (1H, br s).
(43j){(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(43i)で合成した化合物(120mg,0.36mmol)、実施例(43c)で合成した化合物(69mg,0.36mmol)をアセトニトリル(3mL)に溶解し、炭酸カリウム(99mg,0.72mmol)を加えて、窒素雰囲気下室温で3時間撹拌した。水(10mL)を加え、酢酸エチル(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(132mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.22 (3H, s), 3.64-3.73 (2H, m), 3.80 (1H, dd, J = 3.1, 12.5 Hz), 3.94 (1H, dd, J = 9.8, 14.1 Hz), 4.43-4.69 (3H, m), 4.70-4.77 (1H, m), 6.42 (1H, d, J = 3.9 Hz), 6.62-6.64 (2H, m), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.77 (1H, s).
MS (ESI) m/z: 491.13903 (M+H)+。 (43i) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Il] -1H-pyrrol-2-yl} phenol Compound (4.15 g, 6.41 mmol) synthesized in Example (43h), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 13.50 mL, 13. The target compound (2.02 g, yield 94%) as a white solid was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.78 (1H, dd, J = 5.5, 12.1 Hz), 3.93-3.99 (2H, m), 4.18 (1H, dd, J = 9.8, 13.3 Hz), 4.42-4.69 (3H, m), 4.87-4.94 (1H, m), 6.34 (1H, t, J = 2.3 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.08 (1H, t, J = 1.6 Hz), 10.99 (1H, br s).
(43j) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (120 mg, 0.36 mmol) synthesized in Example (43i), Example (43c) The compound synthesized in (69 mg, 0.36 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (99 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (132 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.22 (3H, s), 3.64-3.73 (2H, m), 3.80 (1H, dd, J = 3.1, 12.5 Hz), 3.94 (1H, dd, J = 9.8, 14.1 Hz), 4.43-4.69 (3H, m), 4.70-4.77 (1H, m), 6.42 (1H, d, J = 3.9 Hz), 6.62-6.64 (2H, m), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.77 (1H, s).
MS (ESI) m / z: 491.13903 (M + H) <+> .
実施例(43h)で合成した化合物(4.15g,6.41mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,13.50mL,13.50mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(2.02g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.78 (1H, dd, J = 5.5, 12.1 Hz), 3.93-3.99 (2H, m), 4.18 (1H, dd, J = 9.8, 13.3 Hz), 4.42-4.69 (3H, m), 4.87-4.94 (1H, m), 6.34 (1H, t, J = 2.3 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.08 (1H, t, J = 1.6 Hz), 10.99 (1H, br s).
(43j){(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール
実施例(43i)で合成した化合物(120mg,0.36mmol)、実施例(43c)で合成した化合物(69mg,0.36mmol)をアセトニトリル(3mL)に溶解し、炭酸カリウム(99mg,0.72mmol)を加えて、窒素雰囲気下室温で3時間撹拌した。水(10mL)を加え、酢酸エチル(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(132mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.22 (3H, s), 3.64-3.73 (2H, m), 3.80 (1H, dd, J = 3.1, 12.5 Hz), 3.94 (1H, dd, J = 9.8, 14.1 Hz), 4.43-4.69 (3H, m), 4.70-4.77 (1H, m), 6.42 (1H, d, J = 3.9 Hz), 6.62-6.64 (2H, m), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.77 (1H, s).
MS (ESI) m/z: 491.13903 (M+H)+。 (43i) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Il] -1H-pyrrol-2-yl} phenol Compound (4.15 g, 6.41 mmol) synthesized in Example (43h), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 13.50 mL, 13. The target compound (2.02 g, yield 94%) as a white solid was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.2, 6.3 Hz), 3.78 (1H, dd, J = 5.5, 12.1 Hz), 3.93-3.99 (2H, m), 4.18 (1H, dd, J = 9.8, 13.3 Hz), 4.42-4.69 (3H, m), 4.87-4.94 (1H, m), 6.34 (1H, t, J = 2.3 Hz), 6.48 (1H, d, J = 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.79 (1H, d, J = 3.9 Hz), 7.08 (1H, t, J = 1.6 Hz), 10.99 (1H, br s).
(43j) {(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol Compound (120 mg, 0.36 mmol) synthesized in Example (43i), Example (43c) The compound synthesized in (69 mg, 0.36 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (99 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (132 mg, yield) as a white solid. 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, dd, J = 1.2, 6.3 Hz), 3.22 (3H, s), 3.64-3.73 (2H, m), 3.80 (1H, dd, J = 3.1, 12.5 Hz), 3.94 (1H, dd, J = 9.8, 14.1 Hz), 4.43-4.69 (3H, m), 4.70-4.77 (1H, m), 6.42 (1H, d, J = 3.9 Hz), 6.62-6.64 (2H, m), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.45 (1H, s), 8.77 (1H, s).
MS (ESI) m / z: 491.13903 (M + H) <+> .
(実施例44)
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 44)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 44)
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
(44a)メチル N-[(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)カルボニル]-L-セリネート
実施例(43e)で合成した化合物(7.01g,16.09mmol)、L-セリン メチルエステル塩酸塩(2.75g,17.70mmol)、HOBT・H2O(2.39g,17.70mmol)、N-メチルモルホリン(3.54mL,32.19mmol)、WSCI・HCl(3.70g,19.31mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(7.88g,収率91%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.12 (18H, d, J = 7.4 Hz), 1.22-1.32 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.82 (3H, s), 3.99-4.10 (2H, m), 4.41-4.66 (3H, m), 4.82-4.86 (1H, m), 6.41 (1H, t, J = 2.3 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.72-6.75 (2H, m), 6.83 (1H, d, J = 7.0 Hz), 9.57 (1H, br s).
(44b)メチル (4S)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(44a)で合成した化合物(7.77g,14.48mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.47mL,18.8mmol)、炭酸カリウム(3.00g,21.72mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(7.21g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.12 (18H, d, J = 7.3 Hz), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H, s), 4.42-4.68 (5H, m), 4.91 (1H, dd, J = 7.8, 10.7 Hz), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.71-6.73 (2H, m), 6.81 (1H, d, J = 3.9 Hz).
(44c)[(4R)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(44b)で合成した化合物(7.21g,13.90mmol)をテトラヒドロフラン(150mL)に溶解し、0℃で水素化リチウムアルミニウム(1.06g,27.80mmol)を加えた。窒素雰囲気下30分攪拌後、水(1.0mL)、5規定水酸化ナトリウム水溶液(1.0mL)、水(3.0mL)の順に加え、10分間攪拌した。酢酸エチル(70mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~70%)を用いて精製することにより、橙色固体の目的化合物(3.73g,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.13 (18H, d, J = 7.4 Hz), 1.23-1.32 (3H, m), 1.36 (3H, d, J = 6.3 Hz), 3.65 (1H, d, J = 12.5 Hz), 4.04 (1H, d, J = 12.5 Hz), 4.17-4.23 (1H, m), 4.31-4.40 (2H, m), 4.42-4.66 (3H, m), 6.33 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.45 (1H, d, J = 3.9 Hz), 6.76 (2H, br s)。 (44a) Methyl N-[(5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) carbonyl ] -L-Selinate Compound (7.01 g, 16.09 mmol) synthesized in Example (43e), L-serine methyl ester hydrochloride (2.75 g, 17.70 mmol), HOBT.H 2 O (2.39 g) , 17.70 mmol), N-methylmorpholine (3.54 mL, 32.19 mmol), WSCI.HCl (3.70 g, 19.31 mmol), and the target compound as a white solid in the same manner as in Example (29a) (7.88 g, 91% yield) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ1.12 (18H, d, J = 7.4 Hz), 1.22-1.32 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.82 ( 3H, s), 3.99-4.10 (2H, m), 4.41-4.66 (3H, m), 4.82-4.86 (1H, m), 6.41 (1H, t, J = 2.3 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.72-6.75 (2H, m), 6.83 (1H, d, J = 7.0 Hz), 9.57 (1H, br s).
(44b) Methyl (4S) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Ile-4,5-dihydro-1,3-oxazole-4-carboxylate Compound (7.77 g, 14.48 mmol) synthesized in Example (44a), bis (2-methoxyethyl) aminosulfur trifluoride (3 .47 mL, 18.8 mmol) and potassium carbonate (3.00 g, 21.72 mmol) were used to obtain the target compound (7.21 g, 96%) as a white solid in the same manner as in Example (38b).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.12 (18H, d, J = 7.3 Hz), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H , s), 4.42-4.68 (5H, m), 4.91 (1H, dd, J = 7.8, 10.7 Hz), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.71-6.73 (2H, m), 6.81 (1H, d, J = 3.9 Hz).
(44c) [(4R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Yl) -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (7.21 g, 13.90 mmol) synthesized in Example (44b) was dissolved in tetrahydrofuran (150 mL) at 0 ° C. Lithium aluminum hydride (1.06 g, 27.80 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (1.0 mL), 5N aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound (3.73 g, 3.73 g, Yield 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.13 (18H, d, J = 7.4 Hz), 1.23-1.32 (3H, m), 1.36 (3H, d, J = 6.3 Hz), 3.65 (1H, d , J = 12.5 Hz), 4.04 (1H, d, J = 12.5 Hz), 4.17-4.23 (1H, m), 4.31-4.40 (2H, m), 4.42-4.66 (3H, m), 6.33 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.45 (1H, d, J = 3.9 Hz), 6.76 (2H, br s).
実施例(43e)で合成した化合物(7.01g,16.09mmol)、L-セリン メチルエステル塩酸塩(2.75g,17.70mmol)、HOBT・H2O(2.39g,17.70mmol)、N-メチルモルホリン(3.54mL,32.19mmol)、WSCI・HCl(3.70g,19.31mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(7.88g,収率91%)を得た。
1H-NMR (CDCl3, 500MHz):δ1.12 (18H, d, J = 7.4 Hz), 1.22-1.32 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.82 (3H, s), 3.99-4.10 (2H, m), 4.41-4.66 (3H, m), 4.82-4.86 (1H, m), 6.41 (1H, t, J = 2.3 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.72-6.75 (2H, m), 6.83 (1H, d, J = 7.0 Hz), 9.57 (1H, br s).
(44b)メチル (4S)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(44a)で合成した化合物(7.77g,14.48mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(3.47mL,18.8mmol)、炭酸カリウム(3.00g,21.72mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(7.21g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.12 (18H, d, J = 7.3 Hz), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H, s), 4.42-4.68 (5H, m), 4.91 (1H, dd, J = 7.8, 10.7 Hz), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.71-6.73 (2H, m), 6.81 (1H, d, J = 3.9 Hz).
(44c)[(4R)-2-(5-{3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(44b)で合成した化合物(7.21g,13.90mmol)をテトラヒドロフラン(150mL)に溶解し、0℃で水素化リチウムアルミニウム(1.06g,27.80mmol)を加えた。窒素雰囲気下30分攪拌後、水(1.0mL)、5規定水酸化ナトリウム水溶液(1.0mL)、水(3.0mL)の順に加え、10分間攪拌した。酢酸エチル(70mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~70%)を用いて精製することにより、橙色固体の目的化合物(3.73g,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.13 (18H, d, J = 7.4 Hz), 1.23-1.32 (3H, m), 1.36 (3H, d, J = 6.3 Hz), 3.65 (1H, d, J = 12.5 Hz), 4.04 (1H, d, J = 12.5 Hz), 4.17-4.23 (1H, m), 4.31-4.40 (2H, m), 4.42-4.66 (3H, m), 6.33 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.45 (1H, d, J = 3.9 Hz), 6.76 (2H, br s)。 (44a) Methyl N-[(5- {3-[(1S) -2-fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) carbonyl ] -L-Selinate Compound (7.01 g, 16.09 mmol) synthesized in Example (43e), L-serine methyl ester hydrochloride (2.75 g, 17.70 mmol), HOBT.H 2 O (2.39 g) , 17.70 mmol), N-methylmorpholine (3.54 mL, 32.19 mmol), WSCI.HCl (3.70 g, 19.31 mmol), and the target compound as a white solid in the same manner as in Example (29a) (7.88 g, 91% yield) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ1.12 (18H, d, J = 7.4 Hz), 1.22-1.32 (3H, m), 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.82 ( 3H, s), 3.99-4.10 (2H, m), 4.41-4.66 (3H, m), 4.82-4.86 (1H, m), 6.41 (1H, t, J = 2.3 Hz), 6.48 (1H, dd, J = 2.7, 3.9 Hz), 6.70 (1H, t, J = 1.6 Hz), 6.72-6.75 (2H, m), 6.83 (1H, d, J = 7.0 Hz), 9.57 (1H, br s).
(44b) Methyl (4S) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Ile-4,5-dihydro-1,3-oxazole-4-carboxylate Compound (7.77 g, 14.48 mmol) synthesized in Example (44a), bis (2-methoxyethyl) aminosulfur trifluoride (3 .47 mL, 18.8 mmol) and potassium carbonate (3.00 g, 21.72 mmol) were used to obtain the target compound (7.21 g, 96%) as a white solid in the same manner as in Example (38b).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.12 (18H, d, J = 7.3 Hz), 1.23-1.31 (3H, m), 1.35 (3H, dd, J = 1.5, 6.3 Hz), 3.82 (3H , s), 4.42-4.68 (5H, m), 4.91 (1H, dd, J = 7.8, 10.7 Hz), 6.40 (1H, t, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz) , 6.71-6.73 (2H, m), 6.81 (1H, d, J = 3.9 Hz).
(44c) [(4R) -2- (5- {3-[(1S) -2-Fluoro-1-methylethoxy] -5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2- Yl) -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound (7.21 g, 13.90 mmol) synthesized in Example (44b) was dissolved in tetrahydrofuran (150 mL) at 0 ° C. Lithium aluminum hydride (1.06 g, 27.80 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (1.0 mL), 5N aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (70 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 70%) to give the target compound (3.73 g, 3.73 g, Yield 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.13 (18H, d, J = 7.4 Hz), 1.23-1.32 (3H, m), 1.36 (3H, d, J = 6.3 Hz), 3.65 (1H, d , J = 12.5 Hz), 4.04 (1H, d, J = 12.5 Hz), 4.17-4.23 (1H, m), 4.31-4.40 (2H, m), 4.42-4.66 (3H, m), 6.33 (1H, d, J = 3.9 Hz), 6.39 (1H, t, J = 2.0 Hz), 6.45 (1H, d, J = 3.9 Hz), 6.76 (2H, br s).
(44d)3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノール
実施例(44c)で合成した化合物(3.73g,7.60mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,8.36mL,8.36mmol)を用い、実施例(16k)と同様の方法で淡橙色固体の目的化合物(2.05g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.80 (1H, dd, J = 3.9, 11.3 Hz), 3.99 (1H, dd, J = 3.1, 11.3 Hz), 4.31-4.67 (6H, m), 6.47-6.50 (2H, m), 6.73 (1H, t, J = 1.6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (1H, t, J = 1.6 Hz), 11.03 (1H, br s).
(44e){(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(44d)で合成した化合物(250mg,0.75mmol)、実施例(43c)で合成した化合物(144mg,0.75mmol)をアセトニトリル(8mL)に溶解し、炭酸カリウム(207mg,1.50mmol)を加えて、窒素雰囲気下室温で8時間撹拌した。水(10mL)を加え、酢酸エチル(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(320mg,87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.39 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.64 (1H, dd, J = 3.5, 12.1 Hz), 3.97 (1H, dd, J = 2.7, 11.7 Hz), 4.21 (1H, t, J = 6.6 Hz), 4.33-4.44 (2H, m), 4.45-4.73 (3H, m), 6.41 (1H, d, J = 3.9 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.97 (1H, t, J = 1.8 Hz), 7.09 (1H, t, J = 1.8 Hz), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz).
MS (ESI) m/z: 491.13903 (M+H)+。 (44d) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenol Compound (3.73 g, 7.60 mmol) synthesized in Example (44c), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 8.36 mL, 8. 36 mmol), and the target compound (2.05 g, yield 81%) was obtained as a pale orange solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.80 (1H, dd, J = 3.9, 11.3 Hz), 3.99 (1H, dd, J = 3.1, 11.3 Hz), 4.31-4.67 (6H, m), 6.47-6.50 (2H, m), 6.73 (1H, t, J = 1.6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (1H, t, J = 1.6 Hz), 11.03 (1H, br s).
(44e) {(4R) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Compound (250 mg, 0.75 mmol) synthesized in Example (44d), Example (43c) The compound synthesized in step (144 mg, 0.75 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (207 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (320 mg, 87%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.64 (1H, dd, J = 3.5, 12.1 Hz), 3.97 (1H , dd, J = 2.7, 11.7 Hz), 4.21 (1H, t, J = 6.6 Hz), 4.33-4.44 (2H, m), 4.45-4.73 (3H, m), 6.41 (1H, d, J = 3.9 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.97 (1H, t, J = 1.8 Hz), 7.09 (1H, t, J = 1.8 Hz) , 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 491.13903 (M + H) <+> .
実施例(44c)で合成した化合物(3.73g,7.60mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,8.36mL,8.36mmol)を用い、実施例(16k)と同様の方法で淡橙色固体の目的化合物(2.05g,収率81%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.80 (1H, dd, J = 3.9, 11.3 Hz), 3.99 (1H, dd, J = 3.1, 11.3 Hz), 4.31-4.67 (6H, m), 6.47-6.50 (2H, m), 6.73 (1H, t, J = 1.6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (1H, t, J = 1.6 Hz), 11.03 (1H, br s).
(44e){(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(44d)で合成した化合物(250mg,0.75mmol)、実施例(43c)で合成した化合物(144mg,0.75mmol)をアセトニトリル(8mL)に溶解し、炭酸カリウム(207mg,1.50mmol)を加えて、窒素雰囲気下室温で8時間撹拌した。水(10mL)を加え、酢酸エチル(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(320mg,87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.39 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.64 (1H, dd, J = 3.5, 12.1 Hz), 3.97 (1H, dd, J = 2.7, 11.7 Hz), 4.21 (1H, t, J = 6.6 Hz), 4.33-4.44 (2H, m), 4.45-4.73 (3H, m), 6.41 (1H, d, J = 3.9 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.97 (1H, t, J = 1.8 Hz), 7.09 (1H, t, J = 1.8 Hz), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz).
MS (ESI) m/z: 491.13903 (M+H)+。 (44d) 3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenol Compound (3.73 g, 7.60 mmol) synthesized in Example (44c), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 8.36 mL, 8. 36 mmol), and the target compound (2.05 g, yield 81%) was obtained as a pale orange solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, dd, J = 1.6, 6.3 Hz), 3.80 (1H, dd, J = 3.9, 11.3 Hz), 3.99 (1H, dd, J = 3.1, 11.3 Hz), 4.31-4.67 (6H, m), 6.47-6.50 (2H, m), 6.73 (1H, t, J = 1.6 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.07 (1H, t, J = 1.6 Hz), 11.03 (1H, br s).
(44e) {(4R) -2- [5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl ) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Compound (250 mg, 0.75 mmol) synthesized in Example (44d), Example (43c) The compound synthesized in step (144 mg, 0.75 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (207 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. Water (10 mL) was added and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (320 mg, 87%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 1.6, 6.3 Hz), 3.24 (3H, s), 3.64 (1H, dd, J = 3.5, 12.1 Hz), 3.97 (1H , dd, J = 2.7, 11.7 Hz), 4.21 (1H, t, J = 6.6 Hz), 4.33-4.44 (2H, m), 4.45-4.73 (3H, m), 6.41 (1H, d, J = 3.9 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.97 (1H, t, J = 1.8 Hz), 7.09 (1H, t, J = 1.8 Hz) , 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz).
MS (ESI) m / z: 491.13903 (M + H) <+> .
(実施例45)
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-カルボキサミド (Example 45)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-カルボキサミド (Example 45)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide
(45a)5-クロロ-N-メチルピラジン-2-カルボキサミド
5-クロロピラジン-2-カルボン酸(1.99g,12.6mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、HOBt・H2O(2.11g,13.8mmol)、WSCI・HCl(2.89g,15.1mmol)、N-メチルモルホリン(2.76mL,25.1mmol)、40%メチルアミン/メタノール溶液(2.92mL,37.6mmol)を加え、18時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~75%)を用いて精製することで、白色固体の目的化合物(585mg,収率27%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.03 (3H, d, J = 4.9 Hz), 7.60 (1H, br s), 8.09 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.0 Hz).
(45b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-カルボキサミド
実施例(45a)で合成した化合物(170mg,0.99mmol)と、実施例(44d)で合成した化合物(331mg,0.99mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(274mg,1.88mmol)を加えて、窒素雰囲気下90℃で2時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~3%)を用いて精製することにより、白色固体の目的化合物(445mg,収率92%)を得た。
1H-NMR (CDCl3, 400MHz): δ1.39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d, J = 4.9 Hz), 3.62 (1H, dd, J = 12.2, 3.4 Hz), 3.97 (1H, d, J = 12.2 Hz), 4.17 (1H, t, J = 6.3 Hz), 4.32-4.39 (2H, m), 4.46-4.51 (1H, m), 4.55-4.61 (1H, m), 4.63-4.70 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.4 Hz), 6.67 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.7 Hz), 7.06 (1H, s), 7.63 (1H, q, J = 4.9 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.94 (1H, d, J = 1.5 Hz), 10.26 (1H, br s).
MS (ESI) m/z: 470.18368 (M+H)+。 (45a) 5-chloro-N-methylpyrazine-2-carboxamide 5-chloropyrazine-2-carboxylic acid (1.99 g, 12.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and HOBt · H 2 O (2.11g, 13.8mmol), WSCI · HCl (2.89g, 15.1mmol), N- methylmorpholine (2.76mL, 25.1mmol), 40% methylamine / methanol solution (2.92 mL 37.6 mmol) and stirred for 18 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 75%) to give the target compound (585 mg, yield) as a white solid. 27%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.03 (3H, d, J = 4.9 Hz), 7.60 (1H, br s), 8.09 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.0 Hz).
(45b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide with the compound (170 mg, 0.99 mmol) synthesized in Example (45a) and Example (44d) The synthesized compound (331 mg, 0.99 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (274 mg, 1.88 mmol) was added, and the mixture was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the target compound (445 mg, yield) as a white solid. 92%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d, J = 4.9 Hz), 3.62 (1H, dd, J = 12.2, 3.4 Hz), 3.97 (1H, d, J = 12.2 Hz), 4.17 (1H, t, J = 6.3 Hz), 4.32-4.39 (2H, m), 4.46-4.51 (1H, m), 4.55-4.61 (1H , m), 4.63-4.70 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.4 Hz), 6.67 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.7 Hz), 7.06 (1H, s), 7.63 (1H, q, J = 4.9 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.94 (1H, d, J = 1.5 Hz), 10.26 (1H, br s).
MS (ESI) m / z: 470.18368 (M + H) <+> .
5-クロロピラジン-2-カルボン酸(1.99g,12.6mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、HOBt・H2O(2.11g,13.8mmol)、WSCI・HCl(2.89g,15.1mmol)、N-メチルモルホリン(2.76mL,25.1mmol)、40%メチルアミン/メタノール溶液(2.92mL,37.6mmol)を加え、18時間攪拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~75%)を用いて精製することで、白色固体の目的化合物(585mg,収率27%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.03 (3H, d, J = 4.9 Hz), 7.60 (1H, br s), 8.09 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.0 Hz).
(45b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-カルボキサミド
実施例(45a)で合成した化合物(170mg,0.99mmol)と、実施例(44d)で合成した化合物(331mg,0.99mmol)をN,N-ジメチルホルムアミド(3mL)に溶解させ、炭酸カリウム(274mg,1.88mmol)を加えて、窒素雰囲気下90℃で2時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~3%)を用いて精製することにより、白色固体の目的化合物(445mg,収率92%)を得た。
1H-NMR (CDCl3, 400MHz): δ1.39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d, J = 4.9 Hz), 3.62 (1H, dd, J = 12.2, 3.4 Hz), 3.97 (1H, d, J = 12.2 Hz), 4.17 (1H, t, J = 6.3 Hz), 4.32-4.39 (2H, m), 4.46-4.51 (1H, m), 4.55-4.61 (1H, m), 4.63-4.70 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.4 Hz), 6.67 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.7 Hz), 7.06 (1H, s), 7.63 (1H, q, J = 4.9 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.94 (1H, d, J = 1.5 Hz), 10.26 (1H, br s).
MS (ESI) m/z: 470.18368 (M+H)+。 (45a) 5-chloro-N-methylpyrazine-2-carboxamide 5-chloropyrazine-2-carboxylic acid (1.99 g, 12.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and HOBt · H 2 O (2.11g, 13.8mmol), WSCI · HCl (2.89g, 15.1mmol), N- methylmorpholine (2.76mL, 25.1mmol), 40% methylamine / methanol solution (2.92 mL 37.6 mmol) and stirred for 18 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 75%) to give the target compound (585 mg, yield) as a white solid. 27%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.03 (3H, d, J = 4.9 Hz), 7.60 (1H, br s), 8.09 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.0 Hz).
(45b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-carboxamide with the compound (170 mg, 0.99 mmol) synthesized in Example (45a) and Example (44d) The synthesized compound (331 mg, 0.99 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (274 mg, 1.88 mmol) was added, and the mixture was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the target compound (445 mg, yield) as a white solid. 92%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.39 (3H, dd, J = 6.3, 1.5 Hz), 3.05 (3H, d, J = 4.9 Hz), 3.62 (1H, dd, J = 12.2, 3.4 Hz), 3.97 (1H, d, J = 12.2 Hz), 4.17 (1H, t, J = 6.3 Hz), 4.32-4.39 (2H, m), 4.46-4.51 (1H, m), 4.55-4.61 (1H , m), 4.63-4.70 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.4 Hz), 6.67 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.7 Hz), 7.06 (1H, s), 7.63 (1H, q, J = 4.9 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.94 (1H, d, J = 1.5 Hz), 10.26 (1H, br s).
MS (ESI) m / z: 470.18368 (M + H) <+> .
(実施例46)
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド (Example 46)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド (Example 46)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide
(46a)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-(4-メトキシベンジル)-N-メチルピリジン-2-スルホンアミド
実施例(24c)で合成した化合物(379mg,1.10mmol)と、実施例(44d)で合成した化合物(368mg,1.10mmol)をN,N-ジメチルホルムアミド(5mL)に溶解させ、炭酸セシウム(718mg,2.20mmol)を加えて、窒素雰囲気下90℃で3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(520mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.38 (3H, dd, J = 6.3, 1.6 Hz), 2.78 (3H, s), 3.64 (1H, dd, J = 11.9, 3.3 Hz), 3.80 (3H, s), 3.96 (1H, d, J = 11.3 Hz), 4.19-4.22 (1H, m), 4.35-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63-4.72 (1H, m), 6.43 (1H, s), 6.58 (2H, t, J = 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.90 (1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 7.95 (1H, d, J = 9.4 Hz), 8.48 (1H, d, J = 3.1 Hz).
(46b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド
窒素雰囲気下、実施例(46a)で合成した化合物(540mg,0.86mmol)をトリフルオロ酢酸(3mL)に溶解し、45℃にて5時間撹拌した。減圧下溶媒を留去し、残渣に塩化メチレン、トリエチルアミンを少量加えて再び減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、白色固体の目的化合物(257mg,収率59%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.39 (3H, dd, J = 6.3, 1.6 Hz), 2.69 (3H, d, J = 3.5 Hz), 3.62 (1H, dd, J = 12.1, 5.5 Hz), 3.84 (1H, dd, J = 11.9, 2.9 Hz), 4.13 (1H, t, J = 7.8 Hz), 4.33-4.39 (1H, m), 4.42-4.48 (2H, m), 4.57-4.60 (1H, m), 4.66-4.74 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.61 (1H, t, J = 2.7 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.06 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 3.3 Hz).
MS (ESI) m/z: 505.15374 (M+H)+。 (46a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound synthesized in Example (24c) (379 mg, 1. 10 mmol) and the compound synthesized in Example (44d) (368 mg, 1.10 mmol) were dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (718 mg, 2.20 mmol) was added, and nitrogen atmosphere was added. Stir at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (520 mg, yield) as a white solid. 76%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 6.3, 1.6 Hz), 2.78 (3H, s), 3.64 (1H, dd, J = 11.9, 3.3 Hz), 3.80 (3H , s), 3.96 (1H, d, J = 11.3 Hz), 4.19-4.22 (1H, m), 4.35-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63-4.72 (1H, m), 6.43 (1H, s), 6.58 (2H, t, J = 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.90 ( 1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 7.95 ( 1H, d, J = 9.4 Hz), 8.48 (1H, d, J = 3.1 Hz).
(46b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide Under nitrogen atmosphere, the compound (540 mg, 0.86 mmol) synthesized in Example (46a) was treated with trifluoro Dissolved in acetic acid (3 mL) and stirred at 45 ° C. for 5 hours. The solvent was distilled off under reduced pressure, a small amount of methylene chloride and triethylamine were added to the residue, and the solvent was distilled off again under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: methanol / methylene chloride = 0% -4%) to give the target compound (257 mg, yield 59%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.6 Hz), 2.69 (3H, d, J = 3.5 Hz), 3.62 (1H, dd, J = 12.1, 5.5 Hz) ), 3.84 (1H, dd, J = 11.9, 2.9 Hz), 4.13 (1H, t, J = 7.8 Hz), 4.33-4.39 (1H, m), 4.42-4.48 (2H, m), 4.57-4.60 ( 1H, m), 4.66-4.74 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.61 (1H, t, J = 2.7 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.06 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.44 (1H, d , J = 3.3 Hz).
MS (ESI) m / z: 505.15374 (M + H) <+> .
実施例(24c)で合成した化合物(379mg,1.10mmol)と、実施例(44d)で合成した化合物(368mg,1.10mmol)をN,N-ジメチルホルムアミド(5mL)に溶解させ、炭酸セシウム(718mg,2.20mmol)を加えて、窒素雰囲気下90℃で3時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、酢酸エチル(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することで、白色固体の目的化合物(520mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.38 (3H, dd, J = 6.3, 1.6 Hz), 2.78 (3H, s), 3.64 (1H, dd, J = 11.9, 3.3 Hz), 3.80 (3H, s), 3.96 (1H, d, J = 11.3 Hz), 4.19-4.22 (1H, m), 4.35-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63-4.72 (1H, m), 6.43 (1H, s), 6.58 (2H, t, J = 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.90 (1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 7.95 (1H, d, J = 9.4 Hz), 8.48 (1H, d, J = 3.1 Hz).
(46b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピリジン-2-スルホンアミド
窒素雰囲気下、実施例(46a)で合成した化合物(540mg,0.86mmol)をトリフルオロ酢酸(3mL)に溶解し、45℃にて5時間撹拌した。減圧下溶媒を留去し、残渣に塩化メチレン、トリエチルアミンを少量加えて再び減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、白色固体の目的化合物(257mg,収率59%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.39 (3H, dd, J = 6.3, 1.6 Hz), 2.69 (3H, d, J = 3.5 Hz), 3.62 (1H, dd, J = 12.1, 5.5 Hz), 3.84 (1H, dd, J = 11.9, 2.9 Hz), 4.13 (1H, t, J = 7.8 Hz), 4.33-4.39 (1H, m), 4.42-4.48 (2H, m), 4.57-4.60 (1H, m), 4.66-4.74 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.61 (1H, t, J = 2.7 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.06 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 3.3 Hz).
MS (ESI) m/z: 505.15374 (M+H)+。 (46a) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N- (4-methoxybenzyl) -N-methylpyridine-2-sulfonamide Compound synthesized in Example (24c) (379 mg, 1. 10 mmol) and the compound synthesized in Example (44d) (368 mg, 1.10 mmol) were dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (718 mg, 2.20 mmol) was added, and nitrogen atmosphere was added. Stir at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (520 mg, yield) as a white solid. 76%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 6.3, 1.6 Hz), 2.78 (3H, s), 3.64 (1H, dd, J = 11.9, 3.3 Hz), 3.80 (3H , s), 3.96 (1H, d, J = 11.3 Hz), 4.19-4.22 (1H, m), 4.35-4.43 (4H, m), 4.47 (1H, d, J = 5.1 Hz), 4.59 (1H, d, J = 4.7 Hz), 4.63-4.72 (1H, m), 6.43 (1H, s), 6.58 (2H, t, J = 2.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 6.90 ( 1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.27 (2H, d, J = 7.0 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 7.95 ( 1H, d, J = 9.4 Hz), 8.48 (1H, d, J = 3.1 Hz).
(46b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyridine-2-sulfonamide Under nitrogen atmosphere, the compound (540 mg, 0.86 mmol) synthesized in Example (46a) was treated with trifluoro Dissolved in acetic acid (3 mL) and stirred at 45 ° C. for 5 hours. The solvent was distilled off under reduced pressure, a small amount of methylene chloride and triethylamine were added to the residue, and the solvent was distilled off again under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: methanol / methylene chloride = 0% -4%) to give the target compound (257 mg, yield 59%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.6 Hz), 2.69 (3H, d, J = 3.5 Hz), 3.62 (1H, dd, J = 12.1, 5.5 Hz) ), 3.84 (1H, dd, J = 11.9, 2.9 Hz), 4.13 (1H, t, J = 7.8 Hz), 4.33-4.39 (1H, m), 4.42-4.48 (2H, m), 4.57-4.60 ( 1H, m), 4.66-4.74 (1H, m), 6.46 (1H, d, J = 3.9 Hz), 6.61 (1H, t, J = 2.7 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.98 (1H, s), 7.06 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.44 (1H, d , J = 3.3 Hz).
MS (ESI) m / z: 505.15374 (M + H) <+> .
(実施例47)
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド (Example 47)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド (Example 47)
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide
(47a)5-ブロモピラジン-2-チオール
窒素雰囲気下、2,5-ジブロモピラジン(300mg,1.26mmol)をジメチルスルホキシド(3mL)に溶解し、二硫化ナトリウム九水和物(454mg,1.89mmol)を加えた後、100℃で1.5時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、5N塩酸で中和した。生じた沈殿をろ取し、水で洗浄後、得られた固体をジエチルエーテル/テトラヒドロフランに溶解し、不溶物をろ過した。減圧下溶媒を留去し、真空乾燥することで橙色固体の目的化合物(163mg,収率68%)を得た
1H-NMR (CDCl3, 400MHz) δ 3.19 (1H, s), 7.97 (1H, d, J = 1.0 Hz), 8.34 (1H, d, J = 1.0 Hz).
(47b)5-ブロモ-N-メチルピラジン-2-スルホンアミド
実施例(47a)で合成した化合物(988mg,5.17mmol)を塩化メチレン(15mL)/1N塩酸(15mL)に溶解し、-10℃に冷却した。反応液を-5℃以下に保ちながら、氷冷した7%過塩素酸ナトリウム水溶液(15mL)を滴下し、そのまま1時間攪拌した。予め氷冷した分液ロートで有機層を分液し、0℃に冷却して市販の40%メチルアミン/メタノール溶液(1.00mL,12.9mmol)を加え、室温に戻して17時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~30%)を用いて精製することで、白色固体の目的化合物(147mg,収率11%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.83 (3H, d, J = 5.5 Hz), 4.80 (1H, s), 8.76 (1H, d, J = 1.6 Hz), 8.96 (1H, d, J = 1.2 Hz).
(47c)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド
実施例(47b)で合成した化合物(103mg,0.41mmol)と、実施例(44d)で合成した化合物(130mg,0.39mmol)をN,N-ジメチルホルムアミド(2mL)に溶解させ、炭酸カリウム(107mg,0.78mmol)を加えて、窒素雰囲気下室温で15時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~3.5%)を用いて精製することで、白色固体の目的化合物(131mg,収率66%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.39 (3H, dd, J = 6.3, 1.5 Hz), 2.81 (3H, d, J = 4.9 Hz), 3.64 (1H, dd, J = 11.7, 3.4 Hz), 3.95 (1H, dd, J = 11.2, 2.9 Hz), 4.23 (1H, s), 4.36-4.45 (2H, m), 4.49 (1H, dd, J = 4.6, 2.2 Hz), 4.59 (1H, dd, J = 4.4, 2.4 Hz), 4.65-4.72 (1H, m), 5.10 (1H, br s), 6.44 (1H, s), 6.61 (1H, s), 6.68 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.5 Hz), 7.09 (1H, t, J = 1.7 Hz), 8.47 (1H, d, J = 1.0 Hz), 8.73 (1H, d, J = 1.0 Hz).
MS (ESI) m/z: 506.14859 (M+H)+。 (47a) 5-Bromopyrazine-2-thiol 2,5-Dibromopyrazine (300 mg, 1.26 mmol) was dissolved in dimethyl sulfoxide (3 mL) under a nitrogen atmosphere, and sodium disulfide nonahydrate (454 mg, 1. 89 mmol) and then stirred at 100 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The obtained solid was dissolved in diethyl ether / tetrahydrofuran, and insoluble matter was filtered off. The target compound (163 mg, yield 68%) as an orange solid was obtained by evaporating the solvent under reduced pressure and drying in vacuo.
1 H-NMR (CDCl 3 , 400 MHz) δ 3.19 (1H, s), 7.97 (1H, d, J = 1.0 Hz), 8.34 (1H, d, J = 1.0 Hz).
(47b) 5-Bromo-N-methylpyrazine-2-sulfonamide The compound (988 mg, 5.17 mmol) synthesized in Example (47a) was dissolved in methylene chloride (15 mL) / 1N hydrochloric acid (15 mL), and −10 Cooled to ° C. While maintaining the reaction solution at −5 ° C. or lower, ice-cooled 7% sodium perchlorate aqueous solution (15 mL) was added dropwise and stirred as it was for 1 hour. The organic layer was separated with an ice-cooled separatory funnel, cooled to 0 ° C., added with a commercially available 40% methylamine / methanol solution (1.00 mL, 12.9 mmol), returned to room temperature, and stirred for 17 hours. . Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 30%) to give the target compound (147 mg, yield) as a white solid. 11%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.83 (3H, d, J = 5.5 Hz), 4.80 (1H, s), 8.76 (1H, d, J = 1.6 Hz), 8.96 (1H, d, J = 1.2 Hz).
(47c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide The compound synthesized in Example (47b) (103 mg, 0.41 mmol) and Example (44d) The compound synthesized in (1) (130 mg, 0.39 mmol) was dissolved in N, N-dimethylformamide (2 mL), potassium carbonate (107 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3.5%) to give the target compound (131 mg, Yield 66%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.5 Hz), 2.81 (3H, d, J = 4.9 Hz), 3.64 (1H, dd, J = 11.7, 3.4 Hz) ), 3.95 (1H, dd, J = 11.2, 2.9 Hz), 4.23 (1H, s), 4.36-4.45 (2H, m), 4.49 (1H, dd, J = 4.6, 2.2 Hz), 4.59 (1H, dd, J = 4.4, 2.4 Hz), 4.65-4.72 (1H, m), 5.10 (1H, br s), 6.44 (1H, s), 6.61 (1H, s), 6.68 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.5 Hz), 7.09 (1H, t, J = 1.7 Hz), 8.47 (1H, d, J = 1.0 Hz), 8.73 (1H, d, J = 1.0 Hz) .
MS (ESI) m / z: 506.14859 (M + H) <+> .
窒素雰囲気下、2,5-ジブロモピラジン(300mg,1.26mmol)をジメチルスルホキシド(3mL)に溶解し、二硫化ナトリウム九水和物(454mg,1.89mmol)を加えた後、100℃で1.5時間撹拌した。反応液を室温まで冷却し、水(30mL)を加え、5N塩酸で中和した。生じた沈殿をろ取し、水で洗浄後、得られた固体をジエチルエーテル/テトラヒドロフランに溶解し、不溶物をろ過した。減圧下溶媒を留去し、真空乾燥することで橙色固体の目的化合物(163mg,収率68%)を得た
1H-NMR (CDCl3, 400MHz) δ 3.19 (1H, s), 7.97 (1H, d, J = 1.0 Hz), 8.34 (1H, d, J = 1.0 Hz).
(47b)5-ブロモ-N-メチルピラジン-2-スルホンアミド
実施例(47a)で合成した化合物(988mg,5.17mmol)を塩化メチレン(15mL)/1N塩酸(15mL)に溶解し、-10℃に冷却した。反応液を-5℃以下に保ちながら、氷冷した7%過塩素酸ナトリウム水溶液(15mL)を滴下し、そのまま1時間攪拌した。予め氷冷した分液ロートで有機層を分液し、0℃に冷却して市販の40%メチルアミン/メタノール溶液(1.00mL,12.9mmol)を加え、室温に戻して17時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~30%)を用いて精製することで、白色固体の目的化合物(147mg,収率11%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.83 (3H, d, J = 5.5 Hz), 4.80 (1H, s), 8.76 (1H, d, J = 1.6 Hz), 8.96 (1H, d, J = 1.2 Hz).
(47c)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド
実施例(47b)で合成した化合物(103mg,0.41mmol)と、実施例(44d)で合成した化合物(130mg,0.39mmol)をN,N-ジメチルホルムアミド(2mL)に溶解させ、炭酸カリウム(107mg,0.78mmol)を加えて、窒素雰囲気下室温で15時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で二回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~3.5%)を用いて精製することで、白色固体の目的化合物(131mg,収率66%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.39 (3H, dd, J = 6.3, 1.5 Hz), 2.81 (3H, d, J = 4.9 Hz), 3.64 (1H, dd, J = 11.7, 3.4 Hz), 3.95 (1H, dd, J = 11.2, 2.9 Hz), 4.23 (1H, s), 4.36-4.45 (2H, m), 4.49 (1H, dd, J = 4.6, 2.2 Hz), 4.59 (1H, dd, J = 4.4, 2.4 Hz), 4.65-4.72 (1H, m), 5.10 (1H, br s), 6.44 (1H, s), 6.61 (1H, s), 6.68 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.5 Hz), 7.09 (1H, t, J = 1.7 Hz), 8.47 (1H, d, J = 1.0 Hz), 8.73 (1H, d, J = 1.0 Hz).
MS (ESI) m/z: 506.14859 (M+H)+。 (47a) 5-Bromopyrazine-2-thiol 2,5-Dibromopyrazine (300 mg, 1.26 mmol) was dissolved in dimethyl sulfoxide (3 mL) under a nitrogen atmosphere, and sodium disulfide nonahydrate (454 mg, 1. 89 mmol) and then stirred at 100 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was neutralized with 5N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The obtained solid was dissolved in diethyl ether / tetrahydrofuran, and insoluble matter was filtered off. The target compound (163 mg, yield 68%) as an orange solid was obtained by evaporating the solvent under reduced pressure and drying in vacuo.
1 H-NMR (CDCl 3 , 400 MHz) δ 3.19 (1H, s), 7.97 (1H, d, J = 1.0 Hz), 8.34 (1H, d, J = 1.0 Hz).
(47b) 5-Bromo-N-methylpyrazine-2-sulfonamide The compound (988 mg, 5.17 mmol) synthesized in Example (47a) was dissolved in methylene chloride (15 mL) / 1N hydrochloric acid (15 mL), and −10 Cooled to ° C. While maintaining the reaction solution at −5 ° C. or lower, ice-cooled 7% sodium perchlorate aqueous solution (15 mL) was added dropwise and stirred as it was for 1 hour. The organic layer was separated with an ice-cooled separatory funnel, cooled to 0 ° C., added with a commercially available 40% methylamine / methanol solution (1.00 mL, 12.9 mmol), returned to room temperature, and stirred for 17 hours. . Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 30%) to give the target compound (147 mg, yield) as a white solid. 11%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.83 (3H, d, J = 5.5 Hz), 4.80 (1H, s), 8.76 (1H, d, J = 1.6 Hz), 8.96 (1H, d, J = 1.2 Hz).
(47c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide The compound synthesized in Example (47b) (103 mg, 0.41 mmol) and Example (44d) The compound synthesized in (1) (130 mg, 0.39 mmol) was dissolved in N, N-dimethylformamide (2 mL), potassium carbonate (107 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3.5%) to give the target compound (131 mg, Yield 66%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, dd, J = 6.3, 1.5 Hz), 2.81 (3H, d, J = 4.9 Hz), 3.64 (1H, dd, J = 11.7, 3.4 Hz) ), 3.95 (1H, dd, J = 11.2, 2.9 Hz), 4.23 (1H, s), 4.36-4.45 (2H, m), 4.49 (1H, dd, J = 4.6, 2.2 Hz), 4.59 (1H, dd, J = 4.4, 2.4 Hz), 4.65-4.72 (1H, m), 5.10 (1H, br s), 6.44 (1H, s), 6.61 (1H, s), 6.68 (1H, t, J = 2.2 Hz), 6.98 (1H, t, J = 1.5 Hz), 7.09 (1H, t, J = 1.7 Hz), 8.47 (1H, d, J = 1.0 Hz), 8.73 (1H, d, J = 1.0 Hz) .
MS (ESI) m / z: 506.14859 (M + H) <+> .
(実施例48)
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 48)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 48)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide
(48a)3-[4-(メチルスルホニル)フェノキシ]-5-{[(トリフルオロメチル)スルホニル]オキシ}安息香酸メチル
3,5-ジヒドロキシ安息香酸メチル(9.10g,54.1mmol)と4-フルオロフェニルメチルスルホン(7.10g,40.8mmol)をN,N-ジメチルホルムアミド(80mL)に溶解し、炭酸カリウム(30.0g,217mmol)を加え、窒素雰囲気下100℃で15時間撹拌した。反応液を室温まで冷却し、1規定塩酸(500mL)を加え、酢酸エチル(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製し、白色固体の化合物を得た。 (48a) Methyl 3- [4- (methylsulfonyl) phenoxy] -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Methyl 3,5-dihydroxybenzoate (9.10 g, 54.1 mmol) and 4 -Fluorophenylmethylsulfone (7.10 g, 40.8 mmol) was dissolved in N, N-dimethylformamide (80 mL), potassium carbonate (30.0 g, 217 mmol) was added, and the mixture was stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, 1N hydrochloric acid (500 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to obtain a white solid compound.
3,5-ジヒドロキシ安息香酸メチル(9.10g,54.1mmol)と4-フルオロフェニルメチルスルホン(7.10g,40.8mmol)をN,N-ジメチルホルムアミド(80mL)に溶解し、炭酸カリウム(30.0g,217mmol)を加え、窒素雰囲気下100℃で15時間撹拌した。反応液を室温まで冷却し、1規定塩酸(500mL)を加え、酢酸エチル(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製し、白色固体の化合物を得た。 (48a) Methyl 3- [4- (methylsulfonyl) phenoxy] -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Methyl 3,5-dihydroxybenzoate (9.10 g, 54.1 mmol) and 4 -Fluorophenylmethylsulfone (7.10 g, 40.8 mmol) was dissolved in N, N-dimethylformamide (80 mL), potassium carbonate (30.0 g, 217 mmol) was added, and the mixture was stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, 1N hydrochloric acid (500 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to obtain a white solid compound.
これを塩化メチレン(100mL)に溶解し、ピリジン(7.50mL,92.7mmol)とトリフルオロメタンスルホン酸無水物(7.80mL,46.4mmol)を0℃で加え、窒素雰囲気下0℃で3時間半撹拌した。反応液を室温に戻し、飽和塩化アンモニウム水溶液(200mL)を加え、塩化メチレン(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~60%)を用いて精製し、白色固体の目的化合物(9.58g,収率52%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.10 (3H, s), 3.95 (3H, s), 7.17 (2H, dd, J = 7.0, 2.2 Hz), 7.22 (1H, t, J = 2.3 Hz), 7.74 (1H, dd, J = 2.2, 1.4 Hz), 7.77 (1H, dd, J = 2.3, 1.6 Hz), 7.98 (2H, dd, J = 7.0, 2.2 Hz).
(48b)3-[4-(メチルスルホニル)フェノキシ]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル
実施例(48a)で合成した化合物(9.58g,21.1mmol)、ビス(ピナコレート)ジボロン(7.45g,29.3mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(850mg,1.04mmol)、酢酸カリウム(10.6g,108mmol)を用い、実施例(1d)と同様の方法で淡赤色固体の目的化合物(6.83g,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (12H, s), 3.07 (3H, s), 3.93 (3H, s), 7.07 (2H, dd, J = 6.8, 2.0 Hz), 7.69 (1H, dd, J = 2.3, 0.8 Hz), 7.83 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, dd, J = 6.8, 2.0 Hz), 8.33 (1H, dd, J = 1.6, 0.8 Hz).
(48c)2-ベンジル 1-t-ブチル 5-{3-(メトキシカルボニル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(16d)で合成した化合物(9.40g,24.7mmol)、実施例(48b)で合成した化合物(6.58g,15.2mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.10g,1.35mmol)、炭酸カリウム(8.70g,63.0mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(7.79g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (9H, s), 3.07 (3H, s), 3.92 (3H, s), 5.32 (2H, s), 6.29 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.26-7.29 (1H, m), 7.31-7.44 (5H, m), 7.71-7.72 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.95-7.96 (1H, m)。 This was dissolved in methylene chloride (100 mL), pyridine (7.50 mL, 92.7 mmol) and trifluoromethanesulfonic anhydride (7.80 mL, 46.4 mmol) were added at 0 ° C., and 3 ° C. was added at 0 ° C. under a nitrogen atmosphere. Stir for half an hour. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 60%) to give the desired compound (9.58 g, yield) as a white solid. 52%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.10 (3H, s), 3.95 (3H, s), 7.17 (2H, dd, J = 7.0, 2.2 Hz), 7.22 (1H, t, J = 2.3 Hz ), 7.74 (1H, dd, J = 2.2, 1.4 Hz), 7.77 (1H, dd, J = 2.3, 1.6 Hz), 7.98 (2H, dd, J = 7.0, 2.2 Hz).
(48b) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate In Example (48a) Synthesized compound (9.58 g, 21.1 mmol), bis (pinacolato) diboron (7.45 g, 29.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( Using 850 mg, 1.04 mmol) and potassium acetate (10.6 g, 108 mmol), the target compound (6.83 g, yield 75%) was obtained as a pale red solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (12H, s), 3.07 (3H, s), 3.93 (3H, s), 7.07 (2H, dd, J = 6.8, 2.0 Hz), 7.69 (1H , dd, J = 2.3, 0.8 Hz), 7.83 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, dd, J = 6.8, 2.0 Hz), 8.33 (1H, dd, J = 1.6, 0.8 Hz).
(48c) 2-Benzyl 1-t-butyl 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Example (16d) ) (9.40 g, 24.7 mmol), the compound synthesized in Example (48b) (6.58 g, 15.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (1.10 g, 1.35 mmol) and potassium carbonate (8.70 g, 63.0 mmol) were used in the same manner as in Example (16e) to give the desired compound (7.79 g, yield) as a brown oil. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (9H, s), 3.07 (3H, s), 3.92 (3H, s), 5.32 (2H, s), 6.29 (1H, d, J = 3.5 Hz ), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.26-7.29 (1H, m), 7.31-7.44 (5H, m), 7.71-7.72 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.95-7.96 (1H, m).
1H-NMR (CDCl3, 400MHz):δ 3.10 (3H, s), 3.95 (3H, s), 7.17 (2H, dd, J = 7.0, 2.2 Hz), 7.22 (1H, t, J = 2.3 Hz), 7.74 (1H, dd, J = 2.2, 1.4 Hz), 7.77 (1H, dd, J = 2.3, 1.6 Hz), 7.98 (2H, dd, J = 7.0, 2.2 Hz).
(48b)3-[4-(メチルスルホニル)フェノキシ]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル
実施例(48a)で合成した化合物(9.58g,21.1mmol)、ビス(ピナコレート)ジボロン(7.45g,29.3mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(850mg,1.04mmol)、酢酸カリウム(10.6g,108mmol)を用い、実施例(1d)と同様の方法で淡赤色固体の目的化合物(6.83g,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (12H, s), 3.07 (3H, s), 3.93 (3H, s), 7.07 (2H, dd, J = 6.8, 2.0 Hz), 7.69 (1H, dd, J = 2.3, 0.8 Hz), 7.83 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, dd, J = 6.8, 2.0 Hz), 8.33 (1H, dd, J = 1.6, 0.8 Hz).
(48c)2-ベンジル 1-t-ブチル 5-{3-(メトキシカルボニル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(16d)で合成した化合物(9.40g,24.7mmol)、実施例(48b)で合成した化合物(6.58g,15.2mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.10g,1.35mmol)、炭酸カリウム(8.70g,63.0mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(7.79g,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (9H, s), 3.07 (3H, s), 3.92 (3H, s), 5.32 (2H, s), 6.29 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.26-7.29 (1H, m), 7.31-7.44 (5H, m), 7.71-7.72 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.95-7.96 (1H, m)。 This was dissolved in methylene chloride (100 mL), pyridine (7.50 mL, 92.7 mmol) and trifluoromethanesulfonic anhydride (7.80 mL, 46.4 mmol) were added at 0 ° C., and 3 ° C. was added at 0 ° C. under a nitrogen atmosphere. Stir for half an hour. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 20% to 60%) to give the desired compound (9.58 g, yield) as a white solid. 52%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.10 (3H, s), 3.95 (3H, s), 7.17 (2H, dd, J = 7.0, 2.2 Hz), 7.22 (1H, t, J = 2.3 Hz ), 7.74 (1H, dd, J = 2.2, 1.4 Hz), 7.77 (1H, dd, J = 2.3, 1.6 Hz), 7.98 (2H, dd, J = 7.0, 2.2 Hz).
(48b) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate In Example (48a) Synthesized compound (9.58 g, 21.1 mmol), bis (pinacolato) diboron (7.45 g, 29.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( Using 850 mg, 1.04 mmol) and potassium acetate (10.6 g, 108 mmol), the target compound (6.83 g, yield 75%) was obtained as a pale red solid in the same manner as in Example (1d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (12H, s), 3.07 (3H, s), 3.93 (3H, s), 7.07 (2H, dd, J = 6.8, 2.0 Hz), 7.69 (1H , dd, J = 2.3, 0.8 Hz), 7.83 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, dd, J = 6.8, 2.0 Hz), 8.33 (1H, dd, J = 1.6, 0.8 Hz).
(48c) 2-Benzyl 1-t-butyl 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Example (16d) ) (9.40 g, 24.7 mmol), the compound synthesized in Example (48b) (6.58 g, 15.2 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloride Dichloromethane complex (1.10 g, 1.35 mmol) and potassium carbonate (8.70 g, 63.0 mmol) were used in the same manner as in Example (16e) to give the desired compound (7.79 g, yield) as a brown oil. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (9H, s), 3.07 (3H, s), 3.92 (3H, s), 5.32 (2H, s), 6.29 (1H, d, J = 3.5 Hz ), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.26-7.29 (1H, m), 7.31-7.44 (5H, m), 7.71-7.72 (1H, m), 7.92 (2H, d, J = 9.0 Hz), 7.95-7.96 (1H, m).
(48d)5-{3-(メトキシカルボニル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボン酸
実施例(48c)で合成した化合物(7.79g,12.9mmol)をトリフルオロ酢酸(15.0mL)に溶解し、室温で45分間撹拌した。減圧下溶媒を留去した後、トリエチルアミン(5mL)を加え、5分間撹拌した。減圧下トリエチルアミンを留去することで淡黄色固体が得られた。 (48d) 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (48c) (7.79 g, 12 .9 mmol) was dissolved in trifluoroacetic acid (15.0 mL) and stirred at room temperature for 45 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.
実施例(48c)で合成した化合物(7.79g,12.9mmol)をトリフルオロ酢酸(15.0mL)に溶解し、室温で45分間撹拌した。減圧下溶媒を留去した後、トリエチルアミン(5mL)を加え、5分間撹拌した。減圧下トリエチルアミンを留去することで淡黄色固体が得られた。 (48d) 5- {3- (methoxycarbonyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylic acid The compound synthesized in Example (48c) (7.79 g, 12 .9 mmol) was dissolved in trifluoroacetic acid (15.0 mL) and stirred at room temperature for 45 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.
これを酢酸エチル(100mL)に溶解し、パラジウム炭素(1.50g)を加え、水素雰囲気下室温で1日撹拌した。セライト濾過後、減圧下溶媒を留去し、ジエチルエーテルを加え、析出した固体を濾取することで、白色固体の目的化合物(3.50g,収率66%)を得た。
1H-NMR (CD3OD, 500MHz):δ 3.13 (3H, s), 3.94 (3H, s), 6.65 (1H, d, J = 3.9 Hz), 6.93 (1H, d, J = 3.9 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 2.4 Hz), 7.97 (2H, d, J = 8.8 Hz), 8.23 (1H, s).
MS (FAB) m/z: 415(M+).
(48e)3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-[4-(メチルスルホニル)フェノキシ]安息香酸メチル
実施例(48d)で合成した化合物(2.86g,6.88mmol)を塩化メチレン(70mL)とN,N-ジメチルホルムアミド(45mL)の混合溶媒に溶解し、 (R)-(-)-1-アミノ-2-プロパノール(1.20g,15.98mmol)、WSCI・HCl(2.80g,14.61mmol)、4-ジメチルアミノピリジン(900mg,7.37mmol)を加え、窒素雰囲気下室温で3日間撹拌した。減圧下溶媒を留去し、食塩水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0~3%)を用いて精製することにより、黄色固体の目的化合物(2.24g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.26 (3H, d, J = 6.3 Hz), 2.41 (1H, br s), 3.09 (3H, s), 3.27-3.34 (1H, m), 3.61-3.67 (1H, m), 3.95 (3H, s), 4.03 (1H, br s), 6.33 (1H, s), 6.60 (1H, t, J = 3.3 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.12-7.15 (2H, m), 7.44 (1H, t, J = 2.2 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.92-7.95 (2H, m), 8.07 (1H, t, J = 1.6 Hz), 9.57 (1H, s).
(48f)3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]安息香酸メチル
実施例(48e)で合成した化合物(2.24g,4.74mmol)、メタンスルホン酸無水物(1.25g,7.17mmol)、トリエチルアミン(2.00mL,14.3mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(1.99g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s), 4.06 (1H, dd, J = 14.9, 10.2 Hz), 4.80-4.88 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dt, J = 9.4, 2.4 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz), 7.93 (2H, dt, J = 9.3, 2.4 Hz), 8.06 (1H, t, J = 1.6 Hz).
MS (ESI) m/z: 455.13005 (M+H)+。 This was dissolved in ethyl acetate (100 mL), palladium carbon (1.50 g) was added, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. After filtration through celite, the solvent was distilled off under reduced pressure, diethyl ether was added, and the precipitated solid was collected by filtration to obtain the target compound (3.50 g, yield 66%) as a white solid.
1 H-NMR (CD 3 OD, 500 MHz): δ 3.13 (3H, s), 3.94 (3H, s), 6.65 (1H, d, J = 3.9 Hz), 6.93 (1H, d, J = 3.9 Hz) , 7.23 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 2.4 Hz), 7.97 (2H, d, J = 8.8 Hz) , 8.23 (1H, s).
MS (FAB) m / z: 415 (M + ).
(48e) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized in step (2.86 g, 6.88 mmol) was dissolved in a mixed solvent of methylene chloride (70 mL) and N, N-dimethylformamide (45 mL), and (R)-(−)-1-amino-2- Propanol (1.20 g, 15.98 mmol), WSCI.HCl (2.80 g, 14.61 mmol) and 4-dimethylaminopyridine (900 mg, 7.37 mmol) were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (2.24 g, yield) as a yellow solid. Yield 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.26 (3H, d, J = 6.3 Hz), 2.41 (1H, br s), 3.09 (3H, s), 3.27-3.34 (1H, m), 3.61- 3.67 (1H, m), 3.95 (3H, s), 4.03 (1H, br s), 6.33 (1H, s), 6.60 (1H, t, J = 3.3 Hz), 6.64 (1H, dd, J = 3.9 , 2.3 Hz), 7.12-7.15 (2H, m), 7.44 (1H, t, J = 2.2 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.92-7.95 (2H, m), 8.07 (1H , t, J = 1.6 Hz), 9.57 (1H, s).
(48f) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] methyl benzoate Compound synthesized in Example (48e) (2.24 g, 4.74 mmol), methanesulfonic anhydride (1.25 g, 7.17 mmol), triethylamine (2.00 mL, 14.3 mmol) ) Was used to obtain the target compound (1.99 g, yield 92%) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s ), 4.06 (1H, dd, J = 14.9, 10.2 Hz), 4.80-4.88 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dt, J = 9.4, 2.4 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz), 7.93 (2H, dt, J = 9.3, 2.4 Hz) , 8.06 (1H, t, J = 1.6 Hz).
MS (ESI) m / z: 455.13005 (M + H) <+> .
1H-NMR (CD3OD, 500MHz):δ 3.13 (3H, s), 3.94 (3H, s), 6.65 (1H, d, J = 3.9 Hz), 6.93 (1H, d, J = 3.9 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 2.4 Hz), 7.97 (2H, d, J = 8.8 Hz), 8.23 (1H, s).
MS (FAB) m/z: 415(M+).
(48e)3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-[4-(メチルスルホニル)フェノキシ]安息香酸メチル
実施例(48d)で合成した化合物(2.86g,6.88mmol)を塩化メチレン(70mL)とN,N-ジメチルホルムアミド(45mL)の混合溶媒に溶解し、 (R)-(-)-1-アミノ-2-プロパノール(1.20g,15.98mmol)、WSCI・HCl(2.80g,14.61mmol)、4-ジメチルアミノピリジン(900mg,7.37mmol)を加え、窒素雰囲気下室温で3日間撹拌した。減圧下溶媒を留去し、食塩水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0~3%)を用いて精製することにより、黄色固体の目的化合物(2.24g,収率69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.26 (3H, d, J = 6.3 Hz), 2.41 (1H, br s), 3.09 (3H, s), 3.27-3.34 (1H, m), 3.61-3.67 (1H, m), 3.95 (3H, s), 4.03 (1H, br s), 6.33 (1H, s), 6.60 (1H, t, J = 3.3 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.12-7.15 (2H, m), 7.44 (1H, t, J = 2.2 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.92-7.95 (2H, m), 8.07 (1H, t, J = 1.6 Hz), 9.57 (1H, s).
(48f)3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]安息香酸メチル
実施例(48e)で合成した化合物(2.24g,4.74mmol)、メタンスルホン酸無水物(1.25g,7.17mmol)、トリエチルアミン(2.00mL,14.3mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(1.99g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s), 4.06 (1H, dd, J = 14.9, 10.2 Hz), 4.80-4.88 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dt, J = 9.4, 2.4 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz), 7.93 (2H, dt, J = 9.3, 2.4 Hz), 8.06 (1H, t, J = 1.6 Hz).
MS (ESI) m/z: 455.13005 (M+H)+。 This was dissolved in ethyl acetate (100 mL), palladium carbon (1.50 g) was added, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. After filtration through celite, the solvent was distilled off under reduced pressure, diethyl ether was added, and the precipitated solid was collected by filtration to obtain the target compound (3.50 g, yield 66%) as a white solid.
1 H-NMR (CD 3 OD, 500 MHz): δ 3.13 (3H, s), 3.94 (3H, s), 6.65 (1H, d, J = 3.9 Hz), 6.93 (1H, d, J = 3.9 Hz) , 7.23 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 2.4 Hz), 7.97 (2H, d, J = 8.8 Hz) , 8.23 (1H, s).
MS (FAB) m / z: 415 (M + ).
(48e) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized in step (2.86 g, 6.88 mmol) was dissolved in a mixed solvent of methylene chloride (70 mL) and N, N-dimethylformamide (45 mL), and (R)-(−)-1-amino-2- Propanol (1.20 g, 15.98 mmol), WSCI.HCl (2.80 g, 14.61 mmol) and 4-dimethylaminopyridine (900 mg, 7.37 mmol) were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (2.24 g, yield) as a yellow solid. Yield 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.26 (3H, d, J = 6.3 Hz), 2.41 (1H, br s), 3.09 (3H, s), 3.27-3.34 (1H, m), 3.61- 3.67 (1H, m), 3.95 (3H, s), 4.03 (1H, br s), 6.33 (1H, s), 6.60 (1H, t, J = 3.3 Hz), 6.64 (1H, dd, J = 3.9 , 2.3 Hz), 7.12-7.15 (2H, m), 7.44 (1H, t, J = 2.2 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.92-7.95 (2H, m), 8.07 (1H , t, J = 1.6 Hz), 9.57 (1H, s).
(48f) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] methyl benzoate Compound synthesized in Example (48e) (2.24 g, 4.74 mmol), methanesulfonic anhydride (1.25 g, 7.17 mmol), triethylamine (2.00 mL, 14.3 mmol) ) Was used to obtain the target compound (1.99 g, yield 92%) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.53 (1H, dd, J = 13.5, 6.8 Hz), 3.94 (3H, s ), 4.06 (1H, dd, J = 14.9, 10.2 Hz), 4.80-4.88 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dt, J = 9.4, 2.4 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz), 7.93 (2H, dt, J = 9.3, 2.4 Hz) , 8.06 (1H, t, J = 1.6 Hz).
MS (ESI) m / z: 455.13005 (M + H) <+> .
(48g)3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]安息香酸
実施例(48f)で合成した化合物(820mg,1.80mmol)をテトラヒドロフラン(10mL)と水(2mL)の混合溶媒に溶解し、水酸化リチウム一水和物(200mg,4.77mmol)を室温で加え、50℃で5時間撹拌した。5規定塩酸(3mL)を加え、生じた析出物を濾取した。得られた固体をジエチルエーテル(20mL)で洗浄することで白色固体の目的化合物(810mg,収率~100%)を得た。
MS (FAB) m/z: 441 (M+H)+.
(48h)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(48g)で合成した化合物(78mg,0.18mmol)を塩化メチレン(10mL)に溶解し、ジメチルアミン塩酸塩(170mg,2.08mmol)、WSCI・HCl(140mg,0.73mmol)、トリエチルアミン(0.40mL,2.87mmol)を加え、窒素雰囲気下室温で一晩撹拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(35mg,収率43%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.11 (3H, s), 3.48 (1H, dd, J = 13.9, 7.6 Hz), 4.00 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.85 (1H, m), 6.55 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.97 (1H, t, J = 1.0 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.8 Hz), 7.45 (1H, t, J = 1.4 Hz), 7.90 (2H, dd, J = 6.5, 5.3 Hz).
