WO2019189717A1 - Method for producing tetrahydronaphthylurea derivative - Google Patents

Method for producing tetrahydronaphthylurea derivative Download PDF

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WO2019189717A1
WO2019189717A1 PCT/JP2019/013916 JP2019013916W WO2019189717A1 WO 2019189717 A1 WO2019189717 A1 WO 2019189717A1 JP 2019013916 W JP2019013916 W JP 2019013916W WO 2019189717 A1 WO2019189717 A1 WO 2019189717A1
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formula
group
solvent
mixed solution
alkyl group
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PCT/JP2019/013916
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French (fr)
Japanese (ja)
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鈴木　雄太
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持田製薬株式会社
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Priority to JP2020511064A priority Critical patent/JP7431155B2/en
Publication of WO2019189717A1 publication Critical patent/WO2019189717A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention provides a method for producing a tetrahydronaphthyl urea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) of Scheme 7 and a compound represented by formula (I): And a process for producing a compound represented by the formula (AM-X).
  • TrkA tropomyosin receptor kinase A
  • a tetrahydronaphthyl urea derivative represented by the formula (I) is produced by a urea reaction using an amino compound represented by the formula (AM-1) and an amine salt represented by the formula (AM-2-RRS). (Scheme 1) (Patent Document 1).
  • the amine salt represented by the formula (AM-2-RRS) is a compound (RAM-2) obtained through two steps using a compound represented by the formula (TH-1) as a starting material. ) Can be produced by fractional recrystallization after conversion to the salt represented by the formula (RAM-2-S) with D-tartaric acid.
  • the production method using fractional recrystallization is excellent in that the formula (AM-2-RRS) is obtained as a compound having high optical purity, but other isomers after the resolution (for example, (1S, 2S) isomers , Etc.) is difficult to reuse, and in the mass synthesis or industrial production of the compound represented by formula (I), an improved production method is required. That is, when mass synthesis or industrial production of the compound represented by the formula (I) is considered, a novel production method different from the production method using the amine salt represented by the formula (AM-2-RRS) is found.
  • the synthesis method of the compound represented by Formula (EP-1), which can be a synthetic intermediate of the compound represented by Formula (AM-X), is Chemistry® Letters, (11), P2231-4, 1992 (Non-patent document 1), or Bulletin of the Chemical Society of Japan, 67 (8), p2248-56, 1994 (Non-patent document 2).
  • the synthesis method is an oxidation reaction using oxygen gas and a manganese catalyst and is not suitable for mass synthesis.
  • the chemical yield is as low as 35% and the optical purity is as low as 63% for use as a pharmaceutical raw material. Therefore, this reaction condition is not used in mass synthesis or industrial production of the compound represented by the formula (AM-X).
  • P 0, 1,2-dihydronaphthalene ring
  • the compound from which the dimethyl group at the 1-position was removed was oxidized using hydrogen peroxide and a titanium catalyst in Synlett, 20, p3545-3547, 2006 (Non-patent Document 3), or Synlett, 15, p2445 -2447, 2007 (Non-patent Document 4) (Scheme 6).
  • the production method of the compound represented by the formula (I) through the fractional recrystallization method of the represented compound that is, using the compound represented by the formula (AM-X), represented by the formula (I)
  • the present inventors have conducted intensive research to solve the above problems. As a result, in the following (Scheme 7), by performing an asymmetric epoxidation reaction using a titanium catalyst using a compound represented by the formula (TH-1) as a starting material and hydrogen peroxide as an oxygen source.
  • the present inventors have found that an epoxy compound having a desired configuration represented by the formula (EP-1) can be obtained with high chemical yield and high optical purity. Further, it has been found that the compound represented by the formula (AM-X) can be obtained with high chemical yield and high optical purity by the subsequent aminohydroxylation reaction.
  • the present inventors have found a process for producing a compound of formula (AM-X), which can suppress the formation of an isomer of the compound of formula (AM-X) by these successive reactions.
  • ring A is the following formula: 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group.
  • the present invention relates to a method for producing a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by formula (I), and (1R, 2R) -1 represented by formula (AM-X)
  • the present invention relates to a production method for synthesizing a large amount of amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol derivative with high yield and high optical purity.
  • the present invention provides an intermediate used for the production of a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) with a good chemical yield and high optical activity purity. It is possible to provide a novel method for producing by a short process, an easy and industrially advantageous method, and the industrial utility is high.
  • TrkA tropomyosin receptor kinase A
  • the present invention relates to a tetrahydronaphthyl urea derivative represented by the following formula (I) shown in the following embodiment, (1R, 2R) -1-amino-4,4-dimethyl-
  • the present invention relates to a method for producing a 1,2,3,4-tetrahydronaphthalen-2-ol derivative and an epoxy derivative represented by the formula (EP-1). More specifically, exemplary embodiments of the present invention can be as described in [1] to [5] below.
  • a first aspect of the present invention is the following formula (I):
  • p is an integer selected from 0, 1, and 2;
  • R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group;
  • ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps: (1) The following formula (TH-1):
  • p and R 1 are as defined in the formula (I)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide, titanium Alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), titanium tetra Normal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 , etc.) and the following formula (LG-1) as a ligand ):
  • a titanium catalyst for example, titanium tetrachloride, titanium tetrabromide, titanium Alkoxide (titanium tetramethoxide, titanium tetraethoxide,
  • a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
  • a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
  • the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
  • ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group
  • triphosgene Phosgene
  • trichloromethyl chloroformate 2,2,2-trichloroethyl chloroformate
  • phenyl chloroformate p-nitrophenyl chloroformate
  • p-tolyl chloroformate N, N′-carbonyldiimidazole, and N, N ′
  • the reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
  • Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, (7) a compound represented by the formula (AM-X) obtained in the step (4), and a compound represented by the formula (CB-1).