MS (ESI) m/z: 468.15943 (M+H)+。 (48 g) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl Sulfonyl) phenoxy] benzoic acid The compound synthesized in Example (48f) (820 mg, 1.80 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL), and lithium hydroxide monohydrate (200 mg, 4 .77 mmol) at room temperature and stirred at 50 ° C. for 5 hours. 5N hydrochloric acid (3 mL) was added, and the resulting precipitate was collected by filtration. The obtained solid was washed with diethyl ether (20 mL) to obtain the target compound (810 mg, yield˜100%) as a white solid.
MS (FAB) m / z: 441 (M + H) + .
(48h) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (78 mg, 0.18 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10 mL), and dimethylamine hydrochloride (170 mg, 2.08 mmol), WSCI -HCl (140 mg, 0.73 mmol) and triethylamine (0.40 mL, 2.87 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (35 mg, yield) as a white solid. 43%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.11 (3H, s), 3.48 (1H, dd , J = 13.9, 7.6 Hz), 4.00 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.85 (1H, m), 6.55 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.97 (1H, t, J = 1.0 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.8 Hz), 7.45 (1H, t, J = 1.4 Hz), 7.90 (2H, dd, J = 6.5, 5.3 Hz).
MS (ESI) m / z: 468.15943 (M + H) <+> .
実施例(48f)で合成した化合物(820mg,1.80mmol)をテトラヒドロフラン(10mL)と水(2mL)の混合溶媒に溶解し、水酸化リチウム一水和物(200mg,4.77mmol)を室温で加え、50℃で5時間撹拌した。5規定塩酸(3mL)を加え、生じた析出物を濾取した。得られた固体をジエチルエーテル(20mL)で洗浄することで白色固体の目的化合物(810mg,収率~100%)を得た。
MS (FAB) m/z: 441 (M+H)+.
(48h)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(48g)で合成した化合物(78mg,0.18mmol)を塩化メチレン(10mL)に溶解し、ジメチルアミン塩酸塩(170mg,2.08mmol)、WSCI・HCl(140mg,0.73mmol)、トリエチルアミン(0.40mL,2.87mmol)を加え、窒素雰囲気下室温で一晩撹拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(35mg,収率43%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.11 (3H, s), 3.48 (1H, dd, J = 13.9, 7.6 Hz), 4.00 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.85 (1H, m), 6.55 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.97 (1H, t, J = 1.0 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.8 Hz), 7.45 (1H, t, J = 1.4 Hz), 7.90 (2H, dd, J = 6.5, 5.3 Hz).
MS (ESI) m/z: 468.15943 (M+H)+。 (48 g) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl Sulfonyl) phenoxy] benzoic acid The compound synthesized in Example (48f) (820 mg, 1.80 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL), and lithium hydroxide monohydrate (200 mg, 4 .77 mmol) at room temperature and stirred at 50 ° C. for 5 hours. 5N hydrochloric acid (3 mL) was added, and the resulting precipitate was collected by filtration. The obtained solid was washed with diethyl ether (20 mL) to obtain the target compound (810 mg, yield˜100%) as a white solid.
MS (FAB) m / z: 441 (M + H) + .
(48h) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (78 mg, 0.18 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10 mL), and dimethylamine hydrochloride (170 mg, 2.08 mmol), WSCI -HCl (140 mg, 0.73 mmol) and triethylamine (0.40 mL, 2.87 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (35 mg, yield) as a white solid. 43%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.11 (3H, s), 3.48 (1H, dd , J = 13.9, 7.6 Hz), 4.00 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.85 (1H, m), 6.55 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.97 (1H, t, J = 1.0 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.8 Hz), 7.45 (1H, t, J = 1.4 Hz), 7.90 (2H, dd, J = 6.5, 5.3 Hz).
MS (ESI) m / z: 468.15943 (M + H) <+> .
(実施例49)
N-エチル-N-メチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 49)
N-ethyl-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide
N-エチル-N-メチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 49)
N-ethyl-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide
実施例(48g)で合成した化合物(97mg,0.22mmol)を塩化メチレン(10.0mL)に溶解し、N-エチルメチルアミン(0.10mL,1.16mmol)、HATU(250mg,0.66mmol)、N,N-ジイソプロピルエチルアミン(0.20mL,1.15mmol)を加え、窒素雰囲気下室温で一晩撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~3%)を用いて精製することにより、白色固体の目的化合物(77mg,収率73%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.11-1.27 (3H, m), 1.43 (3H, d, J = 6.3 Hz), 2.97 (3H, br s), 3.08 (3H, s), 3.32 (1H, br s), 3.54 (1H, dd, J = 14.3, 7.2 Hz), 3.58 (1H, br s), 4.08 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 6.95 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.26 (1H, s), 7.42 (1H, s), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 482.17604 (M+H)+。 The compound (97 mg, 0.22 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10.0 mL), and N-ethylmethylamine (0.10 mL, 1.16 mmol), HATU (250 mg, 0.66 mmol) was dissolved. ), N, N-diisopropylethylamine (0.20 mL, 1.15 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the desired compound (77 mg, yield) as a white solid. 73%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.11-1.27 (3H, m), 1.43 (3H, d, J = 6.3 Hz), 2.97 (3H, br s), 3.08 (3H, s), 3.32 ( 1H, br s), 3.54 (1H, dd, J = 14.3, 7.2 Hz), 3.58 (1H, br s), 4.08 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.88 (1H, m) , 6.56 (1H, d, J = 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 6.95 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.26 (1H, s) , 7.42 (1H, s), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 482.17604 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.11-1.27 (3H, m), 1.43 (3H, d, J = 6.3 Hz), 2.97 (3H, br s), 3.08 (3H, s), 3.32 (1H, br s), 3.54 (1H, dd, J = 14.3, 7.2 Hz), 3.58 (1H, br s), 4.08 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 6.95 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.26 (1H, s), 7.42 (1H, s), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 482.17604 (M+H)+。 The compound (97 mg, 0.22 mmol) synthesized in Example (48 g) was dissolved in methylene chloride (10.0 mL), and N-ethylmethylamine (0.10 mL, 1.16 mmol), HATU (250 mg, 0.66 mmol) was dissolved. ), N, N-diisopropylethylamine (0.20 mL, 1.15 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 3%) to give the desired compound (77 mg, yield) as a white solid. 73%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.11-1.27 (3H, m), 1.43 (3H, d, J = 6.3 Hz), 2.97 (3H, br s), 3.08 (3H, s), 3.32 ( 1H, br s), 3.54 (1H, dd, J = 14.3, 7.2 Hz), 3.58 (1H, br s), 4.08 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.88 (1H, m) , 6.56 (1H, d, J = 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 6.95 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.26 (1H, s) , 7.42 (1H, s), 7.92 (2H, d, J = 9.0 Hz).
MS (ESI) m / z: 482.17604 (M + H) <+> .
(実施例50)
(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)(ピロリジン-1-イル)メタノン (Example 50)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (pyrrolidin-1-yl) methanone
(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)(ピロリジン-1-イル)メタノン (Example 50)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (pyrrolidin-1-yl) methanone
実施例(48g)で合成した化合物(102mg,0.23mmol)、ピロール(0.15mL,2.16mmol)、HATU(250mg,0.66mmol)、N,N-ジイソプロピルエチルアミン(0.20mL,1.15mmol)を用い、(実施例49)と同様の方法で白色固体の目的化合物(61mg,収率53%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.43 (3H, d, J = 6.3 Hz), 1.89-1.94 (2H, m), 1.95-2.01 (2H, m), 3.08 (3H, s), 3.45 (2H, t, J = 6.3 Hz), 3.55 (1H, dd, J = 13.9, 7.1 Hz), 3.65 (2H, t, J = 7.1 Hz), 4.09 (1H, dd, J = 13.9, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.08 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.54 (1H, s), 7.92 (2H, d, J = 8.8 Hz).
MS (ESI) m/z: 494.17477 (M+H)+。 Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), pyrrole (0.15 mL, 2.16 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to give the target compound (61 mg, 53% yield) as a white solid in the same manner as in (Example 49).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 1.89-1.94 (2H, m), 1.95-2.01 (2H, m), 3.08 (3H, s), 3.45 (2H, t, J = 6.3 Hz), 3.55 (1H, dd, J = 13.9, 7.1 Hz), 3.65 (2H, t, J = 7.1 Hz), 4.09 (1H, dd, J = 13.9, 9.0 Hz) , 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.08 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.54 (1H, s), 7.92 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 494.17477 (M + H) <+> .
1H-NMR (CDCl3, 500MHz):δ 1.43 (3H, d, J = 6.3 Hz), 1.89-1.94 (2H, m), 1.95-2.01 (2H, m), 3.08 (3H, s), 3.45 (2H, t, J = 6.3 Hz), 3.55 (1H, dd, J = 13.9, 7.1 Hz), 3.65 (2H, t, J = 7.1 Hz), 4.09 (1H, dd, J = 13.9, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.08 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.54 (1H, s), 7.92 (2H, d, J = 8.8 Hz).
MS (ESI) m/z: 494.17477 (M+H)+。 Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), pyrrole (0.15 mL, 2.16 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to give the target compound (61 mg, 53% yield) as a white solid in the same manner as in (Example 49).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 1.89-1.94 (2H, m), 1.95-2.01 (2H, m), 3.08 (3H, s), 3.45 (2H, t, J = 6.3 Hz), 3.55 (1H, dd, J = 13.9, 7.1 Hz), 3.65 (2H, t, J = 7.1 Hz), 4.09 (1H, dd, J = 13.9, 9.0 Hz) , 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.08 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.26 (1H, s), 7.54 (1H, s), 7.92 (2H, d, J = 8.8 Hz).
MS (ESI) m / z: 494.17477 (M + H) <+> .
(実施例51)
(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)(モルホリン-4-イル)メタノン (Example 51)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (morpholin-4-yl) methanone
(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)(モルホリン-4-イル)メタノン (Example 51)
(3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methylsulfonyl) Phenoxy] phenyl) (morpholin-4-yl) methanone
実施例(48g)で合成した化合物(102mg,0.23mmol)、モルホリン(0.15mL,1.72mmol)、HATU(250mg,0.66mmol)、N,N-ジイソプロピルエチルアミン(0.20mL,1.15mmol)を用い、(実施例49)と同様の方法で白色固体の目的化合物(121mg,収率~100%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.44-3.88 (6H, m), 3.55 (1H, dd, J = 14.2, 7.3 Hz), 4.08 (1H, dd, J = 13.7, 9.3 Hz), 4.81-4.91 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.4 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.15 (2H, dt, J = 9.4, 2.4 Hz), 7.28 (1H, s), 7.43 (1H, s), 7.93 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m/z: 510.16861 (M+H)+。 Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), morpholine (0.15 mL, 1.72 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to obtain the target compound (121 mg, yield˜100%) as a white solid in the same manner as in (Example 49).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.44-3.88 (6H, m ), 3.55 (1H, dd, J = 14.2, 7.3 Hz), 4.08 (1H, dd, J = 13.7, 9.3 Hz), 4.81-4.91 (1H, m), 6.56 (1H, d, J = 3.9 Hz) , 6.78 (1H, d, J = 3.4 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.15 (2H, dt, J = 9.4, 2.4 Hz), 7.28 (1H, s), 7.43 (1H, s), 7.93 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 510.16861 (M + H) + .
1H-NMR (CDCl3, 500MHz):δ 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.44-3.88 (6H, m), 3.55 (1H, dd, J = 14.2, 7.3 Hz), 4.08 (1H, dd, J = 13.7, 9.3 Hz), 4.81-4.91 (1H, m), 6.56 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.4 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.15 (2H, dt, J = 9.4, 2.4 Hz), 7.28 (1H, s), 7.43 (1H, s), 7.93 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m/z: 510.16861 (M+H)+。 Compound (102 mg, 0.23 mmol) synthesized in Example (48 g), morpholine (0.15 mL, 1.72 mmol), HATU (250 mg, 0.66 mmol), N, N-diisopropylethylamine (0.20 mL, 1. 15 mmol) was used to obtain the target compound (121 mg, yield˜100%) as a white solid in the same manner as in (Example 49).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.44-3.88 (6H, m ), 3.55 (1H, dd, J = 14.2, 7.3 Hz), 4.08 (1H, dd, J = 13.7, 9.3 Hz), 4.81-4.91 (1H, m), 6.56 (1H, d, J = 3.9 Hz) , 6.78 (1H, d, J = 3.4 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.15 (2H, dt, J = 9.4, 2.4 Hz), 7.28 (1H, s), 7.43 (1H, s), 7.93 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 510.16861 (M + H) + .
(実施例52)
N-メトキシ-N-メチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 52)
N-methoxy-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide
N-メトキシ-N-メチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 52)
N-methoxy-N-methyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 [4- (Methylsulfonyl) phenoxy] benzamide
実施例(48g)で合成した化合物(152mg,0.35mmol)、N,O-ジメチルヒドロキシルアミン塩酸塩(170mg,1.74mmol)、HATU(325mg,0.86mmol)、N,N-ジイソプロピルエチルアミン(0.30mL,1.72mmol)を用い、(実施例49)と同様の方法で白色固体の目的化合物(132mg,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47-3.57 (1H, m), 3.58 (3H, s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1H, m), 6.58 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.14 (2H, dt, J = 9.4, 2.4 Hz), 7.29 (1H, s), 7.33 (1H, s), 7.72 (1H, s), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m/z: 484.15489 (M+H)+。 Compound (152 mg, 0.35 mmol) synthesized in Example (48 g), N, O-dimethylhydroxylamine hydrochloride (170 mg, 1.74 mmol), HATU (325 mg, 0.86 mmol), N, N-diisopropylethylamine ( 0.30 mL, 1.72 mmol) was used to obtain the target compound as a white solid (132 mg, yield 79%) in the same manner as in Example 49.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47-3.57 (1H, m), 3.58 (3H , s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1H, m), 6.58 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz) , 7.14 (2H, dt, J = 9.4, 2.4 Hz), 7.29 (1H, s), 7.33 (1H, s), 7.72 (1H, s), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 484.15489 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47-3.57 (1H, m), 3.58 (3H, s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1H, m), 6.58 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.14 (2H, dt, J = 9.4, 2.4 Hz), 7.29 (1H, s), 7.33 (1H, s), 7.72 (1H, s), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m/z: 484.15489 (M+H)+。 Compound (152 mg, 0.35 mmol) synthesized in Example (48 g), N, O-dimethylhydroxylamine hydrochloride (170 mg, 1.74 mmol), HATU (325 mg, 0.86 mmol), N, N-diisopropylethylamine ( 0.30 mL, 1.72 mmol) was used to obtain the target compound as a white solid (132 mg, yield 79%) in the same manner as in Example 49.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.08 (3H, s), 3.38 (3H, s), 3.47-3.57 (1H, m), 3.58 (3H , s), 4.10 (1H, dd, J = 14.3, 9.2 Hz), 4.82-4.89 (1H, m), 6.58 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.5 Hz) , 7.14 (2H, dt, J = 9.4, 2.4 Hz), 7.29 (1H, s), 7.33 (1H, s), 7.72 (1H, s), 7.92 (2H, dt, J = 9.4, 2.4 Hz).
MS (ESI) m / z: 484.15489 (M + H) <+> .
(実施例53)
アゼチジン-1-イル(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)メタノン (Example 53)
Azetidin-1-yl (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] phenyl) methanone
アゼチジン-1-イル(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)メタノン (Example 53)
Azetidin-1-yl (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] phenyl) methanone
実施例(48g)で合成した化合物(80mg,0.18mmol)、アゼチジン塩酸塩(120mg,1.28mmol)、WSCI・HCl(100mg,0.52mmol)、トリエチルアミン(0.10mL,0.72mmol)を用い、実施例(48h)と同様の方法で白色固体の目的化合物(12mg,収率14%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 2.33-2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 (1H, m), 4.20-4.28 (2H, m), 4.28-4.35 (2H, m), 4.81-4.89 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.16 (1H, s), 7.32 (1H, s), 7.67 (1H, s), 7.93 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 480.15870 (M+H)+。 Compound (80 mg, 0.18 mmol) synthesized in Example (48 g), azetidine hydrochloride (120 mg, 1.28 mmol), WSCI · HCl (100 mg, 0.52 mmol), triethylamine (0.10 mL, 0.72 mmol) The target compound (12 mg, 14% yield) was obtained as a white solid in the same manner as in Example (48h).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 2.33-2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 (1H, m), 4.20-4.28 (2H, m), 4.28-4.35 (2H, m), 4.81-4.89 (1H, m), 6.57 (1H, d, J = 3.9 Hz ), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.16 (1H, s), 7.32 (1H, s), 7.67 (1H, s), 7.93 (2H , d, J = 9.0 Hz).
MS (ESI) m / z: 480.15870 (M + H) + .
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.3 Hz), 2.33-2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 (1H, m), 4.20-4.28 (2H, m), 4.28-4.35 (2H, m), 4.81-4.89 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.16 (1H, s), 7.32 (1H, s), 7.67 (1H, s), 7.93 (2H, d, J = 9.0 Hz).
MS (ESI) m/z: 480.15870 (M+H)+。 Compound (80 mg, 0.18 mmol) synthesized in Example (48 g), azetidine hydrochloride (120 mg, 1.28 mmol), WSCI · HCl (100 mg, 0.52 mmol), triethylamine (0.10 mL, 0.72 mmol) The target compound (12 mg, 14% yield) was obtained as a white solid in the same manner as in Example (48h).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 2.33-2.40 (2H, m), 3.08 (3H, s), 3.56 (1H, dd, J = 14.1, 7.4 Hz), 3.73-3.78 (1H, m), 4.20-4.28 (2H, m), 4.28-4.35 (2H, m), 4.81-4.89 (1H, m), 6.57 (1H, d, J = 3.9 Hz ), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.16 (1H, s), 7.32 (1H, s), 7.67 (1H, s), 7.93 (2H , d, J = 9.0 Hz).
MS (ESI) m / z: 480.15870 (M + H) + .
(実施例54)
3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 54)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -[4- (Methylsulfonyl) phenoxy] benzamide
3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 54)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -[4- (Methylsulfonyl) phenoxy] benzamide
(54a)メチル 3-(5-{[(2S)-2,3-ジヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(48d)で合成した化合物(1.58g,3.80mmol)をメタノール(30mL)とテトラヒドロフラン(30mL)の混合溶媒にけん濁させ、(S)-(-)-3-アミノ-1,2-プロパンジオール(544mg,5.97mmol)、DMT-MM(2.56g,8.18mmol)を加え、窒素雰囲気下6時間撹拌した。反応液を濃縮後、水を加え酢酸エチルで抽出した。飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~10%)を用いて精製することで、白色固体の目的物(1.25g,67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.08 (3H, s), 3.12 (1H, t, J = 6.3 Hz), 3.19 (1H, d, J = 5.9 Hz), 3.51-3.65 (4H, m), 3.83-3.90 (1H, m), 3.94 (3H, s), 6.50 (1H, t, J = 6.3 Hz), 6.59 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.7, 2.5 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.3, 1.6 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.97 (1H, br s).
MS (FAB) m/z: 489 (M+H)+.
(54b)メチル 3-[5-({(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}カルバモイル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(54a)で合成した化合物(1.25g,2.56mmol)を塩化メチレン(25mL)に溶解し、トリエチルアミン(1.05mL,7.57mmol)、トリイソプロピルシリルクロリド(610μL,2.85mmol)、4-ジメチルアミノピリジン(314mg,2.57mmmol)を加え、窒素雰囲気下で5時間攪拌した。反応液を酢酸エチル(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することで、白色固体の目的物(1.16g,70%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.05-1.16 (21H, m), 3.08 (3H, s), 3.11 (1H, d, J = 4.7 Hz), 3.37-3.43 (1H, m), 3.65-3.80 (3H, m), 3.85-3.90 (1H, m), 3.95 (3H, s), 6.40 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.60 (1H, t, J = 2.0 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.74 (1H, br s).
MS (FAB) m/z: 645 (M+H)+.
(54c)メチル 3-[4-(メチルスルホニル)フェノキシ]-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(54b)で合成した化合物(1.16g,1.80mmol)、メタンスルホン酸無水物(633mg,3.63mmol)、トリエチルアミン(0.99mL,7.14mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(1.11g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83-3.92 (3H, m), 3.94 (3H, s), 4.01 (1H, dd, J = 14.5, 9.8 Hz), 4.73-4.80 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.45 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.08 (1H, t, J = 1.6 Hz).
MS (FAB) m/z: 627 (M+H)+。 (54a) Methyl 3- (5-{[(2S) -2,3-dihydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized (1.58 g, 3.80 mmol) is suspended in a mixed solvent of methanol (30 mL) and tetrahydrofuran (30 mL), and (S)-(−)-3-amino-1,2-propanediol is suspended. (544 mg, 5.97 mmol) and DMT-MM (2.56 g, 8.18 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 6 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 10%) to give the desired product (1.25 g, 67%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.08 (3H, s), 3.12 (1H, t, J = 6.3 Hz), 3.19 (1H, d, J = 5.9 Hz), 3.51-3.65 (4H, m ), 3.83-3.90 (1H, m), 3.94 (3H, s), 6.50 (1H, t, J = 6.3 Hz), 6.59 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.7, 2.5 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.3, 1.6 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.97 (1H, br s).
MS (FAB) m / z: 489 (M + H) + .
(54b) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5- [4- (methyl [Sulfonyl) phenoxy] benzoate The compound synthesized in Example (54a) (1.25 g, 2.56 mmol) was dissolved in methylene chloride (25 mL), triethylamine (1.05 mL, 7.57 mmol), triisopropylsilyl chloride (610 μL). , 2.85 mmol) and 4-dimethylaminopyridine (314 mg, 2.57 mmol) were added and stirred under a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (1.16 g, 70%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.16 (21H, m), 3.08 (3H, s), 3.11 (1H, d, J = 4.7 Hz), 3.37-3.43 (1H, m), 3.65 -3.80 (3H, m), 3.85-3.90 (1H, m), 3.95 (3H, s), 6.40 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.60 (1H, t, J = 2.0 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.74 (1H, br s).
MS (FAB) m / z: 645 (M + H) + .
(54c) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} benzoate Compound (1.16 g, 1.80 mmol) synthesized in Example (54b), methanesulfonic anhydride (633 mg, 3.63 mmol), triethylamine ( The target compound (1.11 g, yield 98%) was obtained as a pale yellow solid in the same manner as in Example (16j) using 0.99 mL, 7.14 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83-3.92 (3H, m), 3.94 (3H, s), 4.01 (1H, dd, J = 14.5, 9.8 Hz), 4.73-4.80 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.45 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.08 (1H, t, J = 1.6 Hz) .
MS (FAB) m / z: 627 (M + H) + .
実施例(48d)で合成した化合物(1.58g,3.80mmol)をメタノール(30mL)とテトラヒドロフラン(30mL)の混合溶媒にけん濁させ、(S)-(-)-3-アミノ-1,2-プロパンジオール(544mg,5.97mmol)、DMT-MM(2.56g,8.18mmol)を加え、窒素雰囲気下6時間撹拌した。反応液を濃縮後、水を加え酢酸エチルで抽出した。飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~10%)を用いて精製することで、白色固体の目的物(1.25g,67%)を得た。
1H-NMR (CDCl3, 400MHz): δ 3.08 (3H, s), 3.12 (1H, t, J = 6.3 Hz), 3.19 (1H, d, J = 5.9 Hz), 3.51-3.65 (4H, m), 3.83-3.90 (1H, m), 3.94 (3H, s), 6.50 (1H, t, J = 6.3 Hz), 6.59 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.7, 2.5 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.3, 1.6 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.97 (1H, br s).
MS (FAB) m/z: 489 (M+H)+.
(54b)メチル 3-[5-({(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}カルバモイル)-1H-ピロール-2-イル]-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(54a)で合成した化合物(1.25g,2.56mmol)を塩化メチレン(25mL)に溶解し、トリエチルアミン(1.05mL,7.57mmol)、トリイソプロピルシリルクロリド(610μL,2.85mmol)、4-ジメチルアミノピリジン(314mg,2.57mmmol)を加え、窒素雰囲気下で5時間攪拌した。反応液を酢酸エチル(100mL)で希釈し、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~60%)を用いて精製することで、白色固体の目的物(1.16g,70%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.05-1.16 (21H, m), 3.08 (3H, s), 3.11 (1H, d, J = 4.7 Hz), 3.37-3.43 (1H, m), 3.65-3.80 (3H, m), 3.85-3.90 (1H, m), 3.95 (3H, s), 6.40 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.60 (1H, t, J = 2.0 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.74 (1H, br s).
MS (FAB) m/z: 645 (M+H)+.
(54c)メチル 3-[4-(メチルスルホニル)フェノキシ]-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(54b)で合成した化合物(1.16g,1.80mmol)、メタンスルホン酸無水物(633mg,3.63mmol)、トリエチルアミン(0.99mL,7.14mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(1.11g,収率98%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83-3.92 (3H, m), 3.94 (3H, s), 4.01 (1H, dd, J = 14.5, 9.8 Hz), 4.73-4.80 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.45 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.08 (1H, t, J = 1.6 Hz).
MS (FAB) m/z: 627 (M+H)+。 (54a) Methyl 3- (5-{[(2S) -2,3-dihydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Example (48d) The compound synthesized (1.58 g, 3.80 mmol) is suspended in a mixed solvent of methanol (30 mL) and tetrahydrofuran (30 mL), and (S)-(−)-3-amino-1,2-propanediol is suspended. (544 mg, 5.97 mmol) and DMT-MM (2.56 g, 8.18 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 6 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 10%) to give the desired product (1.25 g, 67%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.08 (3H, s), 3.12 (1H, t, J = 6.3 Hz), 3.19 (1H, d, J = 5.9 Hz), 3.51-3.65 (4H, m ), 3.83-3.90 (1H, m), 3.94 (3H, s), 6.50 (1H, t, J = 6.3 Hz), 6.59 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.7, 2.5 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.3, 1.6 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.97 (1H, br s).
MS (FAB) m / z: 489 (M + H) + .
(54b) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5- [4- (methyl [Sulfonyl) phenoxy] benzoate The compound synthesized in Example (54a) (1.25 g, 2.56 mmol) was dissolved in methylene chloride (25 mL), triethylamine (1.05 mL, 7.57 mmol), triisopropylsilyl chloride (610 μL). , 2.85 mmol) and 4-dimethylaminopyridine (314 mg, 2.57 mmol) were added and stirred under a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 40% -60%) to give the desired product (1.16 g, 70%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.05-1.16 (21H, m), 3.08 (3H, s), 3.11 (1H, d, J = 4.7 Hz), 3.37-3.43 (1H, m), 3.65 -3.80 (3H, m), 3.85-3.90 (1H, m), 3.95 (3H, s), 6.40 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.3 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.60 (1H, t, J = 2.0 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.74 (1H, br s).
MS (FAB) m / z: 645 (M + H) + .
(54c) Methyl 3- [4- (methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3- Oxazol-2-yl] -1H-pyrrol-2-yl} benzoate Compound (1.16 g, 1.80 mmol) synthesized in Example (54b), methanesulfonic anhydride (633 mg, 3.63 mmol), triethylamine ( The target compound (1.11 g, yield 98%) was obtained as a pale yellow solid in the same manner as in Example (16j) using 0.99 mL, 7.14 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.02-1.14 (21H, m), 3.08 (3H, s), 3.83-3.92 (3H, m), 3.94 (3H, s), 4.01 (1H, dd, J = 14.5, 9.8 Hz), 4.73-4.80 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.45 (1H, t, J = 1.8 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.93 (2H, d, J = 9.0 Hz), 8.08 (1H, t, J = 1.6 Hz) .
MS (FAB) m / z: 627 (M + H) + .
(54d)3-[4-(メチルスルホニル)フェノキシ]-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}安息香酸
実施例(54c)で合成した化合物(1.01g,1.75mmol)をエタノール(15mL)に溶解させ、2規定の水酸化ナトリウム水溶液(5mL)を加え、70℃で1時間撹拌した。反応液に水(100mL)を加えた後に氷冷し、1規定の塩酸(15mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、橙色固体の目的化合物(951mg,収率89%)を得た。
MS (FAB) m/z: 613 (M+H)+.
(54e)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(54d)で合成した化合物(944mg,1.54mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、ジメチルアミン塩酸塩(289mg,3.54mmol)、HATU(1.21g,3.18mmol)、N,N-ジイソプロピルエチルアミン(1.08mL,6.18mmol)を加え、窒素雰囲気下室温で15時間撹拌した。反応液に水(50mL)、1規定塩酸(15mL)を加え、酢酸エチル(100mL)で抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~5%)を用いて精製することにより、橙色油状の化合物(1.20g)を得た。 (54d) 3- [4- (Methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzoic acid The compound synthesized in Example (54c) (1.01 g, 1.75 mmol) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (15 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (951 mg, yield 89%) as an orange solid.
MS (FAB) m / z: 613 (M + H) + .
(54e) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5- [4- (methylsulfonyl) phenoxy] benzamide The compound synthesized in Example (54d) (944 mg, 1.54 mmol) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (289 mg). 3.54 mmol), HATU (1.21 g, 3.18 mmol) and N, N-diisopropylethylamine (1.08 mL, 6.18 mmol) were added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (50 mL) and 1N hydrochloric acid (15 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 5%) to give an orange oily compound (1.20 g). )
実施例(54c)で合成した化合物(1.01g,1.75mmol)をエタノール(15mL)に溶解させ、2規定の水酸化ナトリウム水溶液(5mL)を加え、70℃で1時間撹拌した。反応液に水(100mL)を加えた後に氷冷し、1規定の塩酸(15mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、橙色固体の目的化合物(951mg,収率89%)を得た。
MS (FAB) m/z: 613 (M+H)+.
(54e)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(54d)で合成した化合物(944mg,1.54mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、ジメチルアミン塩酸塩(289mg,3.54mmol)、HATU(1.21g,3.18mmol)、N,N-ジイソプロピルエチルアミン(1.08mL,6.18mmol)を加え、窒素雰囲気下室温で15時間撹拌した。反応液に水(50mL)、1規定塩酸(15mL)を加え、酢酸エチル(100mL)で抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0.5%~5%)を用いて精製することにより、橙色油状の化合物(1.20g)を得た。 (54d) 3- [4- (Methylsulfonyl) phenoxy] -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzoic acid The compound synthesized in Example (54c) (1.01 g, 1.75 mmol) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (15 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (951 mg, yield 89%) as an orange solid.
MS (FAB) m / z: 613 (M + H) + .
(54e) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5- [4- (methylsulfonyl) phenoxy] benzamide The compound synthesized in Example (54d) (944 mg, 1.54 mmol) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (289 mg). 3.54 mmol), HATU (1.21 g, 3.18 mmol) and N, N-diisopropylethylamine (1.08 mL, 6.18 mmol) were added, and the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Water (50 mL) and 1N hydrochloric acid (15 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0.5% to 5%) to give an orange oily compound (1.20 g). )
これをテトラヒドロフラン(15mL)に溶解し、テトラブチルアンモニウムフルオリド(1.0mol/Lテトラヒドロフラン溶液,1.60mL,1.60mmol)を加え、窒素雰囲気下で1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(50mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~7%)を用いて精製することにより、白色固体の目的化合物(514mg,収率69%)を得た。
1H-NMR (CDCl3, 400MHz): δ 2.99 (3H, br s), 3.07 (3H, s), 3.11 (3H, br s), 3.66 (1H, dd, J = 12.3, 5.3 Hz), 3.75 (1H, dd, J = 14.1, 7.4 Hz), 3.83 (1H, dd, J = 12.5, 3.1 Hz), 4.00 (1H, dd, J = 14.5, 9.8 Hz), 4.75-4.81 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.5 Hz), 6.96 (1H, dd, J = 2.3, 1.6 Hz), 7.13 (2H, dt, J = 9.5, 2.3 Hz), 7.28 (1H, t, J = 2.0 Hz), 7.40 (1H, t, J = 1.6 Hz), 7.91 (2H, dt, J = 9.5, 2.3 Hz).
MS (ESI) m/z: 484.15459 (M+H)+。 This was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.60 mL, 1.60 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (514 mg, yield) as a white solid. 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.99 (3H, br s), 3.07 (3H, s), 3.11 (3H, br s), 3.66 (1H, dd, J = 12.3, 5.3 Hz), 3.75 (1H, dd, J = 14.1, 7.4 Hz), 3.83 (1H, dd, J = 12.5, 3.1 Hz), 4.00 (1H, dd, J = 14.5, 9.8 Hz), 4.75-4.81 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.5 Hz), 6.96 (1H, dd, J = 2.3, 1.6 Hz), 7.13 (2H, dt, J = 9.5, 2.3 Hz ), 7.28 (1H, t, J = 2.0 Hz), 7.40 (1H, t, J = 1.6 Hz), 7.91 (2H, dt, J = 9.5, 2.3 Hz).
MS (ESI) m / z: 484.15459 (M + H) <+> .
1H-NMR (CDCl3, 400MHz): δ 2.99 (3H, br s), 3.07 (3H, s), 3.11 (3H, br s), 3.66 (1H, dd, J = 12.3, 5.3 Hz), 3.75 (1H, dd, J = 14.1, 7.4 Hz), 3.83 (1H, dd, J = 12.5, 3.1 Hz), 4.00 (1H, dd, J = 14.5, 9.8 Hz), 4.75-4.81 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.5 Hz), 6.96 (1H, dd, J = 2.3, 1.6 Hz), 7.13 (2H, dt, J = 9.5, 2.3 Hz), 7.28 (1H, t, J = 2.0 Hz), 7.40 (1H, t, J = 1.6 Hz), 7.91 (2H, dt, J = 9.5, 2.3 Hz).
MS (ESI) m/z: 484.15459 (M+H)+。 This was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 1.60 mL, 1.60 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 7%) to give the target compound (514 mg, yield) as a white solid. 69%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.99 (3H, br s), 3.07 (3H, s), 3.11 (3H, br s), 3.66 (1H, dd, J = 12.3, 5.3 Hz), 3.75 (1H, dd, J = 14.1, 7.4 Hz), 3.83 (1H, dd, J = 12.5, 3.1 Hz), 4.00 (1H, dd, J = 14.5, 9.8 Hz), 4.75-4.81 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.73 (1H, d, J = 3.5 Hz), 6.96 (1H, dd, J = 2.3, 1.6 Hz), 7.13 (2H, dt, J = 9.5, 2.3 Hz ), 7.28 (1H, t, J = 2.0 Hz), 7.40 (1H, t, J = 1.6 Hz), 7.91 (2H, dt, J = 9.5, 2.3 Hz).
MS (ESI) m / z: 484.15459 (M + H) <+> .
(実施例55)
3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 55)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide
3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 55)
3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide
(55a)メチル 3-ヒドロキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(16a)で合成した化合物(17.4g,90.8mmol)をN,N-ジメチルホルムアミド(500mL)に溶解した。3,5-ジヒドロキシ安息香酸メチル(30.5g,181mmol)、炭酸カリウム(37.7g,273mmol)を加え、窒素雰囲気下100℃で5.5時間攪拌した。反応液を室温まで冷却後、水(500mL)を加え、ジエチルエーテル(400mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的化合物(18.9g,収率64%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.91 (3H, s), 6.36 (1H, brs), 6.82 (1H, t, J=2.4Hz), 7.28 (1H, brs), 7.43 (1H, brs), 7.44 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(55b)メチル 3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{[(トリフルオロメチル)スルホニル]オキシ}ベンゾエート
実施例(55a)で合成した化合物(18.9g,58.5mmol)を塩化メチレン(500mL)に溶解した。0℃にてトリフルオロメタンスルホン酸無水物(13.8mL,82.0mmol)、ピリジン(14.2mL,176mmol)を加え、窒素雰囲気下室温で2時間攪拌した。水(400mL)を加え、塩化メチレン(400mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的化合物(20.9g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.26 (3H, s), 3.96 (3H, s), 7.28 (1H, m), 7.52 (1H, dd, J=2.7, 8.6Hz), 7.75 (1H, brt, J=2.4Hz), 7.83 (1H, brt, J=2.4Hz), 8.14 (1H, d, J=8.6 Hz), 8.51 (1H, d, J=2.7Hz).
(55c)ベンジル 5-[3-(メトキシカルボニル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(55b)で合成した化合物(20.9g,45.9mmol)、実施例(19e)で合成した化合物(18.0g,55.0mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.13g,1.38mmol)、炭酸カリウム(12.7g,91.9mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(19.3g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.96 (3H, s), 5.35 (2H, s), 6.63 (1H, dd, J=2.4, 3.9Hz), 7.01 (1H, dd, J=2.4, 3.9Hz), 7.35-7.47 (6H, m), 7.48 (1H, brs), 7.62 (1H, m), 8.08 (1H, d, J=8.9Hz), 8.11 (1H, brs), 8.50 (1H, d, J=2.9Hz), 9.49 (1H, brs)。 (55a) Methyl 3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound (17.4 g, 90.8 mmol) synthesized in Example (16a) was converted to N, N— Dissolved in dimethylformamide (500 mL). Methyl 3,5-dihydroxybenzoate (30.5 g, 181 mmol) and potassium carbonate (37.7 g, 273 mmol) were added, and the mixture was stirred at 100 ° C. for 5.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (500 mL) was added, and the mixture was extracted 3 times with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (18.9 g, 18.9 g, Yield 64%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.91 (3H, s), 6.36 (1H, brs), 6.82 (1H, t, J = 2.4 Hz), 7.28 (1H, brs), 7.43 (1H, brs), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(55b) Methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Compound (18.9 g) synthesized in Example (55a) , 58.5 mmol) was dissolved in methylene chloride (500 mL). Trifluoromethanesulfonic anhydride (13.8 mL, 82.0 mmol) and pyridine (14.2 mL, 176 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (400 mL) was added and extracted twice with methylene chloride (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (20.9 g, Yield 79%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.26 (3H, s), 3.96 (3H, s), 7.28 (1H, m), 7.52 (1H, dd, J = 2.7, 8.6Hz), 7.75 ( 1H, brt, J = 2.4Hz), 7.83 (1H, brt, J = 2.4Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7Hz).
(55c) Benzyl 5- [3- (methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (55b) Compound (20.9 g, 45.9 mmol), compound synthesized in Example (19e) (18.0 g, 55.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using the dichloromethane complex (1.13 g, 1.38 mmol) and potassium carbonate (12.7 g, 91.9 mmol), the target compound (19.3 g, yield 83%) was obtained in the same manner as in Example (16e). )
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.96 (3H, s), 5.35 (2H, s), 6.63 (1H, dd, J = 2.4, 3.9Hz), 7.01 ( 1H, dd, J = 2.4, 3.9Hz), 7.35-7.47 (6H, m), 7.48 (1H, brs), 7.62 (1H, m), 8.08 (1H, d, J = 8.9Hz), 8.11 (1H , brs), 8.50 (1H, d, J = 2.9Hz), 9.49 (1H, brs).
実施例(16a)で合成した化合物(17.4g,90.8mmol)をN,N-ジメチルホルムアミド(500mL)に溶解した。3,5-ジヒドロキシ安息香酸メチル(30.5g,181mmol)、炭酸カリウム(37.7g,273mmol)を加え、窒素雰囲気下100℃で5.5時間攪拌した。反応液を室温まで冷却後、水(500mL)を加え、ジエチルエーテル(400mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~60%)を用いて精製することにより、白色固体の目的化合物(18.9g,収率64%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.91 (3H, s), 6.36 (1H, brs), 6.82 (1H, t, J=2.4Hz), 7.28 (1H, brs), 7.43 (1H, brs), 7.44 (1H, dd, J=2.7, 8.6Hz), 8.06 (1H, d, J=8.6Hz), 8.46 (1H, d, J=2.7Hz).
(55b)メチル 3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{[(トリフルオロメチル)スルホニル]オキシ}ベンゾエート
実施例(55a)で合成した化合物(18.9g,58.5mmol)を塩化メチレン(500mL)に溶解した。0℃にてトリフルオロメタンスルホン酸無水物(13.8mL,82.0mmol)、ピリジン(14.2mL,176mmol)を加え、窒素雰囲気下室温で2時間攪拌した。水(400mL)を加え、塩化メチレン(400mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的化合物(20.9g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.26 (3H, s), 3.96 (3H, s), 7.28 (1H, m), 7.52 (1H, dd, J=2.7, 8.6Hz), 7.75 (1H, brt, J=2.4Hz), 7.83 (1H, brt, J=2.4Hz), 8.14 (1H, d, J=8.6 Hz), 8.51 (1H, d, J=2.7Hz).
(55c)ベンジル 5-[3-(メトキシカルボニル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(55b)で合成した化合物(20.9g,45.9mmol)、実施例(19e)で合成した化合物(18.0g,55.0mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.13g,1.38mmol)、炭酸カリウム(12.7g,91.9mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(19.3g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.24 (3H, s), 3.96 (3H, s), 5.35 (2H, s), 6.63 (1H, dd, J=2.4, 3.9Hz), 7.01 (1H, dd, J=2.4, 3.9Hz), 7.35-7.47 (6H, m), 7.48 (1H, brs), 7.62 (1H, m), 8.08 (1H, d, J=8.9Hz), 8.11 (1H, brs), 8.50 (1H, d, J=2.9Hz), 9.49 (1H, brs)。 (55a) Methyl 3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound (17.4 g, 90.8 mmol) synthesized in Example (16a) was converted to N, N— Dissolved in dimethylformamide (500 mL). Methyl 3,5-dihydroxybenzoate (30.5 g, 181 mmol) and potassium carbonate (37.7 g, 273 mmol) were added, and the mixture was stirred at 100 ° C. for 5.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (500 mL) was added, and the mixture was extracted 3 times with diethyl ether (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% -60%) to give the target compound (18.9 g, 18.9 g, Yield 64%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.91 (3H, s), 6.36 (1H, brs), 6.82 (1H, t, J = 2.4 Hz), 7.28 (1H, brs), 7.43 (1H, brs), 7.44 (1H, dd, J = 2.7, 8.6Hz), 8.06 (1H, d, J = 8.6Hz), 8.46 (1H, d, J = 2.7Hz).
(55b) Methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-{[(trifluoromethyl) sulfonyl] oxy} benzoate Compound (18.9 g) synthesized in Example (55a) , 58.5 mmol) was dissolved in methylene chloride (500 mL). Trifluoromethanesulfonic anhydride (13.8 mL, 82.0 mmol) and pyridine (14.2 mL, 176 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (400 mL) was added and extracted twice with methylene chloride (400 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (20.9 g, Yield 79%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.26 (3H, s), 3.96 (3H, s), 7.28 (1H, m), 7.52 (1H, dd, J = 2.7, 8.6Hz), 7.75 ( 1H, brt, J = 2.4Hz), 7.83 (1H, brt, J = 2.4Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7Hz).
(55c) Benzyl 5- [3- (methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate synthesized in Example (55b) Compound (20.9 g, 45.9 mmol), compound synthesized in Example (19e) (18.0 g, 55.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Using the dichloromethane complex (1.13 g, 1.38 mmol) and potassium carbonate (12.7 g, 91.9 mmol), the target compound (19.3 g, yield 83%) was obtained in the same manner as in Example (16e). )
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.96 (3H, s), 5.35 (2H, s), 6.63 (1H, dd, J = 2.4, 3.9Hz), 7.01 ( 1H, dd, J = 2.4, 3.9Hz), 7.35-7.47 (6H, m), 7.48 (1H, brs), 7.62 (1H, m), 8.08 (1H, d, J = 8.9Hz), 8.11 (1H , brs), 8.50 (1H, d, J = 2.9Hz), 9.49 (1H, brs).
(55d)メチル 3-[5-({(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}カルバモイル)-1H-ピロール-2-イル]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(55c)で合成した化合物(19.3g, 38.1mmol)を酢酸エチル(200mL)とテトラヒドロフラン(200mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(7.80g)を加えて水素雰囲気下室温で3.5時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (55d) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound synthesized in Example (55c) (19.3 g, 38.1 mmol) was dissolved in a mixed solvent of ethyl acetate (200 mL) and tetrahydrofuran (200 mL), and 10% A palladium carbon catalyst (7.80 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
実施例(55c)で合成した化合物(19.3g, 38.1mmol)を酢酸エチル(200mL)とテトラヒドロフラン(200mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(7.80g)を加えて水素雰囲気下室温で3.5時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去した。 (55d) Methyl 3- [5-({(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} carbamoyl) -1H-pyrrol-2-yl] -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} benzoate The compound synthesized in Example (55c) (19.3 g, 38.1 mmol) was dissolved in a mixed solvent of ethyl acetate (200 mL) and tetrahydrofuran (200 mL), and 10% A palladium carbon catalyst (7.80 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure.
得られた残渣をメタノール(300mL)に溶解し、(S)-(-)-3-アミノ-1,2-プロパンジオール(5.00g,54.9mmol)、DMT-MM(26.4g, 95.4mmol)を加え、窒素雰囲気下室温で19時間撹拌した。減圧下溶媒を留去し、水(200mL)を加え、酢酸エチル(100mL)で10回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
The obtained residue was dissolved in methanol (300 mL), and (S)-(−)-3-amino-1,2-propanediol (5.00 g, 54.9 mmol), DMT-MM (26.4 g, 95) was dissolved. .4 mmol) was added, and the mixture was stirred at room temperature for 19 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (200 mL) was added, and the mixture was extracted 10 times with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣を塩化メチレン(300mL)に溶解し、トリイソプロピルシリルクロリド(12.2mL,57.0mmol)、トリエチルアミン(16.0mL, 115mol)、4-ジメチルアミノピリジン(4.66g,38.1mmol)を加え、窒素雰囲気下室温で17時間撹拌した。水(200mL)を加え、塩化メチレン(200mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~70%)を用いて精製することにより、白色固体の目的物(19.4g,収率79%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.16 (21H, m), 3.12 (1H, d, J=4.7Hz), 3.24 (3H, s), 3.39 (1H, ddd, J=4.7, 7.0, 14.1Hz), 3.67 (1H, dd, J=6.3, 9.8Hz), 3.74 (1H, ddd, J=3.1, 7.0, 14.1Hz), 3.78 (1H, dd, J=4.7, 10.2Hz), 3.87 (1H, m), 3.95 (1H, s), 6.44 (1H, brt, J=6.3Hz), 6.61 (1H, dd, J=2.7, 3.9Hz), 6.64 (1H, dd, J=2.4, 3.9Hz), 7.44 (1H, dd, J=2.7, 8.6Hz), 7.49 (1H, t, J=2.4Hz), 7.59 (1H, t, J=2.0Hz), 8.07 (1H, d, J=8.6Hz), 8.12 (1H, t, J=2.0Hz), 8.49 (1H, d, J=2.7Hz), 9.92 (1H, brs).
(55e)メチル 3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(55d)で合成した化合物(19.4g,30.0mmol)、メタンスルホン酸無水物(11.0g,63.1mmol)、トリエチルアミン(21.0mL, 151mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(15.6g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.13 (21H, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd, J=9.8, 14.5Hz), 4.77 (1H, m), 6.61 (1H, d, J=3.9Hz), 6.76 (1H, d, J=3.9Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 7.46 (1H, t, J=2.4Hz), 7.58 (1H, t, J=2.4Hz), 8.08 (1H, d, J=8.6Hz), 8.10 (1H, t, J=1.6Hz), 8.50 (1H, d, J=2.7Hz)。 The obtained residue was dissolved in methylene chloride (300 mL), triisopropylsilyl chloride (12.2 mL, 57.0 mmol), triethylamine (16.0 mL, 115 mol), 4-dimethylaminopyridine (4.66 g, 38.1 mmol). And stirred at room temperature for 17 hours under a nitrogen atmosphere. Water (200 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) to give the desired product as a white solid (19.4 g, Yield 79%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.16 (21H, m), 3.12 (1H, d, J = 4.7 Hz), 3.24 (3H, s), 3.39 (1H, ddd, J = 4.7 , 7.0, 14.1Hz), 3.67 (1H, dd, J = 6.3, 9.8Hz), 3.74 (1H, ddd, J = 3.1, 7.0, 14.1Hz), 3.78 (1H, dd, J = 4.7, 10.2Hz) , 3.87 (1H, m), 3.95 (1H, s), 6.44 (1H, brt, J = 6.3Hz), 6.61 (1H, dd, J = 2.7, 3.9Hz), 6.64 (1H, dd, J = 2.4 , 3.9Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 7.49 (1H, t, J = 2.4Hz), 7.59 (1H, t, J = 2.0Hz), 8.07 (1H, d, J = 8.6Hz), 8.12 (1H, t, J = 2.0Hz), 8.49 (1H, d, J = 2.7Hz), 9.92 (1H, brs).
(55e) methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzoate The compound synthesized in Example (55d) (19.4 g, 30.0 mmol), methanesulfonic anhydride (11. 0 g, 63.1 mmol) and triethylamine (21.0 mL, 151 mol) were used to obtain the desired product (15.6 g, yield 83%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.13 (21H, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd , J = 9.8, 14.5Hz), 4.77 (1H, m), 6.61 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 7.46 (1H, t, J = 2.4Hz), 7.58 (1H, t, J = 2.4Hz), 8.08 (1H, d, J = 8.6Hz), 8.10 (1H, t, J = 1.6Hz) ), 8.50 (1H, d, J = 2.7Hz).
1H-NMR (CDCl3, 400MHz):δ1.03-1.16 (21H, m), 3.12 (1H, d, J=4.7Hz), 3.24 (3H, s), 3.39 (1H, ddd, J=4.7, 7.0, 14.1Hz), 3.67 (1H, dd, J=6.3, 9.8Hz), 3.74 (1H, ddd, J=3.1, 7.0, 14.1Hz), 3.78 (1H, dd, J=4.7, 10.2Hz), 3.87 (1H, m), 3.95 (1H, s), 6.44 (1H, brt, J=6.3Hz), 6.61 (1H, dd, J=2.7, 3.9Hz), 6.64 (1H, dd, J=2.4, 3.9Hz), 7.44 (1H, dd, J=2.7, 8.6Hz), 7.49 (1H, t, J=2.4Hz), 7.59 (1H, t, J=2.0Hz), 8.07 (1H, d, J=8.6Hz), 8.12 (1H, t, J=2.0Hz), 8.49 (1H, d, J=2.7Hz), 9.92 (1H, brs).
(55e)メチル 3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(55d)で合成した化合物(19.4g,30.0mmol)、メタンスルホン酸無水物(11.0g,63.1mmol)、トリエチルアミン(21.0mL, 151mol)を用い、実施例(16j)と同様の方法で白色固体の目的物(15.6g,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.03-1.13 (21H, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd, J=9.8, 14.5Hz), 4.77 (1H, m), 6.61 (1H, d, J=3.9Hz), 6.76 (1H, d, J=3.9Hz), 7.45 (1H, dd, J=2.7, 8.6Hz), 7.46 (1H, t, J=2.4Hz), 7.58 (1H, t, J=2.4Hz), 8.08 (1H, d, J=8.6Hz), 8.10 (1H, t, J=1.6Hz), 8.50 (1H, d, J=2.7Hz)。 The obtained residue was dissolved in methylene chloride (300 mL), triisopropylsilyl chloride (12.2 mL, 57.0 mmol), triethylamine (16.0 mL, 115 mol), 4-dimethylaminopyridine (4.66 g, 38.1 mmol). And stirred at room temperature for 17 hours under a nitrogen atmosphere. Water (200 mL) was added and extracted twice with methylene chloride (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) to give the desired product as a white solid (19.4 g, Yield 79%).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.16 (21H, m), 3.12 (1H, d, J = 4.7 Hz), 3.24 (3H, s), 3.39 (1H, ddd, J = 4.7 , 7.0, 14.1Hz), 3.67 (1H, dd, J = 6.3, 9.8Hz), 3.74 (1H, ddd, J = 3.1, 7.0, 14.1Hz), 3.78 (1H, dd, J = 4.7, 10.2Hz) , 3.87 (1H, m), 3.95 (1H, s), 6.44 (1H, brt, J = 6.3Hz), 6.61 (1H, dd, J = 2.7, 3.9Hz), 6.64 (1H, dd, J = 2.4 , 3.9Hz), 7.44 (1H, dd, J = 2.7, 8.6Hz), 7.49 (1H, t, J = 2.4Hz), 7.59 (1H, t, J = 2.0Hz), 8.07 (1H, d, J = 8.6Hz), 8.12 (1H, t, J = 2.0Hz), 8.49 (1H, d, J = 2.7Hz), 9.92 (1H, brs).
(55e) methyl 3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl} -4,5 -Dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzoate The compound synthesized in Example (55d) (19.4 g, 30.0 mmol), methanesulfonic anhydride (11. 0 g, 63.1 mmol) and triethylamine (21.0 mL, 151 mol) were used to obtain the desired product (15.6 g, yield 83%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ1.03-1.13 (21H, m), 3.25 (3H, s), 3.83-3.93 (3H, m), 3.95 (3H, s), 4.02 (1H, dd , J = 9.8, 14.5Hz), 4.77 (1H, m), 6.61 (1H, d, J = 3.9Hz), 6.76 (1H, d, J = 3.9Hz), 7.45 (1H, dd, J = 2.7, 8.6Hz), 7.46 (1H, t, J = 2.4Hz), 7.58 (1H, t, J = 2.4Hz), 8.08 (1H, d, J = 8.6Hz), 8.10 (1H, t, J = 1.6Hz) ), 8.50 (1H, d, J = 2.7Hz).
(55f)N,N-ジメチル-3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(55e)で合成した化合物(4.02g,6.40mmol)をエタノール(100mL)に溶解し、2規定水酸化ナトリウム水溶液(50mL)を加え、窒素雰囲気下1時間加熱還流した。反応液に2規定塩酸(55mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (55f) N, N-dimethyl-3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl } -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide The compound (4.02 g, 6.40 mmol) synthesized in Example (55e) was dissolved in ethanol (100 mL). ), 2N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. 2N Hydrochloric acid (55 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
実施例(55e)で合成した化合物(4.02g,6.40mmol)をエタノール(100mL)に溶解し、2規定水酸化ナトリウム水溶液(50mL)を加え、窒素雰囲気下1時間加熱還流した。反応液に2規定塩酸(55mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (55f) N, N-dimethyl-3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] methyl } -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide The compound (4.02 g, 6.40 mmol) synthesized in Example (55e) was dissolved in ethanol (100 mL). ), 2N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. 2N Hydrochloric acid (55 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣をメタノール(70mL)に溶解し、ジメチルアミン(2.0mol/Lメタノール溶液,8.00mL,16.0mmol)、DMT-MM(4.43g, 16.0mmol)を用い、実施例(5d)と同様の方法で白色固体の目的化合物(1.84g,収率45%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.02-1.13 (21H, m), 3.02 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.82-3.92 (3H, m), 4.00 (1H, m), 4.76 (1H, m), 6.55 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.99 (1H, brs), 7.29 (1H, t, J=2.0Hz), 7.45-7.50 (2H, m), 8.07 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.4Hz).
(55g)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(55f)で合成した化合物(1.84g,2.87mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.45mL,3.45mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.27g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.98 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.65 (1H, dd, J=4.7, 12.5Hz), 3.74 (1H, dd, J=7.4, 14.1Hz), 3.83 (1H, dd, J=3.1, 12.5Hz), 4.00 (1H, dd, J=9.8, 14.1Hz), 4.78 (1H, m), 6.49 (1H, d, J=3.9Hz), 6.71 (1H, d, J=3.9Hz), 6.97 (1H, brs), 7.29 (1H, brs), 7.40 (1H, brs), 7.44 (1H, dd, J=2.4, 9.0Hz), 8.05 (1H, d, J=9.0Hz), 8.48 (1H, d, J=2.4Hz).
MS (ESI) m/z: 485.14948(M+H)+。 The obtained residue was dissolved in methanol (70 mL), and dimethylamine (2.0 mol / L methanol solution, 8.00 mL, 16.0 mmol) and DMT-MM (4.43 g, 16.0 mmol) were used. The target compound (1.84 g, yield 45%) was obtained as a white solid in the same manner as in (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.13 (21H, m), 3.02 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.82-3.92 (3H, m ), 4.00 (1H, m), 4.76 (1H, m), 6.55 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.99 (1H, brs), 7.29 (1H , t, J = 2.0Hz), 7.45-7.50 (2H, m), 8.07 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.4Hz).
(55 g) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (1.84 g, 2.87 mmol) synthesized in Example (55f), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran) Using the solution, 3.45 mL, 3.45 mmol), the target compound (1.27 g, yield 91%) as a white solid was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ2.98 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.65 (1H, dd, J = 4.7, 12.5Hz), 3.74 ( 1H, dd, J = 7.4, 14.1Hz), 3.83 (1H, dd, J = 3.1, 12.5Hz), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.78 (1H, m), 6.49 (1H , d, J = 3.9Hz), 6.71 (1H, d, J = 3.9Hz), 6.97 (1H, brs), 7.29 (1H, brs), 7.40 (1H, brs), 7.44 (1H, dd, J = 2.4, 9.0Hz), 8.05 (1H, d, J = 9.0Hz), 8.48 (1H, d, J = 2.4Hz).
MS (ESI) m / z: 485.14948 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ1.02-1.13 (21H, m), 3.02 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.82-3.92 (3H, m), 4.00 (1H, m), 4.76 (1H, m), 6.55 (1H, d, J=3.9Hz), 6.75 (1H, d, J=3.9Hz), 6.99 (1H, brs), 7.29 (1H, t, J=2.0Hz), 7.45-7.50 (2H, m), 8.07 (1H, d, J=8.6Hz), 8.50 (1H, d, J=2.4Hz).
(55g)3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(55f)で合成した化合物(1.84g,2.87mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,3.45mL,3.45mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(1.27g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.98 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.65 (1H, dd, J=4.7, 12.5Hz), 3.74 (1H, dd, J=7.4, 14.1Hz), 3.83 (1H, dd, J=3.1, 12.5Hz), 4.00 (1H, dd, J=9.8, 14.1Hz), 4.78 (1H, m), 6.49 (1H, d, J=3.9Hz), 6.71 (1H, d, J=3.9Hz), 6.97 (1H, brs), 7.29 (1H, brs), 7.40 (1H, brs), 7.44 (1H, dd, J=2.4, 9.0Hz), 8.05 (1H, d, J=9.0Hz), 8.48 (1H, d, J=2.4Hz).
MS (ESI) m/z: 485.14948(M+H)+。 The obtained residue was dissolved in methanol (70 mL), and dimethylamine (2.0 mol / L methanol solution, 8.00 mL, 16.0 mmol) and DMT-MM (4.43 g, 16.0 mmol) were used. The target compound (1.84 g, yield 45%) was obtained as a white solid in the same manner as in (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ1.02-1.13 (21H, m), 3.02 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.82-3.92 (3H, m ), 4.00 (1H, m), 4.76 (1H, m), 6.55 (1H, d, J = 3.9Hz), 6.75 (1H, d, J = 3.9Hz), 6.99 (1H, brs), 7.29 (1H , t, J = 2.0Hz), 7.45-7.50 (2H, m), 8.07 (1H, d, J = 8.6Hz), 8.50 (1H, d, J = 2.4Hz).
(55 g) 3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N- Dimethyl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (1.84 g, 2.87 mmol) synthesized in Example (55f), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran) Using the solution, 3.45 mL, 3.45 mmol), the target compound (1.27 g, yield 91%) as a white solid was obtained in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ2.98 (3H, s), 3.12 (3H, s), 3.24 (3H, s), 3.65 (1H, dd, J = 4.7, 12.5Hz), 3.74 ( 1H, dd, J = 7.4, 14.1Hz), 3.83 (1H, dd, J = 3.1, 12.5Hz), 4.00 (1H, dd, J = 9.8, 14.1Hz), 4.78 (1H, m), 6.49 (1H , d, J = 3.9Hz), 6.71 (1H, d, J = 3.9Hz), 6.97 (1H, brs), 7.29 (1H, brs), 7.40 (1H, brs), 7.44 (1H, dd, J = 2.4, 9.0Hz), 8.05 (1H, d, J = 9.0Hz), 8.48 (1H, d, J = 2.4Hz).
MS (ESI) m / z: 485.14948 (M + H) <+> .
(実施例56)
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 56)
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 56)
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide
実施例(55g)で合成した化合物(563mg,1.16mmol)を1,2-ジメトキシエタン(15mL)に溶解し、窒素雰囲気下0℃でビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.32mL,1.7mmol)を滴下した。自然に室温まで昇温し、途中でビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.32mL,1.7mmol)を追加し、7時間撹拌した。メタノール(2mL)を加え10分攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~100%)を用いて精製することにより、白色固体の目的化合物(105mg,19%)を得た。
1H-NMR (CDCl3, 500MHz): δ 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 4.06-4.11 (1H, m), 4.44-4.66 (2H, m), 4.86-4.95 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.4, 1.5 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.45-7.49 (2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.50 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 487.14624 (M+H)+。 The compound (563 mg, 1.16 mmol) synthesized in Example (55 g) was dissolved in 1,2-dimethoxyethane (15 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0. 32 mL, 1.7 mmol) was added dropwise. The temperature was naturally raised to room temperature, and bis (2-methoxyethyl) aminosulfur trifluoride (0.32 mL, 1.7 mmol) was added on the way, followed by stirring for 7 hours. Methanol (2 mL) was added, and the mixture was stirred for 10 min, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 60% -100%) to give the target compound (105 mg, 19%) as a white solid. )
1 H-NMR (CDCl 3 , 500 MHz): δ 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 4.06 -4.11 (1H, m), 4.44-4.66 (2H, m), 4.86-4.95 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.4, 1.5 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.45-7.49 (2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.50 (1H , d, J = 2.4 Hz).
MS (ESI) m / z: 487.14624 (M + H) <+> .
1H-NMR (CDCl3, 500MHz): δ 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 4.06-4.11 (1H, m), 4.44-4.66 (2H, m), 4.86-4.95 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.4, 1.5 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.45-7.49 (2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.50 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 487.14624 (M+H)+。 The compound (563 mg, 1.16 mmol) synthesized in Example (55 g) was dissolved in 1,2-dimethoxyethane (15 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0. 32 mL, 1.7 mmol) was added dropwise. The temperature was naturally raised to room temperature, and bis (2-methoxyethyl) aminosulfur trifluoride (0.32 mL, 1.7 mmol) was added on the way, followed by stirring for 7 hours. Methanol (2 mL) was added, and the mixture was stirred for 10 min, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 60% -100%) to give the target compound (105 mg, 19%) as a white solid. )
1 H-NMR (CDCl 3 , 500 MHz): δ 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.82 (1H, dd, J = 14.6, 7.3 Hz), 4.06 -4.11 (1H, m), 4.44-4.66 (2H, m), 4.86-4.95 (1H, m), 6.57 (1H, d, J = 3.4 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.4, 1.5 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.45-7.49 (2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.50 (1H , d, J = 2.4 Hz).
MS (ESI) m / z: 487.14624 (M + H) <+> .
(実施例57)
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 57)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 57)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide
(57a)5-[3-(メトキシカルボニル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボン酸
実施例(55c)で合成した化合物(2.29g,4.52mmol)をテトラヒドロフラン(150mL)に溶解し、10%パラジウム炭素触媒(2.53g)を加えて水素雰囲気下室温で6時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去して、灰色固体の目的化合物(1.52g,81%)を得た。
1H-NMR (DMSO-D6, 400MHz) δ: 3.28 (3H, s), 3.89 (3H, s), 6.80 (2H, s), 7.55 (1H, dd, J = 2.2, 1.4 Hz), 7.69 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.09 (1H, t, J = 2.0 Hz), 8.34 (1H, t, J = 1.4 Hz), 8.66 (1H, d, J = 2.7 Hz), 12.26 (1H, br s).
(57b)メチル 3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(57a)で合成した化合物(1.52g,3.65mmol)、(R)-(-)-1-アミノ-2-プロパノール(450μL,5.69mmol)、DMT-MM(2.80g,8.94mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.28g,74%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.25 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.26-3.32 (1H, m), 3.59-3.65 (1H, m), 3.95 (3H, s), 4.00-4.04 (1H, m), 6.41 (1H, t, J = 5.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 7.48 (1H, t, J = 2.2 Hz), 7.60 (1H, dd, J = 2.3, 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.96 (1H, br s).
MS (FAB) m/z: 474 (M+H)+。 (57a) 5- [3- (Methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylic acid Synthesized in Example (55c) The compound (2.29 g, 4.52 mmol) was dissolved in tetrahydrofuran (150 mL), 10% palladium carbon catalyst (2.53 g) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the target compound (1.52 g, 81%) as a gray solid.
1 H-NMR (DMSO-D6, 400 MHz) δ: 3.28 (3H, s), 3.89 (3H, s), 6.80 (2H, s), 7.55 (1H, dd, J = 2.2, 1.4 Hz), 7.69 ( 1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.09 (1H, t, J = 2.0 Hz), 8.34 (1H, t, J = 1.4 Hz), 8.66 ( 1H, d, J = 2.7 Hz), 12.26 (1H, br s).
(57b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Benzoate Compound synthesized in Example (57a) (1.52 g, 3.65 mmol), (R)-(−)-1-amino-2-propanol (450 μL, 5.69 mmol), DMT-MM (2.80 g) , 8.94 mmol), and the white solid target product (1.28 g, 74%) was obtained in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.26-3.32 (1H, m), 3.59-3.65 (1H, m), 3.95 (3H, s), 4.00-4.04 (1H, m), 6.41 (1H, t, J = 5.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9 , 2.7 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 7.48 (1H, t, J = 2.2 Hz), 7.60 (1H, dd, J = 2.3, 1.6 Hz), 8.07 (1H, d , J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) <+> .
実施例(55c)で合成した化合物(2.29g,4.52mmol)をテトラヒドロフラン(150mL)に溶解し、10%パラジウム炭素触媒(2.53g)を加えて水素雰囲気下室温で6時間撹拌した。セライト濾過によりパラジウム炭素触媒を除去し、酢酸エチルで洗浄した。減圧下溶媒を留去して、灰色固体の目的化合物(1.52g,81%)を得た。
1H-NMR (DMSO-D6, 400MHz) δ: 3.28 (3H, s), 3.89 (3H, s), 6.80 (2H, s), 7.55 (1H, dd, J = 2.2, 1.4 Hz), 7.69 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.09 (1H, t, J = 2.0 Hz), 8.34 (1H, t, J = 1.4 Hz), 8.66 (1H, d, J = 2.7 Hz), 12.26 (1H, br s).
(57b)メチル 3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(57a)で合成した化合物(1.52g,3.65mmol)、(R)-(-)-1-アミノ-2-プロパノール(450μL,5.69mmol)、DMT-MM(2.80g,8.94mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.28g,74%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.25 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.26-3.32 (1H, m), 3.59-3.65 (1H, m), 3.95 (3H, s), 4.00-4.04 (1H, m), 6.41 (1H, t, J = 5.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9, 2.7 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 7.48 (1H, t, J = 2.2 Hz), 7.60 (1H, dd, J = 2.3, 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.96 (1H, br s).
MS (FAB) m/z: 474 (M+H)+。 (57a) 5- [3- (Methoxycarbonyl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylic acid Synthesized in Example (55c) The compound (2.29 g, 4.52 mmol) was dissolved in tetrahydrofuran (150 mL), 10% palladium carbon catalyst (2.53 g) was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the target compound (1.52 g, 81%) as a gray solid.
1 H-NMR (DMSO-D6, 400 MHz) δ: 3.28 (3H, s), 3.89 (3H, s), 6.80 (2H, s), 7.55 (1H, dd, J = 2.2, 1.4 Hz), 7.69 ( 1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 9.0 Hz), 8.09 (1H, t, J = 2.0 Hz), 8.34 (1H, t, J = 1.4 Hz), 8.66 ( 1H, d, J = 2.7 Hz), 12.26 (1H, br s).
(57b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Benzoate Compound synthesized in Example (57a) (1.52 g, 3.65 mmol), (R)-(−)-1-amino-2-propanol (450 μL, 5.69 mmol), DMT-MM (2.80 g) , 8.94 mmol), and the white solid target product (1.28 g, 74%) was obtained in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.26-3.32 (1H, m), 3.59-3.65 (1H, m), 3.95 (3H, s), 4.00-4.04 (1H, m), 6.41 (1H, t, J = 5.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.65 (1H, dd, J = 3.9 , 2.7 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 7.48 (1H, t, J = 2.2 Hz), 7.60 (1H, dd, J = 2.3, 1.6 Hz), 8.07 (1H, d , J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) <+> .
(57c)メチル 3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(57b)で合成した化合物(1.26g,2.67mmol)、メタンスルホン酸無水物(936mg,5.37mmol)、トリエチルアミン(1.5mL,11mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(0.92g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.55 (1H, dd, J = 14.1, 7.4 Hz), 3.95 (3H, s), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.87 (1H, m), 6.62 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.44-7.48 (2H, m), 7.58 (1H, dd, J = 2.3, 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 456.12143 (M+H)+.
(57d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(57c)で合成した化合物(920mg,2.02mmol)をエタノール(15mL)に溶解させ、2規定の水酸化ナトリウム水溶液(5mL)を加え、70℃で1時間撹拌した。反応液に水(100mL)を加えた後に氷冷し、1規定の塩酸(10mL)を加え、析出した白色の固体(730mg)をろ取した。 (57c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound (1.26 g, 2.67 mmol) synthesized in Example (57b), methanesulfonic anhydride (936 mg, 5.37 mmol), triethylamine (1.5 mL) , 11 mmol), and the target compound (0.92 g, yield 76%) was obtained as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.55 (1H, dd, J = 14.1, 7.4 Hz), 3.95 (3H, s ), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.87 (1H, m), 6.62 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.44 -7.48 (2H, m), 7.58 (1H, dd, J = 2.3, 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 456.12143 (M + H) + .
(57d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide The compound (920 mg, 2.02 mmol) synthesized in Example (57c) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (10 mL) was added, and the precipitated white solid (730 mg) was collected by filtration.
実施例(57b)で合成した化合物(1.26g,2.67mmol)、メタンスルホン酸無水物(936mg,5.37mmol)、トリエチルアミン(1.5mL,11mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(0.92g,収率76%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.55 (1H, dd, J = 14.1, 7.4 Hz), 3.95 (3H, s), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.87 (1H, m), 6.62 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.44-7.48 (2H, m), 7.58 (1H, dd, J = 2.3, 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 456.12143 (M+H)+.
(57d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(57c)で合成した化合物(920mg,2.02mmol)をエタノール(15mL)に溶解させ、2規定の水酸化ナトリウム水溶液(5mL)を加え、70℃で1時間撹拌した。反応液に水(100mL)を加えた後に氷冷し、1規定の塩酸(10mL)を加え、析出した白色の固体(730mg)をろ取した。 (57c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound (1.26 g, 2.67 mmol) synthesized in Example (57b), methanesulfonic anhydride (936 mg, 5.37 mmol), triethylamine (1.5 mL) , 11 mmol), and the target compound (0.92 g, yield 76%) was obtained as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.3 Hz), 3.24 (3H, s), 3.55 (1H, dd, J = 14.1, 7.4 Hz), 3.95 (3H, s ), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.87 (1H, m), 6.62 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.44 -7.48 (2H, m), 7.58 (1H, dd, J = 2.3, 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.4 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 456.12143 (M + H) + .
(57d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide The compound (920 mg, 2.02 mmol) synthesized in Example (57c) was dissolved in ethanol (15 mL), and 2N aqueous sodium hydroxide solution was dissolved. (5 mL) was added and stirred at 70 ° C. for 1 hour. Water (100 mL) was added to the reaction solution, followed by ice cooling, 1N hydrochloric acid (10 mL) was added, and the precipitated white solid (730 mg) was collected by filtration.
これをN,N-ジメチルホルムアミド(8mL)にけん濁させ、ジメチルアミン塩酸塩(283mg,3.47mmol)、HATU(1.25g,3.28mmol)、N,N-ジイソプロピルエチルアミン(1.15mL,6.58mmol)を加え、窒素雰囲気下室温で6時間撹拌した。反応液に水(50mL)を加え、酢酸エチル(100mL)で抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1.5%~6%)を用いて精製することにより、白色固体の目的化合物(676mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.42 (3H, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.07 (1H, dd, J = 14.1, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.2, 1.4 Hz), 7.29 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 469.15449 (M+H)+。 This was suspended in N, N-dimethylformamide (8 mL), dimethylamine hydrochloride (283 mg, 3.47 mmol), HATU (1.25 g, 3.28 mmol), N, N-diisopropylethylamine (1.15 mL, 6.58 mmol) was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1.5% to 6%) to give the target compound (676 mg, Yield 71%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.54 (1H , dd, J = 14.1, 7.4 Hz), 4.07 (1H, dd, J = 14.1, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.2, 1.4 Hz), 7.29 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 469.15449 (M + H) <+> .
1H-NMR (CDCl3, 400MHz): δ 1.42 (3H, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.07 (1H, dd, J = 14.1, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.2, 1.4 Hz), 7.29 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 469.15449 (M+H)+。 This was suspended in N, N-dimethylformamide (8 mL), dimethylamine hydrochloride (283 mg, 3.47 mmol), HATU (1.25 g, 3.28 mmol), N, N-diisopropylethylamine (1.15 mL, 6.58 mmol) was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1.5% to 6%) to give the target compound (676 mg, Yield 71%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.54 (1H , dd, J = 14.1, 7.4 Hz), 4.07 (1H, dd, J = 14.1, 9.0 Hz), 4.79-4.88 (1H, m), 6.56 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.2, 1.4 Hz), 7.29 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 469.15449 (M + H) <+> .
(実施例58)
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 58)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド (Example 58)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide
(58a)メチル 3-(5-{[(1R)-2-ヒドロキシ-1-メチルエチル]カルバモイル}-1H-ピロール-2-イル)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(57a)で合成した化合物(1.53g,3.67mmol)、D-アラニノール(570μL,7.36mmol)、DMT-MM(2.89g,9.23mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.00g,収率58%)を得た。
1H-NMR (CDCl3, 500MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 (1H, m), 3.74-3.80 (1H, m), 3.95 (3H, s), 4.22-4.30 (1H, m), 6.11 (1H, d, J = 7.3 Hz), 6.59 (1H, dd, J = 3.9, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.4 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 7.48 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.4, 1.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 1.5 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.96 (1H, br s).
MS (FAB) m/z: 474 (M+H)+.
(58b)メチル 3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(58a)で合成した化合物(990mg,2.09mmol)、メタンスルホン酸無水物(730mg,4.19mmol)、トリエチルアミン(1.2mL,8.7mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(899mg,収率94%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.34 (3H, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, dd, J = 9.2, 8.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 2.2 Hz), 7.59 (1H, dd, J = 2.3, 1.2 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (FAB) m/z: 456 (M+H)+.
(58c)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(58b)で合成した化合物(899mg,1.97mmol)、2規定の水酸化ナトリウム水溶液(5mL)、ジメチルアミン塩酸塩(208mg,2.55mmol)、HATU(927mg,2.44mmol)、N,N-ジイソプロピルエチルアミン(850μL,4.87mmol)を用い、実施例(57d)と同様の方法で白色固体の目的化合物(353mg,収率38%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.94 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.50 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.3, 1.6 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.3 Hz).
MS (ESI) m/z: 469.15449 (M+H)+。 (58a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridine-3- Yl] oxy} benzoate Using the compound synthesized in Example (57a) (1.53 g, 3.67 mmol), D-alaninol (570 μL, 7.36 mmol), DMT-MM (2.89 g, 9.23 mmol), The target product (1.00 g, yield 58%) was obtained as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.95 (3H, s), 4.22-4.30 (1H, m), 6.11 (1H, d, J = 7.3 Hz), 6.59 (1H, dd, J = 3.9, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.4 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 7.48 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.4, 1.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 1.5 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) + .
(58b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound synthesized in Example (58a) (990 mg, 2.09 mmol), methanesulfonic anhydride (730 mg, 4.19 mmol), triethylamine (1.2 mL, 8 .7 mmol) was used to obtain the target compound (899 mg, 94% yield) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, dd, J = 9.2, 8.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 2.2 Hz), 7.59 (1H, dd, J = 2.3, 1.2 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 456 (M + H) + .
(58c) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (899 mg, 1.97 mmol) synthesized in Example (58b), 2N aqueous sodium hydroxide solution (5 mL), dimethylamine hydrochloride (208 mg, 2.55 mmol), HATU (927 mg, 2.44 mmol) and N, N-diisopropylethylamine (850 μL, 4.87 mmol) were used in the same manner as in Example (57d) to give the target compound (353 mg) as a white solid. Yield 38%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.50 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.3, 1.6 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz) , 8.50 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 469.15449 (M + H) <+> .
実施例(57a)で合成した化合物(1.53g,3.67mmol)、D-アラニノール(570μL,7.36mmol)、DMT-MM(2.89g,9.23mmol)を用い、実施例(5d)と同様の方法で白色固体の目的物(1.00g,収率58%)を得た。
1H-NMR (CDCl3, 500MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 (1H, m), 3.74-3.80 (1H, m), 3.95 (3H, s), 4.22-4.30 (1H, m), 6.11 (1H, d, J = 7.3 Hz), 6.59 (1H, dd, J = 3.9, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.4 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 7.48 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.4, 1.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 1.5 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.96 (1H, br s).
MS (FAB) m/z: 474 (M+H)+.
(58b)メチル 3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンゾエート
実施例(58a)で合成した化合物(990mg,2.09mmol)、メタンスルホン酸無水物(730mg,4.19mmol)、トリエチルアミン(1.2mL,8.7mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(899mg,収率94%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.34 (3H, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, dd, J = 9.2, 8.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 2.2 Hz), 7.59 (1H, dd, J = 2.3, 1.2 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (FAB) m/z: 456 (M+H)+.
(58c)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
実施例(58b)で合成した化合物(899mg,1.97mmol)、2規定の水酸化ナトリウム水溶液(5mL)、ジメチルアミン塩酸塩(208mg,2.55mmol)、HATU(927mg,2.44mmol)、N,N-ジイソプロピルエチルアミン(850μL,4.87mmol)を用い、実施例(57d)と同様の方法で白色固体の目的化合物(353mg,収率38%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.94 (1H, t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.50 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.3, 1.6 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.3 Hz).
MS (ESI) m/z: 469.15449 (M+H)+。 (58a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5-{[6- (methylsulfonyl) pyridine-3- Yl] oxy} benzoate Using the compound synthesized in Example (57a) (1.53 g, 3.67 mmol), D-alaninol (570 μL, 7.36 mmol), DMT-MM (2.89 g, 9.23 mmol), The target product (1.00 g, yield 58%) was obtained as a white solid in the same manner as in Example (5d).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.75 (1H, br s), 3.24 (3H, s), 3.60-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.95 (3H, s), 4.22-4.30 (1H, m), 6.11 (1H, d, J = 7.3 Hz), 6.59 (1H, dd, J = 3.9, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.4 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 7.48 (1H, t, J = 2.0 Hz), 7.59 (1H, dd, J = 2.4, 1.5 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.12 (1H, t, J = 1.5 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.96 (1H, br s).
MS (FAB) m / z: 474 (M + H) + .
(58b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzoate Compound synthesized in Example (58a) (990 mg, 2.09 mmol), methanesulfonic anhydride (730 mg, 4.19 mmol), triethylamine (1.2 mL, 8 .7 mmol) was used to obtain the target compound (899 mg, 94% yield) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 3.25 (3H, s), 3.92-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, dd, J = 9.2, 8.0 Hz), 6.62 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 2.2 Hz), 7.59 (1H, dd, J = 2.3, 1.2 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.12 (1H, t, J = 1.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (FAB) m / z: 456 (M + H) + .
(58c) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} benzamide Compound (899 mg, 1.97 mmol) synthesized in Example (58b), 2N aqueous sodium hydroxide solution (5 mL), dimethylamine hydrochloride (208 mg, 2.55 mmol), HATU (927 mg, 2.44 mmol) and N, N-diisopropylethylamine (850 μL, 4.87 mmol) were used in the same manner as in Example (57d) to give the target compound (353 mg) as a white solid. Yield 38%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.12 (3H, br s), 3.24 (3H, s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.37 (1H, m), 4.50 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.99 (1H, dd, J = 2.3, 1.6 Hz), 7.30 (1H, t, J = 2.0 Hz), 7.46-7.49 (2H, m), 8.07 (1H, d, J = 8.6 Hz) , 8.50 (1H, d, J = 2.3 Hz).
MS (ESI) m / z: 469.15449 (M + H) <+> .
(実施例59)
2-メチル-1-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)プロパン-1-オン (Example 59)
2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [ 4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one
2-メチル-1-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)プロパン-1-オン (Example 59)
2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [ 4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one
(59a)1-(3,5-ジメトキシフェニル)-2-メチルプロパン-1-オール
3,5-ジメトキシベンズアルデヒド(6.67g,40.1mmol)をテトラヒドロフラン(40mL)に溶解し、イソプロピルマグネシウムブロミド(0.72mol/Lテトラヒドロフラン溶液,90mL,64.8mmol)を-78℃で滴下し、窒素雰囲気下室温で4時間半撹拌した。飽和塩化アンモニウム水溶液(200mL)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製し、無色液体の目的化合物(3.79g,収率45%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.82 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.81 (1H, d, J = 3.1 Hz), 1.89-1.98 (1H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.48 (2H, d, J = 2.0 Hz).
(59b)1-(3,5-ジメトキシフェニル)-2-メチルプロパン-1-オン
実施例(59a)で合成した化合物(3.79g,18.2mmol)を塩化メチレン(200mL)に溶解し、二酸化マンガン(15.0g,173mmol)を室温で加え、窒素雰囲気下加熱還流で一日撹拌した。反応液を室温まで冷却した後、セライト濾過を行った。母液を減圧下溶媒留去することにより、無色液体の目的化合物(2.55g,収率67%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 7.0 Hz), 3.46-3.53 (1H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz), 7.09 (2H, d, J = 2.0 Hz).
(59c)1-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-2-メチルプロパン-1-オン
実施例(59b)で合成した化合物(2.55g,12.2mmol)を1-メチル-2-ピロリドン(30mL)に溶解し、ナトリウムチオメトキシド(1.75g,25.0mmol)を室温で加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却した後、2規定塩酸(150mL)を加え、ジエチルエーテル(300mL)を用いて抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (59a) 1- (3,5-Dimethoxyphenyl) -2-methylpropan-1-ol 3,5-dimethoxybenzaldehyde (6.67 g, 40.1 mmol) was dissolved in tetrahydrofuran (40 mL) and isopropylmagnesium bromide ( 0.72 mol / L tetrahydrofuran solution, 90 mL, 64.8 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours and a half in a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound as a colorless liquid (3.79 g, yield). 45%).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.82 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.81 (1H, d, J = 3.1 Hz), 1.89- 1.98 (1H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.48 (2H, d, J = 2.0 Hz ).
(59b) 1- (3,5-dimethoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59a) (3.79 g, 18.2 mmol) was dissolved in methylene chloride (200 mL). Manganese dioxide (15.0 g, 173 mmol) was added at room temperature, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered through celite. The mother liquor was evaporated under reduced pressure to give the target compound (2.55 g, yield 67%) as a colorless liquid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.46-3.53 (1H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz ), 7.09 (2H, d, J = 2.0 Hz).
(59c) 1- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59b) (2.55 g, 12.2 mmol) Was dissolved in 1-methyl-2-pyrrolidone (30 mL), sodium thiomethoxide (1.75 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 2N hydrochloric acid (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
3,5-ジメトキシベンズアルデヒド(6.67g,40.1mmol)をテトラヒドロフラン(40mL)に溶解し、イソプロピルマグネシウムブロミド(0.72mol/Lテトラヒドロフラン溶液,90mL,64.8mmol)を-78℃で滴下し、窒素雰囲気下室温で4時間半撹拌した。飽和塩化アンモニウム水溶液(200mL)を加え、酢酸エチル(200mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製し、無色液体の目的化合物(3.79g,収率45%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.82 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.81 (1H, d, J = 3.1 Hz), 1.89-1.98 (1H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.48 (2H, d, J = 2.0 Hz).
(59b)1-(3,5-ジメトキシフェニル)-2-メチルプロパン-1-オン
実施例(59a)で合成した化合物(3.79g,18.2mmol)を塩化メチレン(200mL)に溶解し、二酸化マンガン(15.0g,173mmol)を室温で加え、窒素雰囲気下加熱還流で一日撹拌した。反応液を室温まで冷却した後、セライト濾過を行った。母液を減圧下溶媒留去することにより、無色液体の目的化合物(2.55g,収率67%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 7.0 Hz), 3.46-3.53 (1H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz), 7.09 (2H, d, J = 2.0 Hz).
(59c)1-{3-メトキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-2-メチルプロパン-1-オン
実施例(59b)で合成した化合物(2.55g,12.2mmol)を1-メチル-2-ピロリドン(30mL)に溶解し、ナトリウムチオメトキシド(1.75g,25.0mmol)を室温で加え、窒素雰囲気下100℃で3時間撹拌した。反応液を室温まで冷却した後、2規定塩酸(150mL)を加え、ジエチルエーテル(300mL)を用いて抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。 (59a) 1- (3,5-Dimethoxyphenyl) -2-methylpropan-1-ol 3,5-dimethoxybenzaldehyde (6.67 g, 40.1 mmol) was dissolved in tetrahydrofuran (40 mL) and isopropylmagnesium bromide ( 0.72 mol / L tetrahydrofuran solution, 90 mL, 64.8 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours and a half in a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound as a colorless liquid (3.79 g, yield). 45%).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.82 (3H, d, J = 6.6 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.81 (1H, d, J = 3.1 Hz), 1.89- 1.98 (1H, m), 3.80 (6H, s), 4.29 (1H, dd, J = 7.0, 3.1 Hz), 6.37 (1H, t, J = 2.3 Hz), 6.48 (2H, d, J = 2.0 Hz ).
(59b) 1- (3,5-dimethoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59a) (3.79 g, 18.2 mmol) was dissolved in methylene chloride (200 mL). Manganese dioxide (15.0 g, 173 mmol) was added at room temperature, and the mixture was stirred for one day with heating under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature and then filtered through celite. The mother liquor was evaporated under reduced pressure to give the target compound (2.55 g, yield 67%) as a colorless liquid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.46-3.53 (1H, m), 3.84 (6H, s), 6.65 (1H, t, J = 2.2 Hz ), 7.09 (2H, d, J = 2.0 Hz).
(59c) 1- {3-methoxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59b) (2.55 g, 12.2 mmol) Was dissolved in 1-methyl-2-pyrrolidone (30 mL), sodium thiomethoxide (1.75 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 2N hydrochloric acid (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
得られた残渣をN,N-ジメチルホルムアミド(30mL)に溶解し、4-フルオロフェニルメチルスルホン(4.40g,25.3mmol)、炭酸カリウム(7.05g,51.0mmol)を室温で加え、窒素雰囲気下100℃で一晩撹拌した。反応液を室温まで冷却した後、水(150mL)を加え、ジエチルエーテル(300mL)を用いて抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去した。シリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~40%)を用いて精製し、黄色固体の目的化合物(3.98g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1H, m), 3.86 (3H, s), 6.81 (1H, t, J = 2.2 Hz), 7.12 (2H, dd, J = 9.3, 2.4 Hz), 7.22 (1H, t, J = 1.7 Hz), 7.35 (1H, dd, J = 2.4, 1.5 Hz), 7.91 (2H, dd, J = 9.5, 2.2 Hz)。 The obtained residue was dissolved in N, N-dimethylformamide (30 mL), 4-fluorophenylmethylsulfone (4.40 g, 25.3 mmol) and potassium carbonate (7.05 g, 51.0 mmol) were added at room temperature, The mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The product was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to obtain the target compound (3.98 g, yield 94%) as a yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1H, m), 3.86 (3H, s), 6.81 (1H , t, J = 2.2 Hz), 7.12 (2H, dd, J = 9.3, 2.4 Hz), 7.22 (1H, t, J = 1.7 Hz), 7.35 (1H, dd, J = 2.4, 1.5 Hz), 7.91 (2H, dd, J = 9.5, 2.2 Hz).
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1H, m), 3.86 (3H, s), 6.81 (1H, t, J = 2.2 Hz), 7.12 (2H, dd, J = 9.3, 2.4 Hz), 7.22 (1H, t, J = 1.7 Hz), 7.35 (1H, dd, J = 2.4, 1.5 Hz), 7.91 (2H, dd, J = 9.5, 2.2 Hz)。 The obtained residue was dissolved in N, N-dimethylformamide (30 mL), 4-fluorophenylmethylsulfone (4.40 g, 25.3 mmol) and potassium carbonate (7.05 g, 51.0 mmol) were added at room temperature, The mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with diethyl ether (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The product was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to obtain the target compound (3.98 g, yield 94%) as a yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.8 Hz), 3.07 (3H, s), 3.42-3.47 (1H, m), 3.86 (3H, s), 6.81 (1H , t, J = 2.2 Hz), 7.12 (2H, dd, J = 9.3, 2.4 Hz), 7.22 (1H, t, J = 1.7 Hz), 7.35 (1H, dd, J = 2.4, 1.5 Hz), 7.91 (2H, dd, J = 9.5, 2.2 Hz).
(59d)1-{3-ヒドロキシ-5-[4-(メチルスルホニル)フェノキシ]フェニル}-2-メチルプロパン-1-オン
実施例(59c)で合成した化合物(3.78g,10.9mmol)を塩化メチレン(30mL)に溶解し、三臭化ホウ素(1.0mol/L塩化メチレン溶液,35.0mL,35.0mmol)を-78℃で滴下し、窒素雰囲気下室温で4時間撹拌した。この反応液に飽和塩化アンモニウム水溶液(10mL)を加え、塩化メチレン(20mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~50%)を用いて精製することにより、白色泡状の目的化合物(926mg,収率26%)を得た。1H-NMR (CDCl3, 400MHz):δ 1.20 (6H, d, J = 6.8 Hz), 3.08 (3H, s), 3.41-3.46 (1H, m), 6.79 (1H, t, J = 2.2 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.36 (1H, t, J = 1.7 Hz), 7.91 (2H, d, J = 8.8 Hz).
(59e)3-(2-メチルプロパノイル)-5-[4-(メチルスルホニル)フェノキシ]フェニル トリフルオロメタンスルホネート
実施例(59d)で合成した化合物(920mg,2.75mmol)を塩化メチレン(10mL)に溶解し、ピリジン(0.70mL,8.65mmol)とトリフルオロメタンスルホン酸無水物(0.70mL,4.16mmol)を0℃で加え、窒素雰囲気下0℃で1時間半撹拌した。反応液を室温に戻し、飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~40%)を用いて精製し、白色固体の目的化合物(1.17g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.23 (6H, d, J = 7.0 Hz), 3.10 (3H, s), 3.39-3.46 (1H, m), 7.17 (1H, t, J = 2.5 Hz), 7.19-7.21 (2H, m), 7.65 (2H, dd, J = 3.7, 1.8 Hz), 7.97-8.00 (2H, m).
(59f)2-メチル-1-{3-[4-(メチルスルホニル)フェノキシ]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル}プロパン-1-オン
実施例(59e)で合成した化合物(1.17g,2.51mmol)、ビス(ピナコレート)ジボロン(0.90g,3.54mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(200mg,0.25mmol)、酢酸カリウム(1.25g,12.7mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(608mg,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (6H, d, J = 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.57-3.64 (1H, m), 7.07 (2H, d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.75 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.20 (1H, s)。 (59d) 1- {3-Hydroxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59c) (3.78 g, 10.9 mmol) Was dissolved in methylene chloride (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 35.0 mL, 35.0 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. To this reaction solution was added a saturated aqueous ammonium chloride solution (10 mL), and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -50%) to give the desired compound (926 mg, yield) as a white foam. 26%). 1 H-NMR (CDCl 3 , 400 MHz): δ 1.20 (6H, d, J = 6.8 Hz), 3.08 (3H, s), 3.41-3.46 (1H, m), 6.79 (1H, t, J = 2.2 Hz ), 7.12 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.36 (1H, t, J = 1.7 Hz), 7.91 (2H, d, J = 8.8 Hz).
(59e) 3- (2-Methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl trifluoromethanesulfonate Compound (920 mg, 2.75 mmol) synthesized in Example (59d) was dissolved in methylene chloride (10 mL). , Pyridine (0.70 mL, 8.65 mmol) and trifluoromethanesulfonic anhydride (0.70 mL, 4.16 mmol) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and a half under a nitrogen atmosphere. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to give the target compound (1.17 g, yield) as a white solid. 91%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 3.10 (3H, s), 3.39-3.46 (1H, m), 7.17 (1H, t, J = 2.5 Hz ), 7.19-7.21 (2H, m), 7.65 (2H, dd, J = 3.7, 1.8 Hz), 7.97-8.00 (2H, m).
(59f) 2-Methyl-1- {3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl} Propan-1-one Compound (1.17 g, 2.51 mmol) synthesized in Example (59e), bis (pinacolato) diboron (0.90 g, 3.54 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride Dichloromethane complex (200 mg, 0.25 mmol) and potassium acetate (1.25 g, 12.7 mmol) were used in the same manner as in Example (1d) to obtain the target compound (608 mg, Yield 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (6H, d, J = 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.57-3.64 (1H, m), 7.07 (2H , d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.75 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.20 (1H , s).
実施例(59c)で合成した化合物(3.78g,10.9mmol)を塩化メチレン(30mL)に溶解し、三臭化ホウ素(1.0mol/L塩化メチレン溶液,35.0mL,35.0mmol)を-78℃で滴下し、窒素雰囲気下室温で4時間撹拌した。この反応液に飽和塩化アンモニウム水溶液(10mL)を加え、塩化メチレン(20mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~50%)を用いて精製することにより、白色泡状の目的化合物(926mg,収率26%)を得た。1H-NMR (CDCl3, 400MHz):δ 1.20 (6H, d, J = 6.8 Hz), 3.08 (3H, s), 3.41-3.46 (1H, m), 6.79 (1H, t, J = 2.2 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.36 (1H, t, J = 1.7 Hz), 7.91 (2H, d, J = 8.8 Hz).
(59e)3-(2-メチルプロパノイル)-5-[4-(メチルスルホニル)フェノキシ]フェニル トリフルオロメタンスルホネート
実施例(59d)で合成した化合物(920mg,2.75mmol)を塩化メチレン(10mL)に溶解し、ピリジン(0.70mL,8.65mmol)とトリフルオロメタンスルホン酸無水物(0.70mL,4.16mmol)を0℃で加え、窒素雰囲気下0℃で1時間半撹拌した。反応液を室温に戻し、飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=5%~40%)を用いて精製し、白色固体の目的化合物(1.17g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.23 (6H, d, J = 7.0 Hz), 3.10 (3H, s), 3.39-3.46 (1H, m), 7.17 (1H, t, J = 2.5 Hz), 7.19-7.21 (2H, m), 7.65 (2H, dd, J = 3.7, 1.8 Hz), 7.97-8.00 (2H, m).
(59f)2-メチル-1-{3-[4-(メチルスルホニル)フェノキシ]-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル}プロパン-1-オン
実施例(59e)で合成した化合物(1.17g,2.51mmol)、ビス(ピナコレート)ジボロン(0.90g,3.54mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(200mg,0.25mmol)、酢酸カリウム(1.25g,12.7mmol)を用い、実施例(1d)と同様の方法で白色固体の目的化合物(608mg,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (6H, d, J = 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.57-3.64 (1H, m), 7.07 (2H, d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.75 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.20 (1H, s)。 (59d) 1- {3-Hydroxy-5- [4- (methylsulfonyl) phenoxy] phenyl} -2-methylpropan-1-one Compound synthesized in Example (59c) (3.78 g, 10.9 mmol) Was dissolved in methylene chloride (30 mL), boron tribromide (1.0 mol / L methylene chloride solution, 35.0 mL, 35.0 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. To this reaction solution was added a saturated aqueous ammonium chloride solution (10 mL), and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% -50%) to give the desired compound (926 mg, yield) as a white foam. 26%). 1 H-NMR (CDCl 3 , 400 MHz): δ 1.20 (6H, d, J = 6.8 Hz), 3.08 (3H, s), 3.41-3.46 (1H, m), 6.79 (1H, t, J = 2.2 Hz ), 7.12 (2H, d, J = 8.8 Hz), 7.19 (1H, d, J = 1.5 Hz), 7.36 (1H, t, J = 1.7 Hz), 7.91 (2H, d, J = 8.8 Hz).
(59e) 3- (2-Methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl trifluoromethanesulfonate Compound (920 mg, 2.75 mmol) synthesized in Example (59d) was dissolved in methylene chloride (10 mL). , Pyridine (0.70 mL, 8.65 mmol) and trifluoromethanesulfonic anhydride (0.70 mL, 4.16 mmol) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and a half under a nitrogen atmosphere. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 5% to 40%) to give the target compound (1.17 g, yield) as a white solid. 91%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 3.10 (3H, s), 3.39-3.46 (1H, m), 7.17 (1H, t, J = 2.5 Hz ), 7.19-7.21 (2H, m), 7.65 (2H, dd, J = 3.7, 1.8 Hz), 7.97-8.00 (2H, m).
(59f) 2-Methyl-1- {3- [4- (methylsulfonyl) phenoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl} Propan-1-one Compound (1.17 g, 2.51 mmol) synthesized in Example (59e), bis (pinacolato) diboron (0.90 g, 3.54 mmol), [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II) dichloride Dichloromethane complex (200 mg, 0.25 mmol) and potassium acetate (1.25 g, 12.7 mmol) were used in the same manner as in Example (1d) to obtain the target compound (608 mg, Yield 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (6H, d, J = 6.6 Hz), 1.36 (12H, s), 3.07 (3H, s), 3.57-3.64 (1H, m), 7.07 (2H , d, J = 8.6 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.75 (1H, dd, J = 2.3, 1.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.20 (1H , s).
(59g)2-ベンジル 1-t-ブチル 5-{3-(2-メチルプロパノイル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-1,2-ジカルボキシレート
実施例(59f)で合成した化合物(608mg,1.37mmol)、実施例(16d)で合成した化合物(1.10g,2.89mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(115mg,0.14mmol)、炭酸カリウム(810mg,5.86mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(630mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 (1H, m), 5.32 (2H, s), 6.28 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.32-7.44 (6H, m), 7.63 (1H, t, J = 2.0 Hz), 7.87 (1H, t, J = 1.4 Hz), 7.93 (2H, d, J = 8.6 Hz).
(59h)N-[(2R)-2-ヒドロキシプロピル]-5-{3-(2-メチルプロパノイル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(59g)で合成した化合物(630mg,1.02mmol)をトリフルオロ酢酸(5.0mL)に溶解し、室温で40分間撹拌した。減圧下溶媒を留去した後、トリエチルアミン(5mL)を加え、5分間撹拌した。減圧下トリエチルアミンを留去することで淡黄色固体が得られた。 (59 g) 2-Benzyl 1-t-butyl 5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Compound (608 mg, 1.37 mmol) synthesized in Example (59f), Compound (1.10 g, 2.89 mmol) synthesized in Example (16d), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride Using a dichloromethane complex (115 mg, 0.14 mmol) and potassium carbonate (810 mg, 5.86 mmol), the target compound (630 mg, yield 74%) as a brown oil was obtained in the same manner as in Example (16e). Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 (1H, m), 5.32 (2H , s), 6.28 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.32-7.44 (6H, m), 7.63 (1H, t, J = 2.0 Hz), 7.87 (1H, t, J = 1.4 Hz), 7.93 (2H, d, J = 8.6 Hz).
(59h) N-[(2R) -2-hydroxypropyl] -5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide The compound (630 mg, 1.02 mmol) synthesized in Example (59 g) was dissolved in trifluoroacetic acid (5.0 mL) and stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.
実施例(59f)で合成した化合物(608mg,1.37mmol)、実施例(16d)で合成した化合物(1.10g,2.89mmol)、[1,1´-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(115mg,0.14mmol)、炭酸カリウム(810mg,5.86mmol)を用い、実施例(16e)と同様の方法で茶色油状の目的化合物(630mg,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 (1H, m), 5.32 (2H, s), 6.28 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.32-7.44 (6H, m), 7.63 (1H, t, J = 2.0 Hz), 7.87 (1H, t, J = 1.4 Hz), 7.93 (2H, d, J = 8.6 Hz).
(59h)N-[(2R)-2-ヒドロキシプロピル]-5-{3-(2-メチルプロパノイル)-5-[4-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(59g)で合成した化合物(630mg,1.02mmol)をトリフルオロ酢酸(5.0mL)に溶解し、室温で40分間撹拌した。減圧下溶媒を留去した後、トリエチルアミン(5mL)を加え、5分間撹拌した。減圧下トリエチルアミンを留去することで淡黄色固体が得られた。 (59 g) 2-Benzyl 1-t-butyl 5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-1,2-dicarboxylate Compound (608 mg, 1.37 mmol) synthesized in Example (59f), Compound (1.10 g, 2.89 mmol) synthesized in Example (16d), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride Using a dichloromethane complex (115 mg, 0.14 mmol) and potassium carbonate (810 mg, 5.86 mmol), the target compound (630 mg, yield 74%) as a brown oil was obtained in the same manner as in Example (16e). Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (6H, d, J = 7.0 Hz), 1.42 (9H, s), 3.07 (3H, s), 3.45-3.53 (1H, m), 5.32 (2H , s), 6.28 (1H, d, J = 3.5 Hz), 6.96 (1H, d, J = 3.9 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.32-7.44 (6H, m), 7.63 (1H, t, J = 2.0 Hz), 7.87 (1H, t, J = 1.4 Hz), 7.93 (2H, d, J = 8.6 Hz).
(59h) N-[(2R) -2-hydroxypropyl] -5- {3- (2-methylpropanoyl) -5- [4- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxamide The compound (630 mg, 1.02 mmol) synthesized in Example (59 g) was dissolved in trifluoroacetic acid (5.0 mL) and stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, triethylamine (5 mL) was added, and the mixture was stirred for 5 minutes. A pale yellow solid was obtained by distilling off triethylamine under reduced pressure.
これを酢酸エチル(15mL)に溶解し、パラジウム炭素(115mg)を加え、水素雰囲気下室温で一晩撹拌した。セライト濾過後、減圧下溶媒を留去し、茶色液体の化合物を得た。
This was dissolved in ethyl acetate (15 mL), palladium carbon (115 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure to obtain a brown liquid compound.
これを塩化メチレン(10mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.20mL,2.54mmol)、WSCI・HCl(400mg,2.09mmol)、4-ジメチルアミノピリジン(130mg,1.06mmol)を加え、窒素雰囲気下室温で1日撹拌した。飽和塩化アンモニウム水溶液(20mL)を加え、塩化メチレン(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0~3%)を用いて精製することにより、黄色固体の目的化合物(150mg,収率30%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21-1.25 (9H, m), 3.08 (3H, s), 3.22-3.33 (1H, m), 3.47-3.55 (1H, m), 3.61 (1H, dd, J = 14.3, 3.7 Hz), 3.97-4.05 (1H, m), 6.45 (1H, br s), 6.59 (1H, s), 6.66 (1H, d, J = 3.5 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.46 (1H, s), 7.50 (1H, s), 7.93 (2H, d, J = 8.6 Hz), 7.98 (1H, s), 10.05 (1H, br s).
(59i)2-メチル-1-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)プロパン-1-オン
実施例(59h)で合成した化合物(150mg,0.31mmol)、メタンスルホン酸無水物(90mg,0.52mmol)、トリエチルアミン(0.20mL,1.43mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(70mg,収率48%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.23 (6H, d, J = 7.0 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.88 (1H, m), 6.60 (1H, d, J = 3.5 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dd, J = 9.2, 2.5 Hz), 7.43 (1H, t, J = 2.0 Hz), 7.50 (1H, t, J = 1.8 Hz), 7.93 (2H, dd, J = 9.2, 2.5 Hz), 7.96 (1H, t, J = 1.2 Hz).
MS (ESI) m/z: 467.16454 (M+H)+。 This was dissolved in methylene chloride (10 mL), and (R)-(−)-1-amino-2-propanol (0.20 mL, 2.54 mmol), WSCI · HCl (400 mg, 2.09 mmol), 4-dimethyl Aminopyridine (130 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with methylene chloride (20 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (150 mg, yield 30) as a yellow solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21-1.25 (9H, m), 3.08 (3H, s), 3.22-3.33 (1H, m), 3.47-3.55 (1H, m), 3.61 (1H, dd, J = 14.3, 3.7 Hz), 3.97-4.05 (1H, m), 6.45 (1H, br s), 6.59 (1H, s), 6.66 (1H, d, J = 3.5 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.46 (1H, s), 7.50 (1H, s), 7.93 (2H, d, J = 8.6 Hz), 7.98 (1H, s), 10.05 (1H, br s).
(59i) 2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5- [4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one The compound synthesized in Example (59h) (150 mg, 0.31 mmol), methanesulfonic anhydride (90 mg, 0.52 mmol), triethylamine ( 0.20 mL, 1.43 mmol) was used to obtain the target compound (70 mg, 48% yield) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.88 (1H, m), 6.60 (1H, d, J = 3.5 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dd, J = 9.2, 2.5 Hz), 7.43 (1H, t, J = 2.0 Hz), 7.50 (1H, t, J = 1.8 Hz), 7.93 (2H, dd, J = 9.2, 2.5 Hz) , 7.96 (1H, t, J = 1.2 Hz).
MS (ESI) m / z: 467.16454 (M + H) <+> .
1H-NMR (CDCl3, 400MHz):δ 1.21-1.25 (9H, m), 3.08 (3H, s), 3.22-3.33 (1H, m), 3.47-3.55 (1H, m), 3.61 (1H, dd, J = 14.3, 3.7 Hz), 3.97-4.05 (1H, m), 6.45 (1H, br s), 6.59 (1H, s), 6.66 (1H, d, J = 3.5 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.46 (1H, s), 7.50 (1H, s), 7.93 (2H, d, J = 8.6 Hz), 7.98 (1H, s), 10.05 (1H, br s).
(59i)2-メチル-1-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]フェニル)プロパン-1-オン
実施例(59h)で合成した化合物(150mg,0.31mmol)、メタンスルホン酸無水物(90mg,0.52mmol)、トリエチルアミン(0.20mL,1.43mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的化合物(70mg,収率48%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.23 (6H, d, J = 7.0 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.88 (1H, m), 6.60 (1H, d, J = 3.5 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dd, J = 9.2, 2.5 Hz), 7.43 (1H, t, J = 2.0 Hz), 7.50 (1H, t, J = 1.8 Hz), 7.93 (2H, dd, J = 9.2, 2.5 Hz), 7.96 (1H, t, J = 1.2 Hz).
MS (ESI) m/z: 467.16454 (M+H)+。 This was dissolved in methylene chloride (10 mL), and (R)-(−)-1-amino-2-propanol (0.20 mL, 2.54 mmol), WSCI · HCl (400 mg, 2.09 mmol), 4-dimethyl Aminopyridine (130 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with methylene chloride (20 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0 to 3%) to give the target compound (150 mg, yield 30) as a yellow solid. %).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21-1.25 (9H, m), 3.08 (3H, s), 3.22-3.33 (1H, m), 3.47-3.55 (1H, m), 3.61 (1H, dd, J = 14.3, 3.7 Hz), 3.97-4.05 (1H, m), 6.45 (1H, br s), 6.59 (1H, s), 6.66 (1H, d, J = 3.5 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.46 (1H, s), 7.50 (1H, s), 7.93 (2H, d, J = 8.6 Hz), 7.98 (1H, s), 10.05 (1H, br s).
(59i) 2-Methyl-1- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5- [4- (Methylsulfonyl) phenoxy] phenyl) propan-1-one The compound synthesized in Example (59h) (150 mg, 0.31 mmol), methanesulfonic anhydride (90 mg, 0.52 mmol), triethylamine ( 0.20 mL, 1.43 mmol) was used to obtain the target compound (70 mg, 48% yield) as a yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.23 (6H, d, J = 7.0 Hz), 1.43 (3H, d, J = 5.9 Hz), 3.08 (3H, s), 3.45-3.56 (2H, m ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.80-4.88 (1H, m), 6.60 (1H, d, J = 3.5 Hz), 6.78 (1H, d, J = 3.5 Hz), 7.13 (2H, dd, J = 9.2, 2.5 Hz), 7.43 (1H, t, J = 2.0 Hz), 7.50 (1H, t, J = 1.8 Hz), 7.93 (2H, dd, J = 9.2, 2.5 Hz) , 7.96 (1H, t, J = 1.2 Hz).
MS (ESI) m / z: 467.16454 (M + H) <+> .
(実施例60)
{(4R)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 60)
{(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
{(4R)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 60)
{(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
(60a)5-{3-ブロモ-5-[2-フルオロ-1-(フルオロメチル)エトキシ]フェノキシ}-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(4.20g,12.2mmol)をトルエン(85mL)とテトラヒドロフラン(15mL)の混合溶媒に溶解し、1,3-ジフルオロ-2-プロパノール(1.04mL,13.4mmol)、及びトリフェニルホスフィン(8.03g,30.5mmol)を加え、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,13.00mL,28.6mmol)を0℃で滴下し、窒素雰囲気下室温で10時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、無色油状の目的化合物(3.51g,収率68%)を得た。
1H-NMR (CDCl3, 500MHz):δ 3.23 (3H, s), 4.58-4.74 (5H, m), 6.67 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 2.9, 8.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(60b)ベンジル 5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(60a)で合成した化合物(3.51g,8.31mmol)、実施例(19e)で合成した化合物(3.81g,11.64mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.34g,0.42mmol)、炭酸カリウム(5.74g,41.56mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(3.80g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.23 (3H, s), 4.59-4.79 (5H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, t, J = 2.3 Hz), 6.93 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.07 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.38 (1H, br s).
(60c)5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(60b)で合成した化合物(3.86g,7.11mmol)をエタノール(120mL)と酢酸エチル(30mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(0.7g)を加えて水素雰囲気下に6時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで黄色固体の目的化合物(3.28g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.23 (3H, s), 4.59-4.82 (5H, m), 6.56 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, dd, J = 2.3, 3.9 Hz), 7.11 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.55 (1H, br s)。 (60a) 5- {3-Bromo-5- [2-fluoro-1- (fluoromethyl) ethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (4.20 g, 12 .2 mmol) in a mixed solvent of toluene (85 mL) and tetrahydrofuran (15 mL), 1,3-difluoro-2-propanol (1.04 mL, 13.4 mmol), and triphenylphosphine (8.03 g, 30. 5 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 13.00 mL, 28.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 10 hours in a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the desired compound (3.51 g, 3.51 g, Yield 68%).
1 H-NMR (CDCl 3 , 500 MHz): δ 3.23 (3H, s), 4.58-4.74 (5H, m), 6.67 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 2.0 Hz ), 7.04 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 2.9, 8.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz) ).
(60b) Benzyl 5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylate Compound (3.51 g, 8.31 mmol) synthesized in Example (60a), Compound (3.81 g, 11.64 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (0.34 g, 0.42 mmol), potassium carbonate (5.74 g, 41.56 mmol) and the same target compound as yellow oil in the same manner as in Example (16e) (3.80 g, 84% yield) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 4.59-4.79 (5H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, t, J = 2.3 Hz), 6.93 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.07 (1H, t, J = 2.0 Hz), 7.33 -7.47 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.38 (1H, br s).
(60c) 5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carvone Acid The compound (3.86 g, 7.11 mmol) synthesized in Example (60b) was dissolved in a mixed solvent of ethanol (120 mL) and ethyl acetate (30 mL), and 10% palladium carbon catalyst (0.7 g) was added. Stir for 6 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (3.28 g, yield ˜100%) as a yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 4.59-4.82 (5H, m), 6.56 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, dd, J = 2.3, 3.9 Hz), 7.11 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
実施例(19b)で合成した化合物(4.20g,12.2mmol)をトルエン(85mL)とテトラヒドロフラン(15mL)の混合溶媒に溶解し、1,3-ジフルオロ-2-プロパノール(1.04mL,13.4mmol)、及びトリフェニルホスフィン(8.03g,30.5mmol)を加え、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,13.00mL,28.6mmol)を0℃で滴下し、窒素雰囲気下室温で10時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~50%)を用いて精製することにより、無色油状の目的化合物(3.51g,収率68%)を得た。
1H-NMR (CDCl3, 500MHz):δ 3.23 (3H, s), 4.58-4.74 (5H, m), 6.67 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 2.9, 8.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(60b)ベンジル 5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(60a)で合成した化合物(3.51g,8.31mmol)、実施例(19e)で合成した化合物(3.81g,11.64mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.34g,0.42mmol)、炭酸カリウム(5.74g,41.56mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(3.80g,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.23 (3H, s), 4.59-4.79 (5H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, t, J = 2.3 Hz), 6.93 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.07 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.38 (1H, br s).
(60c)5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(60b)で合成した化合物(3.86g,7.11mmol)をエタノール(120mL)と酢酸エチル(30mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(0.7g)を加えて水素雰囲気下に6時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで黄色固体の目的化合物(3.28g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.23 (3H, s), 4.59-4.82 (5H, m), 6.56 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, dd, J = 2.3, 3.9 Hz), 7.11 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.55 (1H, br s)。 (60a) 5- {3-Bromo-5- [2-fluoro-1- (fluoromethyl) ethoxy] phenoxy} -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (4.20 g, 12 .2 mmol) in a mixed solvent of toluene (85 mL) and tetrahydrofuran (15 mL), 1,3-difluoro-2-propanol (1.04 mL, 13.4 mmol), and triphenylphosphine (8.03 g, 30. 5 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 13.00 mL, 28.6 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 10 hours in a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -50%) to give the desired compound (3.51 g, 3.51 g, Yield 68%).
1 H-NMR (CDCl 3 , 500 MHz): δ 3.23 (3H, s), 4.58-4.74 (5H, m), 6.67 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 2.0 Hz ), 7.04 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 2.9, 8.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz) ).
(60b) Benzyl 5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylate Compound (3.51 g, 8.31 mmol) synthesized in Example (60a), Compound (3.81 g, 11.64 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (0.34 g, 0.42 mmol), potassium carbonate (5.74 g, 41.56 mmol) and the same target compound as yellow oil in the same manner as in Example (16e) (3.80 g, 84% yield) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 4.59-4.79 (5H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 2.7, 3.9 Hz), 6.64 (1H, t, J = 2.3 Hz), 6.93 (1H, t, J = 2.0 Hz), 6.99 (1H, dd, J = 2.3, 3.9 Hz), 7.07 (1H, t, J = 2.0 Hz), 7.33 -7.47 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.38 (1H, br s).
(60c) 5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carvone Acid The compound (3.86 g, 7.11 mmol) synthesized in Example (60b) was dissolved in a mixed solvent of ethanol (120 mL) and ethyl acetate (30 mL), and 10% palladium carbon catalyst (0.7 g) was added. Stir for 6 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (3.28 g, yield ˜100%) as a yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.23 (3H, s), 4.59-4.82 (5H, m), 6.56 (1H, dd, J = 2.7, 3.9 Hz), 6.68 (1H, t, J = 2.0 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.06 (1H, dd, J = 2.3, 3.9 Hz), 7.11 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(60d)メチル N-{[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]カルボニル}-L-セリネート
実施例(60c)で合成した化合物(3.20g,7.35mmol)、L-セリンメチルエステル塩酸塩(1.26g,8.08mmol)、HOBT・H2O(1.09g,8.08mmol)、N-メチルモルホリン(1.62mL,14.69mmol)、WSCI・HCl(1.69g,8.82mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(2.69g,収率66%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2H, m), 4.59-4.80 (5H, m), 4.79-4.84 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.63 (1H, t, J = 2.0 Hz), 6.73 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, d, J = 7.4 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.07 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.74 (1H, br s).
(60e)メチル (4S)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(60d)で合成した化合物(2.69g,4.85mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(1.16mL,6.31mmol)、炭酸カリウム(1.01g,7.28mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(2.50g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.81 (3H, s), 4.55-4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.64 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.91 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.59 (1H, br s).
(60f){(4R)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(60e)で合成した化合物(2.50g,4.67mmol)をテトラヒドロフラン(50mL)に溶解し、0℃で水素化リチウムアルミニウム(0.30g,7.94mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.30mL)、5規定水酸化ナトリウム水溶液(0.30mL)、水(1.00mL)の順に加え、10分間攪拌した。酢酸エチル(150mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(1.04g,44%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.62 (1H, dd, J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz), 4.12-4.17 (1H, m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (1H, d, J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.0 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.09 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 508.13445 (M+H)+。 (60d) Methyl N-{[5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-yl] carbonyl} -L-serineate Compound (3.20 g, 7.35 mmol) synthesized in Example (60c), L-serine methyl ester hydrochloride (1.26 g, 8.08 mmol), HOBT · Similar to Example (29a) using H 2 O (1.09 g, 8.08 mmol), N-methylmorpholine (1.62 mL, 14.69 mmol), and WSCI · HCl (1.69 g, 8.82 mmol). The target compound (2.69 g, yield 66%) was obtained as a white solid by the method.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2H, m), 4.59-4.80 (5H, m), 4.79-4.84 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.63 (1H, t, J = 2.0 Hz), 6.73 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, d, J = 7.4 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.07 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.74 (1H, br s).
(60e) Methyl (4S) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (2.69 g, 4.85 mmol) synthesized in Example (60d), bis (2-methoxy Ethyl) aminosulfur trifluoride (1.16 mL, 6.31 mmol) and potassium carbonate (1.01 g, 7.28 mmol) were used in the same manner as in Example (38b) to give the target compound (2.50 g, 96%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 4.55-4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.64 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.91 (1H, t, J = 1.6 Hz), 7.06 (1H , t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.59 (1H , br s).
(60f) {(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Tetrahydrofuran (50 mL) was obtained from the compound (2.50 g, 4.67 mmol) synthesized in Example (60e). And lithium aluminum hydride (0.30 g, 7.94 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.30 mL), 5N aqueous sodium hydroxide solution (0.30 mL) and water (1.00 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (150 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (1.04 g, 44%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.62 (1H, dd, J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz), 4.12-4.17 (1H, m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (1H, d, J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 ( 1H, t, J = 2.0 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.09 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 ( 1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 508.13445 (M + H) <+> .
実施例(60c)で合成した化合物(3.20g,7.35mmol)、L-セリンメチルエステル塩酸塩(1.26g,8.08mmol)、HOBT・H2O(1.09g,8.08mmol)、N-メチルモルホリン(1.62mL,14.69mmol)、WSCI・HCl(1.69g,8.82mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(2.69g,収率66%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2H, m), 4.59-4.80 (5H, m), 4.79-4.84 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.63 (1H, t, J = 2.0 Hz), 6.73 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, d, J = 7.4 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.07 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.74 (1H, br s).
(60e)メチル (4S)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(60d)で合成した化合物(2.69g,4.85mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(1.16mL,6.31mmol)、炭酸カリウム(1.01g,7.28mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(2.50g,96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.81 (3H, s), 4.55-4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.64 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.91 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.59 (1H, br s).
(60f){(4R)-2-[5-(3-[2-フルオロ-1-(フルオロメチル)エトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(60e)で合成した化合物(2.50g,4.67mmol)をテトラヒドロフラン(50mL)に溶解し、0℃で水素化リチウムアルミニウム(0.30g,7.94mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.30mL)、5規定水酸化ナトリウム水溶液(0.30mL)、水(1.00mL)の順に加え、10分間攪拌した。酢酸エチル(150mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(1.04g,44%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.24 (3H, s), 3.62 (1H, dd, J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz), 4.12-4.17 (1H, m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (1H, d, J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.0 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.09 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 508.13445 (M+H)+。 (60d) Methyl N-{[5- (3- [2-fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-yl] carbonyl} -L-serineate Compound (3.20 g, 7.35 mmol) synthesized in Example (60c), L-serine methyl ester hydrochloride (1.26 g, 8.08 mmol), HOBT · Similar to Example (29a) using H 2 O (1.09 g, 8.08 mmol), N-methylmorpholine (1.62 mL, 14.69 mmol), and WSCI · HCl (1.69 g, 8.82 mmol). The target compound (2.69 g, yield 66%) was obtained as a white solid by the method.
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 3.98-4.10 (2H, m), 4.59-4.80 (5H, m), 4.79-4.84 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.63 (1H, t, J = 2.0 Hz), 6.73 (1H, dd, J = 2.3, 3.9 Hz), 6.87 (1H, d, J = 7.4 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.07 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.74 (1H, br s).
(60e) Methyl (4S) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (2.69 g, 4.85 mmol) synthesized in Example (60d), bis (2-methoxy Ethyl) aminosulfur trifluoride (1.16 mL, 6.31 mmol) and potassium carbonate (1.01 g, 7.28 mmol) were used in the same manner as in Example (38b) to give the target compound (2.50 g, 96%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.81 (3H, s), 4.55-4.80 (7H, m), 4.90 (1H, dd, J = 7.8, 10.2 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.64 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.91 (1H, t, J = 1.6 Hz), 7.06 (1H , t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.59 (1H , br s).
(60f) {(4R) -2- [5- (3- [2-Fluoro-1- (fluoromethyl) ethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol Tetrahydrofuran (50 mL) was obtained from the compound (2.50 g, 4.67 mmol) synthesized in Example (60e). And lithium aluminum hydride (0.30 g, 7.94 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.30 mL), 5N aqueous sodium hydroxide solution (0.30 mL) and water (1.00 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (150 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (1.04 g, 44%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.24 (3H, s), 3.62 (1H, dd, J = 2.7, 12.1 Hz), 3.98 (1H, dd, J = 2.3, 12.1 Hz), 4.12-4.17 (1H, m), 4.31-4.41 (2H, m), 4.60-4.80 (5H, m), 6.38 (1H, d, J = 3.5 Hz), 6.46 (1H, d, J = 3.5 Hz), 6.62 ( 1H, t, J = 2.0 Hz), 6.94 (1H, t, J = 1.6 Hz), 7.09 (1H, t, J = 1.6 Hz), 7.47 (1H, dd, J = 2.7, 8.6 Hz), 8.07 ( 1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 508.13445 (M + H) <+> .
(実施例61)
{(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 61)
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
{(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール (Example 61)
{(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol
(61a)5-{3-ブロモ-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェノキシ}-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(7.07g,20.5mmol)、(R)-3-ヒドロキシテトラヒドロフラン(1.99g,22.6mmol)、トリフェニルホスフィン(11.90g,45.2mmol)、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,20.0mL,44.0mmol)を用い、実施例(40b)と同様の方法で淡黄色油状の目的化合物(6.05g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.09-2.16 (1H, m), 2.18-2.28 (1H, m), 3.24 (3H, s), 3.85-4.02 (4H, m), 4.87-4.91 (1H, m), 6.54 (1H, t, J = 2.3 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(61b)ベンジル 5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-カルボキシレート
実施例(61a)で合成した化合物(6.05g,14.60mmol)、実施例(19e)で合成した化合物(7.17g,21.91mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.66g,0.80mmol)、炭酸カリウム(10.09g,73.02mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(6.73g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.12-2.29 (2H, m), 3.23 (3H, s), 3.88-4.04 (4H, m), 4.93-4.97 (1H, m), 5.33 (2H, s), 6.51-6.53 (2H, m), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.33-7.46 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.29 (1H, br s).
(61c)5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-カルボン酸
実施例(61b)で合成した化合物(6.73g,12.40mmol)をエタノール(200mL)と酢酸エチル(70mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(1.2g)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで褐色固体の目的化合物(5.60g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4H, m), 4.94-4.99 (1H, br m), 6.51-6.55 (2H, m), 6.91 (1H, s), 6.99-7.04 (2H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.71 (1H, br s)。 (61a) 5- {3-Bromo-5-[(3S) -tetrahydrofuran-3-yloxy] phenoxy} -2- (methylsulfonyl) pyridine Compound (7.07 g, 20.5 mmol) synthesized in Example (19b) ), (R) -3-hydroxytetrahydrofuran (1.99 g, 22.6 mmol), triphenylphosphine (11.90 g, 45.2 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 20.0 mL, 44.0 mmol) and the target compound (6.05 g, yield 71%) as a pale yellow oil was obtained in the same manner as in Example (40b).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.09-2.16 (1H, m), 2.18-2.28 (1H, m), 3.24 (3H, s), 3.85-4.02 (4H, m), 4.87-4.91 ( 1H, m), 6.54 (1H, t, J = 2.3 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(61b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylate Compound (6.05 g, 14.60 mmol) synthesized in Example (61a), Compound (7.17 g, 21.91 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride Using dichloromethane complex (0.66 g, 0.80 mmol) and potassium carbonate (10.09 g, 73.02 mmol) in the same manner as in Example (16e), the target compound (6 0.73 g, 86% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.12-2.29 (2H, m), 3.23 (3H, s), 3.88-4.04 (4H, m), 4.93-4.97 (1H, m), 5.33 (2H, s), 6.51-6.53 (2H, m), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.33-7.46 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.29 (1H, br s).
(61c) 5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylic acid The compound (6.73 g, 12.40 mmol) synthesized in Example (61b) was dissolved in a mixed solvent of ethanol (200 mL) and ethyl acetate (70 mL), 10% palladium carbon catalyst (1.2 g) was added, and hydrogen atmosphere was added. Stir down for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.60 g, yield˜100%) as a brown solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4H, m), 4.94-4.99 (1H, br m), 6.51-6.55 (2H, m), 6.91 (1H, s), 6.99-7.04 (2H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 ( 1H, d, J = 2.7 Hz), 9.71 (1H, br s).
実施例(19b)で合成した化合物(7.07g,20.5mmol)、(R)-3-ヒドロキシテトラヒドロフラン(1.99g,22.6mmol)、トリフェニルホスフィン(11.90g,45.2mmol)、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,20.0mL,44.0mmol)を用い、実施例(40b)と同様の方法で淡黄色油状の目的化合物(6.05g,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.09-2.16 (1H, m), 2.18-2.28 (1H, m), 3.24 (3H, s), 3.85-4.02 (4H, m), 4.87-4.91 (1H, m), 6.54 (1H, t, J = 2.3 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(61b)ベンジル 5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-カルボキシレート
実施例(61a)で合成した化合物(6.05g,14.60mmol)、実施例(19e)で合成した化合物(7.17g,21.91mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.66g,0.80mmol)、炭酸カリウム(10.09g,73.02mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(6.73g,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.12-2.29 (2H, m), 3.23 (3H, s), 3.88-4.04 (4H, m), 4.93-4.97 (1H, m), 5.33 (2H, s), 6.51-6.53 (2H, m), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.33-7.46 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.29 (1H, br s).
(61c)5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-カルボン酸
実施例(61b)で合成した化合物(6.73g,12.40mmol)をエタノール(200mL)と酢酸エチル(70mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(1.2g)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで褐色固体の目的化合物(5.60g,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4H, m), 4.94-4.99 (1H, br m), 6.51-6.55 (2H, m), 6.91 (1H, s), 6.99-7.04 (2H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.71 (1H, br s)。 (61a) 5- {3-Bromo-5-[(3S) -tetrahydrofuran-3-yloxy] phenoxy} -2- (methylsulfonyl) pyridine Compound (7.07 g, 20.5 mmol) synthesized in Example (19b) ), (R) -3-hydroxytetrahydrofuran (1.99 g, 22.6 mmol), triphenylphosphine (11.90 g, 45.2 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 20.0 mL, 44.0 mmol) and the target compound (6.05 g, yield 71%) as a pale yellow oil was obtained in the same manner as in Example (40b).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.09-2.16 (1H, m), 2.18-2.28 (1H, m), 3.24 (3H, s), 3.85-4.02 (4H, m), 4.87-4.91 ( 1H, m), 6.54 (1H, t, J = 2.3 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.91 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7 , 8.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(61b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylate Compound (6.05 g, 14.60 mmol) synthesized in Example (61a), Compound (7.17 g, 21.91 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride Using dichloromethane complex (0.66 g, 0.80 mmol) and potassium carbonate (10.09 g, 73.02 mmol) in the same manner as in Example (16e), the target compound (6 0.73 g, 86% yield).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.12-2.29 (2H, m), 3.23 (3H, s), 3.88-4.04 (4H, m), 4.93-4.97 (1H, m), 5.33 (2H, s), 6.51-6.53 (2H, m), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 6.99 (1H, dd, J = 2.7, 3.9 Hz), 7.33-7.46 (6H, m), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.29 (1H, br s).
(61c) 5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole-2-carboxylic acid The compound (6.73 g, 12.40 mmol) synthesized in Example (61b) was dissolved in a mixed solvent of ethanol (200 mL) and ethyl acetate (70 mL), 10% palladium carbon catalyst (1.2 g) was added, and hydrogen atmosphere was added. Stir down for 2 hours. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (5.60 g, yield˜100%) as a brown solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.11-2.30 (2H, m), 3.22 (3H, s), 3.86-4.06 (4H, m), 4.94-4.99 (1H, br m), 6.51-6.55 (2H, m), 6.91 (1H, s), 6.99-7.04 (2H, m), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 ( 1H, d, J = 2.7 Hz), 9.71 (1H, br s).
(61d)メチル N-{[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]カルボニル}-L-セリネート
実施例(61c)で合成した化合物(5.55g,12.49mmol)、L-セリンメチルエステル塩酸塩(2.20g,13.74mmol)、HOBT・H2O(1.86g,13.74mmol)、N-メチルモルホリン(2.75mL,24.97mmol)、WSCI・HCl(2.87g,14.98mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(6.24g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.11-2.29 (2H, m), 3.23 (3H, s), 3.79 (3H, s), 3.86-3.95 (1H, m), 3.96-4.08 (5H, m), 4.79-4.83 (1H, m), 4.93-4.97 (1H, br m), 6.49-6.51 (2H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.97 (1H, br s).
(61e)メチル (4S)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(61d)で合成した化合物(6.24g,11.42mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(2.53mL,13.70mmol)、炭酸カリウム(2.37g,17.13mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(5.45g,91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.12-2.30 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 3.89-3.96 (1H, m), 3.97-4.04 (3H, m), 4.58 (1H, dd, J = 9.0, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.9 Hz), 4.94-4.99 (1H, br m), 6.51-6.52 (2H, m), 6.81 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(61f){(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(61e)で合成した化合物(5.45g,10.33mmol)をテトラヒドロフラン(100mL)に溶解し、0℃で水素化リチウムアルミニウム(0.78g,20.66mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.80mL)、5規定水酸化ナトリウム水溶液(0.80mL)、水(2.40mL)の順に加え、10分間攪拌した。酢酸エチル(300mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(2.32g,45%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.13-2.31 (2H, m), 3.24 (3H, s), 3.61 (1H, dd, J = 2.7, 12.1 Hz), 3.89-4.05 (5H, m), 4.12-4.17 (1H, m), 4.32-4.41 (2H, m), 4.94-4.98 (1H, br m), 6.38 (1H, d, J = 3.9 Hz), 6.47-6.50 (2H, m), 6.88 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 500.14769 (M+H)+。 (61d) Methyl N-{[5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] carbonyl} -L-serineate Compound (5.55 g, 12.49 mmol) synthesized in Example (61c), L-serine methyl ester hydrochloride (2.20 g, 13.74 mmol), HOBT · H 2 Using O (1.86 g, 13.74 mmol), N-methylmorpholine (2.75 mL, 24.97 mmol) and WSCI.HCl (2.87 g, 14.98 mmol) in the same manner as in Example (29a) The target compound (6.24 g, yield 91%) was obtained as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.11-2.29 (2H, m), 3.23 (3H, s), 3.79 (3H, s), 3.86-3.95 (1H, m), 3.96-4.08 (5H, m), 4.79-4.83 (1H, m), 4.93-4.97 (1H, br m), 6.49-6.51 (2H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d , J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.97 (1H, br s).