  • the mixed solution (7) is any one of from 0 ° C. to a temperature at which the mixed solution (7) is refluxed.
  • the reaction is carried out at a temperature of To obtain a compound, a production method including a.
  • the formula (AM-1) is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine shown below.
  • the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
  • “equivalent” means that the molar ratio is 1: 1. That is, when the amount of the hydrogen peroxide solution is 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1), the amount of the hydrogen peroxide solution is 1: 1.5 to 1 in molar ratio. It means 1:10.
  • the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
  • the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
  • the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
  • the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane.
  • a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
  • the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
  • the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus An acid buffer, KH 2 PO 4 / NaOH buffer; more preferably a phosphate buffer, KH 2 PO 4 / NaOH buffer; particularly preferably a phosphate buffer.
  • the pH of the reaction solution can be adjusted with the buffer solution.
  • the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
  • the reaction in the step (4) of the embodiment [1] is preferably a sealed tube reaction using a sealed tube reaction bottle.
  • the reaction temperature of the sealed tube reaction of the embodiment [1-8-1] is preferably 100 ° C.
  • the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
  • the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
  • Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
  • a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
  • the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; 1,2-dichloroethane is more preferable.
  • aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
  • diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
  • ester solvents
  • Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
  • the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
  • Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
  • a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably triethylamine And 1,8-diazabicyclo 5.4.0] -7-undecene (DBU).
  • p is preferably an integer of 0 or 1, more preferably an integer of 0.
  • R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
  • the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
  • the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
  • the titanium catalyst is titanium tetraisopropoxide;
  • the buffer is a phosphate buffer;
  • the solvent (a solvent not involved in the reaction) is dichloromethane;
  • the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
  • the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
  • the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
  • the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
  • a second aspect of the present invention is the following formula (AM-X):
  • p is an integer selected from 0, 1, and 2;
  • R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
  • Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (1) The following formula (TH-1):
  • p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
  • a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
  • a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
  • the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
  • the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
  • step (1) of the embodiment [2] it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.
  • the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
  • the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
  • the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
  • the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane.
  • a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
  • the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
  • the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus
  • the pH of the reaction solution can be adjusted with the buffer solution.
  • the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
  • the reaction in the step (2) of the embodiment [2] is preferably a sealed tube reaction using a sealed tube reaction bottle.
  • the reaction temperature of the sealed tube reaction in the above embodiment [2-8-1] is preferably 100 ° C.
  • p is preferably an integer of 0 or 1, more preferably an integer of 0.
  • R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
  • R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
  • the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
  • the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
  • the titanium catalyst is titanium tetraisopropoxide;
  • the buffer is a phosphate buffer;
  • the solvent (a solvent not involved in the reaction) is dichloromethane;
  • the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
  • the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
  • the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
  • the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
  • a third aspect of the present invention is the following formula (EP-1):
  • p is an integer selected from 0, 1, and 2;
  • R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
  • Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (1) The following formula (TH-1):
  • p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
  • a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
  • a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
  • the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and represented by the formula (EP-1)
  • a production method comprising a step of obtaining a compound.
  • the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
  • the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
  • the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
  • the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
  • the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and still more preferably dichloromethane, 1,2-dichloroethane.
  • a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
  • the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
  • the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus
  • the pH of the reaction solution can be adjusted with the buffer solution.
  • the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
  • p is preferably an integer of 0 or 1, more preferably an integer of 0.
  • R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
  • R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
  • the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
  • the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
  • the titanium catalyst is titanium tetraisopropoxide;
  • the buffer is a phosphate buffer;
  • the solvent (a solvent not involved in the reaction) is dichloromethane;
  • the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
  • the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
  • the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
  • the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
  • a fourth aspect of the present invention is the following formula (AM-X):
  • p is an integer selected from 0, 1, and 2;
  • R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
  • Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (3) The following formula (EP-1):
  • the reaction in the step (4) of the embodiment [4] is preferably a sealed tube reaction using a sealed tube reaction bottle.
  • a preferred reaction temperature for the sealed tube reaction of the embodiment [4-1-1] is 100 ° C.
  • the preferred reaction time for the sealed tube reaction of the embodiment [4-1-1] is 2 hours.
  • p is preferably an integer of 0 or 1, more preferably an integer of 0.
  • R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
  • a fifth aspect of the present invention is the following formula (I):
  • p is an integer selected from 0, 1, and 2;
  • R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group;
  • ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps: (5)
  • ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group
  • triphosgene Phosgene
  • trichloromethyl chloroformate 2,2,2-trichloroethyl chloroformate
  • phenyl chloroformate p-nitrophenyl chloroformate
  • p-tolyl chloroformate N, N′-carbonyldiimidazole, and N, N ′
  • the reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
  • Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, A step of obtaining a compound represented by the formula: A compound represented by the formula (CB-1); The following formula (AM-X):
  • the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
  • the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
  • Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
  • a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
  • the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably tetrahydrofuran.
  • aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
  • diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
  • ester solvents such as
  • Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
  • the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably N-methylpyrrolidone.
  • aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
  • diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
  • ester solvents such as
  • the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene.
  • DBU organic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate
  • metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogenated
  • a metal hydride compound such as calcium, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, triethylamine is there.
  • p is preferably an integer of 0 or 1, more preferably an integer of 0.
  • R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
  • R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
  • C 1-6 means that the number of carbon atoms constituting the compound is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms. For a group containing a chain group and a cyclic group, it means “total number of carbon atoms in the chain and ring”.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the “halogenation” in the “halogenated C 1-6 alkyl group” and the like refers to several, preferably 1 to 5, of the above “halogen atoms” as substituents. It means that you may have.