(61e) Methyl (4S) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrole-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound synthesized in Example (61d) (6.24 g, 11.42 mmol), bis (2-methoxyethyl) Aminosulfur trifluoride (2.53 mL, 13.70 mmol) and potassium carbonate (2.37 g, 17.13 mmol) were used in the same manner as in Example (38b) to give the target compound (5.45 g, 91%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 2.12-2.30 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 3.89-3.96 (1H, m), 3.97-4.04 (3H, m), 4.58 (1H, dd, J = 9.0, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.9 Hz), 4.94-4.99 (1H, br m), 6.51-6.52 (2H, m), 6.81 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.45 ( 1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(61f) {(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound synthesized in Example (61e) (5.45 g, 10.33 mmol) was dissolved in tetrahydrofuran (100 mL). Then, lithium aluminum hydride (0.78 g, 20.66 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.80 mL), 5N aqueous sodium hydroxide solution (0.80 mL) and water (2.40 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (300 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (2.32 g, 45%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.13-2.31 (2H, m), 3.24 (3H, s), 3.61 (1H, dd, J = 2.7, 12.1 Hz), 3.89-4.05 (5H, m) , 4.12-4.17 (1H, m), 4.32-4.41 (2H, m), 4.94-4.98 (1H, br m), 6.38 (1H, d, J = 3.9 Hz), 6.47-6.50 (2H, m), 6.88 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 500.14769 (M + H) <+> .
実施例(61c)で合成した化合物(5.55g,12.49mmol)、L-セリンメチルエステル塩酸塩(2.20g,13.74mmol)、HOBT・H2O(1.86g,13.74mmol)、N-メチルモルホリン(2.75mL,24.97mmol)、WSCI・HCl(2.87g,14.98mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(6.24g,収率91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.11-2.29 (2H, m), 3.23 (3H, s), 3.79 (3H, s), 3.86-3.95 (1H, m), 3.96-4.08 (5H, m), 4.79-4.83 (1H, m), 4.93-4.97 (1H, br m), 6.49-6.51 (2H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.97 (1H, br s).
(61e)メチル (4S)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(61d)で合成した化合物(6.24g,11.42mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(2.53mL,13.70mmol)、炭酸カリウム(2.37g,17.13mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(5.45g,91%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.12-2.30 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 3.89-3.96 (1H, m), 3.97-4.04 (3H, m), 4.58 (1H, dd, J = 9.0, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.9 Hz), 4.94-4.99 (1H, br m), 6.51-6.52 (2H, m), 6.81 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(61f){(4R)-2-[5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(3S)-テトラヒドロフラン-3-イルオキシ]フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール
実施例(61e)で合成した化合物(5.45g,10.33mmol)をテトラヒドロフラン(100mL)に溶解し、0℃で水素化リチウムアルミニウム(0.78g,20.66mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.80mL)、5規定水酸化ナトリウム水溶液(0.80mL)、水(2.40mL)の順に加え、10分間攪拌した。酢酸エチル(300mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(2.32g,45%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.13-2.31 (2H, m), 3.24 (3H, s), 3.61 (1H, dd, J = 2.7, 12.1 Hz), 3.89-4.05 (5H, m), 4.12-4.17 (1H, m), 4.32-4.41 (2H, m), 4.94-4.98 (1H, br m), 6.38 (1H, d, J = 3.9 Hz), 6.47-6.50 (2H, m), 6.88 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 500.14769 (M+H)+。 (61d) Methyl N-{[5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H-pyrrole- 2-yl] carbonyl} -L-serineate Compound (5.55 g, 12.49 mmol) synthesized in Example (61c), L-serine methyl ester hydrochloride (2.20 g, 13.74 mmol), HOBT · H 2 Using O (1.86 g, 13.74 mmol), N-methylmorpholine (2.75 mL, 24.97 mmol) and WSCI.HCl (2.87 g, 14.98 mmol) in the same manner as in Example (29a) The target compound (6.24 g, yield 91%) was obtained as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.11-2.29 (2H, m), 3.23 (3H, s), 3.79 (3H, s), 3.86-3.95 (1H, m), 3.96-4.08 (5H, m), 4.79-4.83 (1H, m), 4.93-4.97 (1H, br m), 6.49-6.51 (2H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d , J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.97 (1H, br s).
(61e) Methyl (4S) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrole-2-yl] -4,5-dihydro-1,3-oxazole-4-carboxylate Compound synthesized in Example (61d) (6.24 g, 11.42 mmol), bis (2-methoxyethyl) Aminosulfur trifluoride (2.53 mL, 13.70 mmol) and potassium carbonate (2.37 g, 17.13 mmol) were used in the same manner as in Example (38b) to give the target compound (5.45 g, 91%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 2.12-2.30 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 3.89-3.96 (1H, m), 3.97-4.04 (3H, m), 4.58 (1H, dd, J = 9.0, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.9 Hz), 4.94-4.99 (1H, br m), 6.51-6.52 (2H, m), 6.81 (1H, d, J = 3.9 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.45 ( 1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(61f) {(4R) -2- [5- (3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5-[(3S) -tetrahydrofuran-3-yloxy] phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol The compound synthesized in Example (61e) (5.45 g, 10.33 mmol) was dissolved in tetrahydrofuran (100 mL). Then, lithium aluminum hydride (0.78 g, 20.66 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (0.80 mL), 5N aqueous sodium hydroxide solution (0.80 mL) and water (2.40 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (300 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (2.32 g, 45%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.13-2.31 (2H, m), 3.24 (3H, s), 3.61 (1H, dd, J = 2.7, 12.1 Hz), 3.89-4.05 (5H, m) , 4.12-4.17 (1H, m), 4.32-4.41 (2H, m), 4.94-4.98 (1H, br m), 6.38 (1H, d, J = 3.9 Hz), 6.47-6.50 (2H, m), 6.88 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 500.14769 (M + H) <+> .
(実施例62)
[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール (Example 62)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol
[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール (Example 62)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol
(62a)5-[3-ブロモ-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(500mg,1.45mmol)、テトラヒドロ-4-ピラノール(0.17mL,1.74mmol)、トリフェニルホスフィン(841mg,3.20mmol)、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,1.40mL,3.08mmol)を用い、実施例(40b)と同様の方法で淡黄色油状の目的化合物(350mg,収率56%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.74-1.83 (2H, m), 1.98-2.05 (2H, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93-4.00 (2H, m), 4.43-4.50 (1H, m), 6.58 (1H, t, J = 2.0 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(62b)ベンジル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(62a)で合成した化合物(350mg,0.82mmol)、実施例(19e)で合成した化合物(400mg,1.23mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(40mg,0.05mmol)、炭酸カリウム(565mg,4.09mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(360mg,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.85 (2H, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.58-3.63 (2H, m), 3.96-4.01 (2H, m), 4.50-4.55 (1H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 2.4, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.85 (1H, t, J = 1.5 Hz), 6.97 (1H, t, J = 1.5 Hz), 6.99 (1H, dd, J = 2.4, 3.9 Hz), 7.33-7.49 (6H, m), 8.06 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.24 (1H, br s).
(62c)5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-カルボン酸
実施例(62b)で合成した化合物(360mg,0.66mmol)をエタノール(10mL)と酢酸エチル(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(100mg)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(276g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.75-1.85 (2H, m), 2.00-2.07 (2H, m), 3.21 (3H, s), 3.56-3.63 (2H, m), 3.94-4.02 (2H, m), 4.50-4.57 (1H, m), 6.51 (1H, s), 6.56 (1H, s), 6.88 (1H, s), 6.96-7.03 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.62 (1H, br s)。 (62a) 5- [3-Bromo-5- (tetrahydro-2H-pyran-4-yloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (500 mg, 1.45 mmol), Tetrahydro-4-pyranol (0.17 mL, 1.74 mmol), triphenylphosphine (841 mg, 3.20 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 1.40 mL, 3.08 mmol) were used. The target compound (350 mg, yield 56%) was obtained as a pale yellow oil in the same manner as in Example (40b).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.74-1.83 (2H, m), 1.98-2.05 (2H, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93-4.00 ( 2H, m), 4.43-4.50 (1H, m), 6.58 (1H, t, J = 2.0 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(62b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylate Compound (350 mg, 0.82 mmol) synthesized in Example (62a), compound (400 mg, 1.23 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (360 mg, yield 80%) as a yellow oil was obtained in the same manner as in Example (16e) using dichloromethane complex (40 mg, 0.05 mmol) and potassium carbonate (565 mg, 4.09 mmol). It was.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.85 (2H, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.58-3.63 (2H, m), 3.96-4.01 ( 2H, m), 4.50-4.55 (1H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 2.4, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.85 (1H , t, J = 1.5 Hz), 6.97 (1H, t, J = 1.5 Hz), 6.99 (1H, dd, J = 2.4, 3.9 Hz), 7.33-7.49 (6H, m), 8.06 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.24 (1H, br s).
(62c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylic acid The compound (360 mg, 0.66 mmol) synthesized in Example (62b) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL), 10% palladium carbon catalyst (100 mg) was added, and the mixture was added under a hydrogen atmosphere for 2 hours. Stir. The palladium carbon catalyst was removed by celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (276 g, yield 92%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.75-1.85 (2H, m), 2.00-2.07 (2H, m), 3.21 (3H, s), 3.56-3.63 (2H, m), 3.94-4.02 ( 2H, m), 4.50-4.57 (1H, m), 6.51 (1H, s), 6.56 (1H, s), 6.88 (1H, s), 6.96-7.03 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.62 (1H, br s).
実施例(19b)で合成した化合物(500mg,1.45mmol)、テトラヒドロ-4-ピラノール(0.17mL,1.74mmol)、トリフェニルホスフィン(841mg,3.20mmol)、アゾジカルボン酸ジエチル(2.2mol/Lトルエン溶液,1.40mL,3.08mmol)を用い、実施例(40b)と同様の方法で淡黄色油状の目的化合物(350mg,収率56%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.74-1.83 (2H, m), 1.98-2.05 (2H, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93-4.00 (2H, m), 4.43-4.50 (1H, m), 6.58 (1H, t, J = 2.0 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(62b)ベンジル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(62a)で合成した化合物(350mg,0.82mmol)、実施例(19e)で合成した化合物(400mg,1.23mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(40mg,0.05mmol)、炭酸カリウム(565mg,4.09mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(360mg,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.85 (2H, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.58-3.63 (2H, m), 3.96-4.01 (2H, m), 4.50-4.55 (1H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 2.4, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.85 (1H, t, J = 1.5 Hz), 6.97 (1H, t, J = 1.5 Hz), 6.99 (1H, dd, J = 2.4, 3.9 Hz), 7.33-7.49 (6H, m), 8.06 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.24 (1H, br s).
(62c)5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-カルボン酸
実施例(62b)で合成した化合物(360mg,0.66mmol)をエタノール(10mL)と酢酸エチル(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(100mg)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(276g,収率92%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.75-1.85 (2H, m), 2.00-2.07 (2H, m), 3.21 (3H, s), 3.56-3.63 (2H, m), 3.94-4.02 (2H, m), 4.50-4.57 (1H, m), 6.51 (1H, s), 6.56 (1H, s), 6.88 (1H, s), 6.96-7.03 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.62 (1H, br s)。 (62a) 5- [3-Bromo-5- (tetrahydro-2H-pyran-4-yloxy) phenoxy] -2- (methylsulfonyl) pyridine The compound synthesized in Example (19b) (500 mg, 1.45 mmol), Tetrahydro-4-pyranol (0.17 mL, 1.74 mmol), triphenylphosphine (841 mg, 3.20 mmol), diethyl azodicarboxylate (2.2 mol / L toluene solution, 1.40 mL, 3.08 mmol) were used. The target compound (350 mg, yield 56%) was obtained as a pale yellow oil in the same manner as in Example (40b).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.74-1.83 (2H, m), 1.98-2.05 (2H, m), 3.23 (3H, s), 3.55-3.62 (2H, m), 3.93-4.00 ( 2H, m), 4.43-4.50 (1H, m), 6.58 (1H, t, J = 2.0 Hz), 6.82 (1H, t, J = 1.6 Hz), 6.96 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(62b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylate Compound (350 mg, 0.82 mmol) synthesized in Example (62a), compound (400 mg, 1.23 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (360 mg, yield 80%) as a yellow oil was obtained in the same manner as in Example (16e) using dichloromethane complex (40 mg, 0.05 mmol) and potassium carbonate (565 mg, 4.09 mmol). It was.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.85 (2H, m), 2.01-2.05 (2H, m), 3.23 (3H, s), 3.58-3.63 (2H, m), 3.96-4.01 ( 2H, m), 4.50-4.55 (1H, m), 5.33 (2H, s), 6.52 (1H, dd, J = 2.4, 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.85 (1H , t, J = 1.5 Hz), 6.97 (1H, t, J = 1.5 Hz), 6.99 (1H, dd, J = 2.4, 3.9 Hz), 7.33-7.49 (6H, m), 8.06 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 9.24 (1H, br s).
(62c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole-2-carboxylic acid The compound (360 mg, 0.66 mmol) synthesized in Example (62b) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL), 10% palladium carbon catalyst (100 mg) was added, and the mixture was added under a hydrogen atmosphere for 2 hours. Stir. The palladium carbon catalyst was removed by celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (276 g, yield 92%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.75-1.85 (2H, m), 2.00-2.07 (2H, m), 3.21 (3H, s), 3.56-3.63 (2H, m), 3.94-4.02 ( 2H, m), 4.50-4.57 (1H, m), 6.51 (1H, s), 6.56 (1H, s), 6.88 (1H, s), 6.96-7.03 (2H, m), 7.43 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 9.62 (1H, br s).
(62d)メチル N-({5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}カルボニル)-L-セリネート
実施例(62c)で合成した化合物(276mg,0.60mmol)、L-セリンメチルエステル塩酸塩(115mg,0.72mmol)、HOBT・H2O(89mg,0.66mmol)、N-メチルモルホリン(0.13mL,1.20mmol)、WSCI・HCl(138mg,0.72mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(252mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.57-3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.50-4.57 (1H, m), 4.81-4.85 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.58 (1H, br s).
(62e)メチル (4S)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(62d)で合成した化合物(252mg,0.45mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.10mL,0.54mmol)、炭酸カリウム(95mg,0.67mol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(217g,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.58-3.65 (2H, m), 3.82 (3H, s), 3.96-4.02 (2H, m), 4.51-4.61 (2H, m), 4.67 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(62f)[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール
実施例(62e)で合成した化合物(217mg,0.40mmol)をテトラヒドロフラン(5mL)に溶解し、0℃で水素化リチウムアルミニウム(30mg,0.80mmol)を加えた。窒素雰囲気下30分攪拌後、水(30μL)、5規定水酸化ナトリウム水溶液(30μL)、水(100μL)の順に加え、10分間攪拌した。酢酸エチル(30mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(128mg,62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.88 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.58-3.64 (3H, m), 3.95-4.03 (3H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.49 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 514.16463 (M+H)+。 (62d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} carbonyl) -L-serineate Compound (276 mg, 0.60 mmol) synthesized in Example (62c), L-serine methyl ester hydrochloride (115 mg, 0.72 mmol), HOBT.H 2 O (89 mg, 0.66 mmol), N-methylmorpholine (0.13 mL, 1.20 mmol) and WSCI.HCl (138 mg, 0.72 mmol) in the same manner as in Example (29a), the target compound (252 mg, Yield 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.57 -3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.50-4.57 (1H, m), 4.81-4.85 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.58 (1H, br s).
(62e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrol-2-yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (252 mg, 0.45 mmol) synthesized in Example (62d), bis (2-methoxyethyl) aminosulfur The target compound (217 g, 89%) as a white solid was obtained in the same manner as in Example (38b) using trifluoride (0.10 mL, 0.54 mmol) and potassium carbonate (95 mg, 0.67 mol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.58-3.65 (2H, m), 3.82 (3H, s), 3.96-4.02 (2H, m), 4.51-4.61 (2H, m), 4.67 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.6 Hz), 6.99 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(62f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (217 mg, 0.40 mmol) synthesized in Example (62e) was dissolved in tetrahydrofuran (5 mL). Lithium aluminum hydride (30 mg, 0.80 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (30 μL), 5N aqueous sodium hydroxide solution (30 μL) and water (100 μL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (30 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (128 mg, 62%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.88 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.58-3.64 (3H, m), 3.95-4.03 ( 3H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.49 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 514.16463 (M + H) <+> .
実施例(62c)で合成した化合物(276mg,0.60mmol)、L-セリンメチルエステル塩酸塩(115mg,0.72mmol)、HOBT・H2O(89mg,0.66mmol)、N-メチルモルホリン(0.13mL,1.20mmol)、WSCI・HCl(138mg,0.72mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(252mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.57-3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.50-4.57 (1H, m), 4.81-4.85 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.58 (1H, br s).
(62e)メチル (4S)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(62d)で合成した化合物(252mg,0.45mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.10mL,0.54mmol)、炭酸カリウム(95mg,0.67mol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(217g,89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.58-3.65 (2H, m), 3.82 (3H, s), 3.96-4.02 (2H, m), 4.51-4.61 (2H, m), 4.67 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(62f)[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール
実施例(62e)で合成した化合物(217mg,0.40mmol)をテトラヒドロフラン(5mL)に溶解し、0℃で水素化リチウムアルミニウム(30mg,0.80mmol)を加えた。窒素雰囲気下30分攪拌後、水(30μL)、5規定水酸化ナトリウム水溶液(30μL)、水(100μL)の順に加え、10分間攪拌した。酢酸エチル(30mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色固体の目的化合物(128mg,62%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.77-1.88 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.58-3.64 (3H, m), 3.95-4.03 (3H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.49 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 514.16463 (M+H)+。 (62d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H-pyrrole- 2-yl} carbonyl) -L-serineate Compound (276 mg, 0.60 mmol) synthesized in Example (62c), L-serine methyl ester hydrochloride (115 mg, 0.72 mmol), HOBT.H 2 O (89 mg, 0.66 mmol), N-methylmorpholine (0.13 mL, 1.20 mmol) and WSCI.HCl (138 mg, 0.72 mmol) in the same manner as in Example (29a), the target compound (252 mg, Yield 75%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 2.53 (1H, t, J = 5.9 Hz), 3.23 (3H, s), 3.57 -3.64 (2H, m), 3.83 (3H, s), 3.95-4.09 (4H, m), 4.50-4.57 (1H, m), 4.81-4.85 (1H, m), 6.52 (1H, dd, J = 2.7, 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.82 (1H, d, J = 7.4 Hz), 6.86 (1H, t, J = 1.8 Hz), 6.99 (1H, t, J = 1.8 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.58 (1H, br s).
(62e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrol-2-yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (252 mg, 0.45 mmol) synthesized in Example (62d), bis (2-methoxyethyl) aminosulfur The target compound (217 g, 89%) as a white solid was obtained in the same manner as in Example (38b) using trifluoride (0.10 mL, 0.54 mmol) and potassium carbonate (95 mg, 0.67 mol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.86 (2H, m), 2.01-2.08 (2H, m), 3.24 (3H, s), 3.58-3.65 (2H, m), 3.82 (3H, s), 3.96-4.02 (2H, m), 4.51-4.61 (2H, m), 4.67 (1H, t, J = 8.2 Hz), 4.91 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H , d, J = 3.9 Hz), 6.56 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.9 Hz), 6.84 (1H, t, J = 1.6 Hz), 6.99 (1H, t , J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.55 (1H, br s).
(62f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydro-2H-pyran-4-yloxy) phenyl] -1H -Pyrrole-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (217 mg, 0.40 mmol) synthesized in Example (62e) was dissolved in tetrahydrofuran (5 mL). Lithium aluminum hydride (30 mg, 0.80 mmol) was added at 0 ° C. After stirring for 30 minutes under a nitrogen atmosphere, water (30 μL), 5N aqueous sodium hydroxide solution (30 μL) and water (100 μL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (30 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the target compound (128 mg, 62%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.77-1.88 (2H, m), 2.02-2.09 (2H, m), 3.24 (3H, s), 3.58-3.64 (3H, m), 3.95-4.03 ( 3H, m), 4.13-4.17 (1H, m), 4.32-4.41 (2H, m), 4.50-4.56 (1H, m), 6.38 (1H, d, J = 3.9 Hz), 6.49 (1H, d, J = 3.9 Hz), 6.54 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 1.6 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 514.16463 (M + H) <+> .
(実施例63)
[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール (Example 63)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol
[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール (Example 63)
[(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} -4,5-dihydro-1,3-oxazol-4-yl] methanol
(63a)5-[3-ブロモ-5-(テトラヒドロフラン-2-イルメトキシ)フェノキシ]-2-(メチルスルホニル)ピリジン
実施例(19b)で合成した化合物(1.50g,4.36mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、テトラヒドロフルフリルブロミド(1.49mL,13.07mmol)、と炭酸カリウム(3.01g,21.79mmol)を加え、窒素雰囲気下80℃で5時間撹拌した。反応液を室温まで冷却後に水(30mL)を加え、酢酸エチル(80mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(1.30g,収率70%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.69-1.78 (1H, m), 1.89-2.00 (2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s), 3.80-3.86 (1H, m), 3.89-3.98 (3H, m), 4.22-4.29 (1H, m), 6.60 (1H, t, J = 2.0 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.98 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(63b)ベンジル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(63a)で合成した化合物(1.30g,3.04mmol)、実施例(19e)で合成した化合物(1.49g,4.55mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.15g,0.18mmol)、炭酸カリウム(2.10g,15.18mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(1.60g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.71-1.81 (1H, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 (1H, m), 3.90-4.04 (3H, m), 4.25-4.32 (1H, m), 5.33 (2H, s), 6.52 (1H, t, J = 2.3 Hz), 6.57 (1H, s), 6.87 (1H, s), 6.98-7.01 (2H, m), 7.32-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.31 (1H, br s).
(63c)5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-カルボン酸
実施例(63b)で合成した化合物(1.60g,2.92mmol)をエタノール(50mL)と酢酸エチル(15mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(0.55g)を加えて水素雰囲気下に1時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(1.21g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.72-1.82 (1H, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 (1H, m), 3.90-4.09 (3H, m), 4.26-4.36 (1H, m), 6.44-6.57 (2H, m), 6.86-6.99 (2H, m), 7.13 (1H, s), 7.42 (1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.46 (1H, s), 10.06 (1H, br s)。 (63a) 5- [3-Bromo-5- (tetrahydrofuran-2-ylmethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (1.50 g, 4.36 mmol) synthesized in Example (19b) was replaced with N, Dissolved in N-dimethylformamide (15 mL), tetrahydrofurfuryl bromide (1.49 mL, 13.07 mmol) and potassium carbonate (3.01 g, 21.79 mmol) were added, and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -60%) to give the desired compound (1.30 g, Yield 70%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.69-1.78 (1H, m), 1.89-2.00 (2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s), 3.80-3.86 ( 1H, m), 3.89-3.98 (3H, m), 4.22-4.29 (1H, m), 6.60 (1H, t, J = 2.0 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.98 (1H , t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(63b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylate Example (63a) ) Compound (1.30 g, 3.04 mmol), the compound synthesized in Example (19e) (1.49 g, 4.55 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (1.60 g, yield) was obtained in the same manner as in Example (16e) using dichloromethane complex (0.15 g, 0.18 mmol) and potassium carbonate (2.10 g, 15.18 mmol). 96%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.71-1.81 (1H, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 ( 1H, m), 3.90-4.04 (3H, m), 4.25-4.32 (1H, m), 5.33 (2H, s), 6.52 (1H, t, J = 2.3 Hz), 6.57 (1H, s), 6.87 (1H, s), 6.98-7.01 (2H, m), 7.32-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.31 ( 1H, br s).
(63c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylic acid Example (63b) The compound synthesized in step (1.60 g, 2.92 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and ethyl acetate (15 mL), 10% palladium carbon catalyst (0.55 g) was added, and the mixture was added under a hydrogen atmosphere for 1 hour. Stir. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.21 g, yield 90%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.72-1.82 (1H, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 ( 1H, m), 3.90-4.09 (3H, m), 4.26-4.36 (1H, m), 6.44-6.57 (2H, m), 6.86-6.99 (2H, m), 7.13 (1H, s), 7.42 ( 1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.46 (1H, s), 10.06 (1H, br s).
実施例(19b)で合成した化合物(1.50g,4.36mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、テトラヒドロフルフリルブロミド(1.49mL,13.07mmol)、と炭酸カリウム(3.01g,21.79mmol)を加え、窒素雰囲気下80℃で5時間撹拌した。反応液を室温まで冷却後に水(30mL)を加え、酢酸エチル(80mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(1.30g,収率70%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.69-1.78 (1H, m), 1.89-2.00 (2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s), 3.80-3.86 (1H, m), 3.89-3.98 (3H, m), 4.22-4.29 (1H, m), 6.60 (1H, t, J = 2.0 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.98 (1H, t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(63b)ベンジル 5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(63a)で合成した化合物(1.30g,3.04mmol)、実施例(19e)で合成した化合物(1.49g,4.55mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(0.15g,0.18mmol)、炭酸カリウム(2.10g,15.18mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(1.60g,収率96%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.71-1.81 (1H, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 (1H, m), 3.90-4.04 (3H, m), 4.25-4.32 (1H, m), 5.33 (2H, s), 6.52 (1H, t, J = 2.3 Hz), 6.57 (1H, s), 6.87 (1H, s), 6.98-7.01 (2H, m), 7.32-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.31 (1H, br s).
(63c)5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-カルボン酸
実施例(63b)で合成した化合物(1.60g,2.92mmol)をエタノール(50mL)と酢酸エチル(15mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(0.55g)を加えて水素雰囲気下に1時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(1.21g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.72-1.82 (1H, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 (1H, m), 3.90-4.09 (3H, m), 4.26-4.36 (1H, m), 6.44-6.57 (2H, m), 6.86-6.99 (2H, m), 7.13 (1H, s), 7.42 (1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.46 (1H, s), 10.06 (1H, br s)。 (63a) 5- [3-Bromo-5- (tetrahydrofuran-2-ylmethoxy) phenoxy] -2- (methylsulfonyl) pyridine The compound (1.50 g, 4.36 mmol) synthesized in Example (19b) was replaced with N, Dissolved in N-dimethylformamide (15 mL), tetrahydrofurfuryl bromide (1.49 mL, 13.07 mmol) and potassium carbonate (3.01 g, 21.79 mmol) were added, and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% -60%) to give the desired compound (1.30 g, Yield 70%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.69-1.78 (1H, m), 1.89-2.00 (2H, m), 2.04-2.12 (1H, m), 3.23 (3H, s), 3.80-3.86 ( 1H, m), 3.89-3.98 (3H, m), 4.22-4.29 (1H, m), 6.60 (1H, t, J = 2.0 Hz), 6.83 (1H, t, J = 2.0 Hz), 6.98 (1H , t, J = 2.0 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(63b) Benzyl 5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylate Example (63a) ) Compound (1.30 g, 3.04 mmol), the compound synthesized in Example (19e) (1.49 g, 4.55 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichlorochloride The target compound (1.60 g, yield) was obtained in the same manner as in Example (16e) using dichloromethane complex (0.15 g, 0.18 mmol) and potassium carbonate (2.10 g, 15.18 mmol). 96%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.71-1.81 (1H, m), 1.90-2.02 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.80-3.88 ( 1H, m), 3.90-4.04 (3H, m), 4.25-4.32 (1H, m), 5.33 (2H, s), 6.52 (1H, t, J = 2.3 Hz), 6.57 (1H, s), 6.87 (1H, s), 6.98-7.01 (2H, m), 7.32-7.45 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.31 ( 1H, br s).
(63c) 5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2-carboxylic acid Example (63b) The compound synthesized in step (1.60 g, 2.92 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and ethyl acetate (15 mL), 10% palladium carbon catalyst (0.55 g) was added, and the mixture was added under a hydrogen atmosphere for 1 hour. Stir. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (1.21 g, yield 90%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.72-1.82 (1H, m), 1.91-2.02 (2H, m), 2.04-2.13 (1H, m), 3.20 (3H, s), 3.81-3.89 ( 1H, m), 3.90-4.09 (3H, m), 4.26-4.36 (1H, m), 6.44-6.57 (2H, m), 6.86-6.99 (2H, m), 7.13 (1H, s), 7.42 ( 1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.46 (1H, s), 10.06 (1H, br s).
(63d)メチル N-({5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}カルボニル)-L-セリネート
実施例(63c)で合成した化合物(1.21g,2.64)mmol)、L-セリンメチルエステル塩酸塩(0.50g,3.17mmol)、HOBT・H2O(0.39g,2.90mmol)、N-メチルモルホリン(0.58mL,5.28mmol)、WSCI・HCl(0.61g,3.17mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(1.33g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.71-1.81 (1H, m), 1.91-2.03 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.82-3.89 (1H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1H, m), 4.81-4.86 (1H, m), 6.51 (1H, t, J = 2.7 Hz), 6.54-6.56 (1H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86-6.91 (2H, m), 7.00 (1H, d, J = 6.3 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.94 (1H, br s).
(63e)メチル (4S)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(63d)で合成した化合物(1.33g,2.37mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.52mL,2.85mmol)、炭酸カリウム(0.49g,3.56mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(1.14g,88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.75-1.83 (1H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.33 (1H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.49 (1H, br s).
(63f)[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール
実施例(63e)で合成した化合物(1.14g,2.10mmol)をテトラヒドロフラン(20mL)に溶解し、0℃で水素化リチウムアルミニウム(0.16g,4.21mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.16mL)、5規定水酸化ナトリウム水溶液(0.16mL)、水(0.48mL)の順に加え、10分間攪拌した。酢酸エチル(80mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色粉の目的化合物(756mg,71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.73-1.83 (1H, m), 1.92-2.02 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H , s), 3.60 (1H, dd, J = 3.1, 12.1 Hz), 3.85 (1H, dd, J = 7.0, 14.9 Hz), 3.91-4.02 (4H, m), 4.09-4.15 (1H, m), 4.26-4.40 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.46 (1H, dd, J = 2.3, 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 514.16351 (M+H)+。 (63d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} Carbonyl) -L-serineate Compound (1.21 g, 2.64) mmol) synthesized in Example (63c), L-serine methyl ester hydrochloride (0.50 g, 3.17 mmol), HOBT.H 2 O ( 0.39 g, 2.90 mmol), N-methylmorpholine (0.58 mL, 5.28 mmol), WSCI.HCl (0.61 g, 3.17 mmol) and a white solid in the same manner as in Example (29a) Of the target compound (1.33 g, yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.71-1.81 (1H, m), 1.91-2.03 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.82-3.89 (1H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1H, m), 4.81-4.86 (1H, m), 6.51 (1H, t, J = 2.7 Hz) , 6.54-6.56 (1H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86-6.91 (2H, m), 7.00 (1H, d, J = 6.3 Hz), 7.43 (1H, dd , J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.94 (1H, br s).
(63e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (1.33 g, 2.37 mmol) synthesized in Example (63d), bis (2-methoxyethyl) aminosulfur trifluoride (0.52 mL, 2.85 mmol) and potassium carbonate (0.49 g, 3.56 mmol) were used to obtain the target compound (1.14 g, 88%) as a white solid in the same manner as in Example (38b). .
1 H-NMR (CDCl 3 , 400 MHz): δ 1.75-1.83 (1H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.33 (1H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H , t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.81 (1H , d, J = 3.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.49 (1H, br s).
(63f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Il} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (1.14 g, 2.10 mmol) synthesized in Example (63e) was dissolved in tetrahydrofuran (20 mL) and dissolved at 0 ° C. Lithium aluminum hydride (0.16 g, 4.21 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.16 mL), 5N aqueous sodium hydroxide solution (0.16 mL) and water (0.48 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (80 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (756 mg, 71%) as a white powder. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.73-1.83 (1H, m), 1.92-2.02 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.60 (1H, dd, J = 3.1, 12.1 Hz), 3.85 (1H, dd, J = 7.0, 14.9 Hz), 3.91-4.02 (4H, m), 4.09-4.15 (1H, m), 4.26-4.40 (3H, m) , 6.37 (1H, d, J = 3.9 Hz), 6.46 (1H, dd, J = 2.3, 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.88 (1H, t, J = 1.6 Hz) , 7.04 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) .
MS (ESI) m / z: 514.16351 (M + H) <+> .
実施例(63c)で合成した化合物(1.21g,2.64)mmol)、L-セリンメチルエステル塩酸塩(0.50g,3.17mmol)、HOBT・H2O(0.39g,2.90mmol)、N-メチルモルホリン(0.58mL,5.28mmol)、WSCI・HCl(0.61g,3.17mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(1.33g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.71-1.81 (1H, m), 1.91-2.03 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.82-3.89 (1H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1H, m), 4.81-4.86 (1H, m), 6.51 (1H, t, J = 2.7 Hz), 6.54-6.56 (1H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86-6.91 (2H, m), 7.00 (1H, d, J = 6.3 Hz), 7.43 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.94 (1H, br s).
(63e)メチル (4S)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-カルボキシレート
実施例(63d)で合成した化合物(1.33g,2.37mmol)、ビス(2-メトキシエチル)アミノサルファー トリフルオリド(0.52mL,2.85mmol)、炭酸カリウム(0.49g,3.56mmol)を用い、実施例(38b)と同様の方法で白色固体の目的化合物(1.14g,88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.75-1.83 (1H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.33 (1H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H, t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.81 (1H, d, J = 3.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.49 (1H, br s).
(63f)[(4R)-2-{5-[3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-(テトラヒドロフラン-2-イルメトキシ)フェニル]-1H-ピロール-2-イル}-4,5-ジヒドロ-1,3-オキサゾール-4-イル]メタノール
実施例(63e)で合成した化合物(1.14g,2.10mmol)をテトラヒドロフラン(20mL)に溶解し、0℃で水素化リチウムアルミニウム(0.16g,4.21mmol)を加えた。窒素雰囲気下30分攪拌後、水(0.16mL)、5規定水酸化ナトリウム水溶液(0.16mL)、水(0.48mL)の順に加え、10分間攪拌した。酢酸エチル(80mL)を加え5分攪拌後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~5%)を用いて精製することにより、白色粉の目的化合物(756mg,71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.73-1.83 (1H, m), 1.92-2.02 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H , s), 3.60 (1H, dd, J = 3.1, 12.1 Hz), 3.85 (1H, dd, J = 7.0, 14.9 Hz), 3.91-4.02 (4H, m), 4.09-4.15 (1H, m), 4.26-4.40 (3H, m), 6.37 (1H, d, J = 3.9 Hz), 6.46 (1H, dd, J = 2.3, 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.04 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 514.16351 (M+H)+。 (63d) Methyl N-({5- [3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrol-2-yl} Carbonyl) -L-serineate Compound (1.21 g, 2.64) mmol) synthesized in Example (63c), L-serine methyl ester hydrochloride (0.50 g, 3.17 mmol), HOBT.H 2 O ( 0.39 g, 2.90 mmol), N-methylmorpholine (0.58 mL, 5.28 mmol), WSCI.HCl (0.61 g, 3.17 mmol) and a white solid in the same manner as in Example (29a) Of the target compound (1.33 g, yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.71-1.81 (1H, m), 1.91-2.03 (2H, m), 2.05-2.14 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.82-3.89 (1H, m), 3.91-4.08 (5H, m), 4.25-4.32 (1H, m), 4.81-4.86 (1H, m), 6.51 (1H, t, J = 2.7 Hz) , 6.54-6.56 (1H, m), 6.74 (1H, dd, J = 2.3, 3.9 Hz), 6.86-6.91 (2H, m), 7.00 (1H, d, J = 6.3 Hz), 7.43 (1H, dd , J = 2.7, 8.6 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.94 (1H, br s).
(63e) Methyl (4S) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Yl} -4,5-dihydro-1,3-oxazole-4-carboxylate Compound (1.33 g, 2.37 mmol) synthesized in Example (63d), bis (2-methoxyethyl) aminosulfur trifluoride (0.52 mL, 2.85 mmol) and potassium carbonate (0.49 g, 3.56 mmol) were used to obtain the target compound (1.14 g, 88%) as a white solid in the same manner as in Example (38b). .
1 H-NMR (CDCl 3 , 400 MHz): δ 1.75-1.83 (1H, m), 1.91-2.03 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.81 (3H, s), 3.86 (1H, t, J = 7.0 Hz), 3.91-4.04 (3H, m), 4.26-4.33 (1H, m), 4.57 (1H, dd, J = 8.6, 10.6 Hz), 4.67 (1H , t, J = 8.6 Hz), 4.90 (1H, dd, J = 7.8, 10.6 Hz), 6.52 (1H, d, J = 3.9 Hz), 6.57 (1H, t, J = 2.0 Hz), 6.81 (1H , d, J = 3.5 Hz), 6.85 (1H, t, J = 1.6 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.49 (1H, br s).
(63f) [(4R) -2- {5- [3-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} -5- (tetrahydrofuran-2-ylmethoxy) phenyl] -1H-pyrrole-2 -Il} -4,5-dihydro-1,3-oxazol-4-yl] methanol The compound (1.14 g, 2.10 mmol) synthesized in Example (63e) was dissolved in tetrahydrofuran (20 mL) and dissolved at 0 ° C. Lithium aluminum hydride (0.16 g, 4.21 mmol) was added. After stirring for 30 minutes under a nitrogen atmosphere, water (0.16 mL), 5N aqueous sodium hydroxide solution (0.16 mL) and water (0.48 mL) were added in this order, and the mixture was stirred for 10 minutes. Ethyl acetate (80 mL) was added and stirred for 5 minutes, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 5%) to give the desired compound (756 mg, 71%) as a white powder. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.73-1.83 (1H, m), 1.92-2.02 (2H, m), 2.05-2.15 (1H, m), 3.23 (3H, s), 3.60 (1H, dd, J = 3.1, 12.1 Hz), 3.85 (1H, dd, J = 7.0, 14.9 Hz), 3.91-4.02 (4H, m), 4.09-4.15 (1H, m), 4.26-4.40 (3H, m) , 6.37 (1H, d, J = 3.9 Hz), 6.46 (1H, dd, J = 2.3, 3.9 Hz), 6.55 (1H, t, J = 2.0 Hz), 6.88 (1H, t, J = 1.6 Hz) , 7.04 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 2.7, 8.6 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz) .
MS (ESI) m / z: 514.16351 (M + H) <+> .
(実施例64)
3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェノキシ)ジヒドロフラン-2(3H)-オン (Example 64)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one
3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェノキシ)ジヒドロフラン-2(3H)-オン (Example 64)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one
(64a)N-[(2R)-2-ヒドロキシプロピル]-5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-カルボキサミド
実施例(21a)で合成した化合物(2.70g,8.35mmol)を塩化メチレン(20mL)に溶解し、トリエチルアミン(3.80mL,27.3mmol)、トリイソプロピルシリルクロリド(3.00mL,14.0mmol)、4-ジメチルアミノピリジン(1.10g,9.00mmol)を加え、窒素雰囲気下で18時間攪拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、茶色液体を得た。これを酢酸エチル(20mL)に溶解し、10%パラジウム炭素触媒(1.15g)を加えて水素雰囲気下室温で4時間撹拌した。セライト濾過を行い、減圧下溶媒を留去することで茶色泡状の化合物を得た。この化合物を塩化メチレン(50mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(1.42mL,18.0mmol)、WSCI・HCl(3.85g,20.1mmol)、4-ジメチルアミノピリジン(1.23g,10.1mmol)を加え、窒素雰囲気下室温で1日撹拌した。飽和塩化アンモニウム水溶液(60mL)を加え、塩化メチレン(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10~40%)を用いて精製することにより、黄色液体の目的化合物(1.20g,収率32%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.11 (18H, d, J = 7.3 Hz), 1.23 (3H, d, J = 5.9 Hz), 1.24-1.32 (3H, m), 2.84-2.97 (1H, br m), 3.25-3.31 (1H, m), 3.62 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 3.80 (3H, s), 4.01 (1H, t, J = 6.8 Hz), 6.37 (1H, t, J = 2.2 Hz), 6.43-6.48 (2H, m), 6.62-6.64 (1H, m), 6.70 (2H, s), 9.78 (1H, br s).
(64b)(5S)-2-(5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール
実施例(64a)で合成した化合物(1.20g,2.69mmol)、メタンスルホン酸無水物(1.30g,7.46mmol)、トリエチルアミン(2.00mL,14.35mmol)を用い、実施例(16j)と同様の方法で黄色液体の目的化合物(627mg,収率54%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.11 (18H, d, J = 7.0 Hz), 1.22-1.31 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.52 (1H, ddd, J = 14.1, 7.0, 3.1 Hz), 3.79 (3H, s), 4.01-4.10 (1H, m), 4.77-4.85 (1H, m), 6.36 (1H, d, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.67-6.72 (2H, m), 6.76 (1H, d, J = 3.5 Hz).
(64c)2-(3-メトキシ-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-(メチルスルホニル)ピラジン
実施例(64b)で合成した化合物(627mg,1.46mmol)をテトラヒドロフラン(2.0mL)に溶解し、0℃でテトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.0mL,2.0mmol)を加え、窒素雰囲気下30分撹拌した。飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、淡橙色液体の化合物を得た。これをアセトニトリル(15mL)に溶解し、実施例(43c)で合成した化合物(310mg,1.61mmol)、炭酸セシウム(820mg,2.52mmol)を加え、室温で2時間半撹拌した。反応液に水(30mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、黄色固体の目的化合物(657mg,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 5.9 Hz), 3.23 (3H, s), 3.52 (1H, dd, J = 14.1, 7.4 Hz), 3.85 (3H, s), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.78-4.87 (1H, m), 6.52 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.2 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 1.8 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.80 (1H, d, J = 1.2 Hz)。 (64a) N-[(2R) -2-hydroxypropyl] -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide synthesized in Example (21a) The compound (2.70 g, 8.35 mmol) was dissolved in methylene chloride (20 mL), triethylamine (3.80 mL, 27.3 mmol), triisopropylsilyl chloride (3.00 mL, 14.0 mmol), 4-dimethylamino Pyridine (1.10 g, 9.00 mmol) was added and stirred for 18 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to obtain a brown liquid. This was dissolved in ethyl acetate (20 mL), 10% palladium carbon catalyst (1.15 g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. Celite filtration was performed, and the solvent was distilled off under reduced pressure to obtain a brown foamy compound. This compound was dissolved in methylene chloride (50 mL), and (R)-(−)-1-amino-2-propanol (1.42 mL, 18.0 mmol), WSCI • HCl (3.85 g, 20.1 mmol), 4-Dimethylaminopyridine (1.23 g, 10.1 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (60 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10-40%) to give the target compound (1.20 g, yield) as a yellow liquid. 32%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.11 (18H, d, J = 7.3 Hz), 1.23 (3H, d, J = 5.9 Hz), 1.24-1.32 (3H, m), 2.84-2.97 (1H , br m), 3.25-3.31 (1H, m), 3.62 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 3.80 (3H, s), 4.01 (1H, t, J = 6.8 Hz), 6.37 (1H, t, J = 2.2 Hz), 6.43-6.48 (2H, m), 6.62-6.64 (1H, m), 6.70 (2H, s), 9.78 (1H, br s).
(64b) (5S) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-methyl-4,5-dihydro-1 , 3-Oxazole Using the compound synthesized in Example (64a) (1.20 g, 2.69 mmol), methanesulfonic anhydride (1.30 g, 7.46 mmol), triethylamine (2.00 mL, 14.35 mmol). The target compound (627 mg, yield 54%) was obtained as a yellow liquid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.11 (18H, d, J = 7.0 Hz), 1.22-1.31 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.52 (1H, ddd , J = 14.1, 7.0, 3.1 Hz), 3.79 (3H, s), 4.01-4.10 (1H, m), 4.77-4.85 (1H, m), 6.36 (1H, d, J = 2.0 Hz), 6.47 ( 1H, d, J = 3.9 Hz), 6.67-6.72 (2H, m), 6.76 (1H, d, J = 3.5 Hz).
(64c) 2- (3-Methoxy-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy ) -5- (Methylsulfonyl) pyrazine The compound (627 mg, 1.46 mmol) synthesized in Example (64b) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution) was dissolved at 0 ° C. , 2.0 mL, 2.0 mmol) and stirred for 30 minutes under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pale orange liquid compound. This was dissolved in acetonitrile (15 mL), the compound (310 mg, 1.61 mmol) synthesized in Example (43c) and cesium carbonate (820 mg, 2.52 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (657 mg, yield) as a yellow solid. To 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 3.23 (3H, s), 3.52 (1H, dd, J = 14.1, 7.4 Hz), 3.85 (3H, s ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.78-4.87 (1H, m), 6.52 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.2 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 1.8 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.80 (1H , d, J = 1.2 Hz).
実施例(21a)で合成した化合物(2.70g,8.35mmol)を塩化メチレン(20mL)に溶解し、トリエチルアミン(3.80mL,27.3mmol)、トリイソプロピルシリルクロリド(3.00mL,14.0mmol)、4-ジメチルアミノピリジン(1.10g,9.00mmol)を加え、窒素雰囲気下で18時間攪拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~20%)を用いて精製することで、茶色液体を得た。これを酢酸エチル(20mL)に溶解し、10%パラジウム炭素触媒(1.15g)を加えて水素雰囲気下室温で4時間撹拌した。セライト濾過を行い、減圧下溶媒を留去することで茶色泡状の化合物を得た。この化合物を塩化メチレン(50mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(1.42mL,18.0mmol)、WSCI・HCl(3.85g,20.1mmol)、4-ジメチルアミノピリジン(1.23g,10.1mmol)を加え、窒素雰囲気下室温で1日撹拌した。飽和塩化アンモニウム水溶液(60mL)を加え、塩化メチレン(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10~40%)を用いて精製することにより、黄色液体の目的化合物(1.20g,収率32%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.11 (18H, d, J = 7.3 Hz), 1.23 (3H, d, J = 5.9 Hz), 1.24-1.32 (3H, m), 2.84-2.97 (1H, br m), 3.25-3.31 (1H, m), 3.62 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 3.80 (3H, s), 4.01 (1H, t, J = 6.8 Hz), 6.37 (1H, t, J = 2.2 Hz), 6.43-6.48 (2H, m), 6.62-6.64 (1H, m), 6.70 (2H, s), 9.78 (1H, br s).
(64b)(5S)-2-(5-{3-メトキシ-5-[(トリイソプロピルシリル)オキシ]フェニル}-1H-ピロール-2-イル)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール
実施例(64a)で合成した化合物(1.20g,2.69mmol)、メタンスルホン酸無水物(1.30g,7.46mmol)、トリエチルアミン(2.00mL,14.35mmol)を用い、実施例(16j)と同様の方法で黄色液体の目的化合物(627mg,収率54%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.11 (18H, d, J = 7.0 Hz), 1.22-1.31 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.52 (1H, ddd, J = 14.1, 7.0, 3.1 Hz), 3.79 (3H, s), 4.01-4.10 (1H, m), 4.77-4.85 (1H, m), 6.36 (1H, d, J = 2.0 Hz), 6.47 (1H, d, J = 3.9 Hz), 6.67-6.72 (2H, m), 6.76 (1H, d, J = 3.5 Hz).
(64c)2-(3-メトキシ-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-5-(メチルスルホニル)ピラジン
実施例(64b)で合成した化合物(627mg,1.46mmol)をテトラヒドロフラン(2.0mL)に溶解し、0℃でテトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,2.0mL,2.0mmol)を加え、窒素雰囲気下30分撹拌した。飽和塩化アンモニウム水溶液(30mL)を加え、塩化メチレン(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、淡橙色液体の化合物を得た。これをアセトニトリル(15mL)に溶解し、実施例(43c)で合成した化合物(310mg,1.61mmol)、炭酸セシウム(820mg,2.52mmol)を加え、室温で2時間半撹拌した。反応液に水(30mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~4%)を用いて精製することにより、黄色固体の目的化合物(657mg,収率~100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 5.9 Hz), 3.23 (3H, s), 3.52 (1H, dd, J = 14.1, 7.4 Hz), 3.85 (3H, s), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.78-4.87 (1H, m), 6.52 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.2 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 1.8 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.80 (1H, d, J = 1.2 Hz)。 (64a) N-[(2R) -2-hydroxypropyl] -5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrole-2-carboxamide synthesized in Example (21a) The compound (2.70 g, 8.35 mmol) was dissolved in methylene chloride (20 mL), triethylamine (3.80 mL, 27.3 mmol), triisopropylsilyl chloride (3.00 mL, 14.0 mmol), 4-dimethylamino Pyridine (1.10 g, 9.00 mmol) was added and stirred for 18 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 20%) to obtain a brown liquid. This was dissolved in ethyl acetate (20 mL), 10% palladium carbon catalyst (1.15 g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. Celite filtration was performed, and the solvent was distilled off under reduced pressure to obtain a brown foamy compound. This compound was dissolved in methylene chloride (50 mL), and (R)-(−)-1-amino-2-propanol (1.42 mL, 18.0 mmol), WSCI • HCl (3.85 g, 20.1 mmol), 4-Dimethylaminopyridine (1.23 g, 10.1 mmol) was added, and the mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (60 mL) was added, and the mixture was extracted with methylene chloride (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10-40%) to give the target compound (1.20 g, yield) as a yellow liquid. 32%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.11 (18H, d, J = 7.3 Hz), 1.23 (3H, d, J = 5.9 Hz), 1.24-1.32 (3H, m), 2.84-2.97 (1H , br m), 3.25-3.31 (1H, m), 3.62 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 3.80 (3H, s), 4.01 (1H, t, J = 6.8 Hz), 6.37 (1H, t, J = 2.2 Hz), 6.43-6.48 (2H, m), 6.62-6.64 (1H, m), 6.70 (2H, s), 9.78 (1H, br s).
(64b) (5S) -2- (5- {3-methoxy-5-[(triisopropylsilyl) oxy] phenyl} -1H-pyrrol-2-yl) -5-methyl-4,5-dihydro-1 , 3-Oxazole Using the compound synthesized in Example (64a) (1.20 g, 2.69 mmol), methanesulfonic anhydride (1.30 g, 7.46 mmol), triethylamine (2.00 mL, 14.35 mmol). The target compound (627 mg, yield 54%) was obtained as a yellow liquid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.11 (18H, d, J = 7.0 Hz), 1.22-1.31 (3H, m), 1.42 (3H, d, J = 6.3 Hz), 3.52 (1H, ddd , J = 14.1, 7.0, 3.1 Hz), 3.79 (3H, s), 4.01-4.10 (1H, m), 4.77-4.85 (1H, m), 6.36 (1H, d, J = 2.0 Hz), 6.47 ( 1H, d, J = 3.9 Hz), 6.67-6.72 (2H, m), 6.76 (1H, d, J = 3.5 Hz).
(64c) 2- (3-Methoxy-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenoxy ) -5- (Methylsulfonyl) pyrazine The compound (627 mg, 1.46 mmol) synthesized in Example (64b) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution) was dissolved at 0 ° C. , 2.0 mL, 2.0 mmol) and stirred for 30 minutes under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pale orange liquid compound. This was dissolved in acetonitrile (15 mL), the compound (310 mg, 1.61 mmol) synthesized in Example (43c) and cesium carbonate (820 mg, 2.52 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 4%) to give the target compound (657 mg, yield) as a yellow solid. To 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 5.9 Hz), 3.23 (3H, s), 3.52 (1H, dd, J = 14.1, 7.4 Hz), 3.85 (3H, s ), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.78-4.87 (1H, m), 6.52 (1H, d, J = 3.5 Hz), 6.62 (1H, t, J = 2.2 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.94 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 1.8 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.80 (1H , d, J = 1.2 Hz).
(64d)3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェノール
実施例(64c)で合成した化合物(657mg,1.53mmol)、三臭化ホウ素(1.0mol/L塩化メチレン溶液,3.50mL,3.50mmol)を用い、実施例(40g)と同様の方法で白色固体の目的化合物(486mg,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.50 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 3.65 (1H, dd, J = 13.1, 7.6 Hz), 4.19 (1H, dd, J = 13.5, 9.2 Hz), 4.92-5.02 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1H, m), 6.96 (1H, s), 7.44 (1H, s), 8.49 (1H, d, J = 1.2 Hz), 8.82 (1H, d, J = 1.2 Hz).
(64e)3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェノキシ)ジヒドロフラン-2(3H)-オン
実施例(64d)で合成した化合物(100mg,0.24mmol)、α-ブロモ-γ-ブチロラクトン(0.045mL,0.48mmol)、炭酸カリウム(100mg,0.72mmol)を用い、実施例(6b)と同様の方法で白色固体の目的化合物(63mg,収率52%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.47-2.56 (1H, m), 2.72-2.79 (1H, m), 3.24 (3H, s), 3.53 (1H, dd, J = 14.6, 7.3 Hz), 4.06 (1H, dd, J = 14.6, 8.8 Hz), 4.35-4.41 (1H, m), 4.55 (1H, td, J = 8.8, 3.9 Hz), 4.78-4.87 (1H, m), 4.99 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 2.2 Hz), 7.02 (1H, t, J = 1.5 Hz), 7.17 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.0 Hz), 8.79 (1H, d, J = 1.0 Hz).
MS (ESI) m/z: 499.12843 (M+H)+。 (64d) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenol Compound (657 mg, 1.53 mmol) synthesized in Example (64c), boron tribromide (1.0 mol / L methylene chloride solution, 3.50 mL, 3.50 mmol) ) Was used to obtain the target compound (486 mg, yield 77%) as a white solid in the same manner as in Example (40 g).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.50 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 3.65 (1H, dd, J = 13.1, 7.6 Hz), 4.19 (1H, dd , J = 13.5, 9.2 Hz), 4.92-5.02 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1H, m), 6.96 (1H, s), 7.44 (1H, s), 8.49 (1H, d, J = 1.2 Hz), 8.82 (1H, d, J = 1.2 Hz).
(64e) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 5- (Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (100 mg, 0.24 mmol) synthesized in Example (64d), α-bromo-γ-butyrolactone ( 0.045 mL, 0.48 mmol) and potassium carbonate (100 mg, 0.72 mmol) were used to obtain the target compound (63 mg, 52% yield) as a white solid in the same manner as in Example (6b).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.47-2.56 (1H, m), 2.72-2.79 (1H, m), 3.24 (3H, s), 3.53 (1H, dd, J = 14.6, 7.3 Hz), 4.06 (1H, dd, J = 14.6, 8.8 Hz), 4.35-4.41 (1H, m), 4.55 (1H, td, J = 8.8, 3.9 Hz), 4.78-4.87 (1H, m), 4.99 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.80 (1H, t , J = 2.2 Hz), 7.02 (1H, t, J = 1.5 Hz), 7.17 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.0 Hz), 8.79 (1H, d, J = 1.0 Hz).
MS (ESI) m / z: 499.12843 (M + H) <+> .
実施例(64c)で合成した化合物(657mg,1.53mmol)、三臭化ホウ素(1.0mol/L塩化メチレン溶液,3.50mL,3.50mmol)を用い、実施例(40g)と同様の方法で白色固体の目的化合物(486mg,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.50 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 3.65 (1H, dd, J = 13.1, 7.6 Hz), 4.19 (1H, dd, J = 13.5, 9.2 Hz), 4.92-5.02 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1H, m), 6.96 (1H, s), 7.44 (1H, s), 8.49 (1H, d, J = 1.2 Hz), 8.82 (1H, d, J = 1.2 Hz).
(64e)3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェノキシ)ジヒドロフラン-2(3H)-オン
実施例(64d)で合成した化合物(100mg,0.24mmol)、α-ブロモ-γ-ブチロラクトン(0.045mL,0.48mmol)、炭酸カリウム(100mg,0.72mmol)を用い、実施例(6b)と同様の方法で白色固体の目的化合物(63mg,収率52%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.47-2.56 (1H, m), 2.72-2.79 (1H, m), 3.24 (3H, s), 3.53 (1H, dd, J = 14.6, 7.3 Hz), 4.06 (1H, dd, J = 14.6, 8.8 Hz), 4.35-4.41 (1H, m), 4.55 (1H, td, J = 8.8, 3.9 Hz), 4.78-4.87 (1H, m), 4.99 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.80 (1H, t, J = 2.2 Hz), 7.02 (1H, t, J = 1.5 Hz), 7.17 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.0 Hz), 8.79 (1H, d, J = 1.0 Hz).
MS (ESI) m/z: 499.12843 (M+H)+。 (64d) 3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[5- ( Methylsulfonyl) pyrazin-2-yl] oxy} phenol Compound (657 mg, 1.53 mmol) synthesized in Example (64c), boron tribromide (1.0 mol / L methylene chloride solution, 3.50 mL, 3.50 mmol) ) Was used to obtain the target compound (486 mg, yield 77%) as a white solid in the same manner as in Example (40 g).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.50 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 3.65 (1H, dd, J = 13.1, 7.6 Hz), 4.19 (1H, dd , J = 13.5, 9.2 Hz), 4.92-5.02 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.54 (1H, s), 6.80-6.84 (1H, m), 6.96 (1H, s), 7.44 (1H, s), 8.49 (1H, d, J = 1.2 Hz), 8.82 (1H, d, J = 1.2 Hz).
(64e) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 5- (Methylsulfonyl) pyrazin-2-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (100 mg, 0.24 mmol) synthesized in Example (64d), α-bromo-γ-butyrolactone ( 0.045 mL, 0.48 mmol) and potassium carbonate (100 mg, 0.72 mmol) were used to obtain the target compound (63 mg, 52% yield) as a white solid in the same manner as in Example (6b).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.47-2.56 (1H, m), 2.72-2.79 (1H, m), 3.24 (3H, s), 3.53 (1H, dd, J = 14.6, 7.3 Hz), 4.06 (1H, dd, J = 14.6, 8.8 Hz), 4.35-4.41 (1H, m), 4.55 (1H, td, J = 8.8, 3.9 Hz), 4.78-4.87 (1H, m), 4.99 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.80 (1H, t , J = 2.2 Hz), 7.02 (1H, t, J = 1.5 Hz), 7.17 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.0 Hz), 8.79 (1H, d, J = 1.0 Hz).
MS (ESI) m / z: 499.12843 (M + H) <+> .
(実施例65)
1-メチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン (Example 65)
1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
1-メチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン (Example 65)
1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
(65a)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ジヒドロフランー2(3H)-オン
実施例(19b)で合成した化合物(2.00g,5.81mmol)、α-ブロモ-γ-ブチロラクトン(1.07mL,11.6mmol)、炭酸カリウム(2.41g,17.4mmol)を用い、実施例(6b)と同様の方法で白色固体の目的化合物(1.70g,収率68%)を得た。
1H-NMR (CDCl3, 500MHz):δ 2.45-2.54 (1H, m), 2.70-2.78 (1H, m), 3.23 (3H, s), 4.35-4.41 (1H, m), 4.51-4.56 (1H, m), 4.94 (1H, t, J = 7.8 Hz), 6.75 (1H, t, J = 2.4 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.11 (1H, t, J = 2.0 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
(65b)エチル 2-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-4-[(メチルスルホニル)オキシ]ブタノエート
実施例(65a)で合成した化合物(1.37g,3.19mmol)をエタノール(50mL)に溶解し、0℃で炭酸カリウム(0.22g,1.60mmol)を加え、自然に昇温させ室温で30分攪拌した。反応液を濾過後、減圧下溶媒を留去し、得られた残渣を塩化メチレン(50mL)に溶解した。0℃でトリエチルアミン(0.90mL,6.46mmol)、メタンスルホニルクロリド(0.27mL,3.49mmol)を加え、窒素雰囲気下室温で2時間攪拌した。反応液を塩化メチレン(100mL)で希釈し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製することにより、白色固体の目的物(673mg,38%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.28 (3H, t, J = 7.0 Hz), 2.31-2.48 (2H, m), 3.01 (3H, s), 3.23 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 4.38-4.48 (2H, m), 4.77 (1H, dd, J = 8.2, 4.3 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65c)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-1-メチルピロリジン-2-オン
実施例(65b)で合成した化合物(617mg,1.12mmol)をアセトニトリル(2mL)に溶解し、ヨウ化ナトリウム(308mg,2.01mmol)、メチルアミン(2mol/Lテトラヒドロフラン溶液,2.0mL,4.0mmol)を加え、100℃で攪拌した。途中30分ごとにメチルアミン(2mol/Lテトラヒドロフラン溶液,1.0mL,2.0mmol)の追加を3回行い、2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(10mL)を加え、酢酸エチル(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~100%)を用いて精製することにより、白色固体の目的化合物(355mg,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.13-2.22 (1H, m), 2.51-2.60 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.54 (1H, m), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz)。 (65a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (2) synthesized in Example (19b) 0.000 g, 5.81 mmol), α-bromo-γ-butyrolactone (1.07 mL, 11.6 mmol), potassium carbonate (2.41 g, 17.4 mmol) and white in the same manner as in Example (6b) The solid target compound (1.70 g, yield 68%) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ 2.45-2.54 (1H, m), 2.70-2.78 (1H, m), 3.23 (3H, s), 4.35-4.41 (1H, m), 4.51-4.56 ( 1H, m), 4.94 (1H, t, J = 7.8 Hz), 6.75 (1H, t, J = 2.4 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.11 (1H, t, J = 2.0 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
(65b) Ethyl 2- (3-bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -4-[(methylsulfonyl) oxy] butanoate Synthesized in Example (65a) The compound (1.37 g, 3.19 mmol) was dissolved in ethanol (50 mL), potassium carbonate (0.22 g, 1.60 mmol) was added at 0 ° C., the temperature was naturally raised, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride (50 mL). Triethylamine (0.90 mL, 6.46 mmol) and methanesulfonyl chloride (0.27 mL, 3.49 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired product (673 mg, 38%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.28 (3H, t, J = 7.0 Hz), 2.31-2.48 (2H, m), 3.01 (3H, s), 3.23 (3H, s), 4.26 (2H , q, J = 7.2 Hz), 4.38-4.48 (2H, m), 4.77 (1H, dd, J = 8.2, 4.3 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65c) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-methylpyrrolidin-2-one Compound (617 mg) synthesized in Example (65b) , 1.12 mmol) was dissolved in acetonitrile (2 mL), sodium iodide (308 mg, 2.01 mmol) and methylamine (2 mol / L tetrahydrofuran solution, 2.0 mL, 4.0 mmol) were added, and the mixture was stirred at 100 ° C. . On the way, methylamine (2 mol / L tetrahydrofuran solution, 1.0 mL, 2.0 mmol) was added three times every 30 minutes, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 60% -100%) to give the target compound (355 mg, yield) as a white solid. 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.13-2.22 (1H, m), 2.51-2.60 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.54 (1H, m), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
実施例(19b)で合成した化合物(2.00g,5.81mmol)、α-ブロモ-γ-ブチロラクトン(1.07mL,11.6mmol)、炭酸カリウム(2.41g,17.4mmol)を用い、実施例(6b)と同様の方法で白色固体の目的化合物(1.70g,収率68%)を得た。
1H-NMR (CDCl3, 500MHz):δ 2.45-2.54 (1H, m), 2.70-2.78 (1H, m), 3.23 (3H, s), 4.35-4.41 (1H, m), 4.51-4.56 (1H, m), 4.94 (1H, t, J = 7.8 Hz), 6.75 (1H, t, J = 2.4 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.11 (1H, t, J = 2.0 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
(65b)エチル 2-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-4-[(メチルスルホニル)オキシ]ブタノエート
実施例(65a)で合成した化合物(1.37g,3.19mmol)をエタノール(50mL)に溶解し、0℃で炭酸カリウム(0.22g,1.60mmol)を加え、自然に昇温させ室温で30分攪拌した。反応液を濾過後、減圧下溶媒を留去し、得られた残渣を塩化メチレン(50mL)に溶解した。0℃でトリエチルアミン(0.90mL,6.46mmol)、メタンスルホニルクロリド(0.27mL,3.49mmol)を加え、窒素雰囲気下室温で2時間攪拌した。反応液を塩化メチレン(100mL)で希釈し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~80%)を用いて精製することにより、白色固体の目的物(673mg,38%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.28 (3H, t, J = 7.0 Hz), 2.31-2.48 (2H, m), 3.01 (3H, s), 3.23 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 4.38-4.48 (2H, m), 4.77 (1H, dd, J = 8.2, 4.3 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65c)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-1-メチルピロリジン-2-オン
実施例(65b)で合成した化合物(617mg,1.12mmol)をアセトニトリル(2mL)に溶解し、ヨウ化ナトリウム(308mg,2.01mmol)、メチルアミン(2mol/Lテトラヒドロフラン溶液,2.0mL,4.0mmol)を加え、100℃で攪拌した。途中30分ごとにメチルアミン(2mol/Lテトラヒドロフラン溶液,1.0mL,2.0mmol)の追加を3回行い、2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(10mL)を加え、酢酸エチル(30mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~100%)を用いて精製することにより、白色固体の目的化合物(355mg,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.13-2.22 (1H, m), 2.51-2.60 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.54 (1H, m), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz)。 (65a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) dihydrofuran-2 (3H) -one Compound (2) synthesized in Example (19b) 0.000 g, 5.81 mmol), α-bromo-γ-butyrolactone (1.07 mL, 11.6 mmol), potassium carbonate (2.41 g, 17.4 mmol) and white in the same manner as in Example (6b) The solid target compound (1.70 g, yield 68%) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ 2.45-2.54 (1H, m), 2.70-2.78 (1H, m), 3.23 (3H, s), 4.35-4.41 (1H, m), 4.51-4.56 ( 1H, m), 4.94 (1H, t, J = 7.8 Hz), 6.75 (1H, t, J = 2.4 Hz), 6.92 (1H, t, J = 2.0 Hz), 7.11 (1H, t, J = 2.0 Hz), 7.47 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
(65b) Ethyl 2- (3-bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -4-[(methylsulfonyl) oxy] butanoate Synthesized in Example (65a) The compound (1.37 g, 3.19 mmol) was dissolved in ethanol (50 mL), potassium carbonate (0.22 g, 1.60 mmol) was added at 0 ° C., the temperature was naturally raised, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride (50 mL). Triethylamine (0.90 mL, 6.46 mmol) and methanesulfonyl chloride (0.27 mL, 3.49 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with methylene chloride (100 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% -80%) to give the desired product (673 mg, 38%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.28 (3H, t, J = 7.0 Hz), 2.31-2.48 (2H, m), 3.01 (3H, s), 3.23 (3H, s), 4.26 (2H , q, J = 7.2 Hz), 4.38-4.48 (2H, m), 4.77 (1H, dd, J = 8.2, 4.3 Hz), 6.58 (1H, t, J = 2.2 Hz), 6.88 (1H, t, J = 1.6 Hz), 6.93 (1H, t, J = 1.6 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65c) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-methylpyrrolidin-2-one Compound (617 mg) synthesized in Example (65b) , 1.12 mmol) was dissolved in acetonitrile (2 mL), sodium iodide (308 mg, 2.01 mmol) and methylamine (2 mol / L tetrahydrofuran solution, 2.0 mL, 4.0 mmol) were added, and the mixture was stirred at 100 ° C. . On the way, methylamine (2 mol / L tetrahydrofuran solution, 1.0 mL, 2.0 mmol) was added three times every 30 minutes, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 60% -100%) to give the target compound (355 mg, yield) as a white solid. 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.13-2.22 (1H, m), 2.51-2.60 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.54 (1H, m), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(65d)ベンジル 5-(3-[(1-メチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(65c)で合成した化合物(355mg,0.80mmol)、実施例(19e)で合成した化合物(395mg,1.21mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(39mg,0.05mmol)、炭酸カリウム(556mg,4.02mmol)を用い、実施例(16e)と同様の方法で淡黄色油状の目的化合物(217mg,収率48%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.15-2.25 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.49-3.55 (1H, m), 4.90 (1H, t, J = 7.2 Hz), 5.33 (2H, s), 6.52 (1H, t, J = 3.1 Hz), 6.75 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.28 (1H, s).