  • “cyanation” in “cyanated C 1-6 alkyl” and the like has several, preferably 1 to 5 “cyano groups” as substituents. It means that it may be.
  • C 1-6 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Or groups, such as hexyl, are mentioned.
  • halogenated C 1-6 alkyl group means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1 to 5 halogen atoms.
  • a group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. Can be mentioned.
  • the “cyanated C 1-6 alkyl group” means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1-5 cyano. Groups such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and the like.
  • the “C 1-6 alkoxy group” means alkoxy in which the above-mentioned “C 1-6 alkyl” is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, iso Examples include groups such as propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or hexyloxy.
  • the “halogenated C 1-6 alkoxy group” represents a halogenated alkoxy in which the above-mentioned “halogenated C 1-6 alkyl” is bonded to an oxygen atom. Examples include methoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy and the like.
  • the “C 1-6 alkoxy C 1-6 alkyl group” means a group in which the “C 1-6 alkoxy” is substituted with the “C 1-6 alkyl”. To do. Unless otherwise specified, in this specification, examples of the “C 1-6 alkoxy C 1-6 alkyl” include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl, or 1, Examples include groups such as 1-diethoxyethyl.
  • the “mono / di C 2-7 alkanoylamino group” means that one or two hydrogen atoms on the nitrogen atom of the “amino group” are described later in “C 2 ⁇ ⁇ 7 alkanoyl group '' means an amino group substituted with, for example, acetamide, propionamide, butyramide, isobutyramide, valeramide, isovaleramide, pivalamide, hexaneamide, heptanamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, Examples include cyclohexanecarboxamide, 2-methylcyclopropanecarboxamide, or diacetamide.
  • the “C 2-7 alkanoyl group” means a “C 1-6 alkylcarbonyl group” in which a carbonyl group is bonded to the “C 1-6 alkyl group”.
  • a group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, or 2-methylcyclopropylcarbonyl Is mentioned.
  • C 1-6 alkoxycarbonyl group means a group in which a hydrogen atom of a “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”.
  • “Ester group” means a group such as methoxycarbonyl (methyl ester), ethoxycarbonyl (ethyl ester), or tert-butoxycarbonyl (tert-butyl ester).
  • urea agent includes triphosgene, phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, chloroformate p- Examples thereof include nitrophenyl, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N′-disuccinimidyl carbonate. However, it is not necessarily limited to the urea agent described above.
  • examples of the “base” include pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • solvent or “solvent not involved in the reaction” refers to, for example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert- Butyl alcohol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide ( DMSO), acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2 Dimethoxyethanethane, N, N-di
  • an R or S symbol indicating a configuration may be added in the vicinity of the asymmetric carbon.
  • the 1-position and the 2-position are asymmetric carbons, and the symbol of R or S is attached in the vicinity of the asymmetric carbon in each formula. .
  • the compounds herein may form a salt with an inorganic or organic acid (acid addition salt) or a salt with an inorganic or organic base depending on the type of substituent.
  • a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basicity, Or the salt with an acidic amino acid etc. are mentioned.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt.
  • alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt
  • alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
  • aluminum salt for example, besides a mono salt, a disodium salt and a dipotassium salt are also included.
  • the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarbox
  • Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
  • salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
  • salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the salt is formed by, for example, mixing the compound in the present specification with a solution containing an appropriate amount of acid or base to form a desired salt, and then fractionally filtering or removing the mixed solvent. It can be obtained by leaving.
  • the compound in this specification or its salt can form solvates with solvents, such as water, ethanol, and glycerol.
  • solvents such as water, ethanol, and glycerol.
  • solvate means a molecular complex comprising a compound herein and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
  • the compounds in the present specification are represented by geometric isomers (geometric isomers), configurational isomers (configurational isomers), tautomers (tortomeric isomers), optical isomers (optical isomers), stereoisomers (diastereomers). Isomers), positional isomers (regioisomers), rotational isomers (rotational isomers) and the like.
  • each isomer is simply separated by a synthesis method or separation method known per se. It can be obtained as a single compound.
  • the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
  • Fractionation recrystallization method After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound.
  • the optical resolution agent include (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, Examples include cinchonine, ( ⁇ )-cinchonidine, brucine and the like.
  • Diastereomer method An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining an optical isomer.
  • separation means eg, fractional recrystallization, silica gel column chromatography).
  • HPLC High Performance Liquid Chromatography, etc.
  • the compound of the present invention when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Chiral column method This is a method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column).
  • a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column).
  • HPLC high performance liquid chromatography
  • a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, water, various buffers (eg, phosphate buffer)
  • Optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution.
  • separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • the compound in the present specification may be a crystal.
  • the crystal form may be single or a crystal form mixture.
  • the compound herein may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compounds herein include isotopes (eg, hydrogen isotopes: 2 H and 3 H, carbon isotopes: 11 C, 13 C, and 14 C, chlorine isotopes: 36 Cl, etc. , Fluorine isotopes: 18 F, iodine isotopes: 123 I and 125 I, nitrogen isotopes: 13 N and 15 N, oxygen isotopes: 15 O, 17 O, and 18 O, etc. Also included are compounds labeled or substituted with phosphorus isotopes: 32 P, etc., and sulfur isotopes: 35 S, etc.
  • isotopes eg, hydrogen isotopes: 2 H and 3 H, carbon isotopes: 11 C, 13 C, and 14 C, chlorine isotopes: 36 Cl, etc.
  • Fluorine isotopes: 18 F Fluorine isotopes: 18 F, iodine isotopes: 123 I and
  • Compounds of the invention labeled or substituted with certain isotopes can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
  • Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies.
  • 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
  • the isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below.