(65e)N-[(2R)-2-ヒドロキシプロピル]-5-(3-[(1-メチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(65d)で合成した化合物(217mg,0.39mmol)をエタノール(10mL)と酢酸エチル(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(70mg)を加えて水素雰囲気下に1時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去した。得られた白色固体、(R)-(-)-1-アミノ-2-プロパノール(51mg,0.68mmol)、HOBT・H2O(50mg,0.37mmol)、N-メチルモルホリン(75μL,0.68mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、室温でWSCI・HCl(78mg,0.41mmol)を加え、窒素雰囲気下15時間攪拌した。反応液に飽和食塩水(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~8%)を用いて精製することにより、白色固体の目的化合物(148mg,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.20 (3H, d, J = 6.3 Hz), 2.09-2.21 (1H, m), 2.50-2.61 (1H, m), 2.93 (3H, s), 3.20-3.27 (1H, m), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.47-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.4 Hz), 6.43-6.46 (1H, m), 6.63-6.65 (2H, m), 6.67-6.72 (1H, br m), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, dd, J = 1.6, 0.8 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(65f)1-メチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(65e)で合成した化合物(148mg,0.28mmol)、メタンスルホン酸無水物(100mg,0.56mmol)、トリエチルアミン(0.156mL,1.12mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(109mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 13.7, 9.4 Hz), 4.77-4.87 (1H, m), 4.89 (1H, t, J = 7.0 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 511.16648 (M+H)+。 (65d) Benzyl 5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-carboxylate Compound (355 mg, 0.80 mmol) synthesized in Example (65c), Compound (395 mg, 1.21 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (39 mg, 0.05 mmol) and potassium carbonate (556 mg, 4.02 mmol) were used in the same manner as in Example (16e) to give the target compound (217 mg, Yield 48%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.15-2.25 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.49-3.55 (1H, m), 4.90 (1H, t, J = 7.2 Hz), 5.33 (2H, s), 6.52 (1H, t, J = 3.1 Hz), 6.75 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m ), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.28 (1H, s).
(65e) N-[(2R) -2-hydroxypropyl] -5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridine -3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (217 mg, 0.39 mmol) synthesized in Example (65d) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL). 10% palladium on carbon catalyst (70 mg) was added, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained white solid, (R)-(−)-1-amino-2-propanol (51 mg, 0.68 mmol), HOBT · H 2 O (50 mg, 0.37 mmol), N-methylmorpholine (75 μL, 0 .68 mmol) was dissolved in N, N-dimethylformamide (5 mL), WSCI.HCl (78 mg, 0.41 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 15 hours. To the reaction solution was added saturated brine (30 mL), and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 8%) to give a white solid. The target compound (148 mg, 83%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.20 (3H, d, J = 6.3 Hz), 2.09-2.21 (1H, m), 2.50-2.61 (1H, m), 2.93 (3H, s), 3.20 -3.27 (1H, m), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.47-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.4 Hz), 6.43-6.46 (1H, m), 6.63-6.65 (2H, m), 6.67-6.72 (1H, br m), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, dd, J = 1.6, 0.8 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(65f) 1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (148 mg, 0.28 mmol) synthesized in Example (65e), methanesulfonic anhydride (100 mg, 0.56 mmol) and triethylamine (0.156 mL, 1.12 mmol) were used to obtain the desired product (109 mg, yield 76%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 13.7, 9.4 Hz), 4.77-4.87 (1H, m), 4.89 (1H , t, J = 7.0 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d , J = 2.7 Hz).
MS (ESI) m / z: 511.16648 (M + H) <+> .
実施例(65c)で合成した化合物(355mg,0.80mmol)、実施例(19e)で合成した化合物(395mg,1.21mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(39mg,0.05mmol)、炭酸カリウム(556mg,4.02mmol)を用い、実施例(16e)と同様の方法で淡黄色油状の目的化合物(217mg,収率48%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.15-2.25 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.49-3.55 (1H, m), 4.90 (1H, t, J = 7.2 Hz), 5.33 (2H, s), 6.52 (1H, t, J = 3.1 Hz), 6.75 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.28 (1H, s).
(65e)N-[(2R)-2-ヒドロキシプロピル]-5-(3-[(1-メチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(65d)で合成した化合物(217mg,0.39mmol)をエタノール(10mL)と酢酸エチル(5mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(70mg)を加えて水素雰囲気下に1時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去した。得られた白色固体、(R)-(-)-1-アミノ-2-プロパノール(51mg,0.68mmol)、HOBT・H2O(50mg,0.37mmol)、N-メチルモルホリン(75μL,0.68mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、室温でWSCI・HCl(78mg,0.41mmol)を加え、窒素雰囲気下15時間攪拌した。反応液に飽和食塩水(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=0%~8%)を用いて精製することにより、白色固体の目的化合物(148mg,83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.20 (3H, d, J = 6.3 Hz), 2.09-2.21 (1H, m), 2.50-2.61 (1H, m), 2.93 (3H, s), 3.20-3.27 (1H, m), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.47-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.4 Hz), 6.43-6.46 (1H, m), 6.63-6.65 (2H, m), 6.67-6.72 (1H, br m), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, dd, J = 1.6, 0.8 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(65f)1-メチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(65e)で合成した化合物(148mg,0.28mmol)、メタンスルホン酸無水物(100mg,0.56mmol)、トリエチルアミン(0.156mL,1.12mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(109mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 13.7, 9.4 Hz), 4.77-4.87 (1H, m), 4.89 (1H, t, J = 7.0 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 511.16648 (M+H)+。 (65d) Benzyl 5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrol-2-carboxylate Compound (355 mg, 0.80 mmol) synthesized in Example (65c), Compound (395 mg, 1.21 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphine) [Fino) ferrocene] palladium (II) dichloride Dichloromethane complex (39 mg, 0.05 mmol) and potassium carbonate (556 mg, 4.02 mmol) were used in the same manner as in Example (16e) to give the target compound (217 mg, Yield 48%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.15-2.25 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.49-3.55 (1H, m), 4.90 (1H, t, J = 7.2 Hz), 5.33 (2H, s), 6.52 (1H, t, J = 3.1 Hz), 6.75 (1H, t, J = 2.0 Hz), 6.89 (1H, t, J = 1.6 Hz), 6.98 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.33-7.46 (6H, m ), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.28 (1H, s).
(65e) N-[(2R) -2-hydroxypropyl] -5- (3-[(1-methyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridine -3-yl] oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (217 mg, 0.39 mmol) synthesized in Example (65d) was dissolved in a mixed solvent of ethanol (10 mL) and ethyl acetate (5 mL). 10% palladium on carbon catalyst (70 mg) was added, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure. The obtained white solid, (R)-(−)-1-amino-2-propanol (51 mg, 0.68 mmol), HOBT · H 2 O (50 mg, 0.37 mmol), N-methylmorpholine (75 μL, 0 .68 mmol) was dissolved in N, N-dimethylformamide (5 mL), WSCI.HCl (78 mg, 0.41 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 15 hours. To the reaction solution was added saturated brine (30 mL), and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 0% to 8%) to give a white solid. The target compound (148 mg, 83%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.20 (3H, d, J = 6.3 Hz), 2.09-2.21 (1H, m), 2.50-2.61 (1H, m), 2.93 (3H, s), 3.20 -3.27 (1H, m), 3.22 (3H, s), 3.36-3.43 (1H, m), 3.47-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.4 Hz), 6.43-6.46 (1H, m), 6.63-6.65 (2H, m), 6.67-6.72 (1H, br m), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, dd, J = 1.6, 0.8 Hz), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(65f) 1-methyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (148 mg, 0.28 mmol) synthesized in Example (65e), methanesulfonic anhydride (100 mg, 0.56 mmol) and triethylamine (0.156 mL, 1.12 mmol) were used to obtain the desired product (109 mg, yield 76%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.14-2.23 (1H, m), 2.51-2.61 (1H, m), 2.93 (3H, s), 3.23 (3H, s), 3.35-3.43 (1H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 13.7, 9.4 Hz), 4.77-4.87 (1H, m), 4.89 (1H , t, J = 7.0 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.89 (1H, t , J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d , J = 2.7 Hz).
MS (ESI) m / z: 511.16648 (M + H) <+> .
(実施例66)
1-エチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン Example 66
1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
1-エチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン Example 66
1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- { [6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
(66a)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-1-エチルピロリジン-2-オン
実施例(65b)で合成した化合物(1.01g,1.83mmol)をアセトニトリル(10mL)に溶解し、ヨウ化ナトリウム(0.41g,2.74mmol)、エチルアミン(2mol/Lテトラヒドロフラン溶液,2.74mL,5.48mmol)を加え、100℃で2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(20mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的化合物(707mg,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.17 (3H, t, J = 7.3 Hz), 2.12-2.21 (1H, m), 2.50-2.60 (1H, m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.50 (1H, td, J = 9.4, 3.9 Hz), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.79 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(66b)ベンジル 5-(3-[(1-エチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(66a)で合成した化合物(990mg,2.17mmol)、実施例(19e)で合成した化合物(1.10g,3.26mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(105mg,0.13mmol)、炭酸カリウム(1.50g,10.87mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(890mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.17 (3H, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s), 3.35-3.44 (3H, m), 3.51 (1H, td, J = 9.3, 3.6 Hz), 4.91 (1H, dd, J = 8.0, 6.5 Hz), 5.32 (2H, s), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 2.0 Hz), 7.32-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.3 Hz), 9.38 (1H, br s)。 (66a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-ethylpyrrolidin-2-one Compound (1) synthesized in Example (65b) 0.01 g, 1.83 mmol) was dissolved in acetonitrile (10 mL), sodium iodide (0.41 g, 2.74 mmol) and ethylamine (2 mol / L tetrahydrofuran solution, 2.74 mL, 5.48 mmol) were added, and the mixture was added at 100 ° C. For 2 hours. The reaction mixture was cooled to room temperature, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (707 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.17 (3H, t, J = 7.3 Hz), 2.12-2.21 (1H, m), 2.50-2.60 (1H, m), 3.23 (3H, s), 3.35 -3.44 (3H, m), 3.50 (1H, td, J = 9.4, 3.9 Hz), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.79 (1H, t, J = 2.0 Hz), 6.87 ( 1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 ( (1H, d, J = 2.7 Hz).
(66b) Benzyl 5- (3-[(1-ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-carboxylate Compound synthesized in Example (66a) (990 mg, 2.17 mmol), Compound synthesized in Example (19e) (1.10 g, 3.26 mmol), [1,1′-bis ( Diphenylphosphino) ferrocene] palladium (II) dichloride Dichlorophosphine complex (105 mg, 0.13 mmol), potassium carbonate (1.50 g, 10.87 mmol) and the same target compound as a white solid in the same manner as in Example (16e) (890 mg, 71% yield) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.17 (3H, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s), 3.35 -3.44 (3H, m), 3.51 (1H, td, J = 9.3, 3.6 Hz), 4.91 (1H, dd, J = 8.0, 6.5 Hz), 5.32 (2H, s), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t , J = 2.0 Hz), 7.32-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.3 Hz), 9.38 (1H, br s).
実施例(65b)で合成した化合物(1.01g,1.83mmol)をアセトニトリル(10mL)に溶解し、ヨウ化ナトリウム(0.41g,2.74mmol)、エチルアミン(2mol/Lテトラヒドロフラン溶液,2.74mL,5.48mmol)を加え、100℃で2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(20mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~100%)を用いて精製することにより、白色固体の目的化合物(707mg,収率85%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.17 (3H, t, J = 7.3 Hz), 2.12-2.21 (1H, m), 2.50-2.60 (1H, m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.50 (1H, td, J = 9.4, 3.9 Hz), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.79 (1H, t, J = 2.0 Hz), 6.87 (1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(66b)ベンジル 5-(3-[(1-エチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(66a)で合成した化合物(990mg,2.17mmol)、実施例(19e)で合成した化合物(1.10g,3.26mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(105mg,0.13mmol)、炭酸カリウム(1.50g,10.87mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(890mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.17 (3H, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s), 3.35-3.44 (3H, m), 3.51 (1H, td, J = 9.3, 3.6 Hz), 4.91 (1H, dd, J = 8.0, 6.5 Hz), 5.32 (2H, s), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t, J = 2.0 Hz), 7.32-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.3 Hz), 9.38 (1H, br s)。 (66a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-ethylpyrrolidin-2-one Compound (1) synthesized in Example (65b) 0.01 g, 1.83 mmol) was dissolved in acetonitrile (10 mL), sodium iodide (0.41 g, 2.74 mmol) and ethylamine (2 mol / L tetrahydrofuran solution, 2.74 mL, 5.48 mmol) were added, and the mixture was added at 100 ° C. For 2 hours. The reaction mixture was cooled to room temperature, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 100%) to give the target compound (707 mg, yield) as a white solid. 85%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.17 (3H, t, J = 7.3 Hz), 2.12-2.21 (1H, m), 2.50-2.60 (1H, m), 3.23 (3H, s), 3.35 -3.44 (3H, m), 3.50 (1H, td, J = 9.4, 3.9 Hz), 4.84 (1H, dd, J = 7.8, 6.3 Hz), 6.79 (1H, t, J = 2.0 Hz), 6.87 ( 1H, t, J = 2.0 Hz), 7.13 (1H, t, J = 2.0 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 ( (1H, d, J = 2.7 Hz).
(66b) Benzyl 5- (3-[(1-ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H- Pyrrole-2-carboxylate Compound synthesized in Example (66a) (990 mg, 2.17 mmol), Compound synthesized in Example (19e) (1.10 g, 3.26 mmol), [1,1′-bis ( Diphenylphosphino) ferrocene] palladium (II) dichloride Dichlorophosphine complex (105 mg, 0.13 mmol), potassium carbonate (1.50 g, 10.87 mmol) and the same target compound as a white solid in the same manner as in Example (16e) (890 mg, 71% yield) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.17 (3H, t, J = 7.2 Hz), 2.13-2.23 (1H, m), 2.51-2.61 (1H, m), 3.22 (3H, s), 3.35 -3.44 (3H, m), 3.51 (1H, td, J = 9.3, 3.6 Hz), 4.91 (1H, dd, J = 8.0, 6.5 Hz), 5.32 (2H, s), 6.51 (1H, dd, J = 3.9, 2.7 Hz), 6.74 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.15 (1H, t , J = 2.0 Hz), 7.32-7.45 (6H, m), 8.04 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.3 Hz), 9.38 (1H, br s).
(66c)5-(3-[(1-エチル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(66b)で合成した化合物(890mg,1.55mmol)、10%パラジウム炭素触媒(300mg)、(R)-(-)-1-アミノ-2-プロパノール(223mg,2.97mmol)、HOBT・H2O(220mg,1.63mmol)、N-メチルモルホリン(0.326mL,2.97mmol)、WSCI・HCl(341mg,1.78mmol)を用い、実施例(65e)と同様の方法で白色固体の目的化合物(588mg,73%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.18 (3H, t, J = 7.0 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.09-2.19 (1H, m), 2.49-2.61 (1H, m), 3.22-3.28 (1H, m), 3.22 (3H, s), 3.36-3.45 (3H, m), 3.46-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.2 Hz), 6.43-6.46 (1H, m), 6.62-6.66 (2H, m), 6.68-6.73 (1H, br m), 6.90 (1H, t, J = 1.8 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.35 (0.5H, br s), 10.43 (0.5H, br s).
(66d)1-エチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(66c)で合成した化合物(588mg,1.08mmol)、メタンスルホン酸無水物(389mg,2.16mmol)、トリエチルアミン(0.603mL,4.33mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(472mg,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.18 (3H, t, J = 7.4 Hz), 1.42 (3H, d, J = 6.3 Hz), 2.13-2.23 (1H, m), 2.51-2.60 (1H, m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 (1H, m), 4.89 (1H, t, J = 7.2 Hz), 6.51 (1H, d, J = 3.5 Hz), 6.72 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, s), 7.14 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 525.18048 (M+H)+。 (66c) 5- (3-[(1-Ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N- [ (2R) -2-Hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (66b) (890 mg, 1.55 mmol), 10% palladium carbon catalyst (300 mg), (R)-(−) -1-amino-2-propanol (223 mg, 2.97 mmol), HOBT · H 2 O (220 mg, 1.63 mmol), N-methylmorpholine (0.326 mL, 2.97 mmol), WSCI · HCl (341 mg, 1 .78 mmol) was used to obtain the target compound (588 mg, 73%) as a white solid in the same manner as in Example (65e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.18 (3H, t, J = 7.0 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.09-2.19 (1H, m), 2.49-2.61 (1H , m), 3.22-3.28 (1H, m), 3.22 (3H, s), 3.36-3.45 (3H, m), 3.46-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H , t, J = 7.2 Hz), 6.43-6.46 (1H, m), 6.62-6.66 (2H, m), 6.68-6.73 (1H, br m), 6.90 (1H, t, J = 1.8 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.35 (0.5H, br s), 10.43 (0.5H, br s).
(66d) 1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one The compound synthesized in Example (66c) (588 mg, 1.08 mmol), methanesulfonic anhydride (389 mg, 2.16 mmol) and triethylamine (0.603 mL, 4.33 mmol) were used to obtain the desired product (472 mg, 83% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.18 (3H, t, J = 7.4 Hz), 1.42 (3H, d, J = 6.3 Hz), 2.13-2.23 (1H, m), 2.51-2.60 (1H , m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 (1H, m ), 4.89 (1H, t, J = 7.2 Hz), 6.51 (1H, d, J = 3.5 Hz), 6.72 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, s), 7.14 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) ).
MS (ESI) m / z: 525.18048 (M + H) <+> .
実施例(66b)で合成した化合物(890mg,1.55mmol)、10%パラジウム炭素触媒(300mg)、(R)-(-)-1-アミノ-2-プロパノール(223mg,2.97mmol)、HOBT・H2O(220mg,1.63mmol)、N-メチルモルホリン(0.326mL,2.97mmol)、WSCI・HCl(341mg,1.78mmol)を用い、実施例(65e)と同様の方法で白色固体の目的化合物(588mg,73%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.18 (3H, t, J = 7.0 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.09-2.19 (1H, m), 2.49-2.61 (1H, m), 3.22-3.28 (1H, m), 3.22 (3H, s), 3.36-3.45 (3H, m), 3.46-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H, t, J = 7.2 Hz), 6.43-6.46 (1H, m), 6.62-6.66 (2H, m), 6.68-6.73 (1H, br m), 6.90 (1H, t, J = 1.8 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.35 (0.5H, br s), 10.43 (0.5H, br s).
(66d)1-エチル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(66c)で合成した化合物(588mg,1.08mmol)、メタンスルホン酸無水物(389mg,2.16mmol)、トリエチルアミン(0.603mL,4.33mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(472mg,収率83%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.18 (3H, t, J = 7.4 Hz), 1.42 (3H, d, J = 6.3 Hz), 2.13-2.23 (1H, m), 2.51-2.60 (1H, m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 (1H, m), 4.89 (1H, t, J = 7.2 Hz), 6.51 (1H, d, J = 3.5 Hz), 6.72 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, s), 7.14 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 525.18048 (M+H)+。 (66c) 5- (3-[(1-Ethyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N- [ (2R) -2-Hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (66b) (890 mg, 1.55 mmol), 10% palladium carbon catalyst (300 mg), (R)-(−) -1-amino-2-propanol (223 mg, 2.97 mmol), HOBT · H 2 O (220 mg, 1.63 mmol), N-methylmorpholine (0.326 mL, 2.97 mmol), WSCI · HCl (341 mg, 1 .78 mmol) was used to obtain the target compound (588 mg, 73%) as a white solid in the same manner as in Example (65e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.18 (3H, t, J = 7.0 Hz), 1.20 (3H, d, J = 6.3 Hz), 2.09-2.19 (1H, m), 2.49-2.61 (1H , m), 3.22-3.28 (1H, m), 3.22 (3H, s), 3.36-3.45 (3H, m), 3.46-3.60 (2H, m), 3.92-4.01 (1H, m), 4.92 (1H , t, J = 7.2 Hz), 6.43-6.46 (1H, m), 6.62-6.66 (2H, m), 6.68-6.73 (1H, br m), 6.90 (1H, t, J = 1.8 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 10.35 (0.5H, br s), 10.43 (0.5H, br s).
(66d) 1-ethyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl}- 5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one The compound synthesized in Example (66c) (588 mg, 1.08 mmol), methanesulfonic anhydride (389 mg, 2.16 mmol) and triethylamine (0.603 mL, 4.33 mmol) were used to obtain the desired product (472 mg, 83% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.18 (3H, t, J = 7.4 Hz), 1.42 (3H, d, J = 6.3 Hz), 2.13-2.23 (1H, m), 2.51-2.60 (1H , m), 3.23 (3H, s), 3.35-3.44 (3H, m), 3.47-3.55 (2H, m), 4.05 (1H, dd, J = 14.1, 9.4 Hz), 4.77-4.86 (1H, m ), 4.89 (1H, t, J = 7.2 Hz), 6.51 (1H, d, J = 3.5 Hz), 6.72 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, s), 7.14 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz) ).
MS (ESI) m / z: 525.18048 (M + H) <+> .
(実施例67)
1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン (Example 67)
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン (Example 67)
1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 {[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one
(67a)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)-1-シクロプロピルピロリジン-2-オン
実施例(65b)で合成した化合物(530mg,0.96mmol)をアセトニトリル(4mL)に溶解し、ヨウ化ナトリウム(216mg,1.44mmol)、シクロプロピルアミン(0.200mL,2.88mmol)を加え、100℃で2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(10mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~80%)を用いて精製することにより、白色固体の目的化合物(253mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.66-0.76 (1H, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1H, m), 2.68-2.74 (1H, m), 3.23 (3H, s), 3.27-3.35 (1H, m), 3.39-3.46 (1H, m), 4.82 (1H, t, J = 7.2 Hz), 6.78 (1H, t, J = 2.0 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.12 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(67b)ベンジル 5-(3-[(1-シクロプロピル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(67a)で合成した化合物(253mg,0.54mmol)、実施例(19e)で合成した化合物(266mg,0.81mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(27mg,0.03mmol)、炭酸カリウム(374mg,2.71mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(238mg,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.66-0.75 (1H, m), 0.75-0.88 (3H, m), 2.07-2.18 (1H, m), 2.46-2.55 (1H, m), 2.67-2.75 (1H, m), 3.22 (3H, s), 3.27-3.34 (1H, m), 3.39-3.46 (1H, m), 4.89 (1H, t, J = 7.4 Hz), 5.32 (2H, s), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 1.8 Hz), 6.97 (1H, dd, J = 4.3, 2.3 Hz), 7.13 (1H, t, J = 1.8 Hz), 7.31-7.43 (6H, m), 8.03 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.47 (1H, br s)。 (67a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-cyclopropylpyrrolidin-2-one Compound synthesized in Example (65b) ( 530 mg, 0.96 mmol) was dissolved in acetonitrile (4 mL), sodium iodide (216 mg, 1.44 mmol) and cyclopropylamine (0.200 mL, 2.88 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% -80%) to give the target compound (253 mg, yield) as a white solid. 57%).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.66-0.76 (1H, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1H, m), 2.68- 2.74 (1H, m), 3.23 (3H, s), 3.27-3.35 (1H, m), 3.39-3.46 (1H, m), 4.82 (1H, t, J = 7.2 Hz), 6.78 (1H, t, J = 2.0 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.12 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(67b) Benzyl 5- (3-[(1-cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxylate Compound (253 mg, 0.54 mmol) synthesized in Example (67a), Compound (266 mg, 0.81 mmol) synthesized in Example (19e), [1,1'-bis (diphenyl) Phosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (27 mg, 0.03 mmol) and potassium carbonate (374 mg, 2.71 mmol) were used in the same manner as in Example (16e) to give the target compound (238 mg, Yield 77%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.66-0.75 (1H, m), 0.75-0.88 (3H, m), 2.07-2.18 (1H, m), 2.46-2.55 (1H, m), 2.67- 2.75 (1H, m), 3.22 (3H, s), 3.27-3.34 (1H, m), 3.39-3.46 (1H, m), 4.89 (1H, t, J = 7.4 Hz), 5.32 (2H, s) , 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 1.8 Hz), 6.97 (1H, dd, J = 4.3, 2.3 Hz), 7.13 (1H, t, J = 1.8 Hz), 7.31-7.43 (6H, m), 8.03 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.47 ( 1H, br s).
実施例(65b)で合成した化合物(530mg,0.96mmol)をアセトニトリル(4mL)に溶解し、ヨウ化ナトリウム(216mg,1.44mmol)、シクロプロピルアミン(0.200mL,2.88mmol)を加え、100℃で2時間攪拌した。反応液を室温まで冷却後、飽和食塩水(10mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=60%~80%)を用いて精製することにより、白色固体の目的化合物(253mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.66-0.76 (1H, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1H, m), 2.68-2.74 (1H, m), 3.23 (3H, s), 3.27-3.35 (1H, m), 3.39-3.46 (1H, m), 4.82 (1H, t, J = 7.2 Hz), 6.78 (1H, t, J = 2.0 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.12 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(67b)ベンジル 5-(3-[(1-シクロプロピル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(67a)で合成した化合物(253mg,0.54mmol)、実施例(19e)で合成した化合物(266mg,0.81mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(27mg,0.03mmol)、炭酸カリウム(374mg,2.71mmol)を用い、実施例(16e)と同様の方法で黄色油状の目的化合物(238mg,収率77%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.66-0.75 (1H, m), 0.75-0.88 (3H, m), 2.07-2.18 (1H, m), 2.46-2.55 (1H, m), 2.67-2.75 (1H, m), 3.22 (3H, s), 3.27-3.34 (1H, m), 3.39-3.46 (1H, m), 4.89 (1H, t, J = 7.4 Hz), 5.32 (2H, s), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 1.8 Hz), 6.97 (1H, dd, J = 4.3, 2.3 Hz), 7.13 (1H, t, J = 1.8 Hz), 7.31-7.43 (6H, m), 8.03 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.47 (1H, br s)。 (67a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) -1-cyclopropylpyrrolidin-2-one Compound synthesized in Example (65b) ( 530 mg, 0.96 mmol) was dissolved in acetonitrile (4 mL), sodium iodide (216 mg, 1.44 mmol) and cyclopropylamine (0.200 mL, 2.88 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 60% -80%) to give the target compound (253 mg, yield) as a white solid. 57%).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.66-0.76 (1H, m), 0.76-0.89 (3H, m), 2.07-2.17 (1H, m), 2.46-2.55 (1H, m), 2.68- 2.74 (1H, m), 3.23 (3H, s), 3.27-3.35 (1H, m), 3.39-3.46 (1H, m), 4.82 (1H, t, J = 7.2 Hz), 6.78 (1H, t, J = 2.0 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.12 (1H, t, J = 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(67b) Benzyl 5- (3-[(1-cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrole-2-carboxylate Compound (253 mg, 0.54 mmol) synthesized in Example (67a), Compound (266 mg, 0.81 mmol) synthesized in Example (19e), [1,1'-bis (diphenyl) Phosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (27 mg, 0.03 mmol) and potassium carbonate (374 mg, 2.71 mmol) were used in the same manner as in Example (16e) to give the target compound (238 mg, Yield 77%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.66-0.75 (1H, m), 0.75-0.88 (3H, m), 2.07-2.18 (1H, m), 2.46-2.55 (1H, m), 2.67- 2.75 (1H, m), 3.22 (3H, s), 3.27-3.34 (1H, m), 3.39-3.46 (1H, m), 4.89 (1H, t, J = 7.4 Hz), 5.32 (2H, s) , 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.90 (1H, t, J = 1.8 Hz), 6.97 (1H, dd, J = 4.3, 2.3 Hz), 7.13 (1H, t, J = 1.8 Hz), 7.31-7.43 (6H, m), 8.03 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz), 9.47 ( 1H, br s).
(67c)5-(3-[(1-シクロプロピル-2-オキソピロリジン-3-イル)オキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(67b)で合成した化合物(238mg,0.41mmol)、10%パラジウム炭素触媒(200mg)、(R)-(-)-1-アミノ-2-プロパノール(62mg,0.82mmol)、HOBT・H2O(61mg,0.45mmol)、N-メチルモルホリン(0.090mL,0.82mmol)、WSCI・HCl(94mg,0.49mmol)を用い、実施例(65e)と同様の方法で橙色固体の目的化合物(67mg,30%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.68-0.77 (1H, m), 0.77-0.88 (3H, m), 1.21 (3H, dd, J = 6.3, 1.2 Hz), 2.07-2.15 (1H, m), 2.46-2.57 (1H, m), 2.70-2.76 (1H, m), 3.13 (1H, br s), 3.22 (3H, s), 3.24-3.35 (2H, m), 3.38-3.46 (1H, m), 3.57 (1H, ddd, J = 13.7, 6.6, 3.1 Hz), 3.92-4.01 (1H, br m), 4.90 (1H, t, J = 7.4 Hz), 6.44-6.46 (1H, m), 6.62-6.66 (2H, m), 6.69 (1H, dd, J = 12.1, 5.5 Hz), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(67d)1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(67c)で合成した化合物(67mg,0.12mmol)、メタンスルホン酸無水物(45mg,0.24mmol)、トリエチルアミン(0.070mL,0.48mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(30mg,収率46%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.67-0.75 (1H, m), 0.75-0.88 (3H, m), 1.42 (3H, d, J = 5.9 Hz), 2.09-2.19 (1H, m), 2.47-2.56 (1H, m), 2.69-2.75 (1H, m), 3.23 (3H, s), 3.28-3.35 (1H, m), 3.43 (1H, td, J = 9.0, 4.3 Hz), 3.53 (1H, dd, J = 13.7, 7.4 Hz), 4.06 (1H, dd, J = 14.5, 9.0 Hz), 4.77-4.85 (1H, m), 4.87 (1H, t, J = 7.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 537.18059 (M+H)+。 (67c) 5- (3-[(1-Cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N— [(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (67b) (238 mg, 0.41 mmol), 10% palladium carbon catalyst (200 mg), (R)-(- ) -1-amino-2-propanol (62 mg, 0.82 mmol), HOBT.H 2 O (61 mg, 0.45 mmol), N-methylmorpholine (0.090 mL, 0.82 mmol), WSCI · HCl (94 mg, 0.49 mmol) was used in the same manner as in Example (65e) to obtain the target compound (67 mg, 30%) as an orange solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.68-0.77 (1H, m), 0.77-0.88 (3H, m), 1.21 (3H, dd, J = 6.3, 1.2 Hz), 2.07-2.15 (1H, m), 2.46-2.57 (1H, m), 2.70-2.76 (1H, m), 3.13 (1H, br s), 3.22 (3H, s), 3.24-3.35 (2H, m), 3.38-3.46 (1H , m), 3.57 (1H, ddd, J = 13.7, 6.6, 3.1 Hz), 3.92-4.01 (1H, br m), 4.90 (1H, t, J = 7.4 Hz), 6.44-6.46 (1H, m) , 6.62-6.66 (2H, m), 6.69 (1H, dd, J = 12.1, 5.5 Hz), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(67d) 1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (67 mg, 0.12 mmol) synthesized in Example (67c), methanesulfonic anhydride (45 mg) , 0.24 mmol) and triethylamine (0.070 mL, 0.48 mmol) were used to obtain the desired product (30 mg, 46% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.67-0.75 (1H, m), 0.75-0.88 (3H, m), 1.42 (3H, d, J = 5.9 Hz), 2.09-2.19 (1H, m) , 2.47-2.56 (1H, m), 2.69-2.75 (1H, m), 3.23 (3H, s), 3.28-3.35 (1H, m), 3.43 (1H, td, J = 9.0, 4.3 Hz), 3.53 (1H, dd, J = 13.7, 7.4 Hz), 4.06 (1H, dd, J = 14.5, 9.0 Hz), 4.77-4.85 (1H, m), 4.87 (1H, t, J = 7.4 Hz), 6.51 ( 1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 537.18059 (M + H) <+> .
実施例(67b)で合成した化合物(238mg,0.41mmol)、10%パラジウム炭素触媒(200mg)、(R)-(-)-1-アミノ-2-プロパノール(62mg,0.82mmol)、HOBT・H2O(61mg,0.45mmol)、N-メチルモルホリン(0.090mL,0.82mmol)、WSCI・HCl(94mg,0.49mmol)を用い、実施例(65e)と同様の方法で橙色固体の目的化合物(67mg,30%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.68-0.77 (1H, m), 0.77-0.88 (3H, m), 1.21 (3H, dd, J = 6.3, 1.2 Hz), 2.07-2.15 (1H, m), 2.46-2.57 (1H, m), 2.70-2.76 (1H, m), 3.13 (1H, br s), 3.22 (3H, s), 3.24-3.35 (2H, m), 3.38-3.46 (1H, m), 3.57 (1H, ddd, J = 13.7, 6.6, 3.1 Hz), 3.92-4.01 (1H, br m), 4.90 (1H, t, J = 7.4 Hz), 6.44-6.46 (1H, m), 6.62-6.66 (2H, m), 6.69 (1H, dd, J = 12.1, 5.5 Hz), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(67d)1-シクロプロピル-3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ピロリジン-2-オン
実施例(67c)で合成した化合物(67mg,0.12mmol)、メタンスルホン酸無水物(45mg,0.24mmol)、トリエチルアミン(0.070mL,0.48mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(30mg,収率46%)を得た。
1H-NMR (CDCl3, 400MHz):δ 0.67-0.75 (1H, m), 0.75-0.88 (3H, m), 1.42 (3H, d, J = 5.9 Hz), 2.09-2.19 (1H, m), 2.47-2.56 (1H, m), 2.69-2.75 (1H, m), 3.23 (3H, s), 3.28-3.35 (1H, m), 3.43 (1H, td, J = 9.0, 4.3 Hz), 3.53 (1H, dd, J = 13.7, 7.4 Hz), 4.06 (1H, dd, J = 14.5, 9.0 Hz), 4.77-4.85 (1H, m), 4.87 (1H, t, J = 7.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 537.18059 (M+H)+。 (67c) 5- (3-[(1-Cyclopropyl-2-oxopyrrolidin-3-yl) oxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -N— [(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Compound synthesized in Example (67b) (238 mg, 0.41 mmol), 10% palladium carbon catalyst (200 mg), (R)-(- ) -1-amino-2-propanol (62 mg, 0.82 mmol), HOBT.H 2 O (61 mg, 0.45 mmol), N-methylmorpholine (0.090 mL, 0.82 mmol), WSCI · HCl (94 mg, 0.49 mmol) was used in the same manner as in Example (65e) to obtain the target compound (67 mg, 30%) as an orange solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 0.68-0.77 (1H, m), 0.77-0.88 (3H, m), 1.21 (3H, dd, J = 6.3, 1.2 Hz), 2.07-2.15 (1H, m), 2.46-2.57 (1H, m), 2.70-2.76 (1H, m), 3.13 (1H, br s), 3.22 (3H, s), 3.24-3.35 (2H, m), 3.38-3.46 (1H , m), 3.57 (1H, ddd, J = 13.7, 6.6, 3.1 Hz), 3.92-4.01 (1H, br m), 4.90 (1H, t, J = 7.4 Hz), 6.44-6.46 (1H, m) , 6.62-6.66 (2H, m), 6.69 (1H, dd, J = 12.1, 5.5 Hz), 6.90 (1H, t, J = 1.6 Hz), 7.10 (1H, s), 7.41 (1H, dd, J = 8.6, 2.7 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 2.7 Hz).
(67d) 1-cyclopropyl-3- (3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) pyrrolidin-2-one Compound (67 mg, 0.12 mmol) synthesized in Example (67c), methanesulfonic anhydride (45 mg) , 0.24 mmol) and triethylamine (0.070 mL, 0.48 mmol) were used to obtain the desired product (30 mg, 46% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 0.67-0.75 (1H, m), 0.75-0.88 (3H, m), 1.42 (3H, d, J = 5.9 Hz), 2.09-2.19 (1H, m) , 2.47-2.56 (1H, m), 2.69-2.75 (1H, m), 3.23 (3H, s), 3.28-3.35 (1H, m), 3.43 (1H, td, J = 9.0, 4.3 Hz), 3.53 (1H, dd, J = 13.7, 7.4 Hz), 4.06 (1H, dd, J = 14.5, 9.0 Hz), 4.77-4.85 (1H, m), 4.87 (1H, t, J = 7.4 Hz), 6.51 ( 1H, d, J = 3.9 Hz), 6.71 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 1.6 Hz), 7.15 (1H, t, J = 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 537.18059 (M + H) <+> .
(実施例68)
2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン Example 68
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone
2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン Example 68
2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone
(68a)2-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン
実施例(19b)で合成した化合物(1.00g,2.91mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、2-クロロシクロペンタノン(0.88mL,8.72mmol)、炭酸カリウム(0.80g,5.81mmol)を加え、窒素雰囲気下60℃で2時間加熱した。反応液を室温まで冷却後、酢酸エチル(50mL)で希釈し、1規定水酸化ナトリウム水溶液および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色固体の目的化合物(721mg,収率58%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.87-2.06 (2H, m), 2.12-2.20 (1H, m), 2.28-2.53 (3H, m), 3.23 (3H, s), 4.58 (1H, t, J = 8.5 Hz), 6.65 (1H, t, J = 2.0 Hz), 6.86 (6H, t, J = 2.0 Hz), 7.02 (6H, t, J = 2.0 Hz), 7.45 (6H, dd, J = 8.8, 2.9 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(68b)ベンジル 5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(2-オキソシクロペンチル)オキシ]フェニル)-1H-ピロール-2-カルボキシレート
実施例(68a)で合成した化合物(721mg,1.69mmol)、実施例(19e)で合成した化合物(830mg,2.54mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(83mg,0.10mmol)、炭酸カリウム(1.17g,8.46mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(211mg,収率23%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.87-2.06 (2H, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1H, m), 3.23 (3H, s), 4.64 (1H, t, J = 9.0 Hz), 5.33 (2H, s), 6.52 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, t, J = 2.3 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.98 (1H, dd, J = 4.3, 2.3 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.25 (1H, br s)。 (68a) 2- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (1.00 g, 2.91 mmol) synthesized in Example (19b) ) Was dissolved in N, N-dimethylformamide (5 mL), 2-chlorocyclopentanone (0.88 mL, 8.72 mmol) and potassium carbonate (0.80 g, 5.81 mmol) were added, and the mixture was added at 60 ° C. under a nitrogen atmosphere. For 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 1N aqueous sodium hydroxide solution and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the object compound (721 mg, yield 58%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.87-2.06 (2H, m), 2.12-2.20 (1H, m), 2.28-2.53 (3H, m), 3.23 (3H, s), 4.58 (1H, t, J = 8.5 Hz), 6.65 (1H, t, J = 2.0 Hz), 6.86 (6H, t, J = 2.0 Hz), 7.02 (6H, t, J = 2.0 Hz), 7.45 (6H, dd, J = 8.8, 2.9 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(68b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl) -1H-pyrrole-2-carboxylate Compound (721 mg, 1.69 mmol) synthesized in (68a), Compound (830 mg, 2.54 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (83 mg, 0.10 mmol) and potassium carbonate (1.17 g, 8.46 mmol), the target compound (211 mg, 23% yield) as a pale yellow solid was prepared in the same manner as in Example (16e). Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.87-2.06 (2H, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1H, m), 3.23 ( 3H, s), 4.64 (1H, t, J = 9.0 Hz), 5.33 (2H, s), 6.52 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, t, J = 2.3 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.98 (1H, dd, J = 4.3, 2.3 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.25 (1H, br s).
実施例(19b)で合成した化合物(1.00g,2.91mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、2-クロロシクロペンタノン(0.88mL,8.72mmol)、炭酸カリウム(0.80g,5.81mmol)を加え、窒素雰囲気下60℃で2時間加熱した。反応液を室温まで冷却後、酢酸エチル(50mL)で希釈し、1規定水酸化ナトリウム水溶液および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色固体の目的化合物(721mg,収率58%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.87-2.06 (2H, m), 2.12-2.20 (1H, m), 2.28-2.53 (3H, m), 3.23 (3H, s), 4.58 (1H, t, J = 8.5 Hz), 6.65 (1H, t, J = 2.0 Hz), 6.86 (6H, t, J = 2.0 Hz), 7.02 (6H, t, J = 2.0 Hz), 7.45 (6H, dd, J = 8.8, 2.9 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(68b)ベンジル 5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(2-オキソシクロペンチル)オキシ]フェニル)-1H-ピロール-2-カルボキシレート
実施例(68a)で合成した化合物(721mg,1.69mmol)、実施例(19e)で合成した化合物(830mg,2.54mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(83mg,0.10mmol)、炭酸カリウム(1.17g,8.46mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(211mg,収率23%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.87-2.06 (2H, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1H, m), 3.23 (3H, s), 4.64 (1H, t, J = 9.0 Hz), 5.33 (2H, s), 6.52 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, t, J = 2.3 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.98 (1H, dd, J = 4.3, 2.3 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.05 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.25 (1H, br s)。 (68a) 2- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (1.00 g, 2.91 mmol) synthesized in Example (19b) ) Was dissolved in N, N-dimethylformamide (5 mL), 2-chlorocyclopentanone (0.88 mL, 8.72 mmol) and potassium carbonate (0.80 g, 5.81 mmol) were added, and the mixture was added at 60 ° C. under a nitrogen atmosphere. For 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 1N aqueous sodium hydroxide solution and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the object compound (721 mg, yield 58%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.87-2.06 (2H, m), 2.12-2.20 (1H, m), 2.28-2.53 (3H, m), 3.23 (3H, s), 4.58 (1H, t, J = 8.5 Hz), 6.65 (1H, t, J = 2.0 Hz), 6.86 (6H, t, J = 2.0 Hz), 7.02 (6H, t, J = 2.0 Hz), 7.45 (6H, dd, J = 8.8, 2.9 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz).
(68b) Benzyl 5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl) -1H-pyrrole-2-carboxylate Compound (721 mg, 1.69 mmol) synthesized in (68a), Compound (830 mg, 2.54 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Using the dichloride dichloromethane complex (83 mg, 0.10 mmol) and potassium carbonate (1.17 g, 8.46 mmol), the target compound (211 mg, 23% yield) as a pale yellow solid was prepared in the same manner as in Example (16e). Obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.87-2.06 (2H, m), 2.11-2.23 (1H, m), 2.29-2.44 (2H, m), 2.43-2.54 (1H, m), 3.23 ( 3H, s), 4.64 (1H, t, J = 9.0 Hz), 5.33 (2H, s), 6.52 (1H, dd, J = 3.9, 2.7 Hz), 6.63 (1H, t, J = 2.3 Hz), 6.90 (1H, t, J = 2.0 Hz), 6.98 (1H, dd, J = 4.3, 2.3 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.33-7.47 (6H, m), 8.05 (1H , d, J = 8.6 Hz), 8.48 (1H, d, J = 2.7 Hz), 9.25 (1H, br s).
(68c)N-[(2R)-2-ヒドロキシプロピル]-5-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-[(2-オキソシクロペンチル)オキシ]フェニル)-1H-ピロール-2-カルボキサミド
実施例(68b)で合成した化合物(210mg,0.38mmol)、10%パラジウム炭素触媒(80mg)、(R)-(-)-1-アミノ-2-プロパノール(44mg,0.58mmol)、HOBT・H2O(43mg,0.32mmol)、N-メチルモルホリン(0.064mL,0.58mmol)、WSCI・HCl(67mg,0.35mmol)を用い、実施例(65e)と同様の方法で淡黄色固体の目的化合物(67mg,45%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.23 (3H, d, J = 6.3 Hz), 1.91-2.06 (2H, m), 2.13-2.20 (1H, m), 2.30-2.47 (2H, m), 2.47-2.55 (1H, m), 3.23 (3H, s), 3.24-3.29 (1H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, t, J = 3.4 Hz), 6.59-6.62 (2H, m), 6.90 (1H, t, J = 1.5 Hz), 7.04 (1H, t, J = 1.5 Hz), 7.43 (1H, dd, J = 8.8, 2.9 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 (1H, br s).
(68d)2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン
実施例(68c)で合成した化合物(67mg,0.13mmol)、メタンスルホン酸無水物(47mg,0.26mmol)、トリエチルアミン(0.073mL,0.52mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(43mg,収率67%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.41 (3H, d, J = 6.3 Hz), 1.88-2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m), 2.46-2.53 (1H, m), 3.23 (3H, s), 3.50 (1H, ddd, J = 14.2, 7.3, 2.0 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.63 (1H, t, J = 8.5 Hz), 4.77-4.85 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 496.15353 (M+H)+。 (68c) N-[(2R) -2-hydroxypropyl] -5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl ) -1H-pyrrole-2-carboxamide Compound (210 mg, 0.38 mmol) synthesized in Example (68b), 10% palladium carbon catalyst (80 mg), (R)-(−)-1-amino-2-propanol (44 mg, 0.58 mmol), HOBT · H 2 O (43 mg, 0.32 mmol), N-methylmorpholine (0.064 mL, 0.58 mmol), WSCI · HCl (67 mg, 0.35 mmol) The target compound (67 mg, 45%) was obtained as a pale yellow solid in the same manner as in (65e).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.23 (3H, d, J = 6.3 Hz), 1.91-2.06 (2H, m), 2.13-2.20 (1H, m), 2.30-2.47 (2H, m) , 2.47-2.55 (1H, m), 3.23 (3H, s), 3.24-3.29 (1H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, t, J = 3.4 Hz), 6.59-6.62 (2H, m), 6.90 (1H, t, J = 1.5 Hz), 7.04 (1H, t, J = 1.5 Hz), 7.43 (1H, dd, J = 8.8, 2.9 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 (1H, br s).
(68d) 2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (67 mg, 0.13 mmol) synthesized in Example (68c), methanesulfonic anhydride (47 mg, 0.26 mmol), triethylamine (0.073 mL, 0.52 mmol) was used to obtain the target product (43 mg, 67% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 1.88-2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m) , 2.46-2.53 (1H, m), 3.23 (3H, s), 3.50 (1H, ddd, J = 14.2, 7.3, 2.0 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.63 (1H , t, J = 8.5 Hz), 4.77-4.85 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 496.15353 (M + H) <+> .
実施例(68b)で合成した化合物(210mg,0.38mmol)、10%パラジウム炭素触媒(80mg)、(R)-(-)-1-アミノ-2-プロパノール(44mg,0.58mmol)、HOBT・H2O(43mg,0.32mmol)、N-メチルモルホリン(0.064mL,0.58mmol)、WSCI・HCl(67mg,0.35mmol)を用い、実施例(65e)と同様の方法で淡黄色固体の目的化合物(67mg,45%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.23 (3H, d, J = 6.3 Hz), 1.91-2.06 (2H, m), 2.13-2.20 (1H, m), 2.30-2.47 (2H, m), 2.47-2.55 (1H, m), 3.23 (3H, s), 3.24-3.29 (1H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, t, J = 3.4 Hz), 6.59-6.62 (2H, m), 6.90 (1H, t, J = 1.5 Hz), 7.04 (1H, t, J = 1.5 Hz), 7.43 (1H, dd, J = 8.8, 2.9 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 (1H, br s).
(68d)2-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)シクロペンタノン
実施例(68c)で合成した化合物(67mg,0.13mmol)、メタンスルホン酸無水物(47mg,0.26mmol)、トリエチルアミン(0.073mL,0.52mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(43mg,収率67%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.41 (3H, d, J = 6.3 Hz), 1.88-2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m), 2.46-2.53 (1H, m), 3.23 (3H, s), 3.50 (1H, ddd, J = 14.2, 7.3, 2.0 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.63 (1H, t, J = 8.5 Hz), 4.77-4.85 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
MS (ESI) m/z: 496.15353 (M+H)+。 (68c) N-[(2R) -2-hydroxypropyl] -5- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5-[(2-oxocyclopentyl) oxy] phenyl ) -1H-pyrrole-2-carboxamide Compound (210 mg, 0.38 mmol) synthesized in Example (68b), 10% palladium carbon catalyst (80 mg), (R)-(−)-1-amino-2-propanol (44 mg, 0.58 mmol), HOBT · H 2 O (43 mg, 0.32 mmol), N-methylmorpholine (0.064 mL, 0.58 mmol), WSCI · HCl (67 mg, 0.35 mmol) The target compound (67 mg, 45%) was obtained as a pale yellow solid in the same manner as in (65e).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.23 (3H, d, J = 6.3 Hz), 1.91-2.06 (2H, m), 2.13-2.20 (1H, m), 2.30-2.47 (2H, m) , 2.47-2.55 (1H, m), 3.23 (3H, s), 3.24-3.29 (1H, m), 3.59 (1H, dq, J = 14.0, 3.2 Hz), 3.96-4.03 (1H, m), 4.66 (1H, t, J = 8.8 Hz), 6.40 (1H, t, J = 5.9 Hz), 6.48 (1H, t, J = 3.4 Hz), 6.59-6.62 (2H, m), 6.90 (1H, t, J = 1.5 Hz), 7.04 (1H, t, J = 1.5 Hz), 7.43 (1H, dd, J = 8.8, 2.9 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 9.80 (1H, br s).
(68d) 2- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) cyclopentanone Compound (67 mg, 0.13 mmol) synthesized in Example (68c), methanesulfonic anhydride (47 mg, 0.26 mmol), triethylamine (0.073 mL, 0.52 mmol) was used to obtain the target product (43 mg, 67% yield) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 1.88-2.07 (2H, m), 2.12-2.20 (1H, m), 2.29-2.45 (2H, m) , 2.46-2.53 (1H, m), 3.23 (3H, s), 3.50 (1H, ddd, J = 14.2, 7.3, 2.0 Hz), 4.04 (1H, dd, J = 14.2, 9.3 Hz), 4.63 (1H , t, J = 8.5 Hz), 4.77-4.85 (1H, m), 6.50 (1H, d, J = 3.9 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.74 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 2.0 Hz), 7.03 (1H, t, J = 2.0 Hz), 7.44 (1H, dd, J = 8.8, 2.9 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.47 (1H, d, J = 2.4 Hz).
MS (ESI) m / z: 496.15353 (M + H) <+> .
(実施例69)
3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ブタン-2-オン (Example 69)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one
3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ブタン-2-オン (Example 69)
3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[6- ( Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one
(69a)3-(3-ブロモ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ブタン-2-オン
実施例(19b)で合成した化合物(1.00g,2.91mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、3-ブロモ-2-ブタノン(0.88mL,5.81mmol)、炭酸カリウム(1.20g,8.72mmol)を加え、窒素雰囲気下80℃で3時間加熱した。反応液を室温まで冷却後、飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、黄色油状の目的化合物(752mg,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.52 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.22 (3H, s), 4.60 (1H, q, J = 7.0 Hz), 6.53 (1H, t, J = 2.3 Hz), 6.85 (1H, t, J = 2.0 Hz), 6.89 (1H, dd, J = 2.3, 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(69b)ベンジル 5-[3-(1-メチル-2-オキソプロポキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(69a)で合成した化合物(752mg,1.82mmol)、実施例(19e)で合成した化合物(891mg,2.72mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(89mg,0.11mmol)、炭酸カリウム(1.25g,9.08mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(361mg,収率37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.54 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.23 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 5.33 (2H, s), 6.49 (1H, t, J = 2.0 Hz), 6.52 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.93 (1H, dd, J = 2.3, 1.6 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.34-7.46 (6H, m), 8.07 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.23 (1H, br s)。 (69a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound (1.00 g, 2) synthesized in Example (19b) .91 mmol) was dissolved in N, N-dimethylformamide (5 mL), 3-bromo-2-butanone (0.88 mL, 5.81 mmol) and potassium carbonate (1.20 g, 8.72 mmol) were added, and nitrogen atmosphere was added. The mixture was heated at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (752 mg, yield 63%) as a yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.52 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.22 (3H, s), 4.60 (1H, q, J = 7.0 Hz), 6.53 (1H, t, J = 2.3 Hz), 6.85 (1H, t, J = 2.0 Hz), 6.89 (1H, dd, J = 2.3, 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz) ), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(69b) Benzyl 5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate Compound (752 mg, 1.82 mmol) synthesized in Example (69a), compound (891 mg, 2.72 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (89 mg, 0.11 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were used in the same manner as in Example (16e) to give the target compound as a pale yellow solid (361 mg, 37% yield) Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.54 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.23 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 5.33 (2H, s), 6.49 (1H, t, J = 2.0 Hz), 6.52 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.93 (1H, dd , J = 2.3, 1.6 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.34-7.46 (6H, m), 8.07 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.23 (1H, br s).
実施例(19b)で合成した化合物(1.00g,2.91mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、3-ブロモ-2-ブタノン(0.88mL,5.81mmol)、炭酸カリウム(1.20g,8.72mmol)を加え、窒素雰囲気下80℃で3時間加熱した。反応液を室温まで冷却後、飽和炭酸水素ナトリウム水溶液(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、黄色油状の目的化合物(752mg,収率63%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.52 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.22 (3H, s), 4.60 (1H, q, J = 7.0 Hz), 6.53 (1H, t, J = 2.3 Hz), 6.85 (1H, t, J = 2.0 Hz), 6.89 (1H, dd, J = 2.3, 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(69b)ベンジル 5-[3-(1-メチル-2-オキソプロポキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキシレート
実施例(69a)で合成した化合物(752mg,1.82mmol)、実施例(19e)で合成した化合物(891mg,2.72mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(89mg,0.11mmol)、炭酸カリウム(1.25g,9.08mmol)を用い、実施例(16e)と同様の方法で淡黄色固体の目的化合物(361mg,収率37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.54 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.23 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 5.33 (2H, s), 6.49 (1H, t, J = 2.0 Hz), 6.52 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.93 (1H, dd, J = 2.3, 1.6 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.34-7.46 (6H, m), 8.07 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.23 (1H, br s)。 (69a) 3- (3-Bromo-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound (1.00 g, 2) synthesized in Example (19b) .91 mmol) was dissolved in N, N-dimethylformamide (5 mL), 3-bromo-2-butanone (0.88 mL, 5.81 mmol) and potassium carbonate (1.20 g, 8.72 mmol) were added, and nitrogen atmosphere was added. The mixture was heated at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (752 mg, yield 63%) as a yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.52 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.22 (3H, s), 4.60 (1H, q, J = 7.0 Hz), 6.53 (1H, t, J = 2.3 Hz), 6.85 (1H, t, J = 2.0 Hz), 6.89 (1H, dd, J = 2.3, 1.6 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz) ), 8.08 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(69b) Benzyl 5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl] -1H-pyrrole-2-carboxylate Compound (752 mg, 1.82 mmol) synthesized in Example (69a), compound (891 mg, 2.72 mmol) synthesized in Example (19e), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) Dichloride Dichloromethane complex (89 mg, 0.11 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were used in the same manner as in Example (16e) to give the target compound as a pale yellow solid (361 mg, 37% yield) Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.54 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.23 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 5.33 (2H, s), 6.49 (1H, t, J = 2.0 Hz), 6.52 (1H, dd, J = 3.9, 2.3 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.93 (1H, dd , J = 2.3, 1.6 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.34-7.46 (6H, m), 8.07 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz), 9.23 (1H, br s).
(69c)N-[(2R)-2-ヒドロキシプロピル]-5-[3-(1-メチル-2-オキソプロポキシ)-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル]-1H-ピロール-2-カルボキサミド
実施例(69b)で合成した化合物(361mg,0.68mmol)、10%パラジウム炭素触媒(120mg)、(R)-(-)-1-アミノ-2-プロパノール(97mg,1.29mmol)、HOBT・H2O(96mg,0.71mmol)、N-メチルモルホリン(0.142mL,1.29mmol)、WSCI・HCl(149mg,0.77mmol)を用い、実施例(65e)と同様の方法で淡黄色固体の目的化合物(110mg,34%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 7.0 Hz), 1.53 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.25-3.31 (1H, m), 3.60 (1H, dq, J = 13.9, 3.2 Hz), 3.96-4.04 (1H, m), 4.67 (1H, q, J = 6.6 Hz), 6.35-6.41 (1H, m), 6.46-6.51 (2H, m), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (1H, s), 6.94 (1H, s), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(69d)3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ブタン-2-オン
実施例(69c)で合成した化合物(110mg,0.22mmol)、メタンスルホン酸無水物(79mg,0.44mmol)、トリエチルアミン(0.122mL,0.88mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(81mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.6 Hz), 1.53 (3H, d, J = 7.0 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.67 (1H, q, J = 6.9 Hz), 4.79-4.88 (1H, m), 6.47 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 484.15307 (M+H)+。 (69c) N-[(2R) -2-hydroxypropyl] -5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Phenyl] -1H-pyrrole-2-carboxamide Compound (361 mg, 0.68 mmol) synthesized in Example (69b), 10% palladium carbon catalyst (120 mg), (R)-(−)-1-amino-2- Using propanol (97 mg, 1.29 mmol), HOBT.H 2 O (96 mg, 0.71 mmol), N-methylmorpholine (0.142 mL, 1.29 mmol), WSCI · HCl (149 mg, 0.77 mmol) The target compound (110 mg, 34%) was obtained as a pale yellow solid in the same manner as in Example (65e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 7.0 Hz), 1.53 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.25-3.31 (1H, m), 3.60 (1H, dq, J = 13.9, 3.2 Hz), 3.96-4.04 (1H, m), 4.67 (1H, q, J = 6.6 Hz), 6.35-6.41 (1H, m), 6.46-6.51 (2H, m), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (1H, s), 6.94 (1H, s), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(69d) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound synthesized in Example (69c) (110 mg, 0.22 mmol), methanesulfonic anhydride (79 mg, 0.44 mmol) , Triethylamine (0.122 mL, 0.88 mmol) was used to obtain the desired product (81 mg, yield 76%) as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.6 Hz), 1.53 (3H, d, J = 7.0 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.67 (1H, q, J = 6.9 Hz), 4.79-4.88 (1H, m), 6.47 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H , s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15307 (M + H) <+> .
実施例(69b)で合成した化合物(361mg,0.68mmol)、10%パラジウム炭素触媒(120mg)、(R)-(-)-1-アミノ-2-プロパノール(97mg,1.29mmol)、HOBT・H2O(96mg,0.71mmol)、N-メチルモルホリン(0.142mL,1.29mmol)、WSCI・HCl(149mg,0.77mmol)を用い、実施例(65e)と同様の方法で淡黄色固体の目的化合物(110mg,34%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 7.0 Hz), 1.53 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.25-3.31 (1H, m), 3.60 (1H, dq, J = 13.9, 3.2 Hz), 3.96-4.04 (1H, m), 4.67 (1H, q, J = 6.6 Hz), 6.35-6.41 (1H, m), 6.46-6.51 (2H, m), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (1H, s), 6.94 (1H, s), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(69d)3-(3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェノキシ)ブタン-2-オン
実施例(69c)で合成した化合物(110mg,0.22mmol)、メタンスルホン酸無水物(79mg,0.44mmol)、トリエチルアミン(0.122mL,0.88mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的物(81mg,収率76%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.43 (3H, d, J = 6.6 Hz), 1.53 (3H, d, J = 7.0 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.67 (1H, q, J = 6.9 Hz), 4.79-4.88 (1H, m), 6.47 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H, s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 484.15307 (M+H)+。 (69c) N-[(2R) -2-hydroxypropyl] -5- [3- (1-methyl-2-oxopropoxy) -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} Phenyl] -1H-pyrrole-2-carboxamide Compound (361 mg, 0.68 mmol) synthesized in Example (69b), 10% palladium carbon catalyst (120 mg), (R)-(−)-1-amino-2- Using propanol (97 mg, 1.29 mmol), HOBT.H 2 O (96 mg, 0.71 mmol), N-methylmorpholine (0.142 mL, 1.29 mmol), WSCI · HCl (149 mg, 0.77 mmol) The target compound (110 mg, 34%) was obtained as a pale yellow solid in the same manner as in Example (65e).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 7.0 Hz), 1.53 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.25-3.31 (1H, m), 3.60 (1H, dq, J = 13.9, 3.2 Hz), 3.96-4.04 (1H, m), 4.67 (1H, q, J = 6.6 Hz), 6.35-6.41 (1H, m), 6.46-6.51 (2H, m), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (1H, s), 6.94 (1H, s), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz), 9.75 (1H, br s).
(69d) 3- (3- {5-[(5S) -5-Methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenoxy) butan-2-one Compound synthesized in Example (69c) (110 mg, 0.22 mmol), methanesulfonic anhydride (79 mg, 0.44 mmol) , Triethylamine (0.122 mL, 0.88 mmol) was used to obtain the desired product (81 mg, yield 76%) as a pale yellow solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.43 (3H, d, J = 6.6 Hz), 1.53 (3H, d, J = 7.0 Hz), 2.21 (3H, s), 3.24 (3H, s), 3.54 (1H, dd, J = 14.1, 7.4 Hz), 4.08 (1H, dd, J = 14.1, 9.4 Hz), 4.67 (1H, q, J = 6.9 Hz), 4.79-4.88 (1H, m), 6.47 (1H, t, J = 2.2 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.86 (1H, t, J = 1.6 Hz), 6.93 (1H , s), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15307 (M + H) <+> .
(実施例70)
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール (Example 70)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol
(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール (Example 70)
(1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol
(70a)ベンジル 5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(34g)で合成した化合物(986mg,2.59mmol)と、実施例(43c)で合成した化合物(523mg,2.71mmol)をアセトニトリル(25mL)に溶解し、炭酸セシウム(1.68g,5.17mmol)を加え、窒素雰囲気下室温で1.5時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色固体の目的化合物(1.38g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.38 (3H, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45-4.73 (3H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (1H, t, J = 2.2 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.05 (1H, t, J = 1.8 Hz), 7.32-7.46 (5H, m), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz), 9.21 (1H, br s).
(70b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(70a)で合成した化合物(1.34g,2.49mmol)を酢酸エチル(5mL)とエタノール(20mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(250mg)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(719mg,収率65%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 4.44-4.74 (3H, m), 6.53 (1H, s), 6.70 (1H, s), 6.96-7.05 (2H, m), 7.08 (1H, s), 8.49 (1H, s), 8.80 (1H, s), 9.47 (1H, br s)。 (70a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (986 mg, 2.59 mmol) synthesized in Example (34 g) and compound (523 mg, 2.71 mmol) synthesized in Example (43c) were dissolved in acetonitrile (25 mL), and cesium carbonate (1 .68 g, 5.17 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (1.38 g) as a pale yellow solid. Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45-4.73 (3H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (1H, t, J = 2.2 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz) , 7.05 (1H, t, J = 1.8 Hz), 7.32-7.46 (5H, m), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz), 9.21 (1H, br s).
(70b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.34 g, 2.49 mmol) synthesized in Example (70a) was dissolved in a mixed solvent of ethyl acetate (5 mL) and ethanol (20 mL), 10% palladium carbon catalyst (250 mg) was added, and hydrogen was added. Stir for 2 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (719 mg, yield 65%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 4.44-4.74 (3H, m), 6.53 (1H, s), 6.70 (1H , s), 6.96-7.05 (2H, m), 7.08 (1H, s), 8.49 (1H, s), 8.80 (1H, s), 9.47 (1H, br s).
実施例(34g)で合成した化合物(986mg,2.59mmol)と、実施例(43c)で合成した化合物(523mg,2.71mmol)をアセトニトリル(25mL)に溶解し、炭酸セシウム(1.68g,5.17mmol)を加え、窒素雰囲気下室温で1.5時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、淡黄色固体の目的化合物(1.38g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.38 (3H, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45-4.73 (3H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (1H, t, J = 2.2 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.05 (1H, t, J = 1.8 Hz), 7.32-7.46 (5H, m), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz), 9.21 (1H, br s).
(70b)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(70a)で合成した化合物(1.34g,2.49mmol)を酢酸エチル(5mL)とエタノール(20mL)の混合溶媒に溶解し、10%パラジウム炭素触媒(250mg)を加えて水素雰囲気下に2時間撹拌した。セライトろ過によりパラジウム炭素触媒を除去し、減圧下溶媒を留去することで白色固体の目的化合物(719mg,収率65%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.37 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 4.44-4.74 (3H, m), 6.53 (1H, s), 6.70 (1H, s), 6.96-7.05 (2H, m), 7.08 (1H, s), 8.49 (1H, s), 8.80 (1H, s), 9.47 (1H, br s)。 (70a) Benzyl 5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2 -Carboxylate Compound (986 mg, 2.59 mmol) synthesized in Example (34 g) and compound (523 mg, 2.71 mmol) synthesized in Example (43c) were dissolved in acetonitrile (25 mL), and cesium carbonate (1 .68 g, 5.17 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the target compound (1.38 g) as a pale yellow solid. Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.38 (3H, dd, J = 6.6, 1.6 Hz), 3.23 (3H, s), 4.45-4.73 (3H, m), 5.33 (2H, s), 6.53 (1H, dd, J = 3.9, 2.7 Hz), 6.69 (1H, t, J = 2.2 Hz), 6.96 (1H, t, J = 1.8 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz) , 7.05 (1H, t, J = 1.8 Hz), 7.32-7.46 (5H, m), 8.50 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 1.2 Hz), 9.21 (1H, br s).
(70b) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H-pyrrole-2- Carboxylic acid The compound (1.34 g, 2.49 mmol) synthesized in Example (70a) was dissolved in a mixed solvent of ethyl acetate (5 mL) and ethanol (20 mL), 10% palladium carbon catalyst (250 mg) was added, and hydrogen was added. Stir for 2 hours under atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain the target compound (719 mg, yield 65%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.37 (3H, d, J = 6.3 Hz), 3.23 (3H, s), 4.44-4.74 (3H, m), 6.53 (1H, s), 6.70 (1H , s), 6.96-7.05 (2H, m), 7.08 (1H, s), 8.49 (1H, s), 8.80 (1H, s), 9.47 (1H, br s).
(70c)5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-N-[(1S,2R)-2-ヒドロキシ-1-(ヒドロキシメチル)プロピル]-1H-ピロール-2-カルボキサミド
実施例(70b)で合成した化合物(300mg,0.69mmol)、D-アロ-スレオニノール(109mg,1.03mmol)、HOBT・H2O(102mg,0.76mmol)、N-メチルモルホリン(0.152mL,1.38mmol)、WSCI・HCl(159mg,0.83mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(312mg,87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.3 Hz), 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75-2.80 (2H, m), 3.24 (3H, s), 3.79-3.86 (1H, m), 3.91-3.97 (1H, m), 4.06-4.13 (2H, m), 4.45-4.72 (3H, m), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.65-6.68 (2H, m), 6.78 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.79 (1H, d, J = 1.2 Hz), 9.76 (1H, br s).
(70d)(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール
実施例(70c)で合成した化合物(312mg,0.60mmol)、メタンスルホン酸無水物(160mg,0.90mmol)、トリエチルアミン(0.250mL, 1.79mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(121mg,収率40%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.15 (3H, d, J = 6.8 Hz), 1.39 (3H, dd, J = 6.6, 1.7 Hz), 3.24 (3H, s), 4.19-4.31 (4H, m), 4.46-4.72 (3H, m), 6.36 (1H, d, J = 3.9 Hz), 6.41 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.99 (1H, t, J = 1.5 Hz), 7.11 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 8.81 (1H, d, J = 1.5 Hz), 10.14 (1H, br s).
MS (ESI) m/z: 505.15571 (M+H)+。 (70c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -N-[(1S, 2R) -2-Hydroxy-1- (hydroxymethyl) propyl] -1H-pyrrole-2-carboxamide Compound (300 mg, 0.69 mmol) synthesized in Example (70b), D-allo-threoninol (109 mg, 1. 03 mmol), HOBT.H 2 O (102 mg, 0.76 mmol), N-methylmorpholine (0.152 mL, 1.38 mmol), WSCI · HCl (159 mg, 0.83 mmol) and the same as in Example (29a) The target compound (312 mg, 87%) as a white solid was obtained by the method described above.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75-2.80 (2H, m), 3.24 (3H , s), 3.79-3.86 (1H, m), 3.91-3.97 (1H, m), 4.06-4.13 (2H, m), 4.45-4.72 (3H, m), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.65-6.68 (2H, m), 6.78 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.79 (1H, d, J = 1.2 Hz), 9.76 (1H, br s).
(70d) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazine-2 -Il] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol Compound synthesized in Example (70c) (312 mg, 0.60 mmol) , Methanesulfonic anhydride (160 mg, 0.90 mmol) and triethylamine (0.250 mL, 1.79 mmol) were used in the same manner as in Example (16j) to give the target compound as a white solid (121 mg, yield 40%) Got.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.15 (3H, d, J = 6.8 Hz), 1.39 (3H, dd, J = 6.6, 1.7 Hz), 3.24 (3H, s), 4.19-4.31 (4H , m), 4.46-4.72 (3H, m), 6.36 (1H, d, J = 3.9 Hz), 6.41 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.99 (1H, t, J = 1.5 Hz), 7.11 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 8.81 (1H, d, J = 1.5 Hz), 10.14 (1H , br s).
MS (ESI) m / z: 505.15571 (M + H) <+> .
実施例(70b)で合成した化合物(300mg,0.69mmol)、D-アロ-スレオニノール(109mg,1.03mmol)、HOBT・H2O(102mg,0.76mmol)、N-メチルモルホリン(0.152mL,1.38mmol)、WSCI・HCl(159mg,0.83mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(312mg,87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.3 Hz), 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75-2.80 (2H, m), 3.24 (3H, s), 3.79-3.86 (1H, m), 3.91-3.97 (1H, m), 4.06-4.13 (2H, m), 4.45-4.72 (3H, m), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.65-6.68 (2H, m), 6.78 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.79 (1H, d, J = 1.2 Hz), 9.76 (1H, br s).
(70d)(1R)-1-{(4S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}エタノール
実施例(70c)で合成した化合物(312mg,0.60mmol)、メタンスルホン酸無水物(160mg,0.90mmol)、トリエチルアミン(0.250mL, 1.79mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(121mg,収率40%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.15 (3H, d, J = 6.8 Hz), 1.39 (3H, dd, J = 6.6, 1.7 Hz), 3.24 (3H, s), 4.19-4.31 (4H, m), 4.46-4.72 (3H, m), 6.36 (1H, d, J = 3.9 Hz), 6.41 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.99 (1H, t, J = 1.5 Hz), 7.11 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 8.81 (1H, d, J = 1.5 Hz), 10.14 (1H, br s).
MS (ESI) m/z: 505.15571 (M+H)+。 (70c) 5- (3-[(1S) -2-Fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -N-[(1S, 2R) -2-Hydroxy-1- (hydroxymethyl) propyl] -1H-pyrrole-2-carboxamide Compound (300 mg, 0.69 mmol) synthesized in Example (70b), D-allo-threoninol (109 mg, 1. 03 mmol), HOBT.H 2 O (102 mg, 0.76 mmol), N-methylmorpholine (0.152 mL, 1.38 mmol), WSCI · HCl (159 mg, 0.83 mmol) and the same as in Example (29a) The target compound (312 mg, 87%) as a white solid was obtained by the method described above.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.3 Hz), 1.37 (3H, dd, J = 6.3, 1.6 Hz), 2.75-2.80 (2H, m), 3.24 (3H , s), 3.79-3.86 (1H, m), 3.91-3.97 (1H, m), 4.06-4.13 (2H, m), 4.45-4.72 (3H, m), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.65-6.68 (2H, m), 6.78 (1H, d, J = 7.8 Hz), 6.97 (1H, t, J = 1.6 Hz), 7.06 (1H, t, J = 1.6 Hz), 8.49 (1H, d, J = 1.2 Hz), 8.79 (1H, d, J = 1.2 Hz), 9.76 (1H, br s).
(70d) (1R) -1-{(4S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazine-2 -Il] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} ethanol Compound synthesized in Example (70c) (312 mg, 0.60 mmol) , Methanesulfonic anhydride (160 mg, 0.90 mmol) and triethylamine (0.250 mL, 1.79 mmol) were used in the same manner as in Example (16j) to give the target compound as a white solid (121 mg, yield 40%) Got.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.15 (3H, d, J = 6.8 Hz), 1.39 (3H, dd, J = 6.6, 1.7 Hz), 3.24 (3H, s), 4.19-4.31 (4H , m), 4.46-4.72 (3H, m), 6.36 (1H, d, J = 3.9 Hz), 6.41 (1H, d, J = 3.9 Hz), 6.66 (1H, t, J = 2.2 Hz), 6.99 (1H, t, J = 1.5 Hz), 7.11 (1H, t, J = 1.5 Hz), 8.50 (1H, d, J = 1.5 Hz), 8.81 (1H, d, J = 1.5 Hz), 10.14 (1H , br s).
MS (ESI) m / z: 505.15571 (M + H) <+> .
(実施例71)
1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン (Example 71)
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one
1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン (Example 71)
1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ 6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one
(71a)1-(3-ヒドロキシ-5-メトキシフェニル)-2-メチルプロパン-1-オン
実施例(59b)で合成した化合物(6.40g,30.73mmol)、ナトリウムチオメトキシド(2.66g,36.88mmol)を用い、実施例(1a)と同様の方法で黄色油状の目的化合物(6.00g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.6 Hz), 3.41-3.52 (1H, m), 3.83 (3H, s), 5.17 (1H, br s), 6.61 (1H, t, J = 2.3 Hz), 7.04 (1H, dd, J = 2.3, 1.2 Hz), 7.08 (1H, dd, J = 2.3, 1.2 Hz).
(71b)1-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71a)で合成した化合物(980mg,5.05mmol)と実施例(16a)で合成した化合物(1.45g,7.57mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、炭酸セシウム(4.93g,15.14mmol)を加え、窒素雰囲気下100℃で1.5時間撹拌した。反応液を室温まで冷却後に飽和食塩水(10mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、無色油状の目的化合物(975mg,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.6 Hz), 3.23 (3H, s), 3.38-3.50 (1H, m), 3.87 (3H, s), 6.83 (1H, t, J = 2.3 Hz), 7.23 (1H, dd, J = 2.3, 1.2 Hz), 7.38 (1H, dd, J = 2.3, 1.2 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(71c)1-(3-ヒドロキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71b)で合成した化合物(975mg,2.79mmol)、1.0mol/L三臭化ホウ素ジクロロメタン溶液(11.2mL,11.2mmol)を用い、実施例(40g)と同様の方法で白色固体の目的化合物(643mg,69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 7.0 Hz), 3.24 (3H, s), 3.37-3.48 (1H, m), 6.14 (1H, br s), 6.80 (1H, t, J = 2.2 Hz), 7.21 (1H, dd, J = 2.3, 1.2 Hz), 7.35 (1H, dd, J = 2.3, 1.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz)。 (71a) 1- (3-Hydroxy-5-methoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59b) (6.40 g, 30.73 mmol), sodium thiomethoxide (2. The target compound (6.00 g, yield 100%) as a yellow oil was obtained in the same manner as in Example (1a) using 66 g, 36.88 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.41-3.52 (1H, m), 3.83 (3H, s), 5.17 (1H, br s), 6.61 ( 1H, t, J = 2.3 Hz), 7.04 (1H, dd, J = 2.3, 1.2 Hz), 7.08 (1H, dd, J = 2.3, 1.2 Hz).
(71b) 1- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (980 mg) synthesized in Example (71a) , 5.05 mmol) and the compound synthesized in Example (16a) (1.45 g, 7.57 mmol) were dissolved in N, N-dimethylformamide (15 mL), and cesium carbonate (4.93 g, 15.14 mmol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 1.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -40%) to give the desired compound as a colorless oil (975 mg, yield). 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.23 (3H, s), 3.38-3.50 (1H, m), 3.87 (3H, s), 6.83 (1H , t, J = 2.3 Hz), 7.23 (1H, dd, J = 2.3, 1.2 Hz), 7.38 (1H, dd, J = 2.3, 1.2 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz) , 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(71c) 1- (3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (975 mg) synthesized in Example (71b) , 2.79 mmol), 1.0 mol / L boron tribromide dichloromethane solution (11.2 mL, 11.2 mmol) and the same method as in Example (40 g), and the target compound (643 mg, 69%) as a white solid was obtained. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.24 (3H, s), 3.37-3.48 (1H, m), 6.14 (1H, br s), 6.80 ( 1H, t, J = 2.2 Hz), 7.21 (1H, dd, J = 2.3, 1.2 Hz), 7.35 (1H, dd, J = 2.3, 1.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz ), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
実施例(59b)で合成した化合物(6.40g,30.73mmol)、ナトリウムチオメトキシド(2.66g,36.88mmol)を用い、実施例(1a)と同様の方法で黄色油状の目的化合物(6.00g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.6 Hz), 3.41-3.52 (1H, m), 3.83 (3H, s), 5.17 (1H, br s), 6.61 (1H, t, J = 2.3 Hz), 7.04 (1H, dd, J = 2.3, 1.2 Hz), 7.08 (1H, dd, J = 2.3, 1.2 Hz).
(71b)1-(3-メトキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71a)で合成した化合物(980mg,5.05mmol)と実施例(16a)で合成した化合物(1.45g,7.57mmol)をN,N-ジメチルホルムアミド(15mL)に溶解し、炭酸セシウム(4.93g,15.14mmol)を加え、窒素雰囲気下100℃で1.5時間撹拌した。反応液を室温まで冷却後に飽和食塩水(10mL)を加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~40%)を用いて精製することにより、無色油状の目的化合物(975mg,収率55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 6.6 Hz), 3.23 (3H, s), 3.38-3.50 (1H, m), 3.87 (3H, s), 6.83 (1H, t, J = 2.3 Hz), 7.23 (1H, dd, J = 2.3, 1.2 Hz), 7.38 (1H, dd, J = 2.3, 1.2 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(71c)1-(3-ヒドロキシ-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71b)で合成した化合物(975mg,2.79mmol)、1.0mol/L三臭化ホウ素ジクロロメタン溶液(11.2mL,11.2mmol)を用い、実施例(40g)と同様の方法で白色固体の目的化合物(643mg,69%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.21 (6H, d, J = 7.0 Hz), 3.24 (3H, s), 3.37-3.48 (1H, m), 6.14 (1H, br s), 6.80 (1H, t, J = 2.2 Hz), 7.21 (1H, dd, J = 2.3, 1.2 Hz), 7.35 (1H, dd, J = 2.3, 1.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz)。 (71a) 1- (3-Hydroxy-5-methoxyphenyl) -2-methylpropan-1-one The compound synthesized in Example (59b) (6.40 g, 30.73 mmol), sodium thiomethoxide (2. The target compound (6.00 g, yield 100%) as a yellow oil was obtained in the same manner as in Example (1a) using 66 g, 36.88 mmol).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.41-3.52 (1H, m), 3.83 (3H, s), 5.17 (1H, br s), 6.61 ( 1H, t, J = 2.3 Hz), 7.04 (1H, dd, J = 2.3, 1.2 Hz), 7.08 (1H, dd, J = 2.3, 1.2 Hz).
(71b) 1- (3-Methoxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (980 mg) synthesized in Example (71a) , 5.05 mmol) and the compound synthesized in Example (16a) (1.45 g, 7.57 mmol) were dissolved in N, N-dimethylformamide (15 mL), and cesium carbonate (4.93 g, 15.14 mmol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 1.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -40%) to give the desired compound as a colorless oil (975 mg, yield). 55%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 6.6 Hz), 3.23 (3H, s), 3.38-3.50 (1H, m), 3.87 (3H, s), 6.83 (1H , t, J = 2.3 Hz), 7.23 (1H, dd, J = 2.3, 1.2 Hz), 7.38 (1H, dd, J = 2.3, 1.2 Hz), 7.43 (1H, dd, J = 8.6, 2.7 Hz) , 8.06 (1H, d, J = 8.6 Hz), 8.47 (1H, d, J = 2.7 Hz).
(71c) 1- (3-hydroxy-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (975 mg) synthesized in Example (71b) , 2.79 mmol), 1.0 mol / L boron tribromide dichloromethane solution (11.2 mL, 11.2 mmol) and the same method as in Example (40 g), and the target compound (643 mg, 69%) as a white solid was obtained. Got.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.21 (6H, d, J = 7.0 Hz), 3.24 (3H, s), 3.37-3.48 (1H, m), 6.14 (1H, br s), 6.80 ( 1H, t, J = 2.2 Hz), 7.21 (1H, dd, J = 2.3, 1.2 Hz), 7.35 (1H, dd, J = 2.3, 1.2 Hz), 7.44 (1H, dd, J = 8.6, 2.7 Hz ), 8.06 (1H, d, J = 8.6 Hz), 8.46 (1H, d, J = 2.7 Hz).
(71d)3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル トリフルオロメタンスルホネート
実施例(71c)で合成した化合物(643mg,1.92mmol)を塩化メチレン(10mL)に溶解して0℃へ冷却し、窒素雰囲気下、ピリジン(0.46mL,5.75mmol)、トリフルオロメタンスルホン酸無水物(0.48mL,2.88mmol)を加え、1時間攪拌した。飽和塩化アンモニウム水溶液(10mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~40%)を用いて精製することにより、白色固体の目的化合物(735mg,82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.26 (3H, s), 3.37-3.48 (1H, m), 7.24 (1H, t, J = 2.0 Hz), 7.51 (1H, dd, J = 8.6, 2.7 Hz), 7.67 (2H, dd, J = 2.3, 1.6 Hz), 7.70 (1H, t, J = 2.0 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz).
(71e)メチル 5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(71d)で合成した化合物(626mg,1.34mmol)、公知(Adv.Synth.Cat.,345,2003,1103)のメチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(504mg,2.01mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(66mg,0.08mmol)、炭酸カリウム(925mg,6.70mmol)を用い、実施例(16e)と同様の方法で淡黄色油状の目的化合物(521mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.44-7.48 (2H, m), 7.54 (1H, dd, J = 2.3, 1.6 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.42 (1H, br s).
(71f)5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(71e)で合成した化合物(521mg,1.18mmol)をメタノール(12mL)、テトラヒドロフラン(4mL)及び水(4mL)の混合溶媒に溶解し、水酸化リチウム一水和物(250mg,5.89mmol)を加え、50℃で2時間加熱した。1規定塩酸(10mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、淡黄色固体の目的物(510mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.49-3.58 (1H, m), 6.64 (1H, dd, J = 4.3, 2.7 Hz), 7.09 (1H, dd, J = 3.9, 2.3 Hz), 7.47 (1H, dd, J = 8.6, 2.7 Hz), 7.54 (1H, t, J = 1.6 Hz), 7.62 (1H, t, J = 1.6 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 2.7 Hz), 8.96 (1H, s), 11.57 (1H, br s)。 (71d) 3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl trifluoromethanesulfonate Compound (643 mg, 1.92 mmol) synthesized in Example (71c) was dissolved in methylene chloride (10 mL). In a nitrogen atmosphere, pyridine (0.46 mL, 5.75 mmol) and trifluoromethanesulfonic anhydride (0.48 mL, 2.88 mmol) were added and stirred for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 40%) to give the target compound (735 mg, 82%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.26 (3H, s), 3.37-3.48 (1H, m), 7.24 (1H, t, J = 2.0 Hz ), 7.51 (1H, dd, J = 8.6, 2.7 Hz), 7.67 (2H, dd, J = 2.3, 1.6 Hz), 7.70 (1H, t, J = 2.0 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz).
(71e) Methyl 5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (71d) ( 626 mg, 1.34 mmol), known (Adv. Synth. Cat., 345, 2003, 1103) methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (504 mg, 2.01 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (66 mg, 0.08 mmol), potassium carbonate (925 mg , 6.70 mmol) using a method similar to Example (16e) to obtain a light yellow oil. The compound (521 mg, yield 88%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 6.62 (1H , dd, J = 3.9, 2.7 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.44-7.48 (2H, m), 7.54 (1H, dd, J = 2.3, 1.6 Hz), 7.99 ( 1H, t, J = 1.6 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.42 (1H, br s).
(71f) 5- (3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (521 mg) synthesized in Example (71e) , 1.18 mmol) is dissolved in a mixed solvent of methanol (12 mL), tetrahydrofuran (4 mL) and water (4 mL), lithium hydroxide monohydrate (250 mg, 5.89 mmol) is added, and the mixture is heated at 50 ° C. for 2 hours. did. 1N Hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (510 mg, yield 88%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.49-3.58 (1H, m), 6.64 (1H, dd, J = 4.3, 2.7 Hz), 7.09 (1H, dd, J = 3.9, 2.3 Hz), 7.47 (1H, dd, J = 8.6, 2.7 Hz), 7.54 (1H, t, J = 1.6 Hz), 7.62 (1H, t, J = 1.6 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 2.7 Hz), 8.96 (1H, s), 11.57 (1H, br s).
実施例(71c)で合成した化合物(643mg,1.92mmol)を塩化メチレン(10mL)に溶解して0℃へ冷却し、窒素雰囲気下、ピリジン(0.46mL,5.75mmol)、トリフルオロメタンスルホン酸無水物(0.48mL,2.88mmol)を加え、1時間攪拌した。飽和塩化アンモニウム水溶液(10mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=0%~40%)を用いて精製することにより、白色固体の目的化合物(735mg,82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.26 (3H, s), 3.37-3.48 (1H, m), 7.24 (1H, t, J = 2.0 Hz), 7.51 (1H, dd, J = 8.6, 2.7 Hz), 7.67 (2H, dd, J = 2.3, 1.6 Hz), 7.70 (1H, t, J = 2.0 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz).
(71e)メチル 5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキシレート
実施例(71d)で合成した化合物(626mg,1.34mmol)、公知(Adv.Synth.Cat.,345,2003,1103)のメチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(504mg,2.01mmol)、[1,1′-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(66mg,0.08mmol)、炭酸カリウム(925mg,6.70mmol)を用い、実施例(16e)と同様の方法で淡黄色油状の目的化合物(521mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 6.62 (1H, dd, J = 3.9, 2.7 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.44-7.48 (2H, m), 7.54 (1H, dd, J = 2.3, 1.6 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.42 (1H, br s).
(71f)5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボン酸
実施例(71e)で合成した化合物(521mg,1.18mmol)をメタノール(12mL)、テトラヒドロフラン(4mL)及び水(4mL)の混合溶媒に溶解し、水酸化リチウム一水和物(250mg,5.89mmol)を加え、50℃で2時間加熱した。1規定塩酸(10mL)を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、淡黄色固体の目的物(510mg,収率88%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.49-3.58 (1H, m), 6.64 (1H, dd, J = 4.3, 2.7 Hz), 7.09 (1H, dd, J = 3.9, 2.3 Hz), 7.47 (1H, dd, J = 8.6, 2.7 Hz), 7.54 (1H, t, J = 1.6 Hz), 7.62 (1H, t, J = 1.6 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 2.7 Hz), 8.96 (1H, s), 11.57 (1H, br s)。 (71d) 3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl trifluoromethanesulfonate Compound (643 mg, 1.92 mmol) synthesized in Example (71c) was dissolved in methylene chloride (10 mL). In a nitrogen atmosphere, pyridine (0.46 mL, 5.75 mmol) and trifluoromethanesulfonic anhydride (0.48 mL, 2.88 mmol) were added and stirred for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0% to 40%) to give the target compound (735 mg, 82%) as a white solid. )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.26 (3H, s), 3.37-3.48 (1H, m), 7.24 (1H, t, J = 2.0 Hz ), 7.51 (1H, dd, J = 8.6, 2.7 Hz), 7.67 (2H, dd, J = 2.3, 1.6 Hz), 7.70 (1H, t, J = 2.0 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J = 2.7 Hz).
(71e) Methyl 5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylate Compound synthesized in Example (71d) ( 626 mg, 1.34 mmol), known (Adv. Synth. Cat., 345, 2003, 1103) methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (504 mg, 2.01 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (66 mg, 0.08 mmol), potassium carbonate (925 mg , 6.70 mmol) using a method similar to Example (16e) to obtain a light yellow oil. The compound (521 mg, yield 88%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 6.62 (1H , dd, J = 3.9, 2.7 Hz), 6.97 (1H, dd, J = 3.9, 2.3 Hz), 7.44-7.48 (2H, m), 7.54 (1H, dd, J = 2.3, 1.6 Hz), 7.99 ( 1H, t, J = 1.6 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.42 (1H, br s).
(71f) 5- (3-Isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole-2-carboxylic acid Compound (521 mg) synthesized in Example (71e) , 1.18 mmol) is dissolved in a mixed solvent of methanol (12 mL), tetrahydrofuran (4 mL) and water (4 mL), lithium hydroxide monohydrate (250 mg, 5.89 mmol) is added, and the mixture is heated at 50 ° C. for 2 hours. did. 1N Hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (510 mg, yield 88%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (6H, d, J = 6.6 Hz), 3.25 (3H, s), 3.49-3.58 (1H, m), 6.64 (1H, dd, J = 4.3, 2.7 Hz), 7.09 (1H, dd, J = 3.9, 2.3 Hz), 7.47 (1H, dd, J = 8.6, 2.7 Hz), 7.54 (1H, t, J = 1.6 Hz), 7.62 (1H, t, J = 1.6 Hz), 8.10 (1H, d, J = 8.6 Hz), 8.53 (1H, d, J = 2.7 Hz), 8.96 (1H, s), 11.57 (1H, br s).
(71g)N-[(2S)-2,3-ジヒドロキシプロピル]-5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(71f)で合成した化合物(261mg,0.61mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(85mg,0.91mmol)、HOBT・H2O(91mg,0.67mmol)、N-メチルモルホリン(0.135mL,1.22mmol)、WSCI・HCl(140mg,0.73mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(174mg,55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.64 (5H, m), 3.81-3.88 (1H, m), 6.48 (1H, t, J = 6.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.9, 2.3 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 2.3, 1.6 Hz), 8.01 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.04 (1H, br s).
(71h)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(71g)で合成した化合物(174mg,0.34mmol)を塩化メチレン(5mL)に溶解し、トリイソプロピルシリルクロリド(0.108mL,0.50mmol)、トリエチルアミン(0.234mL,1.68mmol)、4-ジメチルアミノピリジン(62mg,0.50mmol)を加え、窒素雰囲気下室温で8時間撹拌した。反応液に1規定塩酸を加え、ジクロロメタン(50mL)で抽出した。有機層を飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的物(110mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.16 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.09 (1H, d, J = 4.7 Hz), 3.24 (3H, s), 3.35-3.43 (1H, m), 3.47-3.56 (1H, m), 3.67 (1H, dd, J = 10.0, 6.1 Hz), 3.70-3.80 (2H, m), 3.84-3.91 (1H, m), 6.41 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 4.3, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.43-7.47 (2H, m), 7.52 (1H, t, J = 1.8 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.81 (1H, br s)。 (71 g) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-carboxamide Compound (261 mg, 0.61 mmol) synthesized in Example (71f), (S)-(−)-3-amino-1,2-propanediol (85 mg, 0.91 mmol), HOBT · H 2 Using O (91 mg, 0.67 mmol), N-methylmorpholine (0.135 mL, 1.22 mmol) and WSCI.HCl (140 mg, 0.73 mmol) in the same manner as in Example (29a), The compound (174 mg, 55%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.64 (5H, m), 3.81-3.88 (1H, m), 6.48 (1H, t, J = 6.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.9, 2.3 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 2.3, 1.6 Hz), 8.01 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.04 (1H, br s).
(71h) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (174 mg, 0.34 mmol) synthesized in Example (71 g) was dissolved in methylene chloride (5 mL), and triisopropylsilyl chloride (0.108 mL, 0.50 mmol) was dissolved. ), Triethylamine (0.234 mL, 1.68 mmol) and 4-dimethylaminopyridine (62 mg, 0.50 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the desired product (110 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.16 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.09 (1H, d, J = 4.7 Hz), 3.24 (3H, s ), 3.35-3.43 (1H, m), 3.47-3.56 (1H, m), 3.67 (1H, dd, J = 10.0, 6.1 Hz), 3.70-3.80 (2H, m), 3.84-3.91 (1H, m ), 6.41 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 4.3, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.43-7.47 (2H, m) , 7.52 (1H, t, J = 1.8 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.81 (1H, br s).
実施例(71f)で合成した化合物(261mg,0.61mmol)、(S)-(-)-3-アミノ-1,2-プロパンジオール(85mg,0.91mmol)、HOBT・H2O(91mg,0.67mmol)、N-メチルモルホリン(0.135mL,1.22mmol)、WSCI・HCl(140mg,0.73mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(174mg,55%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.64 (5H, m), 3.81-3.88 (1H, m), 6.48 (1H, t, J = 6.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.9, 2.3 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 2.3, 1.6 Hz), 8.01 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.04 (1H, br s).
(71h)N-{(2S)-2-ヒドロキシ-3-[(トリイソプロピルシリル)オキシ]プロピル}-5-(3-イソブチリル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-カルボキサミド
実施例(71g)で合成した化合物(174mg,0.34mmol)を塩化メチレン(5mL)に溶解し、トリイソプロピルシリルクロリド(0.108mL,0.50mmol)、トリエチルアミン(0.234mL,1.68mmol)、4-ジメチルアミノピリジン(62mg,0.50mmol)を加え、窒素雰囲気下室温で8時間撹拌した。反応液に1規定塩酸を加え、ジクロロメタン(50mL)で抽出した。有機層を飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=20%~50%)を用いて精製することにより、白色固体の目的物(110mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.04-1.16 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.09 (1H, d, J = 4.7 Hz), 3.24 (3H, s), 3.35-3.43 (1H, m), 3.47-3.56 (1H, m), 3.67 (1H, dd, J = 10.0, 6.1 Hz), 3.70-3.80 (2H, m), 3.84-3.91 (1H, m), 6.41 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 4.3, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.43-7.47 (2H, m), 7.52 (1H, t, J = 1.8 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.81 (1H, br s)。 (71 g) N-[(2S) -2,3-dihydroxypropyl] -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrole- 2-carboxamide Compound (261 mg, 0.61 mmol) synthesized in Example (71f), (S)-(−)-3-amino-1,2-propanediol (85 mg, 0.91 mmol), HOBT · H 2 Using O (91 mg, 0.67 mmol), N-methylmorpholine (0.135 mL, 1.22 mmol) and WSCI.HCl (140 mg, 0.73 mmol) in the same manner as in Example (29a), The compound (174 mg, 55%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.64 (5H, m), 3.81-3.88 (1H, m), 6.48 (1H, t, J = 6.5 Hz), 6.60 (1H, dd, J = 3.9, 2.7 Hz), 6.67 (1H, dd, J = 3.9, 2.3 Hz), 7.45 (1H, dd, J = 8.6, 2.7 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.52 (1H, dd, J = 2.3, 1.6 Hz), 8.01 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.04 (1H, br s).
(71h) N-{(2S) -2-hydroxy-3-[(triisopropylsilyl) oxy] propyl} -5- (3-isobutyryl-5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrole-2-carboxamide The compound (174 mg, 0.34 mmol) synthesized in Example (71 g) was dissolved in methylene chloride (5 mL), and triisopropylsilyl chloride (0.108 mL, 0.50 mmol) was dissolved. ), Triethylamine (0.234 mL, 1.68 mmol) and 4-dimethylaminopyridine (62 mg, 0.50 mmol) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 20% -50%) to give the desired product (110 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.04-1.16 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.09 (1H, d, J = 4.7 Hz), 3.24 (3H, s ), 3.35-3.43 (1H, m), 3.47-3.56 (1H, m), 3.67 (1H, dd, J = 10.0, 6.1 Hz), 3.70-3.80 (2H, m), 3.84-3.91 (1H, m ), 6.41 (1H, t, J = 5.7 Hz), 6.60 (1H, dd, J = 4.3, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.43-7.47 (2H, m) , 7.52 (1H, t, J = 1.8 Hz), 7.99 (1H, t, J = 1.6 Hz), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz), 9.81 (1H, br s).
(71i)2-メチル-1-(3-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}-5-{5-[(5R)-5-{[(トリイソプロピルシリル)オキシ]メチル}-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェニル)プロパン-1-オン
実施例(71h)で合成した化合物(110mg,0.16mmol)、メタンスルホン酸無水物(59mg,0.33mmol)、トリエチルアミン(0.091mL,0.65mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的物(100mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.01-1.12 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.55 (1H, m), 3.83-3.93 (3H, m), 4.01 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.81 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.42-7.47 (2H, m), 7.50 (1H, s), 7.97 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
(71j)1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71i)で合成した化合物(100mg,0.15mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,0.183mL,0.18mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(57mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.57 (1H, m), 3.69-3.80 (2H, m), 3.86 (1H, dd, J = 12.5, 3.1 Hz), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.76-4.83 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.61 (1H, d, J = 3.9 Hz), 7.42 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 7.50 (1H, t, J = 2.0 Hz), 7.98 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 484.15384 (M+H)+。 (71i) 2-Methyl-1- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenyl) propan-1-one Compound (110 mg, 0.16 mmol) synthesized in Example (71h) ), Methanesulfonic anhydride (59 mg, 0.33 mmol), triethylamine (0.091 mL, 0.65 mmol), and a yellow solid target product (100 mg, 93% yield) in the same manner as in Example (16j). )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.01-1.12 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.55 (1H, m), 3.83 -3.93 (3H, m), 4.01 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.81 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.42-7.47 (2H, m), 7.50 (1H, s), 7.97 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz ).
(71j) 1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (100 mg, 0.15 mmol) synthesized in Example (71i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.183 mL, 0.18 mmol) was used to give the target compound (57 mg, yield 75%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.57 (1H, m), 3.69-3.80 (2H, m), 3.86 (1H, dd, J = 12.5, 3.1 Hz), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.76-4.83 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.61 ( 1H, d, J = 3.9 Hz), 7.42 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 7.50 (1H, t, J = 2.0 Hz), 7.98 ( 1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15384 (M + H) <+> .
実施例(71h)で合成した化合物(110mg,0.16mmol)、メタンスルホン酸無水物(59mg,0.33mmol)、トリエチルアミン(0.091mL,0.65mmol)を用い、実施例(16j)と同様の方法で黄色固体の目的物(100mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.01-1.12 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.55 (1H, m), 3.83-3.93 (3H, m), 4.01 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.81 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.42-7.47 (2H, m), 7.50 (1H, s), 7.97 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
(71j)1-(3-{5-[(5R)-5-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-2-メチルプロパン-1-オン
実施例(71i)で合成した化合物(100mg,0.15mmol)、テトラブチルアンモニウムフルオリド(1mol/Lテトラヒドロフラン溶液,0.183mL,0.18mmol)を用い、実施例(16k)と同様の方法で白色固体の目的化合物(57mg,収率75%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.57 (1H, m), 3.69-3.80 (2H, m), 3.86 (1H, dd, J = 12.5, 3.1 Hz), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.76-4.83 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.61 (1H, d, J = 3.9 Hz), 7.42 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 7.50 (1H, t, J = 2.0 Hz), 7.98 (1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m/z: 484.15384 (M+H)+。 (71i) 2-Methyl-1- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} -5- {5-[(5R) -5-{[(triisopropylsilyl) oxy] Methyl} -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} phenyl) propan-1-one Compound (110 mg, 0.16 mmol) synthesized in Example (71h) ), Methanesulfonic anhydride (59 mg, 0.33 mmol), triethylamine (0.091 mL, 0.65 mmol), and a yellow solid target product (100 mg, 93% yield) in the same manner as in Example (16j). )
1 H-NMR (CDCl 3 , 400 MHz): δ 1.01-1.12 (21H, m), 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.55 (1H, m), 3.83 -3.93 (3H, m), 4.01 (1H, dd, J = 14.3, 9.6 Hz), 4.73-4.81 (1H, m), 6.60 (1H, d, J = 3.9 Hz), 6.76 (1H, d, J = 3.9 Hz), 7.42-7.47 (2H, m), 7.50 (1H, s), 7.97 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz ).
(71j) 1- (3- {5-[(5R) -5- (hydroxymethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -{[6- (Methylsulfonyl) pyridin-3-yl] oxy} phenyl) -2-methylpropan-1-one Compound (100 mg, 0.15 mmol) synthesized in Example (71i), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.183 mL, 0.18 mmol) was used to give the target compound (57 mg, yield 75%) as a white solid in the same manner as in Example (16k).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.24 (6H, d, J = 6.6 Hz), 3.24 (3H, s), 3.47-3.57 (1H, m), 3.69-3.80 (2H, m), 3.86 (1H, dd, J = 12.5, 3.1 Hz), 4.04 (1H, dd, J = 14.3, 10.0 Hz), 4.76-4.83 (1H, m), 6.48 (1H, d, J = 3.9 Hz), 6.61 ( 1H, d, J = 3.9 Hz), 7.42 (1H, t, J = 2.0 Hz), 7.46 (1H, dd, J = 8.6, 2.7 Hz), 7.50 (1H, t, J = 2.0 Hz), 7.98 ( 1H, t, J = 1.6 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS (ESI) m / z: 484.15384 (M + H) <+> .
(実施例72)
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 72)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド (Example 72)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4 -(Methylsulfonyl) phenoxy] benzamide
(72a)メチル 3-(5-{[(1R)-2-ヒドロキシ-1-メチルエチル]カルバモイル}-1H-ピロール-2-イル)-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(48d)で合成した化合物(600mg,1.44mmol)、D-アラニノール(0.168mL,2.17mmol)、HOBT・H2O(215mg,1.59mmol)、N-メチルモルホリン(0.318mL,2.89mmol)、WSCI・HCl(332mg,1.73mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(617mg,90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.62 (1H, dd, J = 11.1, 6.1 Hz), 3.77 (1H, dd, J = 10.9, 3.5 Hz), 3.94 (3H, s), 4.21-4.31 (1H, m), 6.14 (1H, d, J = 7.8 Hz), 6.58 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.58 (1H, dd, J = 2.3, 1.2 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.96 (1H, br s).
(72b)メチル 3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(72a)で合成した化合物(617mg,1.31mmol)、メタンスルホン酸無水物(470mg,2.61mmol)、トリエチルアミン(0.910mL,6.53mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(534mg,収率90%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.34 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.93-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.46 (1H, s), 7.59 (1H, s), 7.93 (2H, d, J = 8.8 Hz), 8.08 (1H, s)。 (72a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Examples Compound (600 mg, 1.44 mmol) synthesized in (48d), D-alaninol (0.168 mL, 2.17 mmol), HOBT.H 2 O (215 mg, 1.59 mmol), N-methylmorpholine (0.318 mL, 2.89 mmol) and WSCI.HCl (332 mg, 1.73 mmol) were used to obtain the target compound (617 mg, 90%) as a white solid in the same manner as in Example (29a).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.62 (1H, dd, J = 11.1, 6.1 Hz), 3.77 (1H, dd , J = 10.9, 3.5 Hz), 3.94 (3H, s), 4.21-4.31 (1H, m), 6.14 (1H, d, J = 7.8 Hz), 6.58 (1H, dd, J = 3.9, 2.7 Hz) , 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.58 (1H, dd, J = 2.3, 1.2 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.96 (1H, br s).
(72b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- ( Methylsulfonyl) phenoxy] benzoate Using the compound synthesized in Example (72a) (617 mg, 1.31 mmol), methanesulfonic anhydride (470 mg, 2.61 mmol), triethylamine (0.910 mL, 6.53 mmol) The target product (534 mg, yield 90%) as a white solid was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.34 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.93-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.46 (1H, s), 7.59 (1H, s), 7.93 (2H, d, J = 8.8 Hz), 8.08 (1H, s).
実施例(48d)で合成した化合物(600mg,1.44mmol)、D-アラニノール(0.168mL,2.17mmol)、HOBT・H2O(215mg,1.59mmol)、N-メチルモルホリン(0.318mL,2.89mmol)、WSCI・HCl(332mg,1.73mmol)を用い、実施例(29a)と同様の方法で白色固体の目的化合物(617mg,90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.27 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.62 (1H, dd, J = 11.1, 6.1 Hz), 3.77 (1H, dd, J = 10.9, 3.5 Hz), 3.94 (3H, s), 4.21-4.31 (1H, m), 6.14 (1H, d, J = 7.8 Hz), 6.58 (1H, dd, J = 3.9, 2.7 Hz), 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.58 (1H, dd, J = 2.3, 1.2 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.96 (1H, br s).
(72b)メチル 3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(72a)で合成した化合物(617mg,1.31mmol)、メタンスルホン酸無水物(470mg,2.61mmol)、トリエチルアミン(0.910mL,6.53mmol)を用い、実施例(16j)と同様の方法で白色固体の目的物(534mg,収率90%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.34 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.93-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.46 (1H, s), 7.59 (1H, s), 7.93 (2H, d, J = 8.8 Hz), 8.08 (1H, s)。 (72a) Methyl 3- (5-{[(1R) -2-hydroxy-1-methylethyl] carbamoyl} -1H-pyrrol-2-yl) -5- [4- (methylsulfonyl) phenoxy] benzoate Examples Compound (600 mg, 1.44 mmol) synthesized in (48d), D-alaninol (0.168 mL, 2.17 mmol), HOBT.H 2 O (215 mg, 1.59 mmol), N-methylmorpholine (0.318 mL, 2.89 mmol) and WSCI.HCl (332 mg, 1.73 mmol) were used to obtain the target compound (617 mg, 90%) as a white solid in the same manner as in Example (29a).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.27 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.62 (1H, dd, J = 11.1, 6.1 Hz), 3.77 (1H, dd , J = 10.9, 3.5 Hz), 3.94 (3H, s), 4.21-4.31 (1H, m), 6.14 (1H, d, J = 7.8 Hz), 6.58 (1H, dd, J = 3.9, 2.7 Hz) , 6.64 (1H, dd, J = 3.9, 2.7 Hz), 7.13 (2H, d, J = 9.0 Hz), 7.46 (1H, t, J = 2.0 Hz), 7.58 (1H, dd, J = 2.3, 1.2 Hz), 7.92 (2H, d, J = 9.0 Hz), 8.09 (1H, t, J = 1.6 Hz), 9.96 (1H, br s).
(72b) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- ( Methylsulfonyl) phenoxy] benzoate Using the compound synthesized in Example (72a) (617 mg, 1.31 mmol), methanesulfonic anhydride (470 mg, 2.61 mmol), triethylamine (0.910 mL, 6.53 mmol) The target product (534 mg, yield 90%) as a white solid was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.34 (3H, d, J = 6.8 Hz), 3.08 (3H, s), 3.93-3.97 (1H, m), 3.95 (3H, s), 4.30-4.39 (1H, m), 4.52 (1H, t, J = 8.3 Hz), 6.61 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.46 (1H, s), 7.59 (1H, s), 7.93 (2H, d, J = 8.8 Hz), 8.08 (1H, s).
(72c)3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]安息香酸
実施例(72b)で合成した化合物(534mg,1.17mmol)を、テトラヒドロフラン(9mL)と水(3mL)の混合溶媒に溶解し、水酸化リチウム一水和物(148mg,3.52mmol)を加え、室温で4時間撹拌した。2規定塩酸(2mL)、塩化メチレン(10mL)を加え、析出物をろ取した。このものを水、ジクロロメタンで洗浄後、乾燥することにより、白色固体の目的物(557mg,収率~100%)を得た。
1H-NMR (DMSO-D6, 400MHz):δ 1.32 (3H, d, J = 6.6 Hz), 3.22 (3H, s), 3.73-3.85 (1H, m), 4.37-4.49 (1H, m), 4.64-4.80 (1H, m), 6.86-7.02 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.47 (1H, s), 7.95 (2H, d, J = 8.6 Hz), 8.05 (1H, t, J = 2.0 Hz), 8.32 (1H, s).
(72d)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(72c)で合成した化合物(518mg,1.18mmol)を、N,N-ジメチルホルムアミド(15mL)に溶解し、室温でジメチルアミン塩酸塩(287mg,3.53mmol)、4-ジメチルアミノピリジン(431mg,3.53mmol)、トリエチルアミン(800μL,5.74mmol)、WSCI・HCl(451mg,2.35mmol)を加え、窒素雰囲気下22時間攪拌した。反応液に水(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~5%)を用いて精製することにより、白色固体の目的化合物(195mg,35%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.08 (3H, s), 3.12 (3H, br s), 3.94 (1H, t, J = 7.8 Hz), 4.28-4.39 (1H, m), 4.51 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.6 Hz), 7.46 (1H, s), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m/z: 468.16002 (M+H)+。 (72c) 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] benzoic acid The compound (534 mg, 1.17 mmol) synthesized in Example (72b) was dissolved in a mixed solvent of tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (148 mg, 3.52 mmol) was added and stirred at room temperature for 4 hours. 2N hydrochloric acid (2 mL) and methylene chloride (10 mL) were added, and the precipitate was collected by filtration. This was washed with water and dichloromethane and dried to give the desired product (557 mg, yield ˜100%) as a white solid.
1 H-NMR (DMSO-D6, 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.22 (3H, s), 3.73-3.85 (1H, m), 4.37-4.49 (1H, m), 4.64-4.80 (1H, m), 6.86-7.02 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.47 (1H, s), 7.95 (2H, d, J = 8.6 Hz), 8.05 (1H, t, J = 2.0 Hz), 8.32 (1H, s).
(72d) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (518 mg, 1.18 mmol) synthesized in Example (72c) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (287 mg) was dissolved at room temperature. , 3.53 mmol), 4-dimethylaminopyridine (431 mg, 3.53 mmol), triethylamine (800 μL, 5.74 mmol) and WSCI · HCl (451 mg, 2.35 mmol) were added, and the mixture was stirred for 22 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give a white solid. The target compound (195 mg, 35%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.08 (3H, s), 3.12 (3H, br s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.39 (1H, m), 4.51 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.6 Hz), 7.46 (1H, s), 7.92 (2H , d, J = 8.6 Hz).
MS (ESI) m / z: 468.16002 (M + H) <+> .
実施例(72b)で合成した化合物(534mg,1.17mmol)を、テトラヒドロフラン(9mL)と水(3mL)の混合溶媒に溶解し、水酸化リチウム一水和物(148mg,3.52mmol)を加え、室温で4時間撹拌した。2規定塩酸(2mL)、塩化メチレン(10mL)を加え、析出物をろ取した。このものを水、ジクロロメタンで洗浄後、乾燥することにより、白色固体の目的物(557mg,収率~100%)を得た。
1H-NMR (DMSO-D6, 400MHz):δ 1.32 (3H, d, J = 6.6 Hz), 3.22 (3H, s), 3.73-3.85 (1H, m), 4.37-4.49 (1H, m), 4.64-4.80 (1H, m), 6.86-7.02 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.47 (1H, s), 7.95 (2H, d, J = 8.6 Hz), 8.05 (1H, t, J = 2.0 Hz), 8.32 (1H, s).
(72d)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[4-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(72c)で合成した化合物(518mg,1.18mmol)を、N,N-ジメチルホルムアミド(15mL)に溶解し、室温でジメチルアミン塩酸塩(287mg,3.53mmol)、4-ジメチルアミノピリジン(431mg,3.53mmol)、トリエチルアミン(800μL,5.74mmol)、WSCI・HCl(451mg,2.35mmol)を加え、窒素雰囲気下22時間攪拌した。反応液に水(30mL)を加え、酢酸エチル(100mL)で抽出した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2%~5%)を用いて精製することにより、白色固体の目的化合物(195mg,35%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.08 (3H, s), 3.12 (3H, br s), 3.94 (1H, t, J = 7.8 Hz), 4.28-4.39 (1H, m), 4.51 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.6 Hz), 7.46 (1H, s), 7.92 (2H, d, J = 8.6 Hz).
MS (ESI) m/z: 468.16002 (M+H)+。 (72c) 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [4- (methyl [Sulfonyl) phenoxy] benzoic acid The compound (534 mg, 1.17 mmol) synthesized in Example (72b) was dissolved in a mixed solvent of tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (148 mg, 3.52 mmol) was added and stirred at room temperature for 4 hours. 2N hydrochloric acid (2 mL) and methylene chloride (10 mL) were added, and the precipitate was collected by filtration. This was washed with water and dichloromethane and dried to give the desired product (557 mg, yield ˜100%) as a white solid.
1 H-NMR (DMSO-D6, 400 MHz): δ 1.32 (3H, d, J = 6.6 Hz), 3.22 (3H, s), 3.73-3.85 (1H, m), 4.37-4.49 (1H, m), 4.64-4.80 (1H, m), 6.86-7.02 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.47 (1H, s), 7.95 (2H, d, J = 8.6 Hz), 8.05 (1H, t, J = 2.0 Hz), 8.32 (1H, s).
(72d) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[4- (Methylsulfonyl) phenoxy] benzamide The compound (518 mg, 1.18 mmol) synthesized in Example (72c) was dissolved in N, N-dimethylformamide (15 mL) and dimethylamine hydrochloride (287 mg) was dissolved at room temperature. , 3.53 mmol), 4-dimethylaminopyridine (431 mg, 3.53 mmol), triethylamine (800 μL, 5.74 mmol) and WSCI · HCl (451 mg, 2.35 mmol) were added, and the mixture was stirred for 22 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 2% to 5%) to give a white solid. The target compound (195 mg, 35%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 3.02 (3H, br s), 3.08 (3H, s), 3.12 (3H, br s), 3.94 (1H , t, J = 7.8 Hz), 4.28-4.39 (1H, m), 4.51 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 1.6 Hz), 7.46 (1H, s), 7.92 (2H , d, J = 8.6 Hz).
MS (ESI) m / z: 468.16002 (M + H) <+> .
(実施例73)
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[3-(メチルスルホニル)フェノキシ]ベンズアミド (Example 73)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3 -(Methylsulfonyl) phenoxy] benzamide
N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[3-(メチルスルホニル)フェノキシ]ベンズアミド (Example 73)
N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3 -(Methylsulfonyl) phenoxy] benzamide
(73a)ベンジル 5-[3-ヒドロキシ-5-(メトキシカルボニル)フェニル]-1H-ピロール-2-カルボキシレート
メチル 3-ブロモ-5-ヒドロキシベンゾエート(10.13g,43.8mmol)、実施例(19e)で合成した化合物(19.0g,58.1mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.56g,1.91mmol)、炭酸カリウム(12.5g,90.4mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(13.4g,収率87%)を得た。
1H-NMR (CD3OD, 500MHz):δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1H, d, J = 3.9 Hz), 6.95 (1H, d, J = 3.9 Hz), 7.32-7.34 (3H, m), 7.35-7.38 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m).
(73b)ベンジル 5-{3-(メトキシカルボニル)-5-[3-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、[3-(メチルスルホニル)フェニル]ホウ酸(3.05g,15.25mmol)、酢酸銅(II)(1.80g,9.94mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で4日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、白色固体の目的化合物(1.19g,収率41%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.07 (3H, s), 3.94 (3H, s), 5.35 (2H, s), 6.59-6.61 (1H, m), 6.99-7.01 (1H, m), 7.29 (1H, dd, J = 7.8, 2.4 Hz), 7.33-7.47 (6H, m), 7.55-7.58 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H, s), 9.34 (1H, br s).
(73c)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-[3-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(73b)で合成した化合物(1.38g,2.73mmol)を酢酸エチル(40mL)とメタノール(15mL)の混合溶媒に溶解し、パラジウム炭素(0.55g)を加え、水素雰囲気下室温で3時間半撹拌した。セライト濾過後、減圧下溶媒を留去することで、白色固体を得た。得られた化合物を塩化メチレン(20mL)とテトラヒドロフラン(10mL)の混合溶媒に溶解し、D-アラニノール(0.30mL,3.83mmol)、WSCI・HCl(0.71g,3.70mmol)、HOBT・H2O(0.62g,4.05mmol)、N-メチルモルホリン(0.70mL,6.37mmol)を室温で加え、窒素雰囲気下一晩攪拌した。反応液に水(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~4%)を用いて精製することにより、白色固体の目的化合物(1.06g,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.28 (3H, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 (1H, m), 3.74-3.80 (1H, m), 3.94 (3H, s), 4.23-4.30 (1H, m), 6.09 (1H, s), 6.56-6.58 (1H, m), 6.61-6.64 (1H, m), 7.29 (1H, dd, J = 8.2, 2.3 Hz), 7.41-7.43 (1H, m), 7.53-7.60 (3H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03-8.05 (1H, m), 9.80 (1H, s)。 (73a) Benzyl 5- [3-hydroxy-5- (methoxycarbonyl) phenyl] -1H-pyrrole-2-carboxylate methyl 3-bromo-5-hydroxybenzoate (10.13 g, 43.8 mmol), Example ( 19e) (19.0 g, 58.1 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1.56 g, 1.91 mmol), potassium carbonate ( 12.5 g, 90.4 mmol) was used, and the target compound (13.4 g, yield 87%) was obtained as a white solid in the same manner as in Example (16e).
1 H-NMR (CD 3 OD, 500 MHz): δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1H, d, J = 3.9 Hz), 6.95 (1H, d, J = 3.9 Hz) , 7.32-7.34 (3H, m), 7.35-7.38 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m).
(73b) Benzyl 5- {3- (methoxycarbonyl) -5- [3- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (2.00 g, synthesized in Example (73a)) 5.69 mmol) was dissolved in methylene chloride (60 mL), [3- (methylsulfonyl) phenyl] boric acid (3.05 g, 15.25 mmol), copper (II) acetate (1.80 g, 9.94 mmol), Triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 4 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (1.19 g, Yield 41%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.07 (3H, s), 3.94 (3H, s), 5.35 (2H, s), 6.59-6.61 (1H, m), 6.99-7.01 (1H, m) , 7.29 (1H, dd, J = 7.8, 2.4 Hz), 7.33-7.47 (6H, m), 7.55-7.58 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H , s), 9.34 (1H, br s).
(73c) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- [3- (methylsulfonyl) phenoxy] benzoate Examples Compound (1.38 g, 2.73 mmol) synthesized in (73b) was dissolved in a mixed solvent of ethyl acetate (40 mL) and methanol (15 mL), palladium carbon (0.55 g) was added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stir for half an hour. After filtration through celite, the solvent was distilled off under reduced pressure to obtain a white solid. The obtained compound was dissolved in a mixed solvent of methylene chloride (20 mL) and tetrahydrofuran (10 mL), and D-alaninol (0.30 mL, 3.83 mmol), WSCI · HCl (0.71 g, 3.70 mmol), HOBT · H 2 O (0.62 g, 4.05 mmol) and N-methylmorpholine (0.70 mL, 6.37 mmol) were added at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 4%) to give the target compound (1.06 g, Yield 82%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.28 (3H, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.94 (3H, s), 4.23-4.30 (1H, m), 6.09 (1H, s), 6.56-6.58 (1H, m), 6.61-6.64 (1H, m), 7.29 ( 1H, dd, J = 8.2, 2.3 Hz), 7.41-7.43 (1H, m), 7.53-7.60 (3H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03-8.05 (1H, m) , 9.80 (1H, s).
メチル 3-ブロモ-5-ヒドロキシベンゾエート(10.13g,43.8mmol)、実施例(19e)で合成した化合物(19.0g,58.1mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.56g,1.91mmol)、炭酸カリウム(12.5g,90.4mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(13.4g,収率87%)を得た。
1H-NMR (CD3OD, 500MHz):δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1H, d, J = 3.9 Hz), 6.95 (1H, d, J = 3.9 Hz), 7.32-7.34 (3H, m), 7.35-7.38 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m).
(73b)ベンジル 5-{3-(メトキシカルボニル)-5-[3-(メチルスルホニル)フェノキシ]フェニル}-1H-ピロール-2-カルボキシレート
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、[3-(メチルスルホニル)フェニル]ホウ酸(3.05g,15.25mmol)、酢酸銅(II)(1.80g,9.94mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で4日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、白色固体の目的化合物(1.19g,収率41%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.07 (3H, s), 3.94 (3H, s), 5.35 (2H, s), 6.59-6.61 (1H, m), 6.99-7.01 (1H, m), 7.29 (1H, dd, J = 7.8, 2.4 Hz), 7.33-7.47 (6H, m), 7.55-7.58 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H, s), 9.34 (1H, br s).
(73c)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-[3-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(73b)で合成した化合物(1.38g,2.73mmol)を酢酸エチル(40mL)とメタノール(15mL)の混合溶媒に溶解し、パラジウム炭素(0.55g)を加え、水素雰囲気下室温で3時間半撹拌した。セライト濾過後、減圧下溶媒を留去することで、白色固体を得た。得られた化合物を塩化メチレン(20mL)とテトラヒドロフラン(10mL)の混合溶媒に溶解し、D-アラニノール(0.30mL,3.83mmol)、WSCI・HCl(0.71g,3.70mmol)、HOBT・H2O(0.62g,4.05mmol)、N-メチルモルホリン(0.70mL,6.37mmol)を室温で加え、窒素雰囲気下一晩攪拌した。反応液に水(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~4%)を用いて精製することにより、白色固体の目的化合物(1.06g,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.28 (3H, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 (1H, m), 3.74-3.80 (1H, m), 3.94 (3H, s), 4.23-4.30 (1H, m), 6.09 (1H, s), 6.56-6.58 (1H, m), 6.61-6.64 (1H, m), 7.29 (1H, dd, J = 8.2, 2.3 Hz), 7.41-7.43 (1H, m), 7.53-7.60 (3H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03-8.05 (1H, m), 9.80 (1H, s)。 (73a) Benzyl 5- [3-hydroxy-5- (methoxycarbonyl) phenyl] -1H-pyrrole-2-carboxylate methyl 3-bromo-5-hydroxybenzoate (10.13 g, 43.8 mmol), Example ( 19e) (19.0 g, 58.1 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1.56 g, 1.91 mmol), potassium carbonate ( 12.5 g, 90.4 mmol) was used, and the target compound (13.4 g, yield 87%) was obtained as a white solid in the same manner as in Example (16e).
1 H-NMR (CD 3 OD, 500 MHz): δ 3.90 (3H, s), 5.32 (2H, s), 6.55 (1H, d, J = 3.9 Hz), 6.95 (1H, d, J = 3.9 Hz) , 7.32-7.34 (3H, m), 7.35-7.38 (2H, m), 7.45 (2H, d, J = 6.8 Hz), 7.82-7.84 (1H, m).
(73b) Benzyl 5- {3- (methoxycarbonyl) -5- [3- (methylsulfonyl) phenoxy] phenyl} -1H-pyrrole-2-carboxylate Compound (2.00 g, synthesized in Example (73a)) 5.69 mmol) was dissolved in methylene chloride (60 mL), [3- (methylsulfonyl) phenyl] boric acid (3.05 g, 15.25 mmol), copper (II) acetate (1.80 g, 9.94 mmol), Triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 4 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (1.19 g, Yield 41%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.07 (3H, s), 3.94 (3H, s), 5.35 (2H, s), 6.59-6.61 (1H, m), 6.99-7.01 (1H, m) , 7.29 (1H, dd, J = 7.8, 2.4 Hz), 7.33-7.47 (6H, m), 7.55-7.58 (3H, m), 7.72 (1H, dd, J = 6.8, 1.0 Hz), 8.03 (1H , s), 9.34 (1H, br s).
(73c) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- [3- (methylsulfonyl) phenoxy] benzoate Examples Compound (1.38 g, 2.73 mmol) synthesized in (73b) was dissolved in a mixed solvent of ethyl acetate (40 mL) and methanol (15 mL), palladium carbon (0.55 g) was added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stir for half an hour. After filtration through celite, the solvent was distilled off under reduced pressure to obtain a white solid. The obtained compound was dissolved in a mixed solvent of methylene chloride (20 mL) and tetrahydrofuran (10 mL), and D-alaninol (0.30 mL, 3.83 mmol), WSCI · HCl (0.71 g, 3.70 mmol), HOBT · H 2 O (0.62 g, 4.05 mmol) and N-methylmorpholine (0.70 mL, 6.37 mmol) were added at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 4%) to give the target compound (1.06 g, Yield 82%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.28 (3H, d, J = 7.0 Hz), 2.79 (1H, br s), 3.08 (3H, s), 3.59-3.66 (1H, m), 3.74- 3.80 (1H, m), 3.94 (3H, s), 4.23-4.30 (1H, m), 6.09 (1H, s), 6.56-6.58 (1H, m), 6.61-6.64 (1H, m), 7.29 ( 1H, dd, J = 8.2, 2.3 Hz), 7.41-7.43 (1H, m), 7.53-7.60 (3H, m), 7.71 (1H, d, J = 7.8 Hz), 8.03-8.05 (1H, m) , 9.80 (1H, s).
(73d)メチル 3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[3-(メチルスルホニル)フェノキシ]ベンゾエート
実施例(73c)で合成した化合物(1.06g,2.24mmol)、メタンスルホン酸無水物(800mg,4.59mmol)、トリエチルアミン(1.25mL,8.97mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(873mg,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1H, m), 3.94 (3H, s), 4.33-4.39 (1H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J = 3.5 Hz), 7.29 (1H, dd, J = 8.2, 1.2 Hz), 7.46 (1H, s), 7.55-7.57 (2H, m), 7.58-7.60 (1H, m), 7.70-7.73 (1H, m), 8.05-8.07 (1H, m).
(73e)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[3-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(73d)で合成した化合物(858mg,1.89mmol)をテトラヒドロフラン(12mL)と水(5mL)の混合溶媒に溶解し、水酸化リチウム一水和物(250mg,5.96mmol)を室温で加え、窒素雰囲気下40℃で2時間半撹拌した。反応液に2規定塩酸をpH約3になるまで加え、酢酸エチル(20mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去して白色固体を得た。得られた化合物を塩化メチレン(20mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,2.00mL,4.00mmol)、HATU(1.45g,3.81mmol)、N,N-ジイソプロピルエチルアミン(1.00mL,5.74mmol)を加え、窒素雰囲気下室温で3時間半撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的化合物(745mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, d, J = 6.6 Hz), 3.00-3.13 (6H, br m), 3.08 (3H, s), 3.97 (1H, t, J = 8.0 Hz), 4.32-4.40 (1H, m), 4.53 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.94-6.96 (1H, m), 7.28-7.33 (2H, m), 7.44 (1H, s), 7.56 (1H, dd, J = 8.2, 7.8 Hz), 7.62 (1H, dd, J = 2.3, 1.6 Hz), 7.71 (1H, ddd, J = 7.8, 1.6, 0.8 Hz).
MS (ESI) m/z: 468.15880 (M+H)+。 (73d) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3- ( Methylsulfonyl) phenoxy] benzoate Using the compound (1.06 g, 2.24 mmol) synthesized in Example (73c), methanesulfonic anhydride (800 mg, 4.59 mmol), triethylamine (1.25 mL, 8.97 mmol). In the same manner as in Example (16j), the target compound (873 mg, yield 86%) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1H, m), 3.94 (3H, s), 4.33-4.39 (1H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J = 3.5 Hz), 7.29 (1H, dd, J = 8.2, 1.2 Hz), 7.46 (1H, s), 7.55-7.57 (2H, m), 7.58-7.60 (1H, m), 7.70-7.73 (1H, m), 8.05-8.07 (1H, m).
(73e) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[3- (Methylsulfonyl) phenoxy] benzamide The compound (858 mg, 1.89 mmol) synthesized in Example (73d) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (5 mL), and lithium hydroxide monohydrate (250 mg, 5.96 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. for 2 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The obtained compound was dissolved in methylene chloride (20 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.00 mL, 4.00 mmol), HATU (1.45 g, 3.81 mmol), N, N-diisopropyl. Ethylamine (1.00 mL, 5.74 mmol) was added, and the mixture was stirred at room temperature for 3 hours and a half under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the target compound (745 mg, yield) as a white solid. 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, d, J = 6.6 Hz), 3.00-3.13 (6H, br m), 3.08 (3H, s), 3.97 (1H, t, J = 8.0 Hz), 4.32-4.40 (1H, m), 4.53 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.94- 6.96 (1H, m), 7.28-7.33 (2H, m), 7.44 (1H, s), 7.56 (1H, dd, J = 8.2, 7.8 Hz), 7.62 (1H, dd, J = 2.3, 1.6 Hz) , 7.71 (1H, ddd, J = 7.8, 1.6, 0.8 Hz).
MS (ESI) m / z: 468.15880 (M + H) <+> .
実施例(73c)で合成した化合物(1.06g,2.24mmol)、メタンスルホン酸無水物(800mg,4.59mmol)、トリエチルアミン(1.25mL,8.97mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(873mg,収率86%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.36 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1H, m), 3.94 (3H, s), 4.33-4.39 (1H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J = 3.5 Hz), 7.29 (1H, dd, J = 8.2, 1.2 Hz), 7.46 (1H, s), 7.55-7.57 (2H, m), 7.58-7.60 (1H, m), 7.70-7.73 (1H, m), 8.05-8.07 (1H, m).
(73e)N,N-ジメチル-3-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-[3-(メチルスルホニル)フェノキシ]ベンズアミド
実施例(73d)で合成した化合物(858mg,1.89mmol)をテトラヒドロフラン(12mL)と水(5mL)の混合溶媒に溶解し、水酸化リチウム一水和物(250mg,5.96mmol)を室温で加え、窒素雰囲気下40℃で2時間半撹拌した。反応液に2規定塩酸をpH約3になるまで加え、酢酸エチル(20mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去して白色固体を得た。得られた化合物を塩化メチレン(20mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,2.00mL,4.00mmol)、HATU(1.45g,3.81mmol)、N,N-ジイソプロピルエチルアミン(1.00mL,5.74mmol)を加え、窒素雰囲気下室温で3時間半撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~70%)を用いて精製することにより、白色固体の目的化合物(745mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.35 (3H, d, J = 6.6 Hz), 3.00-3.13 (6H, br m), 3.08 (3H, s), 3.97 (1H, t, J = 8.0 Hz), 4.32-4.40 (1H, m), 4.53 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.94-6.96 (1H, m), 7.28-7.33 (2H, m), 7.44 (1H, s), 7.56 (1H, dd, J = 8.2, 7.8 Hz), 7.62 (1H, dd, J = 2.3, 1.6 Hz), 7.71 (1H, ddd, J = 7.8, 1.6, 0.8 Hz).