  • the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
  • any temperature between 0 ° C. and the temperature at which the mixed solution is refluxed “from 0 ° C. to the temperature at which the solvent is refluxed”
  • the phrase “any temperature in between” means any temperature (constant temperature) within a range from 0 ° C. to the temperature at which each mixed solution (solvent) is refluxed.
  • room temperature means a temperature in a laboratory, laboratory, etc., and is usually about 1 ° C. to about 30 ° C., preferably usually about 5 ° C. to about 30 ° C. More preferably, it usually exhibits a temperature of about 15 ° C. to about 25 ° C., more preferably 20 ⁇ 3 ° C.
  • the solvent to be used one kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio as appropriate depending on the reaction conditions.
  • steps such as compound extraction, drying, and purification can be appropriately performed by a known method.
  • the reaction time in each step may be appropriately selected as long as the reaction proceeds sufficiently unless otherwise specified.
  • a method for producing a compound represented by the formula (TH-1) in the present invention A method for producing a compound represented by the formula (TH-1) in the present invention:
  • the formula (TH-1) [the definitions of p and R 1 in the formula (TH-1) are the same as the definitions of the formula (I) in the embodiment [1]]
  • the method for producing the compound will be described in detail.
  • the compound represented by the formula (TH-1) and a solvate thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods.
  • R A is a C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, or a tert-butyl group, a phenyl group, or a benzyl group unless otherwise specified.
  • SM-1 a compound represented by the formula (SM-1)
  • the compound of formula (SM-1) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature
  • a known method such as “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-82, 1992, Maruzen”, etc., hydrochloric acid, sulfuric acid, thionyl chloride,
  • an acidic reagent such as acetyl chloride, the reaction is performed at a temperature between 0 ° C.
  • an alkyl halide agent for example, methyl iodide, ethyl iodide, etc.
  • a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, N, N-dimethylformamide, dimethyl sulfoxide
  • a polar solvent such as N-methylpyrrolidone to produce a compound represented by the formula (IM-1) by carrying out the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed. it can.
  • SM-1 a compound represented by the formula (SM-1), for example, “Chemical & Pharmaceutical Bulletin, 29 (5), pp. 1475-1478, 1981”
  • the reaction is carried out from 0 ° C. to room temperature in a methylating agent such as diazomethane or trimethylsilyldiazomethane, a solvent that does not participate in the reaction such as ether or methanol, or a mixed solvent thereof.
  • a methylating agent such as diazomethane or trimethylsilyldiazomethane
  • a solvent that does not participate in the reaction such as ether or methanol, or a mixed solvent thereof.
  • the compound represented by -1) can be produced.
  • the compound represented by the formula (SM-1) is converted into a method known in the literature, for example, “Journal of the American Chemical Society”, 109 (24), p7488-7494.
  • a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, thionyl chloride, oxalyl chloride, phosphoryl chloride, chloride
  • Halogenating agents such as sulfuryl, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc.
  • reaction is carried out at any temperature between 0 ° C. and the temperature at which the solvent is refluxed, and then converted to an acid halide, followed by alcohol (eg, methanol, ethanol, benzyl alcohol). Etc.) according to methods known in the literature, for example, the method described in “Experimental Chemistry Course, 4th Edition, 22.
  • ⁇ Step 2> [Production Method A] Using the compound represented by the formula (IM-1) obtained in ⁇ Step 1>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 25, Organic Synthesis VII” In accordance with the method described in "Synthesis with organometallic reagents, pages 13-19, 59-72, 1992, Maruzen", etc., Grignard reagent (eg, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, etc.
  • Grignard reagent eg, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, etc.
  • ⁇ Step 3> [Production Method A] Using the compound represented by the formula (IM-2) obtained in ⁇ Step 2>, a method known in the literature, for example, “Tetrahedron Letters, 54 (32), p4330-4332.
  • an acid reagent such as trifluoromethanesulfonic acid, diphosphorus pentoxide, phosphorous pentachloride, sulfuric acid, phosphoric acid, bismuth (III) trifluoromethanesulfonate
  • a solvent inert to the reaction such as dichloromethane, chloroform, cyclohexane, benzene, toluene, xylene, diethyl ether, 2-propanol, water, or a mixed solvent thereof, the temperature between 0 ° C. and the temperature at which the solvent is refluxed.
  • the reaction can be carried out at any temperature to produce the compound represented by the formula (IM-3).
  • ⁇ Step 4> [Production Method A] Using the compound represented by the formula (IM-3) obtained in ⁇ Step 3>, a method known in the literature, for example, “Chemistry Letters, 70 (10), p1042-1043. In the presence of an oxidizing agent such as Oxone (registered trademark) (DuPont), tert-butyl hydroperoxide (TBHP), potassium permanganate, manganese dioxide, chromic acid, and the like. , Chloroform, carbon tetrachloride, benzene, acetonitrile, tert-butyl alcohol, water, or a solvent inert to the reaction, or a mixed solvent thereof. By reacting at a temperature, a compound represented by the formula (IM-4) can be produced.
  • Oxone registered trademark
  • TBHP tert-butyl hydroperoxide
  • ⁇ Step 6> [Production Method A] Using a compound represented by the formula (IM-5) obtained in ⁇ Step 5>, a method known in the literature, for example, described in “International Publication No. 2014/078454 Pamphlet”, etc. Inactive in the reaction of dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, 1,2-dimethoxyethane, etc. in the presence of an acid reagent such as p-toluenesulfonic acid, etc.
  • a compound represented by the formula (TH-1) can be produced by performing a reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a suitable solvent or a mixed solvent thereof. .
  • [Production Method B] A method for producing a compound represented by the formula (AM-1) in the present invention: Hereinafter, the method for producing the compound represented by the formula (AM-1) in the present invention will be described in detail.