MS (ESI) m/z: 468.15880 (M+H)+。 (73d) Methyl 3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- [3- ( Methylsulfonyl) phenoxy] benzoate Using the compound (1.06 g, 2.24 mmol) synthesized in Example (73c), methanesulfonic anhydride (800 mg, 4.59 mmol), triethylamine (1.25 mL, 8.97 mmol). In the same manner as in Example (16j), the target compound (873 mg, yield 86%) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.36 (3H, d, J = 6.6 Hz), 3.08 (3H, s), 3.92-4.00 (1H, m), 3.94 (3H, s), 4.33-4.39 (1H, m), 4.51-4.57 (1H, m), 6.61 (1H, d, J = 3.9 Hz), 6.80 (1H, d, J = 3.5 Hz), 7.29 (1H, dd, J = 8.2, 1.2 Hz), 7.46 (1H, s), 7.55-7.57 (2H, m), 7.58-7.60 (1H, m), 7.70-7.73 (1H, m), 8.05-8.07 (1H, m).
(73e) N, N-dimethyl-3- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -[3- (Methylsulfonyl) phenoxy] benzamide The compound (858 mg, 1.89 mmol) synthesized in Example (73d) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (5 mL), and lithium hydroxide monohydrate (250 mg, 5.96 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. for 2 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a white solid. The obtained compound was dissolved in methylene chloride (20 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.00 mL, 4.00 mmol), HATU (1.45 g, 3.81 mmol), N, N-diisopropyl. Ethylamine (1.00 mL, 5.74 mmol) was added, and the mixture was stirred at room temperature for 3 hours and a half under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 70%) to give the target compound (745 mg, yield) as a white solid. 84%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.35 (3H, d, J = 6.6 Hz), 3.00-3.13 (6H, br m), 3.08 (3H, s), 3.97 (1H, t, J = 8.0 Hz), 4.32-4.40 (1H, m), 4.53 (1H, t, J = 8.6 Hz), 6.56 (1H, d, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.94- 6.96 (1H, m), 7.28-7.33 (2H, m), 7.44 (1H, s), 7.56 (1H, dd, J = 8.2, 7.8 Hz), 7.62 (1H, dd, J = 2.3, 1.6 Hz) , 7.71 (1H, ddd, J = 7.8, 1.6, 0.8 Hz).
MS (ESI) m / z: 468.15880 (M + H) <+> .
(実施例74)
3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 74)
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 74)
3- (3-methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
(74a)ベンジル 5-[3-(メトキシカルボニル)-5-(3-メトキシフェノキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、(3-メトキシフェニル)ホウ酸(2.20g,14.48mmol)、酢酸銅(II)(1.78g,9.83mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で5日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(1.43g,収率55%)を得た。
1H-NMR (CDCl3, 500MHz):δ 3.79 (3H, s), 3.91 (3H, s), 5.33 (2H, s), 6.57-6.61 (3H, m), 6.71 (1H, d, J = 8.8 Hz), 6.98-7.01 (1H, m), 7.23-7.29 (1H, m), 7.30-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H, br s).
(74b)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-(3-メトキシフェノキシ)ベンゾエート
実施例(74a)で合成した化合物(1.43g,3.13mmol)、パラジウム炭素(0.60g)、D-アラニノール(0.35mL,4.47mmol)、WSCI・HCl(0.85g,4.43mmol)、HOBT・H2O(0.73g,4.77mmol)、N-メチルモルホリン(0.80mL,7.28mmol)を用い、実施例(73c)と同様の方法で黄色固体の目的化合物(1.05g,収率85%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.28 (3H, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 3.92 (3H, s), 4.21-4.31 (1H, m), 6.03 (1H, s), 6.54-6.56 (1H, m), 6.58-6.63 (3H, m), 6.71 (1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1H, m), 9.67 (1H, br s)。 (74a) Benzyl 5- [3- (methoxycarbonyl) -5- (3-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (3-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.78 g, 9.83 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 5 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.43 g, Yield 55%).
1 H-NMR (CDCl 3 , 500 MHz): δ 3.79 (3H, s), 3.91 (3H, s), 5.33 (2H, s), 6.57-6.61 (3H, m), 6.71 (1H, d, J = 8.8 Hz), 6.98-7.01 (1H, m), 7.23-7.29 (1H, m), 7.30-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H, br s).
(74b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (3-methoxyphenoxy) benzoate Example (74a) (1.43 g, 3.13 mmol), palladium carbon (0.60 g), D-alaninol (0.35 mL, 4.47 mmol), WSCI · HCl (0.85 g, 4.43 mmol), HOBT · Using H 2 O (0.73 g, 4.77 mmol) and N-methylmorpholine (0.80 mL, 7.28 mmol), the target compound (1.05 g, yield) was obtained in the same manner as in Example (73c). 85%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 3.92 (3H, s), 4.21-4.31 (1H, m), 6.03 (1H, s), 6.54-6.56 (1H, m), 6.58-6.63 (3H, m), 6.71 ( 1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1H, m), 9.67 (1H, br s).
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、(3-メトキシフェニル)ホウ酸(2.20g,14.48mmol)、酢酸銅(II)(1.78g,9.83mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で5日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(1.43g,収率55%)を得た。
1H-NMR (CDCl3, 500MHz):δ 3.79 (3H, s), 3.91 (3H, s), 5.33 (2H, s), 6.57-6.61 (3H, m), 6.71 (1H, d, J = 8.8 Hz), 6.98-7.01 (1H, m), 7.23-7.29 (1H, m), 7.30-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H, br s).
(74b)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-(3-メトキシフェノキシ)ベンゾエート
実施例(74a)で合成した化合物(1.43g,3.13mmol)、パラジウム炭素(0.60g)、D-アラニノール(0.35mL,4.47mmol)、WSCI・HCl(0.85g,4.43mmol)、HOBT・H2O(0.73g,4.77mmol)、N-メチルモルホリン(0.80mL,7.28mmol)を用い、実施例(73c)と同様の方法で黄色固体の目的化合物(1.05g,収率85%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.28 (3H, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 3.92 (3H, s), 4.21-4.31 (1H, m), 6.03 (1H, s), 6.54-6.56 (1H, m), 6.58-6.63 (3H, m), 6.71 (1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1H, m), 9.67 (1H, br s)。 (74a) Benzyl 5- [3- (methoxycarbonyl) -5- (3-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (3-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.78 g, 9.83 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 5 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.43 g, Yield 55%).
1 H-NMR (CDCl 3 , 500 MHz): δ 3.79 (3H, s), 3.91 (3H, s), 5.33 (2H, s), 6.57-6.61 (3H, m), 6.71 (1H, d, J = 8.8 Hz), 6.98-7.01 (1H, m), 7.23-7.29 (1H, m), 7.30-7.45 (6H, m), 7.56 (1H, s), 7.96 (1H, s), 9.44 (1H, br s).
(74b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (3-methoxyphenoxy) benzoate Example (74a) (1.43 g, 3.13 mmol), palladium carbon (0.60 g), D-alaninol (0.35 mL, 4.47 mmol), WSCI · HCl (0.85 g, 4.43 mmol), HOBT · Using H 2 O (0.73 g, 4.77 mmol) and N-methylmorpholine (0.80 mL, 7.28 mmol), the target compound (1.05 g, yield) was obtained in the same manner as in Example (73c). 85%).
1 H-NMR (CDCl 3 , 500 MHz): δ 1.28 (3H, d, J = 6.8 Hz), 2.74 (1H, br s), 3.61-3.66 (1H, m), 3.75-3.80 (1H, m), 3.80 (3H, s), 3.92 (3H, s), 4.21-4.31 (1H, m), 6.03 (1H, s), 6.54-6.56 (1H, m), 6.58-6.63 (3H, m), 6.71 ( 1H, dd, J = 8.3, 1.5 Hz), 7.24-7.28 (1H, m), 7.38 (1H, s), 7.54 (1H, d, J = 1.5 Hz), 7.94-7.97 (1H, m), 9.67 (1H, br s).
(74c)メチル 3-(3-メトキシフェノキシ)-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(74b)で合成した化合物(1.05g,2.47mmol)、メタンスルホン酸無水物(880mg,5.05mmol)、トリエチルアミン(1.50mL,10.76mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(938mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29-4.39 (1H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.59-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2, 2.2, 1.0 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.24-7.28 (1H, m), 7.39-7.41 (1H, m), 7.53-7.55 (1H, m), 7.96-7.97 (1H, m).
(74d)3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(74c)で合成した化合物(938mg,2.31mmol)をテトラヒドロフラン(15mL)と水(5mL)の混合溶媒に溶解し、水酸化リチウム一水和物(375mg,8.94mmol)を室温で加え、窒素雰囲気下40℃で5時間撹拌した。反応液に2規定塩酸をpH約3になるまで加えると、沈殿物を与えた。これを濾取することにより白色固体を得た。得られた化合物を塩化メチレン(15mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,2.20mL,4.40mmol)、HATU(1.75g,4.60mmol)、N,N-ジイソプロピルエチルアミン(1.25mL,7.18mmol)を加え、窒素雰囲気下室温で5時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~100%)を用いて精製することにより、白色固体の目的化合物(900mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 (1H, m), 4.30-4.37 (1H, m), 4.46-4.54 (1H, m), 6.52 (1H, dd, J = 3.9, 1.2 Hz), 6.60-6.64 (2H, m), 6.71 (1H, dd, J = 8.6, 2.0 Hz), 6.76 (1H, d, J = 3.1 Hz), 6.91 (1H, s), 7.22 (1H, s), 7.25-7.27 (1H, m), 7.33 (1H, s).
MS (ESI) m/z: 420.19167 (M+H)+。 (74c) Methyl 3- (3-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (74b) (1.05 g, 2.47 mmol), methanesulfonic anhydride (880 mg, 5.05 mmol), triethylamine (1.50 mL, 10.76 mmol), Example The target compound (938 mg, yield 93%) was obtained as a pale yellow solid in the same manner as (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29-4.39 (1H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.59-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2 , 2.2, 1.0 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.24-7.28 (1H, m), 7.39-7.41 (1H, m), 7.53-7.55 (1H, m), 7.96-7.97 ( 1H, m).
(74d) 3- (3-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide The compound synthesized in Example (74c) (938 mg, 2.31 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (375 mg). , 8.94 mmol) at room temperature and stirred at 40 ° C. for 5 hours under a nitrogen atmosphere. When 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, a precipitate was obtained. This was collected by filtration to obtain a white solid. The obtained compound was dissolved in methylene chloride (15 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.20 mL, 4.40 mmol), HATU (1.75 g, 4.60 mmol), N, N-diisopropyl. Ethylamine (1.25 mL, 7.18 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (900 mg, yield) as a white solid. 93%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 (1H, m), 4.30-4.37 (1H, m), 4.46-4.54 (1H, m), 6.52 (1H, dd, J = 3.9, 1.2 Hz), 6.60-6.64 (2H, m), 6.71 (1H, dd, J = 8.6 , 2.0 Hz), 6.76 (1H, d, J = 3.1 Hz), 6.91 (1H, s), 7.22 (1H, s), 7.25-7.27 (1H, m), 7.33 (1H, s).
MS (ESI) m / z: 420.19167 (M + H) <+> .
実施例(74b)で合成した化合物(1.05g,2.47mmol)、メタンスルホン酸無水物(880mg,5.05mmol)、トリエチルアミン(1.50mL,10.76mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(938mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29-4.39 (1H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.59-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2, 2.2, 1.0 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.24-7.28 (1H, m), 7.39-7.41 (1H, m), 7.53-7.55 (1H, m), 7.96-7.97 (1H, m).
(74d)3-(3-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(74c)で合成した化合物(938mg,2.31mmol)をテトラヒドロフラン(15mL)と水(5mL)の混合溶媒に溶解し、水酸化リチウム一水和物(375mg,8.94mmol)を室温で加え、窒素雰囲気下40℃で5時間撹拌した。反応液に2規定塩酸をpH約3になるまで加えると、沈殿物を与えた。これを濾取することにより白色固体を得た。得られた化合物を塩化メチレン(15mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,2.20mL,4.40mmol)、HATU(1.75g,4.60mmol)、N,N-ジイソプロピルエチルアミン(1.25mL,7.18mmol)を加え、窒素雰囲気下室温で5時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)を加え、塩化メチレン(40mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=30%~100%)を用いて精製することにより、白色固体の目的化合物(900mg,収率93%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.34 (3H, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 (1H, m), 4.30-4.37 (1H, m), 4.46-4.54 (1H, m), 6.52 (1H, dd, J = 3.9, 1.2 Hz), 6.60-6.64 (2H, m), 6.71 (1H, dd, J = 8.6, 2.0 Hz), 6.76 (1H, d, J = 3.1 Hz), 6.91 (1H, s), 7.22 (1H, s), 7.25-7.27 (1H, m), 7.33 (1H, s).
MS (ESI) m/z: 420.19167 (M+H)+。 (74c) Methyl 3- (3-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (74b) (1.05 g, 2.47 mmol), methanesulfonic anhydride (880 mg, 5.05 mmol), triethylamine (1.50 mL, 10.76 mmol), Example The target compound (938 mg, yield 93%) was obtained as a pale yellow solid in the same manner as (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.6 Hz), 3.80 (3H, s), 3.91-3.98 (1H, m), 3.92 (3H, s), 4.29-4.39 (1H, m), 4.51 (1H, dd, J = 9.0, 8.2 Hz), 6.57 (1H, d, J = 3.5 Hz), 6.59-6.62 (2H, m), 6.71 (1H, ddd, J = 8.2 , 2.2, 1.0 Hz), 6.77 (1H, d, J = 3.9 Hz), 7.24-7.28 (1H, m), 7.39-7.41 (1H, m), 7.53-7.55 (1H, m), 7.96-7.97 ( 1H, m).
(74d) 3- (3-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide The compound synthesized in Example (74c) (938 mg, 2.31 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (375 mg). , 8.94 mmol) at room temperature and stirred at 40 ° C. for 5 hours under a nitrogen atmosphere. When 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, a precipitate was obtained. This was collected by filtration to obtain a white solid. The obtained compound was dissolved in methylene chloride (15 mL), dimethylamine (2.0 mol / L tetrahydrofuran solution, 2.20 mL, 4.40 mmol), HATU (1.75 g, 4.60 mmol), N, N-diisopropyl. Ethylamine (1.25 mL, 7.18 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (40 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 30% to 100%) to give the target compound (900 mg, yield) as a white solid. 93%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.34 (3H, d, J = 6.3 Hz), 2.95-3.12 (6H, br m), 3.79 (3H, s), 3.90-3.96 (1H, m), 4.30-4.37 (1H, m), 4.46-4.54 (1H, m), 6.52 (1H, dd, J = 3.9, 1.2 Hz), 6.60-6.64 (2H, m), 6.71 (1H, dd, J = 8.6 , 2.0 Hz), 6.76 (1H, d, J = 3.1 Hz), 6.91 (1H, s), 7.22 (1H, s), 7.25-7.27 (1H, m), 7.33 (1H, s).
MS (ESI) m / z: 420.19167 (M + H) <+> .
(実施例75)
3-(4-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 75)
3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
3-(4-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 75)
3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
(75a)ベンジル 5-[3-(メトキシカルボニル)-5-(4-メトキシフェノキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、(4-メトキシフェニル)ホウ酸(2.20g,14.48mmol)、酢酸銅(II)(1.75g,9.67mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で7日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(0.93g,収率36%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.83 (3H, s), 3.91 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 3.9, 2.7 Hz), 6.92 (2H, dt, J = 9.4, 2.9 Hz), 6.98-7.02 (3H, m), 7.30-7.32 (1H, m), 7.32-7.48 (6H, m), 7.88-7.89 (1H, m), 9.31 (1H, br s).
(75b)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-(4-メトキシフェノキシ)ベンゾエート
実施例(75a)で合成した化合物(930mg,2.03mmol)、パラジウム炭素(400mg)、D-アラニノール(0.25mL,3.20mmol)、WSCI・HCl(550mg,2.87mmol)、HOBT・H2O(465mg,3.04mmol)、N-メチルモルホリン(0.60mL,5.46mmol)を用い、実施例(73c)と同様の方法で白色固体の目的化合物(725mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (3H, d, J = 7.0 Hz), 3.60 (1H, dd, J = 10.9, 5.9 Hz), 3.74 (1H, dd, J = 10.9, 3.5 Hz), 3.80 (3H, s), 3.88 (3H, s), 4.19-4.26 (1H, m), 5.98 (1H, d, J = 7.0 Hz), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (2H, dt, J = 6.3, 3.8 Hz), 6.97 (2H, dt, J = 6.4, 3.9 Hz), 7.26 (1H, dd, J = 2.0, 2.0 Hz), 7.42 (1H, dd, J = 2.3, 1.2 Hz), 7.86 (1H, dd, J = 1.6, 1.6 Hz), 9.55 (1H, br s)。 (75a) Benzyl 5- [3- (methoxycarbonyl) -5- (4-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (4-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.75 g, 9.67 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (0.93 g, 0.93 g, Yield 36%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.83 (3H, s), 3.91 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 3.9, 2.7 Hz), 6.92 (2H , dt, J = 9.4, 2.9 Hz), 6.98-7.02 (3H, m), 7.30-7.32 (1H, m), 7.32-7.48 (6H, m), 7.88-7.89 (1H, m), 9.31 (1H , br s).
(75b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (4-methoxyphenoxy) benzoate Example (75a) (930 mg, 2.03 mmol), palladium-carbon (400 mg), D-alaninol (0.25 mL, 3.20 mmol), WSCI · HCl (550 mg, 2.87 mmol), HOBT · H 2 O (465 mg, 3.04 mmol) and N-methylmorpholine (0.60 mL, 5.46 mmol) were used to obtain the target compound (725 mg, 84% yield) as a white solid in the same manner as in Example (73c).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 7.0 Hz), 3.60 (1H, dd, J = 10.9, 5.9 Hz), 3.74 (1H, dd, J = 10.9, 3.5 Hz) ), 3.80 (3H, s), 3.88 (3H, s), 4.19-4.26 (1H, m), 5.98 (1H, d, J = 7.0 Hz), 6.50 (1H, dd, J = 3.9, 2.7 Hz) , 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (2H, dt, J = 6.3, 3.8 Hz), 6.97 (2H, dt, J = 6.4, 3.9 Hz), 7.26 (1H, dd, J = 2.0, 2.0 Hz), 7.42 (1H, dd, J = 2.3, 1.2 Hz), 7.86 (1H, dd, J = 1.6, 1.6 Hz), 9.55 (1H, br s).
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(60mL)に溶解し、(4-メトキシフェニル)ホウ酸(2.20g,14.48mmol)、酢酸銅(II)(1.75g,9.67mmol)、トリエチルアミン(4.60mL,33.0mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で7日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(0.93g,収率36%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.83 (3H, s), 3.91 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 3.9, 2.7 Hz), 6.92 (2H, dt, J = 9.4, 2.9 Hz), 6.98-7.02 (3H, m), 7.30-7.32 (1H, m), 7.32-7.48 (6H, m), 7.88-7.89 (1H, m), 9.31 (1H, br s).
(75b)メチル 3-(5-{[(2R)-1-ヒドロキシプロパン-2-イル]カルバモイル}-1H-ピロール-2-イル)-5-(4-メトキシフェノキシ)ベンゾエート
実施例(75a)で合成した化合物(930mg,2.03mmol)、パラジウム炭素(400mg)、D-アラニノール(0.25mL,3.20mmol)、WSCI・HCl(550mg,2.87mmol)、HOBT・H2O(465mg,3.04mmol)、N-メチルモルホリン(0.60mL,5.46mmol)を用い、実施例(73c)と同様の方法で白色固体の目的化合物(725mg,収率84%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (3H, d, J = 7.0 Hz), 3.60 (1H, dd, J = 10.9, 5.9 Hz), 3.74 (1H, dd, J = 10.9, 3.5 Hz), 3.80 (3H, s), 3.88 (3H, s), 4.19-4.26 (1H, m), 5.98 (1H, d, J = 7.0 Hz), 6.50 (1H, dd, J = 3.9, 2.7 Hz), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (2H, dt, J = 6.3, 3.8 Hz), 6.97 (2H, dt, J = 6.4, 3.9 Hz), 7.26 (1H, dd, J = 2.0, 2.0 Hz), 7.42 (1H, dd, J = 2.3, 1.2 Hz), 7.86 (1H, dd, J = 1.6, 1.6 Hz), 9.55 (1H, br s)。 (75a) Benzyl 5- [3- (methoxycarbonyl) -5- (4-methoxyphenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound (2.00 g, 5.69 mmol) synthesized in Example (73a) ) In methylene chloride (60 mL), (4-methoxyphenyl) boric acid (2.20 g, 14.48 mmol), copper (II) acetate (1.75 g, 9.67 mmol), triethylamine (4.60 mL, 33.0 mmol) and molecular sieves 4A (1.00 g) were added, and the mixture was stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 40%) to give the target compound (0.93 g, 0.93 g, Yield 36%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.83 (3H, s), 3.91 (3H, s), 5.34 (2H, s), 6.56 (1H, dd, J = 3.9, 2.7 Hz), 6.92 (2H , dt, J = 9.4, 2.9 Hz), 6.98-7.02 (3H, m), 7.30-7.32 (1H, m), 7.32-7.48 (6H, m), 7.88-7.89 (1H, m), 9.31 (1H , br s).
(75b) Methyl 3- (5-{[(2R) -1-hydroxypropan-2-yl] carbamoyl} -1H-pyrrol-2-yl) -5- (4-methoxyphenoxy) benzoate Example (75a) (930 mg, 2.03 mmol), palladium-carbon (400 mg), D-alaninol (0.25 mL, 3.20 mmol), WSCI · HCl (550 mg, 2.87 mmol), HOBT · H 2 O (465 mg, 3.04 mmol) and N-methylmorpholine (0.60 mL, 5.46 mmol) were used to obtain the target compound (725 mg, 84% yield) as a white solid in the same manner as in Example (73c).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 7.0 Hz), 3.60 (1H, dd, J = 10.9, 5.9 Hz), 3.74 (1H, dd, J = 10.9, 3.5 Hz) ), 3.80 (3H, s), 3.88 (3H, s), 4.19-4.26 (1H, m), 5.98 (1H, d, J = 7.0 Hz), 6.50 (1H, dd, J = 3.9, 2.7 Hz) , 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.88 (2H, dt, J = 6.3, 3.8 Hz), 6.97 (2H, dt, J = 6.4, 3.9 Hz), 7.26 (1H, dd, J = 2.0, 2.0 Hz), 7.42 (1H, dd, J = 2.3, 1.2 Hz), 7.86 (1H, dd, J = 1.6, 1.6 Hz), 9.55 (1H, br s).
(75c)メチル 3-(4-メトキシフェノキシ)-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンゾエート
実施例(75b)で合成した化合物(725mg,1.71mmol)、メタンスルホン酸無水物(620mg,3.56mmol)、トリエチルアミン(1.00mL,7.17mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(680mg,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.39 (3H, d, J = 6.6 Hz), 3.83 (3H, s), 3.91 (3H, s), 4.01 (1H, br s), 4.38 (1H, br s), 4.57 (1H, br s), 6.58 (1H, d, J = 3.5 Hz), 6.80-6.85 (1H, m), 6.92 (2H, dt, J = 6.5, 3.8 Hz), 7.01 (2H, dt, J = 6.3, 3.8 Hz), 7.39 (1H, s), 7.45-7.47 (1H, m), 7.94 (1H, s).
(75d)3-(4-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(75c)で合成した化合物(680mg,1.67mmol)、水酸化リチウム一水和物(220mg,5.24mmol)、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,1.30mL,2.60mmol)、HATU(1.05g,2.76mmol)、N,N-ジイソプロピルエチルアミン(0.80mL,4.59mmol)を用い、実施例(74d)と同様の方法で白色固体の目的化合物(562mg,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.38 (1H, m), 4.50 (1H, t, J = 8.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.82 (1H, dd, J = 2.0, 1.2 Hz), 6.90 (2H, dt, J = 6.5, 3.9 Hz), 7.01 (2H, dt, J = 6.4, 3.9 Hz), 7.15 (1H, dd, J = 2.2, 1.8 Hz), 7.25-7.27 (1H, m).
MS (ESI) m/z: 420.19272(M+H)+。 (75c) Methyl 3- (4-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (75b) (725 mg, 1.71 mmol), methanesulfonic anhydride (620 mg, 3.56 mmol), triethylamine (1.00 mL, 7.17 mmol), Example (16j) ) To give the target compound (680 mg, yield 98%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, d, J = 6.6 Hz), 3.83 (3H, s), 3.91 (3H, s), 4.01 (1H, br s), 4.38 (1H, br s), 4.57 (1H, br s), 6.58 (1H, d, J = 3.5 Hz), 6.80-6.85 (1H, m), 6.92 (2H, dt, J = 6.5, 3.8 Hz), 7.01 (2H , dt, J = 6.3, 3.8 Hz), 7.39 (1H, s), 7.45-7.47 (1H, m), 7.94 (1H, s).
(75d) 3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (680 mg, 1.67 mmol) synthesized in Example (75c), lithium hydroxide monohydrate (220 mg, 5.24 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution) , 1.30 mL, 2.60 mmol), HATU (1.05 g, 2.76 mmol), N, N-diisopropylethylamine (0.80 mL, 4.59 mmol) and white in the same manner as in Example (74d) The solid target compound (562 mg, yield 80%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.38 (1H, m), 4.50 (1H, t, J = 8.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.82 ( 1H, dd, J = 2.0, 1.2 Hz), 6.90 (2H, dt, J = 6.5, 3.9 Hz), 7.01 (2H, dt, J = 6.4, 3.9 Hz), 7.15 (1H, dd, J = 2.2, 1.8 Hz), 7.25-7.27 (1H, m).
MS (ESI) m / z: 420.19272 (M + H) <+> .
実施例(75b)で合成した化合物(725mg,1.71mmol)、メタンスルホン酸無水物(620mg,3.56mmol)、トリエチルアミン(1.00mL,7.17mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(680mg,収率98%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.39 (3H, d, J = 6.6 Hz), 3.83 (3H, s), 3.91 (3H, s), 4.01 (1H, br s), 4.38 (1H, br s), 4.57 (1H, br s), 6.58 (1H, d, J = 3.5 Hz), 6.80-6.85 (1H, m), 6.92 (2H, dt, J = 6.5, 3.8 Hz), 7.01 (2H, dt, J = 6.3, 3.8 Hz), 7.39 (1H, s), 7.45-7.47 (1H, m), 7.94 (1H, s).
(75d)3-(4-メトキシフェノキシ)-N,N-ジメチル-5-{5-[(4R)-4-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(75c)で合成した化合物(680mg,1.67mmol)、水酸化リチウム一水和物(220mg,5.24mmol)、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,1.30mL,2.60mmol)、HATU(1.05g,2.76mmol)、N,N-ジイソプロピルエチルアミン(0.80mL,4.59mmol)を用い、実施例(74d)と同様の方法で白色固体の目的化合物(562mg,収率80%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.33 (3H, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.38 (1H, m), 4.50 (1H, t, J = 8.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.82 (1H, dd, J = 2.0, 1.2 Hz), 6.90 (2H, dt, J = 6.5, 3.9 Hz), 7.01 (2H, dt, J = 6.4, 3.9 Hz), 7.15 (1H, dd, J = 2.2, 1.8 Hz), 7.25-7.27 (1H, m).
MS (ESI) m/z: 420.19272(M+H)+。 (75c) Methyl 3- (4-methoxyphenoxy) -5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole-2- Il} benzoate Using the compound synthesized in Example (75b) (725 mg, 1.71 mmol), methanesulfonic anhydride (620 mg, 3.56 mmol), triethylamine (1.00 mL, 7.17 mmol), Example (16j) ) To give the target compound (680 mg, yield 98%) as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.39 (3H, d, J = 6.6 Hz), 3.83 (3H, s), 3.91 (3H, s), 4.01 (1H, br s), 4.38 (1H, br s), 4.57 (1H, br s), 6.58 (1H, d, J = 3.5 Hz), 6.80-6.85 (1H, m), 6.92 (2H, dt, J = 6.5, 3.8 Hz), 7.01 (2H , dt, J = 6.3, 3.8 Hz), 7.39 (1H, s), 7.45-7.47 (1H, m), 7.94 (1H, s).
(75d) 3- (4-Methoxyphenoxy) -N, N-dimethyl-5- {5-[(4R) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (680 mg, 1.67 mmol) synthesized in Example (75c), lithium hydroxide monohydrate (220 mg, 5.24 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution) , 1.30 mL, 2.60 mmol), HATU (1.05 g, 2.76 mmol), N, N-diisopropylethylamine (0.80 mL, 4.59 mmol) and white in the same manner as in Example (74d) The solid target compound (562 mg, yield 80%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.33 (3H, d, J = 6.6 Hz), 2.93-3.12 (6H, br m), 3.82 (3H, s), 3.93 (1H, t, J = 7.8 Hz), 4.28-4.38 (1H, m), 4.50 (1H, t, J = 8.4 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.82 ( 1H, dd, J = 2.0, 1.2 Hz), 6.90 (2H, dt, J = 6.5, 3.9 Hz), 7.01 (2H, dt, J = 6.4, 3.9 Hz), 7.15 (1H, dd, J = 2.2, 1.8 Hz), 7.25-7.27 (1H, m).
MS (ESI) m / z: 420.19272 (M + H) <+> .
(実施例76)
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-フェノキシベンズアミド (Example 76)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzamide
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-フェノキシベンズアミド (Example 76)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzamide
(76a)ベンジル 5-[3-(メトキシカルボニル)-5-フェノキシフェニル]-1H-ピロール-2-カルボキシレート
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(20mL)に溶解し、フェニルホウ酸(1.90g,15.58mmol)、酢酸銅(II)(1.90g,10.49mmol)、トリエチルアミン(4.70mL,33.7mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で7日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(1.75g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.91 (3H, s), 5.34 (2H, s), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.04-7.06 (1H, m), 7.14-7.19 (1H, m), 7.30-7.45 (8H, m), 7.55 (1H, dd, J = 2.3, 1.2 Hz), 7.95 (1H, dd, J = 1.6, 1.6 Hz), 9.43 (1H, br s).
(76b)メチル 3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-フェノキシベンゾエート
実施例(76a)で合成した化合物(1.75g,4.09mmol)、パラジウム炭素(0.55g)、(R)-(-)-1-アミノ-2-プロパノール(0.55mL,6.99mmol)、WSCI・HCl(1.10g,5.74mmol)、HOBT・H2O(1.05g,6.86mmol)、N-メチルモルホリン(1.30mL,11.82mmol)を用い、実施例(73c)と同様の方法で白色固体の目的化合物(1.19g,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (3H, d, J = 6.3 Hz), 2.51 (1H, d, J = 3.9 Hz), 3.30 (1H, ddd, J = 14.0, 7.7, 5.4 Hz), 3.62 (1H, ddd, J = 14.1, 6.6, 3.1 Hz), 3.92 (3H, s), 4.03 (1H, br s), 6.34 (1H, t, J = 5.9 Hz), 6.55 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.05-7.06 (1H, m), 7.15-7.19 (1H, m), 7.35-7.41 (3H, m), 7.53 (1H, dd, J = 2.3, 1.6 Hz), 7.95 (1H, dd, J = 1.8, 1.4 Hz), 9.65 (1H, br s)。 (76a) Benzyl 5- [3- (methoxycarbonyl) -5-phenoxyphenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (73a) (2.00 g, 5.69 mmol) was converted to methylene chloride ( 20 mL), phenylboric acid (1.90 g, 15.58 mmol), copper (II) acetate (1.90 g, 10.49 mmol), triethylamine (4.70 mL, 33.7 mmol), molecular sieve 4A (1. 00 g) and stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.75 g, Yield 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.91 (3H, s), 5.34 (2H, s), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.04-7.06 (1H, m), 7.14-7.19 (1H, m), 7.30-7.45 (8H, m), 7.55 (1H, dd, J = 2.3, 1.2 Hz), 7.95 (1H, dd, J = 1.6, 1.6 Hz), 9.43 (1H, br s).
(76b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-phenoxybenzoate Compound synthesized in Example (76a) (1.75 g, 4.09 mmol), palladium on carbon (0.55 g), (R)-(−)-1-amino-2-propanol (0.55 mL, 6.99 mmol), WSCI · HCl (1.10 g, 5.74 mmol) , HOBT.H 2 O (1.05 g, 6.86 mmol) and N-methylmorpholine (1.30 mL, 11.82 mmol) were used in the same manner as in Example (73c) to obtain the target compound (1. 19 g, yield 74%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 2.51 (1H, d, J = 3.9 Hz), 3.30 (1H, ddd, J = 14.0, 7.7, 5.4 Hz) ), 3.62 (1H, ddd, J = 14.1, 6.6, 3.1 Hz), 3.92 (3H, s), 4.03 (1H, br s), 6.34 (1H, t, J = 5.9 Hz), 6.55 (1H, dd , J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.05-7.06 (1H, m), 7.15-7.19 (1H, m), 7.35-7.41 (3H, m), 7.53 (1H, dd, J = 2.3, 1.6 Hz), 7.95 (1H, dd, J = 1.8, 1.4 Hz), 9.65 (1H, br s).
実施例(73a)で合成した化合物(2.00g,5.69mmol)を塩化メチレン(20mL)に溶解し、フェニルホウ酸(1.90g,15.58mmol)、酢酸銅(II)(1.90g,10.49mmol)、トリエチルアミン(4.70mL,33.7mmol)、モレキュラーシーヴス4A(1.00g)を加え、窒素雰囲気下室温で7日間撹拌した。この反応液に水(20mL)を加え、析出物をセライト濾過した。この濾液を塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~40%)を用いて精製することにより、黄色固体の目的化合物(1.75g,収率72%)を得た。
1H-NMR (CDCl3, 400MHz):δ 3.91 (3H, s), 5.34 (2H, s), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.04-7.06 (1H, m), 7.14-7.19 (1H, m), 7.30-7.45 (8H, m), 7.55 (1H, dd, J = 2.3, 1.2 Hz), 7.95 (1H, dd, J = 1.6, 1.6 Hz), 9.43 (1H, br s).
(76b)メチル 3-(5-{[(2R)-2-ヒドロキシプロピル]カルバモイル}-1H-ピロール-2-イル)-5-フェノキシベンゾエート
実施例(76a)で合成した化合物(1.75g,4.09mmol)、パラジウム炭素(0.55g)、(R)-(-)-1-アミノ-2-プロパノール(0.55mL,6.99mmol)、WSCI・HCl(1.10g,5.74mmol)、HOBT・H2O(1.05g,6.86mmol)、N-メチルモルホリン(1.30mL,11.82mmol)を用い、実施例(73c)と同様の方法で白色固体の目的化合物(1.19g,収率74%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.25 (3H, d, J = 6.3 Hz), 2.51 (1H, d, J = 3.9 Hz), 3.30 (1H, ddd, J = 14.0, 7.7, 5.4 Hz), 3.62 (1H, ddd, J = 14.1, 6.6, 3.1 Hz), 3.92 (3H, s), 4.03 (1H, br s), 6.34 (1H, t, J = 5.9 Hz), 6.55 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.05-7.06 (1H, m), 7.15-7.19 (1H, m), 7.35-7.41 (3H, m), 7.53 (1H, dd, J = 2.3, 1.6 Hz), 7.95 (1H, dd, J = 1.8, 1.4 Hz), 9.65 (1H, br s)。 (76a) Benzyl 5- [3- (methoxycarbonyl) -5-phenoxyphenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (73a) (2.00 g, 5.69 mmol) was converted to methylene chloride ( 20 mL), phenylboric acid (1.90 g, 15.58 mmol), copper (II) acetate (1.90 g, 10.49 mmol), triethylamine (4.70 mL, 33.7 mmol), molecular sieve 4A (1. 00 g) and stirred at room temperature for 7 days under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the precipitate was filtered through celite. The filtrate was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate / hexane = 10% to 40%) to give the target compound (1.75 g, Yield 72%).
1 H-NMR (CDCl 3 , 400 MHz): δ 3.91 (3H, s), 5.34 (2H, s), 6.57 (1H, dd, J = 3.9, 2.7 Hz), 6.99 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.04-7.06 (1H, m), 7.14-7.19 (1H, m), 7.30-7.45 (8H, m), 7.55 (1H, dd, J = 2.3, 1.2 Hz), 7.95 (1H, dd, J = 1.6, 1.6 Hz), 9.43 (1H, br s).
(76b) Methyl 3- (5-{[(2R) -2-hydroxypropyl] carbamoyl} -1H-pyrrol-2-yl) -5-phenoxybenzoate Compound synthesized in Example (76a) (1.75 g, 4.09 mmol), palladium on carbon (0.55 g), (R)-(−)-1-amino-2-propanol (0.55 mL, 6.99 mmol), WSCI · HCl (1.10 g, 5.74 mmol) , HOBT.H 2 O (1.05 g, 6.86 mmol) and N-methylmorpholine (1.30 mL, 11.82 mmol) were used in the same manner as in Example (73c) to obtain the target compound (1. 19 g, yield 74%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.25 (3H, d, J = 6.3 Hz), 2.51 (1H, d, J = 3.9 Hz), 3.30 (1H, ddd, J = 14.0, 7.7, 5.4 Hz) ), 3.62 (1H, ddd, J = 14.1, 6.6, 3.1 Hz), 3.92 (3H, s), 4.03 (1H, br s), 6.34 (1H, t, J = 5.9 Hz), 6.55 (1H, dd , J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.9, 2.3 Hz), 7.02-7.04 (1H, m), 7.05-7.06 (1H, m), 7.15-7.19 (1H, m), 7.35-7.41 (3H, m), 7.53 (1H, dd, J = 2.3, 1.6 Hz), 7.95 (1H, dd, J = 1.8, 1.4 Hz), 9.65 (1H, br s).
(76c)メチル 3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-フェノキシベンゾエート
実施例(76b)で合成した化合物(1.19g,3.02mmol)、メタンスルホン酸無水物(1.08g,6.20mmol)、トリエチルアミン(1.70mL,12.20mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(1.12g,収率99%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.44 (3H, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.92 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.04 (1H, s), 7.04-7.07 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.35-7.41 (3H, m), 7.52-7.53 (1H, m), 7.96 (1H, s).
(76d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-フェノキシベンズアミド
実施例(76c)で合成した化合物(1.12g,2.98mmol)、水酸化リチウム一水和物(350mg,8.34mmol)、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,1.80mL,3.60mmol)、HATU(1.40g,3.68mmol)、N,N-ジイソプロピルエチルアミン(0.85mL,4.88mmol)を用い、実施例(74d)と同様の方法で白色固体の目的化合物(823mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.98-3.09 (6H, br m), 3.53 (1H, dd, J = 14.1, 7.4 Hz), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.87 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.04 (1H, s), 7.06 (1H, d, J = 1.2 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.21 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.6 Hz), 7.33-7.39 (2H, m).
MS (ESI) m/z: 390.18166 (M+H)+。 (76c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzoate Examples Using the compound synthesized in (76b) (1.19 g, 3.02 mmol), methanesulfonic anhydride (1.08 g, 6.20 mmol), triethylamine (1.70 mL, 12.20 mmol), Example (16j) In the same manner as above, the target compound (1.12 g, yield 99%) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.44 (3H, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd , J = 13.9, 9.2 Hz), 4.80-4.92 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.04 (1H, s), 7.04 -7.07 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.35-7.41 (3H, m), 7.52-7.53 (1H, m), 7.96 (1H, s).
(76d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Phenoxybenzamide Compound (1.12 g, 2.98 mmol) synthesized in Example (76c), lithium hydroxide monohydrate (350 mg, 8.34 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution, 1. 80 mL, 3.60 mmol), HATU (1.40 g, 3.68 mmol) and N, N-diisopropylethylamine (0.85 mL, 4.88 mmol) were used to obtain a white solid in the same manner as in Example (74d). The compound (823 mg, yield 71%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.98-3.09 (6H, br m), 3.53 (1H, dd, J = 14.1, 7.4 Hz), 4.06 ( 1H, dd, J = 14.1, 9.4 Hz), 4.76-4.87 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, dd , J = 2.2, 1.4 Hz), 7.04 (1H, s), 7.06 (1H, d, J = 1.2 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.21 (1H, t, J = 2.0 Hz ), 7.31 (1H, t, J = 1.6 Hz), 7.33-7.39 (2H, m).
MS (ESI) m / z: 390.18166 (M + H) <+> .
実施例(76b)で合成した化合物(1.19g,3.02mmol)、メタンスルホン酸無水物(1.08g,6.20mmol)、トリエチルアミン(1.70mL,12.20mmol)を用い、実施例(16j)と同様の方法で淡黄色固体の目的化合物(1.12g,収率99%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.44 (3H, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd, J = 13.9, 9.2 Hz), 4.80-4.92 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.04 (1H, s), 7.04-7.07 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.35-7.41 (3H, m), 7.52-7.53 (1H, m), 7.96 (1H, s).
(76d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-フェノキシベンズアミド
実施例(76c)で合成した化合物(1.12g,2.98mmol)、水酸化リチウム一水和物(350mg,8.34mmol)、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,1.80mL,3.60mmol)、HATU(1.40g,3.68mmol)、N,N-ジイソプロピルエチルアミン(0.85mL,4.88mmol)を用い、実施例(74d)と同様の方法で白色固体の目的化合物(823mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.42 (3H, d, J = 6.3 Hz), 2.98-3.09 (6H, br m), 3.53 (1H, dd, J = 14.1, 7.4 Hz), 4.06 (1H, dd, J = 14.1, 9.4 Hz), 4.76-4.87 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.04 (1H, s), 7.06 (1H, d, J = 1.2 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.21 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.6 Hz), 7.33-7.39 (2H, m).
MS (ESI) m/z: 390.18166 (M+H)+。 (76c) Methyl 3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-phenoxybenzoate Examples Using the compound synthesized in (76b) (1.19 g, 3.02 mmol), methanesulfonic anhydride (1.08 g, 6.20 mmol), triethylamine (1.70 mL, 12.20 mmol), Example (16j) In the same manner as above, the target compound (1.12 g, yield 99%) was obtained as a pale yellow solid.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.44 (3H, d, J = 6.3 Hz), 3.56 (1H, dd, J = 13.7, 7.4 Hz), 3.92 (3H, s), 4.10 (1H, dd , J = 13.9, 9.2 Hz), 4.80-4.92 (1H, m), 6.57 (1H, d, J = 3.9 Hz), 6.78 (1H, d, J = 3.9 Hz), 7.04 (1H, s), 7.04 -7.07 (1H, m), 7.16 (1H, t, J = 7.4 Hz), 7.35-7.41 (3H, m), 7.52-7.53 (1H, m), 7.96 (1H, s).
(76d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -Phenoxybenzamide Compound (1.12 g, 2.98 mmol) synthesized in Example (76c), lithium hydroxide monohydrate (350 mg, 8.34 mmol), dimethylamine (2.0 mol / L tetrahydrofuran solution, 1. 80 mL, 3.60 mmol), HATU (1.40 g, 3.68 mmol) and N, N-diisopropylethylamine (0.85 mL, 4.88 mmol) were used to obtain a white solid in the same manner as in Example (74d). The compound (823 mg, yield 71%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ 1.42 (3H, d, J = 6.3 Hz), 2.98-3.09 (6H, br m), 3.53 (1H, dd, J = 14.1, 7.4 Hz), 4.06 ( 1H, dd, J = 14.1, 9.4 Hz), 4.76-4.87 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.9 Hz), 6.89 (1H, dd , J = 2.2, 1.4 Hz), 7.04 (1H, s), 7.06 (1H, d, J = 1.2 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.21 (1H, t, J = 2.0 Hz ), 7.31 (1H, t, J = 1.6 Hz), 7.33-7.39 (2H, m).
MS (ESI) m / z: 390.18166 (M + H) <+> .
(実施例77)
3-(4-フルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 77)
3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
3-(4-フルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 77)
3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrole- 2-Il} benzamide
(77a)3-ブロモ-5-フルオロ-N,N-ジメチルベンズアミド
3-ブロモ-5-フルオロ安息香酸(10.1g,46.1mmol)を塩化メチレン(150mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,46.0mL,92.0mmol)、HATU(25.0g,65.7mmol)、N,N-ジイソプロピルエチルアミン(16.0mL,91.9mmol)を加え、窒素雰囲気下室温で4時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(200mL)を加え、塩化メチレン(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(11.3g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.98-3.10 (6H, br m), 7.08 (1H, ddd, J = 8.6, 2.3, 1.6 Hz), 7.30 (1H, ddd, J = 8.2, 2.3, 1.6 Hz), 7.35 (1H, dd, J = 1.6, 1.2 Hz).
(77b)3-ブロモ-5-(4-フルオロフェノキシ)-N,N-ジメチルベンズアミド
実施例(77a)で合成した化合物 (2.02g,8.21mmol)と、4-フルオロフェノール(1.63g,14.5mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(5.55g,17.0mmol)を加え、窒素雰囲気下80℃で3日間、130℃で一日撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(2.49g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.93-3.10 (6H, br m), 6.91 (1H, dd, J = 2.3, 1.2 Hz), 6.99-7.03 (2H, m), 7.05-7.10 (2H, m), 7.11 (1H, dd, J = 2.3, 1.6 Hz), 7.24 (1H, t, J = 1.6 Hz).
(77c)メチル 5-[3-(ジメチルカルバモイル)-5-(4-フルオロフェノキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(77b)で合成した化合物(2.49g,7.36mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(2.75g,11.0mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(380mg,0.47mmol)、炭酸カリウム(4.05g,29.3mmol)を用い、実施例(16e)と同様の方法で黄色泡状の目的化合物(2.64g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.96-3.13 (6H, br m), 3.88 (3H, s), 6.52 (1H, dd, J = 3.7, 2.9 Hz), 6.87 (1H, dd, J = 2.3, 1.6 Hz), 6.93 (1H, dd, J = 3.9, 2.3 Hz), 7.00-7.10 (4H, m), 7.17 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.4 Hz), 9.33 (1H, br s)。 (77a) 3-Bromo-5-fluoro-N, N-dimethylbenzamide 3-Bromo-5-fluorobenzoic acid (10.1 g, 46.1 mmol) was dissolved in methylene chloride (150 mL) and dimethylamine (2. 0 mol / L tetrahydrofuran solution, 46.0 mL, 92.0 mmol), HATU (25.0 g, 65.7 mmol), N, N-diisopropylethylamine (16.0 mL, 91.9 mmol) were added, and 4 at room temperature under a nitrogen atmosphere. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 60%) to give the desired compound (11.3 g, Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ2.98-3.10 (6H, br m), 7.08 (1H, ddd, J = 8.6, 2.3, 1.6 Hz), 7.30 (1H, ddd, J = 8.2, 2.3 , 1.6 Hz), 7.35 (1H, dd, J = 1.6, 1.2 Hz).
(77b) 3-Bromo-5- (4-fluorophenoxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.02 g, 8.21 mmol) and 4-fluorophenol (1.63 g) , 14.5 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.55 g, 17.0 mmol) was added, and the mixture was stirred at 80 ° C. for 3 days and at 130 ° C. for 1 day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.49 g, 2.49 g, Yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.93-3.10 (6H, br m), 6.91 (1H, dd, J = 2.3, 1.2 Hz), 6.99-7.03 (2H, m), 7.05-7.10 (2H , m), 7.11 (1H, dd, J = 2.3, 1.6 Hz), 7.24 (1H, t, J = 1.6 Hz).
(77c) Methyl 5- [3- (dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound synthesized in Example (77b) (2.49 g, 7.36 mmol) ), Methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.75 g, 11.0 mmol), [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (380 mg, 0.47 mmol), potassium carbonate (4.05 g, 29.3 mmol) and the same method as in Example (16e) To obtain the target compound (2.64 g, yield 94%) as a yellow foam.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.96-3.13 (6H, br m), 3.88 (3H, s), 6.52 (1H, dd, J = 3.7, 2.9 Hz), 6.87 (1H, dd, J = 2.3, 1.6 Hz), 6.93 (1H, dd, J = 3.9, 2.3 Hz), 7.00-7.10 (4H, m), 7.17 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.4 Hz), 9.33 (1H, br s).
3-ブロモ-5-フルオロ安息香酸(10.1g,46.1mmol)を塩化メチレン(150mL)に溶解し、ジメチルアミン(2.0mol/Lテトラヒドロフラン溶液,46.0mL,92.0mmol)、HATU(25.0g,65.7mmol)、N,N-ジイソプロピルエチルアミン(16.0mL,91.9mmol)を加え、窒素雰囲気下室温で4時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(200mL)を加え、塩化メチレン(300mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(11.3g,収率100%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.98-3.10 (6H, br m), 7.08 (1H, ddd, J = 8.6, 2.3, 1.6 Hz), 7.30 (1H, ddd, J = 8.2, 2.3, 1.6 Hz), 7.35 (1H, dd, J = 1.6, 1.2 Hz).
(77b)3-ブロモ-5-(4-フルオロフェノキシ)-N,N-ジメチルベンズアミド
実施例(77a)で合成した化合物 (2.02g,8.21mmol)と、4-フルオロフェノール(1.63g,14.5mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(5.55g,17.0mmol)を加え、窒素雰囲気下80℃で3日間、130℃で一日撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(2.49g,収率90%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.93-3.10 (6H, br m), 6.91 (1H, dd, J = 2.3, 1.2 Hz), 6.99-7.03 (2H, m), 7.05-7.10 (2H, m), 7.11 (1H, dd, J = 2.3, 1.6 Hz), 7.24 (1H, t, J = 1.6 Hz).
(77c)メチル 5-[3-(ジメチルカルバモイル)-5-(4-フルオロフェノキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(77b)で合成した化合物(2.49g,7.36mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(2.75g,11.0mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(380mg,0.47mmol)、炭酸カリウム(4.05g,29.3mmol)を用い、実施例(16e)と同様の方法で黄色泡状の目的化合物(2.64g,収率94%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.96-3.13 (6H, br m), 3.88 (3H, s), 6.52 (1H, dd, J = 3.7, 2.9 Hz), 6.87 (1H, dd, J = 2.3, 1.6 Hz), 6.93 (1H, dd, J = 3.9, 2.3 Hz), 7.00-7.10 (4H, m), 7.17 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.4 Hz), 9.33 (1H, br s)。 (77a) 3-Bromo-5-fluoro-N, N-dimethylbenzamide 3-Bromo-5-fluorobenzoic acid (10.1 g, 46.1 mmol) was dissolved in methylene chloride (150 mL) and dimethylamine (2. 0 mol / L tetrahydrofuran solution, 46.0 mL, 92.0 mmol), HATU (25.0 g, 65.7 mmol), N, N-diisopropylethylamine (16.0 mL, 91.9 mmol) were added, and 4 at room temperature under a nitrogen atmosphere. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% to 60%) to give the desired compound (11.3 g, Yield 100%).
1 H-NMR (CDCl 3 , 400 MHz): δ2.98-3.10 (6H, br m), 7.08 (1H, ddd, J = 8.6, 2.3, 1.6 Hz), 7.30 (1H, ddd, J = 8.2, 2.3 , 1.6 Hz), 7.35 (1H, dd, J = 1.6, 1.2 Hz).
(77b) 3-Bromo-5- (4-fluorophenoxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.02 g, 8.21 mmol) and 4-fluorophenol (1.63 g) , 14.5 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.55 g, 17.0 mmol) was added, and the mixture was stirred at 80 ° C. for 3 days and at 130 ° C. for 1 day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.49 g, 2.49 g, Yield 90%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.93-3.10 (6H, br m), 6.91 (1H, dd, J = 2.3, 1.2 Hz), 6.99-7.03 (2H, m), 7.05-7.10 (2H , m), 7.11 (1H, dd, J = 2.3, 1.6 Hz), 7.24 (1H, t, J = 1.6 Hz).
(77c) Methyl 5- [3- (dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -1H-pyrrole-2-carboxylate Compound synthesized in Example (77b) (2.49 g, 7.36 mmol) ), Methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.75 g, 11.0 mmol), [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (380 mg, 0.47 mmol), potassium carbonate (4.05 g, 29.3 mmol) and the same method as in Example (16e) To obtain the target compound (2.64 g, yield 94%) as a yellow foam.
1 H-NMR (CDCl 3 , 400 MHz): δ 2.96-3.13 (6H, br m), 3.88 (3H, s), 6.52 (1H, dd, J = 3.7, 2.9 Hz), 6.87 (1H, dd, J = 2.3, 1.6 Hz), 6.93 (1H, dd, J = 3.9, 2.3 Hz), 7.00-7.10 (4H, m), 7.17 (1H, t, J = 2.0 Hz), 7.31 (1H, t, J = 1.4 Hz), 9.33 (1H, br s).
(77d)5-[3-(ジメチルカルバモイル)-5-(4-フルオロフェノキシ)フェニル]-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(77c)で合成した化合物(2.64g,6.90mmol)をテトラヒドロフラン(5.0mL)、メタノール(15.0mL)及び水(5.0mL)の混合溶媒に溶解し、水酸化リチウム一水和物(1.10g,26.2mmol)を室温で加え、窒素雰囲気下50℃で3時間半撹拌した。反応液に2規定塩酸をpH約3になるまで加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで白色固体を得た。この固体を塩化メチレン(30mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.90mL,11.4mmol),WSCI・HCl(1.90g,9.91mmol),HOBT・H2O(1.72g,11.2mmol)、N-メチルモルホリン(2.20mL,20.0mmol)を室温で加え、窒素雰囲気下3時間攪拌した。反応液に水(40mL)を加え、塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~6%)を用いて精製することにより、白色固体の目的化合物(1.44g,収率49%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.18-1.21 (3H, m), 2.91-3.12 (6H, br m), 3.18-3.24 (1H, m), 3.58 (1H, dd, J = 6.3, 2.9 Hz), 3.61 (1H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 6.3, 2.9 Hz), 3.91-3.96 (1H, m), 6.46 (1H, dd, J = 6.1, 3.2 Hz), 6.55 (1H, br s), 6.64 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.23 (1H, s), 10.32 (1H, br s).
(77e)3-(4-フルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(77d)で合成した化合物(1.44g,3.38mmol)、メタンスルホン酸無水物(865mg,4.97mmol)、トリエチルアミン(1.50mL,10.8mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(788mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.94-3.10 (6H, br m), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.03 (1H, dd, J = 13.9, 9.2 Hz), 4.76-4.86 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.5 Hz), 6.84 (1H, dd, J = 2.2, 1.4 Hz), 6.98-7.08 (4H, m), 7.19 (1H, t, J = 1.8 Hz), 7.30 (1H, t, J = 1.4 Hz).
MS (ESI) m/z: 408.17252 (M+H)+。 (77d) 5- [3- (Dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide In Example (77c) The synthesized compound (2.64 g, 6.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (15.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1. 10 g, 26.2 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3.5 hours under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. This solid was dissolved in methylene chloride (30 mL), and (R)-(−)-1-amino-2-propanol (0.90 mL, 11.4 mmol), WSCI • HCl (1.90 g, 9.91 mmol), HOBT.H 2 O (1.72 g, 11.2 mmol) and N-methylmorpholine (2.20 mL, 20.0 mmol) were added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 3 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 6%) to give the target compound (1.44 g, Yield 49%) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.18-1.21 (3H, m), 2.91-3.12 (6H, br m), 3.18-3.24 (1H, m), 3.58 (1H, dd, J = 6.3, 2.9 Hz), 3.61 (1H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 6.3, 2.9 Hz), 3.91-3.96 (1H, m), 6.46 (1H, dd, J = 6.1, 3.2 Hz), 6.55 (1H, br s), 6.64 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.23 (1H, s), 10.32 (1H, br s).
(77e) 3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (1.44 g, 3.38 mmol) synthesized in Example (77d), methanesulfonic anhydride (865 mg, 4.97 mmol), triethylamine (1.50 mL, 10.8 mmol) Was used to give the target compound (788 mg, yield 57%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.94-3.10 (6H, br m), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.03 ( 1H, dd, J = 13.9, 9.2 Hz), 4.76-4.86 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.5 Hz), 6.84 (1H, dd , J = 2.2, 1.4 Hz), 6.98-7.08 (4H, m), 7.19 (1H, t, J = 1.8 Hz), 7.30 (1H, t, J = 1.4 Hz).
MS (ESI) m / z: 408.17252 (M + H) <+> .
実施例(77c)で合成した化合物(2.64g,6.90mmol)をテトラヒドロフラン(5.0mL)、メタノール(15.0mL)及び水(5.0mL)の混合溶媒に溶解し、水酸化リチウム一水和物(1.10g,26.2mmol)を室温で加え、窒素雰囲気下50℃で3時間半撹拌した。反応液に2規定塩酸をpH約3になるまで加え、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで白色固体を得た。この固体を塩化メチレン(30mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.90mL,11.4mmol),WSCI・HCl(1.90g,9.91mmol),HOBT・H2O(1.72g,11.2mmol)、N-メチルモルホリン(2.20mL,20.0mmol)を室温で加え、窒素雰囲気下3時間攪拌した。反応液に水(40mL)を加え、塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~6%)を用いて精製することにより、白色固体の目的化合物(1.44g,収率49%)を得た。
1H-NMR (CDCl3, 500MHz):δ 1.18-1.21 (3H, m), 2.91-3.12 (6H, br m), 3.18-3.24 (1H, m), 3.58 (1H, dd, J = 6.3, 2.9 Hz), 3.61 (1H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 6.3, 2.9 Hz), 3.91-3.96 (1H, m), 6.46 (1H, dd, J = 6.1, 3.2 Hz), 6.55 (1H, br s), 6.64 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.23 (1H, s), 10.32 (1H, br s).
(77e)3-(4-フルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(77d)で合成した化合物(1.44g,3.38mmol)、メタンスルホン酸無水物(865mg,4.97mmol)、トリエチルアミン(1.50mL,10.8mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(788mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.94-3.10 (6H, br m), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.03 (1H, dd, J = 13.9, 9.2 Hz), 4.76-4.86 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.5 Hz), 6.84 (1H, dd, J = 2.2, 1.4 Hz), 6.98-7.08 (4H, m), 7.19 (1H, t, J = 1.8 Hz), 7.30 (1H, t, J = 1.4 Hz).
MS (ESI) m/z: 408.17252 (M+H)+。 (77d) 5- [3- (Dimethylcarbamoyl) -5- (4-fluorophenoxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide In Example (77c) The synthesized compound (2.64 g, 6.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (15.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1. 10 g, 26.2 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3.5 hours under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 3, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid. This solid was dissolved in methylene chloride (30 mL), and (R)-(−)-1-amino-2-propanol (0.90 mL, 11.4 mmol), WSCI • HCl (1.90 g, 9.91 mmol), HOBT.H 2 O (1.72 g, 11.2 mmol) and N-methylmorpholine (2.20 mL, 20.0 mmol) were added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 3 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 6%) to give the target compound (1.44 g, Yield 49%) was obtained.
1 H-NMR (CDCl 3 , 500 MHz): δ 1.18-1.21 (3H, m), 2.91-3.12 (6H, br m), 3.18-3.24 (1H, m), 3.58 (1H, dd, J = 6.3, 2.9 Hz), 3.61 (1H, d, J = 13.7 Hz), 3.61 (1H, dd, J = 6.3, 2.9 Hz), 3.91-3.96 (1H, m), 6.46 (1H, dd, J = 6.1, 3.2 Hz), 6.55 (1H, br s), 6.64 (1H, dd, J = 3.9, 2.4 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.23 (1H, s), 10.32 (1H, br s).
(77e) 3- (4-Fluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H -Pyrrole-2-yl} benzamide Compound (1.44 g, 3.38 mmol) synthesized in Example (77d), methanesulfonic anhydride (865 mg, 4.97 mmol), triethylamine (1.50 mL, 10.8 mmol) Was used to give the target compound (788 mg, yield 57%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.94-3.10 (6H, br m), 3.51 (1H, dd, J = 14.1, 7.4 Hz), 4.03 ( 1H, dd, J = 13.9, 9.2 Hz), 4.76-4.86 (1H, m), 6.51 (1H, d, J = 3.9 Hz), 6.75 (1H, d, J = 3.5 Hz), 6.84 (1H, dd , J = 2.2, 1.4 Hz), 6.98-7.08 (4H, m), 7.19 (1H, t, J = 1.8 Hz), 7.30 (1H, t, J = 1.4 Hz).
MS (ESI) m / z: 408.17252 (M + H) <+> .
(実施例78)
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-(ピリジン-3-イルオキシ)ベンズアミド (Example 78)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- (pyridine -3-yloxy) benzamide
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-(ピリジン-3-イルオキシ)ベンズアミド (Example 78)
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5- (pyridine -3-yloxy) benzamide
(78a)3-ブロモ-5-(ピリジン-3-イルオキシ)-N,N-ジメチルベンズアミド
実施例(77a)で合成した化合物 (2.01g,8.17mmol)とピリジン-3-オール(1.40g,14.7mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(5.73g,17.6mmol)を加え、窒素雰囲気下130℃で一日撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(2.28g,収率87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.96-3.09 (6H, m), 6.97 (1H, dd, J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31-7.32 (1H, m), 7.33-7.37 (2H, m), 8.43-8.47 (2H, m).
(78b)メチル 5-[3-(ジメチルカルバモイル)-5-(ピリジン-3-イルオキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(78a)で合成した化合物(2.28g,7.10mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(2.71g,10.8mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(355mg,0.43mmol)、炭酸カリウム(4.15g,30.0mmol)を用い、実施例(16e)と同様の方法で白色泡状の目的化合物(2.41g,収率93%)を得た。
1H-NMR (CDCl3, 500MHz):δ 2.99-3.13 (6H, br m), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.9 Hz), 6.93-6.95 (2H, m), 7.24 (1H, t, J = 2.0 Hz), 7.33 (1H, dd, J = 8.5, 4.6 Hz), 7.36-7.37 (1H, m), 7.38 (1H, s), 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.46 (1H, d, J = 2.9 Hz), 9.41 (1H, br s)。 (78a) 3-Bromo-5- (pyridin-3-yloxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.01 g, 8.17 mmol) and pyridin-3-ol (1. 40 g, 14.7 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.73 g, 17.6 mmol) was added, and the mixture was stirred at 130 ° C. for one day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.28 g, Yield 87%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.96-3.09 (6H, m), 6.97 (1H, dd, J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31 -7.32 (1H, m), 7.33-7.37 (2H, m), 8.43-8.47 (2H, m).
(78b) Methyl 5- [3- (dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (78a) (2.28 g, 7. 10 mmol), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.71 g, 10.8 mmol), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (355 mg, 0.43 mmol), potassium carbonate (4.15 g, 30.0 mmol), and similar to Example (16e) The target compound (2.41 g, yield 93%) as a white foam was obtained by the method.
1 H-NMR (CDCl 3 , 500 MHz): δ 2.99-3.13 (6H, br m), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.9 Hz), 6.93-6.95 (2H, m ), 7.24 (1H, t, J = 2.0 Hz), 7.33 (1H, dd, J = 8.5, 4.6 Hz), 7.36-7.37 (1H, m), 7.38 (1H, s), 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.46 (1H, d, J = 2.9 Hz), 9.41 (1H, br s).
実施例(77a)で合成した化合物 (2.01g,8.17mmol)とピリジン-3-オール(1.40g,14.7mmol)をN,N-ジメチルホルムアミド(20mL)に溶解し、炭酸セシウム(5.73g,17.6mmol)を加え、窒素雰囲気下130℃で一日撹拌した。反応液を室温まで冷却し、水(100mL)を加え、酢酸エチル(100mL)で3回抽出した。有機層を飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=10%~60%)を用いて精製することにより、黄色油状の目的化合物(2.28g,収率87%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.96-3.09 (6H, m), 6.97 (1H, dd, J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31-7.32 (1H, m), 7.33-7.37 (2H, m), 8.43-8.47 (2H, m).
(78b)メチル 5-[3-(ジメチルカルバモイル)-5-(ピリジン-3-イルオキシ)フェニル]-1H-ピロール-2-カルボキシレート
実施例(78a)で合成した化合物(2.28g,7.10mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(2.71g,10.8mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(355mg,0.43mmol)、炭酸カリウム(4.15g,30.0mmol)を用い、実施例(16e)と同様の方法で白色泡状の目的化合物(2.41g,収率93%)を得た。
1H-NMR (CDCl3, 500MHz):δ 2.99-3.13 (6H, br m), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.9 Hz), 6.93-6.95 (2H, m), 7.24 (1H, t, J = 2.0 Hz), 7.33 (1H, dd, J = 8.5, 4.6 Hz), 7.36-7.37 (1H, m), 7.38 (1H, s), 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.46 (1H, d, J = 2.9 Hz), 9.41 (1H, br s)。 (78a) 3-Bromo-5- (pyridin-3-yloxy) -N, N-dimethylbenzamide The compound synthesized in Example (77a) (2.01 g, 8.17 mmol) and pyridin-3-ol (1. 40 g, 14.7 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (5.73 g, 17.6 mmol) was added, and the mixture was stirred at 130 ° C. for one day under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 10% -60%) to give the target compound (2.28 g, Yield 87%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.96-3.09 (6H, m), 6.97 (1H, dd, J = 2.3, 1.6 Hz), 7.19 (1H, dd, J = 2.2, 1.8 Hz), 7.31 -7.32 (1H, m), 7.33-7.37 (2H, m), 8.43-8.47 (2H, m).
(78b) Methyl 5- [3- (dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -1H-pyrrole-2-carboxylate The compound synthesized in Example (78a) (2.28 g, 7. 10 mmol), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (2.71 g, 10.8 mmol), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (355 mg, 0.43 mmol), potassium carbonate (4.15 g, 30.0 mmol), and similar to Example (16e) The target compound (2.41 g, yield 93%) as a white foam was obtained by the method.
1 H-NMR (CDCl 3 , 500 MHz): δ 2.99-3.13 (6H, br m), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.9 Hz), 6.93-6.95 (2H, m ), 7.24 (1H, t, J = 2.0 Hz), 7.33 (1H, dd, J = 8.5, 4.6 Hz), 7.36-7.37 (1H, m), 7.38 (1H, s), 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.46 (1H, d, J = 2.9 Hz), 9.41 (1H, br s).