  • the compound represented by the formula (AM-1) and a solvate thereof are known compounds that are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods. In the following production method, [B] is boronic acid, boronic acid ester, boronic acid N-methyliminodiacetic acid (MIDA) ester or the like.
  • MIDA boronic acid N-methyliminodiacetic acid
  • Formula (SM-2) and Formula (RG-1) are commercially available compounds or can be produced from commercially available compounds by known production methods in the literature. Using a compound represented by the above formula, a method known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” And palladium (II) acetate (Pd (OAc) 2 ), tetrakistriphenylphosphinepalladium (Pd (Pd (OAc) 2 )), and the method described in “Journal of Medicinal Chemistry, 48 (20), p6326-6339, 2005”.
  • ⁇ Step 2> [Production Method B] Using the compound of formula (IM-6) obtained in ⁇ Step 1> and N-bromosuccinimide (NBS), methods known in the literature, for example, “International Publication 2009/088103” N-methylpyrrolidone, dimethylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and other solvents (solvents not involved in the reaction), or a mixture thereof.
  • the compound represented by the formula (IM-7) can be produced by performing the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a solvent.
  • the compounds of formula (IM-4), formula (IM-5), formula (IM-6), and formula (IM-7) may form a salt, and as such a salt, pharmaceutically
  • examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic salts, and salts with acidic amino acids. It is done.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt.
  • alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt
  • alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
  • aluminum salt for example, besides a mono salt, a disodium salt and a dipotassium salt are also included.
  • the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
  • Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
  • Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
  • preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the formula (IM-6), and the compound of the formula (IM-7) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. It can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
  • reaction conditions in the production method are as follows unless otherwise specified.
  • the reaction temperature is not limited as long as it is in the range from ⁇ 78 ° C. to the temperature at which the solvent is refluxed.
  • the reaction time is not limited as long as the reaction is sufficiently advanced unless otherwise specified.
  • range of the temperature at which the solvent refluxes from ⁇ 78 ° C.” in the reaction temperature means a temperature within the range from ⁇ 78 ° C. to the temperature at which the solvent (or mixed solvent) used in the reaction refluxes. .
  • “at a temperature at which the solvent is refluxed from ⁇ 78 ° C.” means a temperature within a range from ⁇ 78 ° C. to a temperature at which the methanol is refluxed.
  • “at a temperature at which the reaction solution is refluxed from ⁇ 78 ° C.” means any temperature within a range from ⁇ 78 ° C. to a temperature at which the reaction solution is refluxed.
  • Each step of [Production Method A] or [Production Method B] can be performed without solvent or by dissolving or suspending the raw material compound in an appropriate solvent before the reaction.
  • the solvent is preferably a solvent that does not participate in the reaction.
  • the solvent is preferably a solvent that does not participate in the reaction.
  • solvents can be used alone, or can be appropriately selected depending on the reaction conditions, and two or more solvents can be mixed and used at an appropriate ratio. These solvents are appropriately selected according to the reaction conditions. Unless otherwise specified, in the production method of the present specification, when “solvent”, “solvent not involved in the reaction” or “solvent inert to the reaction” is described, the solvent to be used is a single solvent. Alternatively, it may be selected as appropriate depending on the reaction conditions, and two or more solvents may be mixed and used at an appropriate ratio.
  • Examples of the base (or deoxidizing agent) used in each step of [Production Method A] or [Production Method B] include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, Sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4- Dimethylaminopyridine (DMAP), N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4- Diazabicyclo [2.2.2] octane, 1,8-dia Zabicyclo [5.4.0] -7-undecene (
  • Examples of the acid or acid catalyst used in each step of [Production Method A] or [Production Method B] include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, Phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous chloride Examples include zinc and anhydrous iron chloride. However, it is not necessarily limited to those described above. These acids or acid catalysts are appropriately selected according to the reaction conditions.
  • JEOL JNM-ECX400 FT-NMR or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
  • 1 H-NMR (#) is described in the 1 H-NMR data in the examples, it means that measurement was performed using JEOL JNM-ECX300 FT-NMR (JEOL).
  • the liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method.
  • SFC supercritical fluid liquid chromatography
  • room temperature in the reference examples and examples usually indicates a temperature of about 20 to 25 ° C.
  • DCM in the column of solvent in the table of (Example 2) means dichloromethane
  • DCE means 1,2-dichloroethane.
  • ⁇ Step 2> Synthesis of 1,1-dimethyl-1,2-dihydronaphthalene: (Reference Example 1) A toluene (10 mL) solution of the compound (1.0 g) obtained in ⁇ Step 1> and p-toluenesulfonic acid monohydrate (0.05 g) was stirred at 90 ° C. for 1.5 hours. did. After cooling to room temperature, ethyl acetate (40 mL) and saturated aqueous sodium hydrogencarbonate (30 mL) were added and partitioned.
  • ⁇ Step 2> Synthesis of 6-bromo-5-methyl-2-phenylpyridin-3-amine: (Reference Example 2) N-bromosuccinimide (0.21 g) was added to a solution of the compound (0.19 g) obtained in ⁇ Step 1> in N-methylpyrrolidone (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Water (2.0 mL) was added to the reaction solution, extracted twice with tert-butyl methyl ether, and the organic layer was washed with water.
  • ⁇ Step 3> Synthesis of 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine: Reference Example 2 To a mixed solution of the compound obtained in ⁇ Step 2> (0.40 g) in 1,2-dimethoxyethane (10 mL) and water (2.0 mL) was added 2-methyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (0.44 g), cesium carbonate (1.5 g) and dichloro [1,1′bis (diphenylphosphino) ferrocene] Palladium dichloromethane adduct (0.12 g) was added and stirred at 80 ° C.