(78c)5-[3-(ジメチルカルバモイル)-5-(ピリジン-3-イルオキシ)フェニル]-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(78b)で合成した化合物(2.41g,6.60mmol)をテトラヒドロフラン(5.0mL)、メタノール(10.0mL)及び水(5.0mL)の混合溶媒に溶解し、水酸化リチウム一水和物(1.05g,25.0mmol)を室温で加え、窒素雰囲気下50℃で3時間半撹拌した。反応液に2規定塩酸をpH約2になるまで加え、生じた沈殿物を濾別した。濾液に飽和炭酸水素ナトリウム水溶液をpH約5程度になるまで加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで桃色固体(1.14g)を得た。この固体を塩化メチレン(25mL)に溶解し,(R)-(-)-1-アミノ-2-プロパノール(0.53mL,6.73mmol)、WSCI・HCl(1.07g,5.58mmol)、HOBT・H2O(950mg,6.20mmol)、N-メチルモルホリン(1.20mL,10.9mmol)を室温で加え、窒素雰囲気下7時間半攪拌した。反応液に水(40mL)を加え、塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~8%)を用いて精製することにより、黄色固体の目的化合物(1.02g,収率37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (3H, d, J = 6.3 Hz), 2.87 (1H, br s), 2.94-3.12 (6H, br m), 3.19-3.28 (1H, m), 3.62 (1H, ddd, J = 13.7, 6.5, 2.9 Hz), 3.96 (1H, br s), 6.45 (1H, br s), 6.50 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.7, 2.5 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.23-7.25 (1H, m), 7.27-7.36 (3H, m), 8.42 (1H, dd, J = 4.7, 1.6 Hz), 8.44 (1H, dd, J = 2.7, 0.8 Hz), 10.08 (1H, br s).
(78d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-(ピリジン-3-イルオキシ)ベンズアミド
実施例(78c)で合成した化合物(1.09g,2.67mmol)、メタンスルホン酸無水物(925mg,5.31mmol)、トリエチルアミン(1.50mL,10.8mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(853mg,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.88-3.14 (6H, m), 3.45-3.52 (1H, m), 3.96-4.03 (1H, m), 4.76-4.85 (1H, m), 6.53 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.2 Hz), 7.24-7.36 (4H, m), 8.40 (1H, d, J = 4.7 Hz), 8.44 (1H, dd, J = 2.0, 0.8 Hz).
MS (ESI) m/z: 391.17744 (M+H)+。 (78c) 5- [3- (Dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (78b) The compound synthesized in (1) (2.41 g, 6.60 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (10.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1 .05 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 2, and the resulting precipitate was filtered off. A saturated aqueous sodium bicarbonate solution was added to the filtrate until the pH reached about 5, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pink solid (1.14 g). This solid was dissolved in methylene chloride (25 mL), and (R)-(−)-1-amino-2-propanol (0.53 mL, 6.73 mmol), WSCI • HCl (1.07 g, 5.58 mmol), HOBT.H 2 O (950 mg, 6.20 mmol) and N-methylmorpholine (1.20 mL, 10.9 mmol) were added at room temperature, and the mixture was stirred for 7 hours and a half under a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 8%) to give the target compound (1.02 g, Yield 37%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (3H, d, J = 6.3 Hz), 2.87 (1H, br s), 2.94-3.12 (6H, br m), 3.19-3.28 (1H, m) , 3.62 (1H, ddd, J = 13.7, 6.5, 2.9 Hz), 3.96 (1H, br s), 6.45 (1H, br s), 6.50 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H , dd, J = 3.7, 2.5 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.23-7.25 (1H, m), 7.27-7.36 (3H, m), 8.42 (1H, dd, J = 4.7, 1.6 Hz), 8.44 (1H, dd, J = 2.7, 0.8 Hz), 10.08 (1H, br s).
(78d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -(Pyridin-3-yloxy) benzamide Compound (1.09 g, 2.67 mmol) synthesized in Example (78c), methanesulfonic anhydride (925 mg, 5.31 mmol), triethylamine (1.50 mL, 10.8 mmol) ) Was used to give the target compound (853 mg, yield 82%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.88-3.14 (6H, m), 3.45-3.52 (1H, m), 3.96-4.03 (1H, m) , 4.76-4.85 (1H, m), 6.53 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.2 Hz), 7.24-7.36 ( 4H, m), 8.40 (1H, d, J = 4.7 Hz), 8.44 (1H, dd, J = 2.0, 0.8 Hz).
MS (ESI) m / z: 391.17744 (M + H) + .
実施例(78b)で合成した化合物(2.41g,6.60mmol)をテトラヒドロフラン(5.0mL)、メタノール(10.0mL)及び水(5.0mL)の混合溶媒に溶解し、水酸化リチウム一水和物(1.05g,25.0mmol)を室温で加え、窒素雰囲気下50℃で3時間半撹拌した。反応液に2規定塩酸をpH約2になるまで加え、生じた沈殿物を濾別した。濾液に飽和炭酸水素ナトリウム水溶液をpH約5程度になるまで加え、塩化メチレン(100mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで桃色固体(1.14g)を得た。この固体を塩化メチレン(25mL)に溶解し,(R)-(-)-1-アミノ-2-プロパノール(0.53mL,6.73mmol)、WSCI・HCl(1.07g,5.58mmol)、HOBT・H2O(950mg,6.20mmol)、N-メチルモルホリン(1.20mL,10.9mmol)を室温で加え、窒素雰囲気下7時間半攪拌した。反応液に水(40mL)を加え、塩化メチレン(60mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=1%~8%)を用いて精製することにより、黄色固体の目的化合物(1.02g,収率37%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.22 (3H, d, J = 6.3 Hz), 2.87 (1H, br s), 2.94-3.12 (6H, br m), 3.19-3.28 (1H, m), 3.62 (1H, ddd, J = 13.7, 6.5, 2.9 Hz), 3.96 (1H, br s), 6.45 (1H, br s), 6.50 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H, dd, J = 3.7, 2.5 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.23-7.25 (1H, m), 7.27-7.36 (3H, m), 8.42 (1H, dd, J = 4.7, 1.6 Hz), 8.44 (1H, dd, J = 2.7, 0.8 Hz), 10.08 (1H, br s).
(78d)N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-(ピリジン-3-イルオキシ)ベンズアミド
実施例(78c)で合成した化合物(1.09g,2.67mmol)、メタンスルホン酸無水物(925mg,5.31mmol)、トリエチルアミン(1.50mL,10.8mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(853mg,収率82%)を得た。
1H-NMR (CDCl3, 400MHz):δ 1.41 (3H, d, J = 6.3 Hz), 2.88-3.14 (6H, m), 3.45-3.52 (1H, m), 3.96-4.03 (1H, m), 4.76-4.85 (1H, m), 6.53 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.2 Hz), 7.24-7.36 (4H, m), 8.40 (1H, d, J = 4.7 Hz), 8.44 (1H, dd, J = 2.0, 0.8 Hz).
MS (ESI) m/z: 391.17744 (M+H)+。 (78c) 5- [3- (Dimethylcarbamoyl) -5- (pyridin-3-yloxy) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (78b) The compound synthesized in (1) (2.41 g, 6.60 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.0 mL), methanol (10.0 mL) and water (5.0 mL), and lithium hydroxide monohydrate (1 .05 g, 25.0 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hours and a half under a nitrogen atmosphere. 2N hydrochloric acid was added to the reaction solution until the pH reached about 2, and the resulting precipitate was filtered off. A saturated aqueous sodium bicarbonate solution was added to the filtrate until the pH reached about 5, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pink solid (1.14 g). This solid was dissolved in methylene chloride (25 mL), and (R)-(−)-1-amino-2-propanol (0.53 mL, 6.73 mmol), WSCI • HCl (1.07 g, 5.58 mmol), HOBT.H 2 O (950 mg, 6.20 mmol) and N-methylmorpholine (1.20 mL, 10.9 mmol) were added at room temperature, and the mixture was stirred for 7 hours and a half under a nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (60 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol / methylene chloride = 1% to 8%) to give the target compound (1.02 g, Yield 37%).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.22 (3H, d, J = 6.3 Hz), 2.87 (1H, br s), 2.94-3.12 (6H, br m), 3.19-3.28 (1H, m) , 3.62 (1H, ddd, J = 13.7, 6.5, 2.9 Hz), 3.96 (1H, br s), 6.45 (1H, br s), 6.50 (1H, dd, J = 3.7, 2.9 Hz), 6.63 (1H , dd, J = 3.7, 2.5 Hz), 6.89 (1H, dd, J = 2.2, 1.4 Hz), 7.23-7.25 (1H, m), 7.27-7.36 (3H, m), 8.42 (1H, dd, J = 4.7, 1.6 Hz), 8.44 (1H, dd, J = 2.7, 0.8 Hz), 10.08 (1H, br s).
(78d) N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5 -(Pyridin-3-yloxy) benzamide Compound (1.09 g, 2.67 mmol) synthesized in Example (78c), methanesulfonic anhydride (925 mg, 5.31 mmol), triethylamine (1.50 mL, 10.8 mmol) ) Was used to give the target compound (853 mg, yield 82%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400 MHz): δ 1.41 (3H, d, J = 6.3 Hz), 2.88-3.14 (6H, m), 3.45-3.52 (1H, m), 3.96-4.03 (1H, m) , 4.76-4.85 (1H, m), 6.53 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.89 (1H, t, J = 1.2 Hz), 7.24-7.36 ( 4H, m), 8.40 (1H, d, J = 4.7 Hz), 8.44 (1H, dd, J = 2.0, 0.8 Hz).
MS (ESI) m / z: 391.17744 (M + H) + .
(実施例79)
3-[(3-ブロモピリジン-2-イル)オキシ]-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 79)
3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2- Yl] -1H-pyrrol-2-yl} benzamide
3-[(3-ブロモピリジン-2-イル)オキシ]-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 79)
3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole-2- Yl] -1H-pyrrol-2-yl} benzamide
(79a)3-ブロモ-5-(ジメチルカルバモイル)フェニル アセテート
3-ブロモ-5-ヒドロキシ安息香酸(10.0g,46.1mmol)を無水酢酸(70mL)に溶解し、濃硫酸(0.10mL,1.88mmol)を加え、窒素雰囲気下室温で30分間撹拌した。この反応液に1規定塩酸(50mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた粗精製物に塩化チオニル(30mL)を加え1時間加熱還流した。減圧下塩化チオニルを留去した。得られた粗精製物を塩化メチレン(50mL)に溶解し、ジメチルアミン(2Mテトラフラン溶液、50.0mL,100mmol)を加え、窒素雰囲気下室温で1.5時間攪拌した。この反応液に飽和炭酸水素ナトリウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~70%)を用いて精製することにより、淡黄色固体の目的化合物(11.7g,収率89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.30 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H, m).
(79b)メチル 5-[3-(ジメチルカルバモイル)-5-ヒドロキシフェニル]-1H-ピロール-2-カルボキシレート
実施例(79a)で合成した化合物(11.7g,40.9mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(14.4g,57.3mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.00g,1.22mmol)、炭酸カリウム(17.0g,123mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(10.3g,収率87%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.93 (3H, s), 2.98 (3H, s), 3.78 (3H, s), 6.62 (1H, dd, J=3.9, 2.4Hz), 6.65 (1H, m), 6.85 (1H, dd, J=3.9, 2.4Hz), 7.25 (1H, t, J=1.6Hz), 7.35 (1H, t, J=1.6z), 9.73 (1H, s).
(79c)メチル 5-{3-[(3-ブロモピリジン-2-イル)オキシ]-5-(ジメチルカルバモイル)フェニル}-1H-ピロール-2-カルボキシレート
実施例(79b)で合成した化合物(640mg,2.22mmol)をジメチルアセトアミド(30mL)に溶解した。3-ブロモ-2-クロロピリジン(860mg,4.47mmol)、炭酸セシウム(2.20g,6.75mmol)を加え、窒素雰囲気下100℃で22時間攪拌した。反応液を室温まで冷却後、1規定塩酸(50mL)を加え、酢酸エチル(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~70%)を用いて精製することにより、白色固体の目的化合物(488mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.06 (3H, brs), 3.12 (3H, brs), 3.87 (3H, s), 6.56 (1H, dd, J=3.9, 2.7Hz), 6.93-6.97 (2H, m), 7.13 (1H, t, J=1.6Hz), 7.41 (1H, t, J=1.9Hz), 7.49 (1H, t, J=1.6Hz), 7.97 (1H, dd, J=7.4, 2.0Hz), 8.07 (1H, dd, J=4.7, 1.6Hz), 9.44 (1H, brs)。 (79a) 3-Bromo-5- (dimethylcarbamoyl) phenyl acetate 3-Bromo-5-hydroxybenzoic acid (10.0 g, 46.1 mmol) was dissolved in acetic anhydride (70 mL) and concentrated sulfuric acid (0.10 mL, 1.88 mmol) was added and stirred at room temperature for 30 minutes under a nitrogen atmosphere. 1N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thionyl chloride (30 mL) was added to the obtained crude product, and the mixture was heated to reflux for 1 hour. Thionyl chloride was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (50 mL), dimethylamine (2M tetrafuran solution, 50.0 mL, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 70%) to give the target compound (11.7 g) as a pale yellow solid. Yield 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.30 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H , m).
(79b) Methyl 5- [3- (dimethylcarbamoyl) -5-hydroxyphenyl] -1H-pyrrole-2-carboxylate Compound (11.7 g, 40.9 mmol) synthesized in Example (79a), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (14.4 g, 57.3 mmol), [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (1.00 g, 1.22 mmol) and potassium carbonate (17.0 g, 123 mmol) were used to obtain a white solid in the same manner as in Example (16e). The compound (10.3 g, yield 87%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ2.93 (3H, s), 2.98 (3H, s), 3.78 (3H, s), 6.62 (1H, dd, J = 3.9, 2.4Hz), 6.65 ( 1H, m), 6.85 (1H, dd, J = 3.9, 2.4Hz), 7.25 (1H, t, J = 1.6Hz), 7.35 (1H, t, J = 1.6z), 9.73 (1H, s).
(79c) Methyl 5- {3-[(3-bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -1H-pyrrole-2-carboxylate Compound synthesized in Example (79b) ( (640 mg, 2.22 mmol) was dissolved in dimethylacetamide (30 mL). 3-Bromo-2-chloropyridine (860 mg, 4.47 mmol) and cesium carbonate (2.20 g, 6.75 mmol) were added, and the mixture was stirred at 100 ° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -70%) to give the target compound (488 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.06 (3H, brs), 3.12 (3H, brs), 3.87 (3H, s), 6.56 (1H, dd, J = 3.9, 2.7Hz), 6.93- 6.97 (2H, m), 7.13 (1H, t, J = 1.6Hz), 7.41 (1H, t, J = 1.9Hz), 7.49 (1H, t, J = 1.6Hz), 7.97 (1H, dd, J = 7.4, 2.0Hz), 8.07 (1H, dd, J = 4.7, 1.6Hz), 9.44 (1H, brs).
3-ブロモ-5-ヒドロキシ安息香酸(10.0g,46.1mmol)を無水酢酸(70mL)に溶解し、濃硫酸(0.10mL,1.88mmol)を加え、窒素雰囲気下室温で30分間撹拌した。この反応液に1規定塩酸(50mL)を加え、酢酸エチル(100mL)で2回抽出した。有機層を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた粗精製物に塩化チオニル(30mL)を加え1時間加熱還流した。減圧下塩化チオニルを留去した。得られた粗精製物を塩化メチレン(50mL)に溶解し、ジメチルアミン(2Mテトラフラン溶液、50.0mL,100mmol)を加え、窒素雰囲気下室温で1.5時間攪拌した。この反応液に飽和炭酸水素ナトリウム水溶液(50mL)を加え、塩化メチレン(50mL)で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=50%~70%)を用いて精製することにより、淡黄色固体の目的化合物(11.7g,収率89%)を得た。
1H-NMR (CDCl3, 400MHz):δ 2.30 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H, m).
(79b)メチル 5-[3-(ジメチルカルバモイル)-5-ヒドロキシフェニル]-1H-ピロール-2-カルボキシレート
実施例(79a)で合成した化合物(11.7g,40.9mmol)、メチル 5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-2-カルボキシレート(14.4g,57.3mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1.00g,1.22mmol)、炭酸カリウム(17.0g,123mmol)を用い、実施例(16e)と同様の方法で白色固体の目的化合物(10.3g,収率87%)を得た。
1H-NMR (CDCl3, 400MHz):δ2.93 (3H, s), 2.98 (3H, s), 3.78 (3H, s), 6.62 (1H, dd, J=3.9, 2.4Hz), 6.65 (1H, m), 6.85 (1H, dd, J=3.9, 2.4Hz), 7.25 (1H, t, J=1.6Hz), 7.35 (1H, t, J=1.6z), 9.73 (1H, s).
(79c)メチル 5-{3-[(3-ブロモピリジン-2-イル)オキシ]-5-(ジメチルカルバモイル)フェニル}-1H-ピロール-2-カルボキシレート
実施例(79b)で合成した化合物(640mg,2.22mmol)をジメチルアセトアミド(30mL)に溶解した。3-ブロモ-2-クロロピリジン(860mg,4.47mmol)、炭酸セシウム(2.20g,6.75mmol)を加え、窒素雰囲気下100℃で22時間攪拌した。反応液を室温まで冷却後、1規定塩酸(50mL)を加え、酢酸エチル(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~70%)を用いて精製することにより、白色固体の目的化合物(488mg,収率49%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.06 (3H, brs), 3.12 (3H, brs), 3.87 (3H, s), 6.56 (1H, dd, J=3.9, 2.7Hz), 6.93-6.97 (2H, m), 7.13 (1H, t, J=1.6Hz), 7.41 (1H, t, J=1.9Hz), 7.49 (1H, t, J=1.6Hz), 7.97 (1H, dd, J=7.4, 2.0Hz), 8.07 (1H, dd, J=4.7, 1.6Hz), 9.44 (1H, brs)。 (79a) 3-Bromo-5- (dimethylcarbamoyl) phenyl acetate 3-Bromo-5-hydroxybenzoic acid (10.0 g, 46.1 mmol) was dissolved in acetic anhydride (70 mL) and concentrated sulfuric acid (0.10 mL, 1.88 mmol) was added and stirred at room temperature for 30 minutes under a nitrogen atmosphere. 1N Hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thionyl chloride (30 mL) was added to the obtained crude product, and the mixture was heated to reflux for 1 hour. Thionyl chloride was distilled off under reduced pressure. The obtained crude product was dissolved in methylene chloride (50 mL), dimethylamine (2M tetrafuran solution, 50.0 mL, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 50% to 70%) to give the target compound (11.7 g) as a pale yellow solid. Yield 89%).
1 H-NMR (CDCl 3 , 400 MHz): δ 2.30 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 7.12 (1H, m), 7.34 (1H, m), 7.44 (1H , m).
(79b) Methyl 5- [3- (dimethylcarbamoyl) -5-hydroxyphenyl] -1H-pyrrole-2-carboxylate Compound (11.7 g, 40.9 mmol) synthesized in Example (79a), methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (14.4 g, 57.3 mmol), [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (1.00 g, 1.22 mmol) and potassium carbonate (17.0 g, 123 mmol) were used to obtain a white solid in the same manner as in Example (16e). The compound (10.3 g, yield 87%) was obtained.
1 H-NMR (CDCl 3 , 400 MHz): δ2.93 (3H, s), 2.98 (3H, s), 3.78 (3H, s), 6.62 (1H, dd, J = 3.9, 2.4Hz), 6.65 ( 1H, m), 6.85 (1H, dd, J = 3.9, 2.4Hz), 7.25 (1H, t, J = 1.6Hz), 7.35 (1H, t, J = 1.6z), 9.73 (1H, s).
(79c) Methyl 5- {3-[(3-bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -1H-pyrrole-2-carboxylate Compound synthesized in Example (79b) ( (640 mg, 2.22 mmol) was dissolved in dimethylacetamide (30 mL). 3-Bromo-2-chloropyridine (860 mg, 4.47 mmol) and cesium carbonate (2.20 g, 6.75 mmol) were added, and the mixture was stirred at 100 ° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / hexane = 40% -70%) to give the target compound (488 mg, yield) as a white solid. 49%).
1 H-NMR (CDCl 3 , 400 MHz): δ3.06 (3H, brs), 3.12 (3H, brs), 3.87 (3H, s), 6.56 (1H, dd, J = 3.9, 2.7Hz), 6.93- 6.97 (2H, m), 7.13 (1H, t, J = 1.6Hz), 7.41 (1H, t, J = 1.9Hz), 7.49 (1H, t, J = 1.6Hz), 7.97 (1H, dd, J = 7.4, 2.0Hz), 8.07 (1H, dd, J = 4.7, 1.6Hz), 9.44 (1H, brs).
(79d)5-{3-[(3-ブロモピリジン-2-イル)オキシ]-5-(ジメチルカルバモイル)フェニル}-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(79c)で合成した化合物(448mg, 1.10mmol)をメタノール(20mL)に溶解し、5規定水酸化ナトリウム水溶液(1.1mL,5.50mmol)を加え、65℃で3時間攪拌した。反応液に2規定塩酸(3.0mL)を加え、酢酸エチル(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
得られた残渣をメタノール(20mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.220mL,2.79mmol)、DMT-MM(920mg,3.32mmol)を用い、実施例(5d)と同様の方法で淡黄色油状の目的化合物(237mg,収率44%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.12 (3H, d, J=6.3Hz), 2.95 (3H, s), 3.07 (3H, s), 3.12 (1H, m), 3.52 (1H, m), 3.86 (1H, brs), 4.01 (1H, brs), 6.42 (1H, dd, J=3.9, 2.4Hz), 6.67 (1H, dd, J=3.9, 2.4Hz), 6.91 (1H, dd, J=7.8, 4.7Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (1H, m), 7.92 (1H, dd, J=7.8, 1.6Hz), 8.01 (1H, dd, J=4.7, 1.6Hz), 10.92 (1H, brs).
(79e)3-[(3-ブロモピリジン-2-イル)オキシ]-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(79d)で合成した化合物(237mg,0.486mmol)、メタンスルホン酸無水物(215mg,1.23mmol)、トリエチルアミン(0.41mL,2.94mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(161mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.42 (3H, d, J=6.3Hz), 3.03 (3H, brs), 3.10 (3H, brs), 3.51 (1H, dd, J=14.1, 7.4Hz), 4.04 (1H, dd, J=14.1, 9.0Hz), 4.81 (1H, m), 6.54 (1H, d, J=3.5Hz), 6.75 (1H, d, J=3.9Hz), 6.92 (1H, dd, J=7.8, 4.7Hz), 7.10 (1H, dd, J=1.8, 1.6Hz), 7.39 (1H, t, J=1.6Hz), 7.46 (1H, t, J=1.6Hz), 7.95 (1H, dd, J=7.8, 1.6Hz), 8.05 (1H, dd, J=4.7, 1.8Hz).
MS (ESI) m/z: 469.08753(M+H)+。 (79d) 5- {3-[(3-Bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2- Carboxamide Compound (448 mg, 1.10 mmol) synthesized in Example (79c) was dissolved in methanol (20 mL), 5N aqueous sodium hydroxide solution (1.1 mL, 5.50 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. did. 2N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.220 mL, 2.79 mmol) and DMT-MM (920 mg, 3.32 mmol) were used. In the same manner as in Example (5d), the target compound (237 mg, yield 44%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.12 (3H, d, J = 6.3 Hz), 2.95 (3H, s), 3.07 (3H, s), 3.12 (1H, m), 3.52 (1H, m), 3.86 (1H, brs), 4.01 (1H, brs), 6.42 (1H, dd, J = 3.9, 2.4Hz), 6.67 (1H, dd, J = 3.9, 2.4Hz), 6.91 (1H, dd , J = 7.8, 4.7Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (1H, m), 7.92 (1H, dd, J = 7.8, 1.6Hz) , 8.01 (1H, dd, J = 4.7, 1.6Hz), 10.92 (1H, brs).
(79e) 3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzamide Compound (237 mg, 0.486 mmol) synthesized in Example (79d), methanesulfonic anhydride (215 mg, 1.23 mmol), triethylamine (0.41 mL) , 2.94 mmol) and the white solid target compound (161 mg, 71% yield) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400MHz): δ 1.42 (3H, d, J = 6.3Hz), 3.03 (3H, brs), 3.10 (3H, brs), 3.51 (1H, dd, J = 14.1, 7.4Hz ), 4.04 (1H, dd, J = 14.1, 9.0Hz), 4.81 (1H, m), 6.54 (1H, d, J = 3.5Hz), 6.75 (1H, d, J = 3.9Hz), 6.92 (1H , dd, J = 7.8, 4.7Hz), 7.10 (1H, dd, J = 1.8, 1.6Hz), 7.39 (1H, t, J = 1.6Hz), 7.46 (1H, t, J = 1.6Hz), 7.95 (1H, dd, J = 7.8, 1.6Hz), 8.05 (1H, dd, J = 4.7, 1.8Hz).
MS (ESI) m / z: 469.08753 (M + H) <+> .
実施例(79c)で合成した化合物(448mg, 1.10mmol)をメタノール(20mL)に溶解し、5規定水酸化ナトリウム水溶液(1.1mL,5.50mmol)を加え、65℃で3時間攪拌した。反応液に2規定塩酸(3.0mL)を加え、酢酸エチル(30mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
得られた残渣をメタノール(20mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.220mL,2.79mmol)、DMT-MM(920mg,3.32mmol)を用い、実施例(5d)と同様の方法で淡黄色油状の目的化合物(237mg,収率44%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.12 (3H, d, J=6.3Hz), 2.95 (3H, s), 3.07 (3H, s), 3.12 (1H, m), 3.52 (1H, m), 3.86 (1H, brs), 4.01 (1H, brs), 6.42 (1H, dd, J=3.9, 2.4Hz), 6.67 (1H, dd, J=3.9, 2.4Hz), 6.91 (1H, dd, J=7.8, 4.7Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (1H, m), 7.92 (1H, dd, J=7.8, 1.6Hz), 8.01 (1H, dd, J=4.7, 1.6Hz), 10.92 (1H, brs).
(79e)3-[(3-ブロモピリジン-2-イル)オキシ]-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(79d)で合成した化合物(237mg,0.486mmol)、メタンスルホン酸無水物(215mg,1.23mmol)、トリエチルアミン(0.41mL,2.94mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(161mg,収率71%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.42 (3H, d, J=6.3Hz), 3.03 (3H, brs), 3.10 (3H, brs), 3.51 (1H, dd, J=14.1, 7.4Hz), 4.04 (1H, dd, J=14.1, 9.0Hz), 4.81 (1H, m), 6.54 (1H, d, J=3.5Hz), 6.75 (1H, d, J=3.9Hz), 6.92 (1H, dd, J=7.8, 4.7Hz), 7.10 (1H, dd, J=1.8, 1.6Hz), 7.39 (1H, t, J=1.6Hz), 7.46 (1H, t, J=1.6Hz), 7.95 (1H, dd, J=7.8, 1.6Hz), 8.05 (1H, dd, J=4.7, 1.8Hz).
MS (ESI) m/z: 469.08753(M+H)+。 (79d) 5- {3-[(3-Bromopyridin-2-yl) oxy] -5- (dimethylcarbamoyl) phenyl} -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2- Carboxamide Compound (448 mg, 1.10 mmol) synthesized in Example (79c) was dissolved in methanol (20 mL), 5N aqueous sodium hydroxide solution (1.1 mL, 5.50 mmol) was added, and the mixture was stirred at 65 ° C. for 3 hours. did. 2N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.220 mL, 2.79 mmol) and DMT-MM (920 mg, 3.32 mmol) were used. In the same manner as in Example (5d), the target compound (237 mg, yield 44%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.12 (3H, d, J = 6.3 Hz), 2.95 (3H, s), 3.07 (3H, s), 3.12 (1H, m), 3.52 (1H, m), 3.86 (1H, brs), 4.01 (1H, brs), 6.42 (1H, dd, J = 3.9, 2.4Hz), 6.67 (1H, dd, J = 3.9, 2.4Hz), 6.91 (1H, dd , J = 7.8, 4.7Hz), 7.02 (1H, m), 7.05 (1H, m), 7.38 (1H, brs), 7.41 (1H, m), 7.92 (1H, dd, J = 7.8, 1.6Hz) , 8.01 (1H, dd, J = 4.7, 1.6Hz), 10.92 (1H, brs).
(79e) 3-[(3-Bromopyridin-2-yl) oxy] -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazole -2-yl] -1H-pyrrol-2-yl} benzamide Compound (237 mg, 0.486 mmol) synthesized in Example (79d), methanesulfonic anhydride (215 mg, 1.23 mmol), triethylamine (0.41 mL) , 2.94 mmol) and the white solid target compound (161 mg, 71% yield) was obtained in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400MHz): δ 1.42 (3H, d, J = 6.3Hz), 3.03 (3H, brs), 3.10 (3H, brs), 3.51 (1H, dd, J = 14.1, 7.4Hz ), 4.04 (1H, dd, J = 14.1, 9.0Hz), 4.81 (1H, m), 6.54 (1H, d, J = 3.5Hz), 6.75 (1H, d, J = 3.9Hz), 6.92 (1H , dd, J = 7.8, 4.7Hz), 7.10 (1H, dd, J = 1.8, 1.6Hz), 7.39 (1H, t, J = 1.6Hz), 7.46 (1H, t, J = 1.6Hz), 7.95 (1H, dd, J = 7.8, 1.6Hz), 8.05 (1H, dd, J = 4.7, 1.8Hz).
MS (ESI) m / z: 469.08753 (M + H) <+> .
(実施例80)
3-(2,4-ジフルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 80)
3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H- Pyrrol-2-yl} benzamide
3-(2,4-ジフルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド (Example 80)
3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H- Pyrrol-2-yl} benzamide
(80a)メチル 5-[3-(2,4-ジフルオロフェノキシ)-5-(ジメチルカルバモイル)フェニル]-1H-ピロール-2-カルボキシレート
実施例79bで合成した化合物(520mg,1.80mmol)をジメチルアセトアミド(30mL)に溶解した。1,2,4-トリフルオロベンゼン(720mg,5.45mmol、炭酸セシウム(1.76g,5.40mmol)を加え、窒素雰囲気下100℃で24時間攪拌した。反応液を室温まで冷却後、1規定塩酸(50mL)を加え、酢酸エチル(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~70%)を用いて精製することにより、白色固体の目的化合物(408mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.00 (3H, s), 3.11 (3H, s), 3.88 (3H, s), 6.54 (1H, dd, J=3.9, 2.7Hz), 6.81-6.91 (3H, m), 6.94 (1H, dd, J=3.9, 2.4Hz), 7.17 (1H, m), 7.22 (1H, m), 7.36 (1H, brs), 9.34 (1H, brs).
(80b)5-[3-(2,4-ジフルオロフェノキシ)-5-(ジメチルカルバモイル)フェニル]-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(80a)で合成した化合物(405mg,1.10mmol)をメタノール(6mL)、テトラヒドロフラン(1mL)及び水(2mL)の混合溶媒に溶解し、水酸化リチウム一水和物(130mg,3.10mmol)を加え、70℃で3時間攪拌した。反応液に2規定塩酸(2.0mL)を加え、酢酸エチル(20mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
得られた残渣をメタノール(20mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.160mL,2.03mmol)、DMT-MM(840mg,3.04mmol)を用い、実施例(5d)と同様の方法で淡黄色油状の目的化合物(279mg,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.15 (3H, d, J=6.3Hz), 2.92 (3H, s), 3.08 (3H, s), 3.16 (1H, m), 3.57 (1H, m), 3.88 (1H, m), 6.44 (1H, m), 6.68 (1H, dd, J=3.9, 2.4Hz), 6.75-6.88 (4H, m), 7.13 (1H, m), 7.27-7.29 (2H, m), 10.91(1H, brs).
(80c)3-(2,4-ジフルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(80b)で合成した化合物(279mg,0.629mmol)、メタンスルホン酸無水物(280mg,1.61mmol)、トリエチルアミン(0.53mL,3.80mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(188mg,収率70%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.41 (3H, d, J=6.3Hz), 2.95 (3H, brs), 3.09 (3H, brs), 3.48 (1H, dd, J=14.2, 7.3Hz), 3.99 (1H, dd, J=14.2, 9.3Hz), 4.81 (1H, m), 6.53 (1H, d, J=3.4Hz), 6.75 (1H, d, J=3.4Hz), 6.79-6.85 (2H, m), 6.87 (1H, brs), 7.13 (1H, m), 7.23 (1H, brs), 7.35 (1H, brs).
MS (ESI) m/z: 426.16292(M+H)+。 (80a) Methyl 5- [3- (2,4-difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -1H-pyrrole-2-carboxylate The compound (520 mg, 1.80 mmol) synthesized in Example 79b Dissolved in dimethylacetamide (30 mL). 1,2,4-trifluorobenzene (720 mg, 5.45 mmol, cesium carbonate (1.76 g, 5.40 mmol) was added and stirred for 24 hours under a nitrogen atmosphere at 100 ° C. After cooling the reaction solution to room temperature, 1 Normal hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified on silica gel. Purification by column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) gave the target compound (408 mg, yield 57%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ3.00 (3H, s), 3.11 (3H, s), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.7Hz), 6.81- 6.91 (3H, m), 6.94 (1H, dd, J = 3.9, 2.4Hz), 7.17 (1H, m), 7.22 (1H, m), 7.36 (1H, brs), 9.34 (1H, brs).
(80b) 5- [3- (2,4-Difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (80a ) (405 mg, 1.10 mmol) synthesized in a mixed solvent of methanol (6 mL), tetrahydrofuran (1 mL) and water (2 mL), lithium hydroxide monohydrate (130 mg, 3.10 mmol) was added. , And stirred at 70 ° C. for 3 hours. 2N Hydrochloric acid (2.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.160 mL, 2.03 mmol) and DMT-MM (840 mg, 3.04 mmol) were used. In the same manner as in Example (5d), the target compound (279 mg, yield 62%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.15 (3H, d, J = 6.3 Hz), 2.92 (3H, s), 3.08 (3H, s), 3.16 (1H, m), 3.57 (1H, m), 3.88 (1H, m), 6.44 (1H, m), 6.68 (1H, dd, J = 3.9, 2.4Hz), 6.75-6.88 (4H, m), 7.13 (1H, m), 7.27-7.29 (2H, m), 10.91 (1H, brs).
(80c) 3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide Compound (279 mg, 0.629 mmol) synthesized in Example (80b), methanesulfonic anhydride (280 mg, 1.61 mmol), triethylamine (0.53 mL, 3.80 mmol) Was used to give the target compound (188 mg, yield 70%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400MHz): δ 1.41 (3H, d, J = 6.3Hz), 2.95 (3H, brs), 3.09 (3H, brs), 3.48 (1H, dd, J = 14.2, 7.3Hz ), 3.99 (1H, dd, J = 14.2, 9.3Hz), 4.81 (1H, m), 6.53 (1H, d, J = 3.4Hz), 6.75 (1H, d, J = 3.4Hz), 6.79-6.85 (2H, m), 6.87 (1H, brs), 7.13 (1H, m), 7.23 (1H, brs), 7.35 (1H, brs).
MS (ESI) m / z: 426.16292 (M + H) <+> .
実施例79bで合成した化合物(520mg,1.80mmol)をジメチルアセトアミド(30mL)に溶解した。1,2,4-トリフルオロベンゼン(720mg,5.45mmol、炭酸セシウム(1.76g,5.40mmol)を加え、窒素雰囲気下100℃で24時間攪拌した。反応液を室温まで冷却後、1規定塩酸(50mL)を加え、酢酸エチル(50mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘキサン=40%~70%)を用いて精製することにより、白色固体の目的化合物(408mg,収率57%)を得た。
1H-NMR (CDCl3, 400MHz):δ3.00 (3H, s), 3.11 (3H, s), 3.88 (3H, s), 6.54 (1H, dd, J=3.9, 2.7Hz), 6.81-6.91 (3H, m), 6.94 (1H, dd, J=3.9, 2.4Hz), 7.17 (1H, m), 7.22 (1H, m), 7.36 (1H, brs), 9.34 (1H, brs).
(80b)5-[3-(2,4-ジフルオロフェノキシ)-5-(ジメチルカルバモイル)フェニル]-N-[(2R)-2-ヒドロキシプロピル]-1H-ピロール-2-カルボキサミド
実施例(80a)で合成した化合物(405mg,1.10mmol)をメタノール(6mL)、テトラヒドロフラン(1mL)及び水(2mL)の混合溶媒に溶解し、水酸化リチウム一水和物(130mg,3.10mmol)を加え、70℃で3時間攪拌した。反応液に2規定塩酸(2.0mL)を加え、酢酸エチル(20mL)で2回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
得られた残渣をメタノール(20mL)に溶解し、(R)-(-)-1-アミノ-2-プロパノール(0.160mL,2.03mmol)、DMT-MM(840mg,3.04mmol)を用い、実施例(5d)と同様の方法で淡黄色油状の目的化合物(279mg,収率62%)を得た。
1H-NMR (CDCl3, 400MHz):δ1.15 (3H, d, J=6.3Hz), 2.92 (3H, s), 3.08 (3H, s), 3.16 (1H, m), 3.57 (1H, m), 3.88 (1H, m), 6.44 (1H, m), 6.68 (1H, dd, J=3.9, 2.4Hz), 6.75-6.88 (4H, m), 7.13 (1H, m), 7.27-7.29 (2H, m), 10.91(1H, brs).
(80c)3-(2,4-ジフルオロフェノキシ)-N,N-ジメチル-5-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}ベンズアミド
実施例(80b)で合成した化合物(279mg,0.629mmol)、メタンスルホン酸無水物(280mg,1.61mmol)、トリエチルアミン(0.53mL,3.80mmol)を用い、実施例(16j)と同様の方法で白色固体の目的化合物(188mg,収率70%)を得た。
1H-NMR (CDCl3, 400MHz): δ 1.41 (3H, d, J=6.3Hz), 2.95 (3H, brs), 3.09 (3H, brs), 3.48 (1H, dd, J=14.2, 7.3Hz), 3.99 (1H, dd, J=14.2, 9.3Hz), 4.81 (1H, m), 6.53 (1H, d, J=3.4Hz), 6.75 (1H, d, J=3.4Hz), 6.79-6.85 (2H, m), 6.87 (1H, brs), 7.13 (1H, m), 7.23 (1H, brs), 7.35 (1H, brs).
MS (ESI) m/z: 426.16292(M+H)+。 (80a) Methyl 5- [3- (2,4-difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -1H-pyrrole-2-carboxylate The compound (520 mg, 1.80 mmol) synthesized in Example 79b Dissolved in dimethylacetamide (30 mL). 1,2,4-trifluorobenzene (720 mg, 5.45 mmol, cesium carbonate (1.76 g, 5.40 mmol) was added and stirred for 24 hours under a nitrogen atmosphere at 100 ° C. After cooling the reaction solution to room temperature, 1 Normal hydrochloric acid (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL) The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified on silica gel. Purification by column chromatography (elution solvent: ethyl acetate / hexane = 40% to 70%) gave the target compound (408 mg, yield 57%) as a white solid.
1 H-NMR (CDCl 3 , 400 MHz): δ3.00 (3H, s), 3.11 (3H, s), 3.88 (3H, s), 6.54 (1H, dd, J = 3.9, 2.7Hz), 6.81- 6.91 (3H, m), 6.94 (1H, dd, J = 3.9, 2.4Hz), 7.17 (1H, m), 7.22 (1H, m), 7.36 (1H, brs), 9.34 (1H, brs).
(80b) 5- [3- (2,4-Difluorophenoxy) -5- (dimethylcarbamoyl) phenyl] -N-[(2R) -2-hydroxypropyl] -1H-pyrrole-2-carboxamide Example (80a ) (405 mg, 1.10 mmol) synthesized in a mixed solvent of methanol (6 mL), tetrahydrofuran (1 mL) and water (2 mL), lithium hydroxide monohydrate (130 mg, 3.10 mmol) was added. , And stirred at 70 ° C. for 3 hours. 2N Hydrochloric acid (2.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in methanol (20 mL), and (R)-(−)-1-amino-2-propanol (0.160 mL, 2.03 mmol) and DMT-MM (840 mg, 3.04 mmol) were used. In the same manner as in Example (5d), the target compound (279 mg, yield 62%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 , 400 MHz): δ1.15 (3H, d, J = 6.3 Hz), 2.92 (3H, s), 3.08 (3H, s), 3.16 (1H, m), 3.57 (1H, m), 3.88 (1H, m), 6.44 (1H, m), 6.68 (1H, dd, J = 3.9, 2.4Hz), 6.75-6.88 (4H, m), 7.13 (1H, m), 7.27-7.29 (2H, m), 10.91 (1H, brs).
(80c) 3- (2,4-Difluorophenoxy) -N, N-dimethyl-5- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} benzamide Compound (279 mg, 0.629 mmol) synthesized in Example (80b), methanesulfonic anhydride (280 mg, 1.61 mmol), triethylamine (0.53 mL, 3.80 mmol) Was used to give the target compound (188 mg, yield 70%) as a white solid in the same manner as in Example (16j).
1 H-NMR (CDCl 3 , 400MHz): δ 1.41 (3H, d, J = 6.3Hz), 2.95 (3H, brs), 3.09 (3H, brs), 3.48 (1H, dd, J = 14.2, 7.3Hz ), 3.99 (1H, dd, J = 14.2, 9.3Hz), 4.81 (1H, m), 6.53 (1H, d, J = 3.4Hz), 6.75 (1H, d, J = 3.4Hz), 6.79-6.85 (2H, m), 6.87 (1H, brs), 7.13 (1H, m), 7.23 (1H, brs), 7.35 (1H, brs).
MS (ESI) m / z: 426.16292 (M + H) <+> .
(試験例1)
(1)GKの調製
ヒト膵臓型GKポリペプチドをコードするcDNA(GenBank Accssion No. NM_000162 human glucokinase, variant1)をヒトcDNAライブラリーよりポリメラーゼ連鎖反応(polymerase chain reaction:以下、「PCR」という)によりクローニングして、グルタチオンSトランスフェラーゼ(以下GSTという)融合タンパク質発現ベクター(GEX4T、GEヘルスケアバイオサイエンス)に導入した。大腸菌(BL21、Invitrogen)にベクターを導入し、形質転換された大腸菌を37℃で一晩培養し菌体を回収した。回収した菌体を凍結―融解した後、リン酸緩衝液にトライトン―Xを終濃度1%で添加したものに懸濁し、超音波破砕機にて破砕した。ホモジェネートを低速遠心処理(10,000×g、30分間)した上清をさらに高速遠心処理(100,000×g、10分)して上清を回収し、GST融合タンパク質精製システム(Bulk GST purification module, GEヘルスケアバイオサイエンス)を用いて融合タンパク質を精製した。GK融合タンパク質は小容量に分けて、-80℃にて保存した。
(2)GK活性試験
(1)で精製したGKを用いてGK活性を測定した。具体的には、グルコース測定キット(D-グルコースUVメソッド、ロシュ・ダイアグノスティクス)の溶液1に対し(1)で精製したGK、及びグルコース‐6‐リン酸デヒドロゲナーゼ(シグマ)を添加し酵素液とした。ELISA用96ウェルプレート上にて酵素液、試験化合物希釈液、グルコース(終濃度5mM)を混合し、室温で30分間反応させた。反応終了後、スペクトラマックスプラス(モレキュラープローブ)を用いて波長340ナノメートルの吸光度を測定した。なお、未反応(グルコース未添加時)の吸光度をバックグラウンドとした。 (Test Example 1)
(1) Preparation of GK A cDNA encoding human pancreatic GK polypeptide (GenBank Accssion No. NM_000162 human glucokinase, variant1) is cloned from a human cDNA library by polymerase chain reaction (hereinafter referred to as “PCR”). Then, it was introduced into a glutathione S transferase (hereinafter referred to as GST) fusion protein expression vector (GEX4T, GE Healthcare Bioscience). A vector was introduced into Escherichia coli (BL21, Invitrogen), and the transformed Escherichia coli was cultured overnight at 37 ° C. to recover the cells. The collected cells were frozen and thawed, suspended in phosphate buffer added with Triton-X at a final concentration of 1%, and crushed with an ultrasonic crusher. The supernatant obtained by subjecting the homogenate to low-speed centrifugation (10,000 × g, 30 minutes) is further subjected to high-speed centrifugation (100,000 × g, 10 minutes) to recover the supernatant, and the GST fusion protein purification system (Bulk GST purification module, GE Health) The fusion protein was purified using Care Bioscience. GK fusion protein was divided into small volumes and stored at -80 ° C.
(2) GK activity test GK activity was measured using the GK purified in (1). Specifically, GK purified in (1) and glucose-6-phosphate dehydrogenase (Sigma) were added to solution 1 of the glucose measurement kit (D-glucose UV method, Roche Diagnostics) and the enzyme solution It was. The enzyme solution, test compound dilution, and glucose (final concentration 5 mM) were mixed on a 96-well plate for ELISA, and reacted at room temperature for 30 minutes. After completion of the reaction, absorbance at a wavelength of 340 nm was measured using Spectramax Plus (Molecular Probe). The absorbance of unreacted (when glucose was not added) was used as the background.
(1)GKの調製
ヒト膵臓型GKポリペプチドをコードするcDNA(GenBank Accssion No. NM_000162 human glucokinase, variant1)をヒトcDNAライブラリーよりポリメラーゼ連鎖反応(polymerase chain reaction:以下、「PCR」という)によりクローニングして、グルタチオンSトランスフェラーゼ(以下GSTという)融合タンパク質発現ベクター(GEX4T、GEヘルスケアバイオサイエンス)に導入した。大腸菌(BL21、Invitrogen)にベクターを導入し、形質転換された大腸菌を37℃で一晩培養し菌体を回収した。回収した菌体を凍結―融解した後、リン酸緩衝液にトライトン―Xを終濃度1%で添加したものに懸濁し、超音波破砕機にて破砕した。ホモジェネートを低速遠心処理(10,000×g、30分間)した上清をさらに高速遠心処理(100,000×g、10分)して上清を回収し、GST融合タンパク質精製システム(Bulk GST purification module, GEヘルスケアバイオサイエンス)を用いて融合タンパク質を精製した。GK融合タンパク質は小容量に分けて、-80℃にて保存した。
(2)GK活性試験
(1)で精製したGKを用いてGK活性を測定した。具体的には、グルコース測定キット(D-グルコースUVメソッド、ロシュ・ダイアグノスティクス)の溶液1に対し(1)で精製したGK、及びグルコース‐6‐リン酸デヒドロゲナーゼ(シグマ)を添加し酵素液とした。ELISA用96ウェルプレート上にて酵素液、試験化合物希釈液、グルコース(終濃度5mM)を混合し、室温で30分間反応させた。反応終了後、スペクトラマックスプラス(モレキュラープローブ)を用いて波長340ナノメートルの吸光度を測定した。なお、未反応(グルコース未添加時)の吸光度をバックグラウンドとした。 (Test Example 1)
(1) Preparation of GK A cDNA encoding human pancreatic GK polypeptide (GenBank Accssion No. NM_000162 human glucokinase, variant1) is cloned from a human cDNA library by polymerase chain reaction (hereinafter referred to as “PCR”). Then, it was introduced into a glutathione S transferase (hereinafter referred to as GST) fusion protein expression vector (GEX4T, GE Healthcare Bioscience). A vector was introduced into Escherichia coli (BL21, Invitrogen), and the transformed Escherichia coli was cultured overnight at 37 ° C. to recover the cells. The collected cells were frozen and thawed, suspended in phosphate buffer added with Triton-X at a final concentration of 1%, and crushed with an ultrasonic crusher. The supernatant obtained by subjecting the homogenate to low-speed centrifugation (10,000 × g, 30 minutes) is further subjected to high-speed centrifugation (100,000 × g, 10 minutes) to recover the supernatant, and the GST fusion protein purification system (Bulk GST purification module, GE Health) The fusion protein was purified using Care Bioscience. GK fusion protein was divided into small volumes and stored at -80 ° C.
(2) GK activity test GK activity was measured using the GK purified in (1). Specifically, GK purified in (1) and glucose-6-phosphate dehydrogenase (Sigma) were added to solution 1 of the glucose measurement kit (D-glucose UV method, Roche Diagnostics) and the enzyme solution It was. The enzyme solution, test compound dilution, and glucose (final concentration 5 mM) were mixed on a 96-well plate for ELISA, and reacted at room temperature for 30 minutes. After completion of the reaction, absorbance at a wavelength of 340 nm was measured using Spectramax Plus (Molecular Probe). The absorbance of unreacted (when glucose was not added) was used as the background.
GK活性化率は、(試験化合物添加時、30分間反応後の吸光度)/(試験化合物未添加、30分間反応後の吸光度)の数式で表される数値で示した。試験化合物濃度1μMにおいて得られたGK活性化率の結果を表1に示す。
(表1)
―――――――――――――
実施例 GK活性化率
―――――――――――――
16 2.3
17 2.3
19 2.3
22 2.4
28 2.4
29 2.4
33 2.2
35 2.6
36 2.5
38 2.5
39 2.7
40 2.7
41 2.3
43 2.1
44 2.4
46 2.4
47 2.2
48 2.5
56 2.5
57 2.6
58 2.3
60 2.2
61 2.2
67 2.3
68 2.5
71 2.4
74 2.1
―――――――――――――。 The GK activation rate was represented by a numerical value represented by a formula (absorbance after reaction for 30 minutes when test compound was added) / (absorbance after reaction for 30 minutes without addition of test compound). The results of the GK activation rate obtained at a test compound concentration of 1 μM are shown in Table 1.
(Table 1)
―――――――――――――
Example GK activation rate ―――――――――――――
16 2.3
17 2.3
19 2.3
22 2.4
28 2.4
29 2.4
33 2.2
35 2.6
36 2.5
38 2.5
39 2.7
40 2.7
41 2.3
43 2.1
44 2.4
46 2.4
47 2.2
48 2.5
56 2.5
57 2.6
58 2.3
60 2.2
61 2.2
67 2.3
68 2.5
71 2.4
74 2.1
―――――――――――――.
(表1)
―――――――――――――
実施例 GK活性化率
―――――――――――――
16 2.3
17 2.3
19 2.3
22 2.4
28 2.4
29 2.4
33 2.2
35 2.6
36 2.5
38 2.5
39 2.7
40 2.7
41 2.3
43 2.1
44 2.4
46 2.4
47 2.2
48 2.5
56 2.5
57 2.6
58 2.3
60 2.2
61 2.2
67 2.3
68 2.5
71 2.4
74 2.1
―――――――――――――。 The GK activation rate was represented by a numerical value represented by a formula (absorbance after reaction for 30 minutes when test compound was added) / (absorbance after reaction for 30 minutes without addition of test compound). The results of the GK activation rate obtained at a test compound concentration of 1 μM are shown in Table 1.
(Table 1)
―――――――――――――
Example GK activation rate ―――――――――――――
16 2.3
17 2.3
19 2.3
22 2.4
28 2.4
29 2.4
33 2.2
35 2.6
36 2.5
38 2.5
39 2.7
40 2.7
41 2.3
43 2.1
44 2.4
46 2.4
47 2.2
48 2.5
56 2.5
57 2.6
58 2.3
60 2.2
61 2.2
67 2.3
68 2.5
71 2.4
74 2.1
―――――――――――――.
製剤例1:カプセル剤
実施例1の化合物 50mg
乳糖 128mg
トウモロコシデンプン 70mg
ステアリン酸マグネシウム 2mg
250mg
上記処方の粉末を混合し、60メッシュのふるいを通した後、この粉末を250mgのゼラチンカプセルに入れ、カプセル剤とする。 Formulation Example 1: Capsule Compound of Example 1 50 mg
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
実施例1の化合物 50mg
乳糖 128mg
トウモロコシデンプン 70mg
ステアリン酸マグネシウム 2mg
250mg
上記処方の粉末を混合し、60メッシュのふるいを通した後、この粉末を250mgのゼラチンカプセルに入れ、カプセル剤とする。 Formulation Example 1: Capsule Compound of Example 1 50 mg
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
製剤例2:錠剤
実施例1の化合物 50mg
乳糖 126mg
トウモロコシデンプン 23mg
ステアリン酸マグネシウム 1mg
200mg
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、1錠200mgの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 Formulation Example 2: Tablet Example 1 compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
実施例1の化合物 50mg
乳糖 126mg
トウモロコシデンプン 23mg
ステアリン酸マグネシウム 1mg
200mg
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、1錠200mgの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 Formulation Example 2: Tablet Example 1 compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、優れたGK活性化作用を有し、温血動物(特に、ヒト)用の、糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドローム(特に、糖尿病又は耐糖能異常)の治療剤もしくは予防剤(特に、治療剤)として有用である。
The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is used for warm-blooded animals (particularly, humans) for diabetes, impaired glucose tolerance, Treatment or prevention of gestational diabetes, diabetic chronic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (especially diabetes or impaired glucose tolerance) It is useful as a (especially therapeutic agent).
Claims (27)
- 一般式(I)
[式中、
R1は、同一又は異なって、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基、(C1-C6アルキルチオ)-(C1-C6アルキル)基、カルボキシル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基又はジ-(C1-C6アルキル)アミノカルボニル基を示し、
R2は、置換基群Aから選択される基で独立に1乃至5個置換されていてもよいフェニル基又は置換基群Aから選択される基で独立に1乃至3個置換されていてもよいピリジル基若しくはピラジニル基を示し、
R3は、置換基群Bから選択される基で独立に1乃至5個置換されていてもよいC1-C6アルキル基、C2-C6アルケニル基、(C1-C6アルキル基、C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1乃至3個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環(但し、Uとは炭素原子で結合する。)又は式-NR4R5で表わされる基を示し、
R4、R5は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6アルコキシ基を示すか、R4及びR5が結合する窒素原子と一緒となって、C1-C6アルキル基及びオキソ基からなる群で独立に1乃至3個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。
Uは、酸素原子又はカルボニル基を示し、
(但し、式-U-R3で表わされる基から2-ヒドロキシ-1-メチルエトキシ基を除く。)
nは、0乃至3の整数を示し、
置換基群Aは、ハロゲン原子、C1-C6アルコキシ基、C2-C7アルキルカルボニル基、C2-C7ハロゲン化アルキルカルボニル基、C2-C7アルコキシカルボニル基、C2-C7ハロゲン化アルコキシカルボニル基、C1-C6アルキルスルホニル基、C1-C6ハロゲン化アルキルスルホニル基、C3-C6シクロアルキルスルホニル基、(C1-C6アルコキシ)-(C1-C6アルキルスルホニル)基、(C1-C6ハロゲン化アルコキシ)-(C1-C6アルキルスルホニル)基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子、C1-C6アルキル基又はC1-C6ハロゲン化アルキル基を示すか、R6及びR7が結合する窒素原子と一緒となって、C1-C6アルキル基で独立に1又は2個置換されていてもよい4乃至6員複素飽和環を形成する。4乃至6員複素飽和環は、更に1個の酸素原子又は窒素原子を含んでもよい。)からなる群を示し、
置換基群Bは、ハロゲン原子、C2-C7アルキルカルボニル基、C2-C7アルコキシカルボニル基、カルバモイル基、モノ-C1-C6アルキルアミノカルボニル基、ジ-(C1-C6アルキル)アミノカルボニル基、C1-C6アルキルチオ基、C1-C6アルキルスルホニル基、ヒドロキシ基及び3乃至6員環エーテルからなる群を示す。]を有する化合物又はその薬理上許容される塩。 Formula (I)
[Where:
R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group,
R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A A good pyridyl or pyrazinyl group,
R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with 1 to 5 groups independently selected from the substituent group B , A C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted by 1 to 3 and may contain one oxygen atom or one nitrogen atom; And a group represented by the formula —NR 4 R 5 .
R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group. The 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
U represents an oxygen atom or a carbonyl group;
(However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
n represents an integer of 0 to 3,
Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group and group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) are shown, R 6, R 7 are the same or different, a hydrogen atom, or a C 1 -C 6 alkyl group or a C 1 -C 6 halogenated alkyl group, 6 and a together with the nitrogen atom to which R 7 is bonded, C 1 -C 6 alkyl independently one or two substituted or .4 to form a 4 to 6-membered heterocyclic saturated ring or may have 6 membered group The heterosaturated ring may further comprise one oxygen or nitrogen atom)),
Substituent group B includes halogen atom, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 An alkyl) aminocarbonyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfonyl group, a hydroxy group, and a 3- to 6-membered ring ether. Or a pharmacologically acceptable salt thereof. - 請求項1において、R1が、C1-C6アルキル基、C1-C6ハロゲン化アルキル基、1又は2個のヒドロキシ基で置換されているC1-C6アルキル基又はカルバモイル基である化合物又はその薬理上許容される塩。 In claim 1, R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group. A compound or a pharmacologically acceptable salt thereof.
- 請求項1又は2において、一般式(I)が、一般式(Ib)であり、R1が、メチル基、ヒドロキシメチル基又は2-ヒドロキシエチル基である化合物又はその薬理上許容される塩。
- 請求項1又は2において、一般式(I)が、一般式(Ic)であり、R1が、メチル基、フルオロメチル基、ヒドロキシメチル基、2-ヒドロキシエチル基又は(1S)-1,2-ジヒドロキシエチル基である化合物又はその薬理上許容される塩。
- 請求項1乃至5から選択されるいずれか一項において、R2が、置換基群Cから選択される基で4位又は3位が1個置換されているフェニル基、置換基群Cから選択される基で2位が1個置換されている5-ピリジル基又は置換基群Cから選択される基で5位が1個置換されている2-ピラジニル基である化合物又はその薬理上許容される塩。
置換基群Cは、C1-C6アルコキシ基、C1-C6アルキルスルホニル基及び式-V-NR6R7で表わされる基(Vは、カルボニル基又はスルホニル基を示し、R6、R7は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)からなる群を示す。 6. The group according to claim 1, wherein R 2 is a group selected from Substituent Group C, a phenyl group substituted at the 4- or 3-position with one selected from Substituent Group C, and Substituent Group C Or a pharmacologically acceptable compound thereof, which is a 5-pyridyl group substituted at the 2-position with a group selected from the above, or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C Salt.
Substituent group C includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, R 6 , R 7 is the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl group. - 請求項1乃至5から選択されるいずれか一項において、R2が、3-メトキシフェニル基、2-メチルアミノカルボニル-5-ピリジル基、4-メチルスルホニルフェニル基、2-メチルスルホニル-5-ピリジル基、2-メチルアミノスルホニル-5-ピリジル基、5-メチルスルホニル-2-ピラジニル基又は5-メチルアミノスルホニル-2-ピラジニル基である化合物又はその薬理上許容される塩。 6. The compound according to claim 1, wherein R 2 is a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, or 2-methylsulfonyl-5-. A compound or a pharmaceutically acceptable salt thereof which is a pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2-pyrazinyl group.
- 請求項1乃至7から選択されるいずれか一項において、R3が、ハロゲン原子で独立に1乃至5個置換されていてもよいC1-C6アルキル基又は(C3-C6シクロアルキル基及びオキソ基)からなる群で独立に1又は2個置換されていてもよく酸素原子若しくは窒素原子を1個含んでもよい3乃至6員飽和環であり、Uが、酸素原子である化合物又はその薬理上許容される塩。 The C 1 -C 6 alkyl group or (C 3 -C 6 cycloalkyl) according to any one of claims 1 to 7, wherein R 3 may be independently substituted with 1 to 5 halogen atoms independently. A compound having a 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom, Its pharmacologically acceptable salt.
- 請求項1乃至7から選択されるいずれか一項において、R3が、C1-C6アルキル基又は式-NR4R5で表わされる基(R4、R5は、同一又は異なって、水素原子又はC1-C6アルキル基を示す。)であり、Uが、カルボニル基である化合物又はその薬理上許容される塩。 In any one selected from claims 1 to 7, R 3 is, C 1 -C 6 alkyl or a group of the formula -NR 4 R 5 (R 4, R 5 are the same or different, A hydrogen atom or a C 1 -C 6 alkyl group), wherein U is a carbonyl group, or a pharmacologically acceptable salt thereof.
- 請求項1乃至7から選択されるいずれか一項において、式-U-R3で表わされる基が、メトキシ基、エトキシ基、イソプロポキシ基、(1S)-2-フルオロ-1-メチルエトキシ基、ジフルオロメトキシ基、1,3-ジフルオロ-2-プロポキシ基、シクロペンタノン-2-イルオキシ基、テトラヒドロフラン-3-イルオキシ基、1-シクロプロピルピロリジン-2-オン-3-イルオキシ基、イソプロピルカルボニル基又はジメチルアミノカルボニル基である化合物又はその薬理上許容される塩。 The group represented by the formula -UR 3 is selected from the group consisting of methoxy group, ethoxy group, isopropoxy group, and (1S) -2-fluoro-1-methylethoxy group. , Difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, isopropylcarbonyl group Or a dimethylaminocarbonyl group or a pharmacologically acceptable salt thereof.
- 一般式(I)を有する化合物が、
{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}メタノール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
2-{(5S)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタノール、
(1S)-1-{(5R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-5-イル}エタン-1,2-ジオール、
{(4R)-2-[5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{[5-(メチルスルホニル)ピラジン-2-イル]オキシ}フェニル)-1H-ピロール-2-イル]-4,5-ジヒドロ-1,3-オキサゾール-4-イル}メタノール、
5-(3-[(1S)-2-フルオロ-1-メチルエトキシ]-5-{5-[(4R)-4-(ヒドロキシメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}フェノキシ)-N-メチルピラジン-2-スルホンアミド、
3-{5-[(5R)-5-(フルオロメチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-N,N-ジメチル-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド、又は、
N,N-ジメチル-3-{5-[(5S)-5-メチル-4,5-ジヒドロ-1,3-オキサゾール-2-イル]-1H-ピロール-2-イル}-5-{[6-(メチルスルホニル)ピリジン-3-イル]オキシ}ベンズアミド
である化合物又はその薬理上許容される塩。 A compound having the general formula (I)
{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} methanol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
2-{(5S) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethanol,
(1S) -1-{(5R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[6- (methylsulfonyl) pyridin-3-yl] Oxy} phenyl) -1H-pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-5-yl} ethane-1,2-diol,
{(4R) -2- [5- (3-[(1S) -2-fluoro-1-methylethoxy] -5-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} phenyl) -1H -Pyrrol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl} methanol,
5- (3-[(1S) -2-fluoro-1-methylethoxy] -5- {5-[(4R) -4- (hydroxymethyl) -4,5-dihydro-1,3-oxazole-2 -Yl] -1H-pyrrol-2-yl} phenoxy) -N-methylpyrazine-2-sulfonamide,
3- {5-[(5R) -5- (fluoromethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -N, N-dimethyl-5 -{[6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide, or
N, N-dimethyl-3- {5-[(5S) -5-methyl-4,5-dihydro-1,3-oxazol-2-yl] -1H-pyrrol-2-yl} -5-{[ A compound which is 6- (methylsulfonyl) pyridin-3-yl] oxy} benzamide or a pharmacologically acceptable salt thereof. - 請求項1乃至11から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有するグルコキナーゼ活性化剤。 A glucokinase activator comprising a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.
- 請求項1乃至11から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof as an active ingredient.
- 医薬組成物が、グルコキナーゼ活性化作用を有する請求項13に記載の医薬組成物。 The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition has a glucokinase activating action.
- 医薬組成物が、グルコキナーゼ活性化作用により、治療及び/又は予防される疾病の治療及び/又は予防のための請求項13に記載の医薬組成物。 The pharmaceutical composition according to claim 13, for treating and / or preventing a disease which is treated and / or prevented by a glucokinase activating action.
- 医薬組成物が、グルコキナーゼを活性化させ、グルコースの恒常性の維持又は血糖調節が達成されることにより、症状の治療、改善、軽減及び/又は予防がなされる疾病の治療及び/又は予防のための請求項13に記載の医薬組成物。 The pharmaceutical composition activates glucokinase, maintains glucose homeostasis or regulates blood glucose, and thereby treats and / or prevents diseases that are treated, ameliorated, reduced and / or prevented. A pharmaceutical composition according to claim 13 for.
- 医薬組成物が、糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームの治療及び/又は予防のための請求項13に記載の医薬組成物。 The pharmaceutical composition is used to treat diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome and / or Or the pharmaceutical composition according to claim 13 for prevention.
- 医薬組成物が、糖尿病又は耐糖能異常の治療及び/又は予防のための請求項13に記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, for the treatment and / or prevention of diabetes or impaired glucose tolerance.
- 医薬組成物を製造するための、請求項1乃至11から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。 Use of the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
- 医薬組成物がグルコキナーゼを活性化するための組成物である請求項19に記載の使用。 The use according to claim 19, wherein the pharmaceutical composition is a composition for activating glucokinase.
- 医薬組成物が糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームの治療及び/又は予防のための組成物である請求項19に記載の使用。 Treatment and / or treatment of diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) and / or metabolic syndrome 20. Use according to claim 19 which is a composition for prevention.
- 医薬組成物が糖尿病又は耐糖能異常の治療及び/又は予防のための組成物である請求項19に記載の使用。 20. Use according to claim 19, wherein the pharmaceutical composition is a composition for the treatment and / or prevention of diabetes or impaired glucose tolerance.
- 請求項1乃至11から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与するグルコキナーゼ活性化方法。 A method for activating glucokinase, comprising administering to a warm-blooded animal a pharmacologically effective amount of a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof.
- 請求項1乃至11から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与する疾病の治療及び/又は予防方法。 A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof.
- 疾病が糖尿病、耐糖能異常、妊娠糖尿病、糖尿病慢性合併症(糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症を含む)又はメタボリックシンドロームである請求項24に記載の方法。 25. The disease according to claim 24, wherein the disease is diabetes, glucose intolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome. the method of.
- 疾病が糖尿病又は耐糖能異常である請求項24に記載の方法。 25. The method according to claim 24, wherein the disease is diabetes or impaired glucose tolerance.
- 温血動物がヒトである請求項23乃至26から選択されるいずれか一項に記載の方法。 The method according to any one of claims 23 to 26, wherein the warm-blooded animal is a human.
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