  • the conversion rate in the above table means the ratio to the supply amount of the reaction material (starting material) disappeared by the reaction. That is, it can be understood that the higher the conversion rate, the more the reaction material (starting material) disappears and the reaction proceeds.
  • the pass-through rate was calculated from the UPLC 220 nm UV spectrum intensity. The measurement yield was calculated by comparison with an internal standard substance (dimethyl terephthalate) from NMR.
  • Diazabicycloundecene (0.59 mL) was added to a solution of the compound (0.75 g) obtained in (Example 3) and the compound (1.77 g) obtained in (Example 1) in dimethyl sulfoxide (10 mL). And stirred at room temperature overnight. Water (10 mL) and ethanol (10 mL) were added to the reaction solution obtained by stirring, and the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture obtained by stirring was cooled and stirred at room temperature for 3 hours.
  • a production method suitable for industrial production of the compound represented by formula (I) in a short process in a short process.
  • a useful process for producing a compound represented by the formula (AM-X), which is an intermediate for the production of the compound represented by the formula (I) is provided.

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Abstract

Provided is a novel method for producing a compound represented by formula (I). The invention according to the present application provides: a method for producing a compound represented by formula (I); and methods respectively for producing a compound represented by formula (EP-1) and a compound represented by formula (AM-X) which are intermediates for the production of a compound represented by formula (I).

Description

テトラヒドロナフチルウレア誘導体の製造方法Method for producing tetrahydronaphthylurea derivative
　本発明は、下記Ｓｃｈｅｍｅ ７の式（Ｉ）で表されるトロポミオシン受容体キナーゼＡ（ＴｒｋＡ）阻害作用を有するテトラヒドロナフチルウレア誘導体の製造方法、及び式（Ｉ）で表される化合物を製造する為の中間体である式（ＥＰ－１）で表される化合物並びに式（ＡＭ－Ｘ）で表される化合物の製造方法に関する。 The present invention provides a method for producing a tetrahydronaphthyl urea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) of Scheme 7 and a compound represented by formula (I): And a process for producing a compound represented by the formula (AM-X).
　式（Ｉ）で表されるテトラヒドロナフチルウレア誘導体は、式（ＡＭ－１）で表されるアミノ化合物、及び式（ＡＭ－２－ＲＲＳ）で表されるアミン塩を用いる、ウレア化反応により製造されている（Ｓｃｈｅｍｅ　１）（特許文献１）。 A tetrahydronaphthyl urea derivative represented by the formula (I) is produced by a urea reaction using an amino compound represented by the formula (AM-1) and an amine salt represented by the formula (AM-2-RRS). (Scheme 1) (Patent Document 1).
Figure JPOXMLDOC01-appb-I000021
Figure JPOXMLDOC01-appb-I000021
　式（ＡＭ－２－ＲＲＳ）で表わされるアミン塩は、（Ｓｃｈｅｍｅ　２）に示すように、式（ＴＨ－１）で表わされる化合物を出発原料として、２工程を経て得られる式（ＲＡＭ－２）で表わされる化合物を、Ｄ－酒石酸により式（ＲＡＭ－２－Ｓ）で表わされる塩へ変換した後、分別再結晶により製造ができる。 As shown in (Scheme 2), the amine salt represented by the formula (AM-2-RRS) is a compound (RAM-2) obtained through two steps using a compound represented by the formula (TH-1) as a starting material. ) Can be produced by fractional recrystallization after conversion to the salt represented by the formula (RAM-2-S) with D-tartaric acid.
Figure JPOXMLDOC01-appb-I000022
Figure JPOXMLDOC01-appb-I000022
　前記分別再結晶を用いる製造法は、式（ＡＭ－２－ＲＲＳ）が光学純度の高い化合物として得られる点で優れているものの、分割後の他の異性体（例えば、（１Ｓ，２Ｓ）体、等）の再利用が難しい点が課題であり、式（Ｉ）で表わされる化合物の大量合成又は工業的生産においては、その改良製法が求められる。即ち、式（Ｉ）で表わされる化合物の大量合成もしくは工業的生産を考えた場合には、式（ＡＭ－２－ＲＲＳ）で表わされるアミン塩を用いる製造方法とは異なる新規な製造方法を見出すことが求められており、特に、式（ＡＭ－２－ＲＲＳ）で表わされるアミン塩に代わるＳｃｈｅｍｅ　１のウレア化反応で使用し得るアミン塩であって、式（ＡＭ－２－ＲＲＳ）に比べて分別再結晶後の他の異性体の再利用が容易な化合物が求められている。 The production method using fractional recrystallization is excellent in that the formula (AM-2-RRS) is obtained as a compound having high optical purity, but other isomers after the resolution (for example, (1S, 2S) isomers , Etc.) is difficult to reuse, and in the mass synthesis or industrial production of the compound represented by formula (I), an improved production method is required. That is, when mass synthesis or industrial production of the compound represented by the formula (I) is considered, a novel production method different from the production method using the amine salt represented by the formula (AM-2-RRS) is found. In particular, it is an amine salt that can be used in the ureation reaction of Scheme 1 instead of the amine salt represented by the formula (AM-2-RRS), compared with the formula (AM-2-RRS). Thus, there is a demand for a compound that can be easily reused after other fractional crystallization.
　式（ＡＭ－２－ＲＲＳ）で表わされるアミン塩の等価体の１つである、下記式（ＡＭ－Ｘ）においてｐ＝０の化合物である、（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オールは、国際公開第２０１４／０７８４５４（ｐ１６５、ＩｎｔｅｒｍｅｄｉａｔｅＸ２）にて、その製造方法が開示されている。しかし、当該製造方法は、式（ＲＡＭ－２）で表わされる化合物のキラルカラムを用いたカラム分割方法であることから、当該方法を用いた場合でも対応する異性体（式（ＡＭ－Ｙ））の再利用が出来ない点で、当該製法も前記課題が解決できていない製法であり、又、式（ＡＭ－Ｘ）で表わされる化合物を大量合成又は工業的生産できる製造方法ではない（Ｓｃｈｅｍ ３）。（特許文献２） (1R, 2R) -1-amino-4, which is one of the equivalents of the amine salt represented by the formula (AM-2-RRS), which is a compound with p = 0 in the following formula (AM-X) The production method of 4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol is disclosed in International Publication No. 2014/078454 (p165, IntermediateX2). However, since the production method is a column resolution method using a chiral column of the compound represented by the formula (RAM-2), even when this method is used, the corresponding isomer (formula (AM-Y)) This method is also a method in which the above-mentioned problem cannot be solved because it cannot be reused, and is not a method for mass synthesis or industrial production of the compound represented by the formula (AM-X) (Schem 3). . (Patent Document 2)
Figure JPOXMLDOC01-appb-I000023
Figure JPOXMLDOC01-appb-I000023
よって、式（ＡＭ－Ｘ）で表わされる化合物を高収率かつ高光学純度で大量合成する製造方法は、未だ知られてないことから、式（ＡＭ－Ｘ）で表わされる化合物を短工程、高い化学収率、かつ高い光学純度で大量合成する製造方法を見出すことができれば、上記課題が解決できると考えられる。更に（Ｓｃｈｅｍｅ　４）に示される、式（ＡＭ－Ｘ）で表される化合物を用いる新規製造方法により、式（Ｉ）の化合物を大量又は工業的生産レベルで得ることが可能となり、その方法が望まれていた。 Therefore, since a production method for synthesizing a large amount of the compound represented by the formula (AM-X) with high yield and high optical purity is not yet known, the compound represented by the formula (AM-X) is prepared by a short process, If a production method for mass synthesis with high chemical yield and high optical purity can be found, it is considered that the above problems can be solved. Furthermore, the novel production method using the compound represented by the formula (AM-X) shown in (Scheme 4) makes it possible to obtain the compound of the formula (I) in a large amount or at an industrial production level. It was desired.
Figure JPOXMLDOC01-appb-I000024
Figure JPOXMLDOC01-appb-I000024
　［Ｓｃｈｅｍｅ ４中、ｐ、Ｒ1、Ｙ及び環Ａは、後述する本発明の第１の態様中に定義されている基と同じ基である］ [In Scheme 4, p, R 1 , Y and ring A are the same groups as those defined in the first embodiment of the present invention described later]
　下記（Ｓｃｈｅｍｅ ５）に示されるように、式（ＡＭ－Ｘ）で表わされる化合物の合成中間体になり得る式（ＥＰ－１）で表わされる化合物の合成法が、Chemistry Letters,(11),P2231-4,1992年（非特許文献１）、又はBulletin of the Chemical Society of Japan,67(8),p2248-56,1994年（非特許文献２）に開示されている。しかし、当該合成法は、酸素ガス、マンガン触媒を用いた酸化反応であり大量合成に好適ではなく、更に、化学収率が３５％と低く、光学純度も６３％と医薬品原料として用いるには低いことから、式（ＡＭ－Ｘ）で表わされる化合物の大量合成もしくは工業的生産においては、本反応条件は用いられない。又、式（ＥＰ－１）を用いた式（ＡＭ－Ｘ）への不斉アミノヒドロキシル化反応は、知られていない。（但し、前記式（ＡＭ－Ｘ）、（ＥＰ－１）、及び式（ＲＥＰ－１）においてｐ＝０である） As shown in (Scheme 5) below, the synthesis method of the compound represented by Formula (EP-1), which can be a synthetic intermediate of the compound represented by Formula (AM-X), is Chemistry® Letters, (11), P2231-4, 1992 (Non-patent document 1), or Bulletin of the Chemical Society of Japan, 67 (8), p2248-56, 1994 (Non-patent document 2). However, the synthesis method is an oxidation reaction using oxygen gas and a manganese catalyst and is not suitable for mass synthesis. Furthermore, the chemical yield is as low as 35% and the optical purity is as low as 63% for use as a pharmaceutical raw material. Therefore, this reaction condition is not used in mass synthesis or industrial production of the compound represented by the formula (AM-X). Also, an asymmetric aminohydroxylation reaction to formula (AM-X) using formula (EP-1) is not known. (However, p = 0 in the formulas (AM-X), (EP-1), and (REP-1))
Figure JPOXMLDOC01-appb-I000025
尚、本発明の式（ＴＨ－１）で表わされる化合物とは異なるが、式（ＴＨ－２）で表わされる化合物（式（ＴＨ－１）において、Ｐ＝０、１，２－ジヒドロナフタレン環の１位のジメチル基を除去した化合物）に対して、過酸化水素及びチタン触媒を用いる酸化反応が、Synlett,20,p3545-3547,2006年（非特許文献３）、又はSynlett,15,p2445-2447,2007年（非特許文献４）に開示されている（Ｓｃｈｅｍｅ　６）。
Figure JPOXMLDOC01-appb-I000025
Although different from the compound represented by the formula (TH-1) of the present invention, the compound represented by the formula (TH-2) (in the formula (TH-1), P = 0, 1,2-dihydronaphthalene ring The compound from which the dimethyl group at the 1-position was removed) was oxidized using hydrogen peroxide and a titanium catalyst in Synlett, 20, p3545-3547, 2006 (Non-patent Document 3), or Synlett, 15, p2445 -2447, 2007 (Non-patent Document 4) (Scheme 6).
Figure JPOXMLDOC01-appb-I000026
Figure JPOXMLDOC01-appb-I000026
国際公開第２０１８／１９９１６６号パンフレットInternational Publication No. 2018/1991166 Pamphlet 国際公開第２０１４／０７８４５４号パンフレットInternational Publication No. 2014/078454 Pamphlet
　式（Ｉ）で表されるテトラヒドロナフチルウレア誘導体の大量合成もしくは工業的生産に適した効率的な製造方法、とりわけ、当該誘導体の大量合成もしくは工業的生産するにあたり、前記式（ＲＡＭ－２）で表される化合物の分別再結晶法を経由する式（Ｉ）で表される化合物の製造方法とは異なる、即ち、式（ＡＭ－Ｘ）で表される化合物を用いる、式（Ｉ）で表される化合物の新規な製造方法の提供、及び式（ＡＭ－Ｘ）で表される化合物を高化学収率かつ高光学純度で大量合成する製造方法の提供を目的とする。 An efficient production method suitable for mass synthesis or industrial production of a tetrahydronaphthylurea derivative represented by the formula (I), particularly for mass synthesis or industrial production of the derivative, the formula (RAM-2) Different from the production method of the compound represented by the formula (I) through the fractional recrystallization method of the represented compound, that is, using the compound represented by the formula (AM-X), represented by the formula (I) It is an object of the present invention to provide a novel production method of the compound and a production method for synthesizing a large amount of the compound represented by the formula (AM-X) with high chemical yield and high optical purity.
　本発明者らは、上記の課題を解決すべく、鋭意研究を重ねてきた。その結果、下記（Ｓｃｈｅｍｅ　７）にて、式（ＴＨ－１）で表される化合物を出発物質とし、過酸化水素を酸素源とする、チタン触媒を用いる、不斉エポキシ化反応を行うことで、式（ＥＰ－１）で表わされる望む立体配置を有するエポキシ化合物を高化学収率かつ高光学純度で得られることを見出した。又、続く、アミノヒドロキシル化反応により式（ＡＭ－Ｘ）で表される化合物を、高化学収率かつ高光学純度で得られることを見出した。これら連続する反応により、式（ＡＭ－Ｘ）の化合物の異性体の生成を抑制できた、式（ＡＭ－Ｘ）の化合物の製造方法を見出した。更に、式（ＡＭ－１）で表されるアミノ化合物から導かれる式（ＣＢ－１）の化合物とのウレア化反応により、化学収率良く、高い光学純度で、短工程にて、かつ容易に下記式（Ｉ）で表されるテトラヒドロナフチルウレア誘導体を製造する方法を見出し、これら知見に基づいて本発明を完成するに至った。 The present inventors have conducted intensive research to solve the above problems. As a result, in the following (Scheme 7), by performing an asymmetric epoxidation reaction using a titanium catalyst using a compound represented by the formula (TH-1) as a starting material and hydrogen peroxide as an oxygen source. The present inventors have found that an epoxy compound having a desired configuration represented by the formula (EP-1) can be obtained with high chemical yield and high optical purity. Further, it has been found that the compound represented by the formula (AM-X) can be obtained with high chemical yield and high optical purity by the subsequent aminohydroxylation reaction. The present inventors have found a process for producing a compound of formula (AM-X), which can suppress the formation of an isomer of the compound of formula (AM-X) by these successive reactions. Furthermore, by a urea reaction with the compound of the formula (CB-1) derived from the amino compound represented by the formula (AM-1), the chemical yield is high, the optical purity is high, and the process is easy and easy. A method for producing a tetrahydronaphthylurea derivative represented by the following formula (I) has been found, and the present invention has been completed based on these findings.
Figure JPOXMLDOC01-appb-I000027
Figure JPOXMLDOC01-appb-I000027
［Ｓｃｈｅｍｅ ７中、ｐ、Ｒ1、Ｙは及び環Ａは、後述する本発明の第１の態様中に定義されている基と同じ基である］ [In Scheme 7, p, R 1 , Y and ring A are the same groups as defined in the first embodiment of the present invention described later]
　本明細書において環Ａの構造は下記式：５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である。
Figure JPOXMLDOC01-appb-I000028
In this specification, the structure of ring A is the following formula: 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group.
Figure JPOXMLDOC01-appb-I000028
　本発明は、式（Ｉ）で表されるトロポミオシン受容体キナーゼＡ（ＴｒｋＡ）阻害作用を有するテトラヒドロナフチルウレア誘導体の製造方法、及び式（ＡＭ－Ｘ）で表される（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オール誘導体の高収率かつ高光学純度で大量合成する製造方法に関する。本発明は、下記式（Ｉ）で表されるトロポミオシン受容体キナーゼＡ（ＴｒｋＡ）阻害作用を有するテトラヒドロナフチルウレア誘導体の製造に使用される中間体を、化学収率良く、高い光学活性純度で、短工程、容易、かつ工業的に有利な方法で製造する新規な方法を提供することができ、産業上の有用性が高い。 The present invention relates to a method for producing a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by formula (I), and (1R, 2R) -1 represented by formula (AM-X) The present invention relates to a production method for synthesizing a large amount of amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol derivative with high yield and high optical purity. The present invention provides an intermediate used for the production of a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) with a good chemical yield and high optical activity purity. It is possible to provide a novel method for producing by a short process, an easy and industrially advantageous method, and the industrial utility is high.
　本発明は、以下の態様に示される下記式（Ｉ）で表されるテトラヒドロナフチルウレア誘導体、式（ＡＭ－Ｘ）で表される（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オール誘導体、及び式（ＥＰ－１）で表されるエポキシ誘導体の製造方法に関する。より具体的に、本発明の例示的な態様は、以下の〔１〕～〔５〕のとおりであり得る。 The present invention relates to a tetrahydronaphthyl urea derivative represented by the following formula (I) shown in the following embodiment, (1R, 2R) -1-amino-4,4-dimethyl- The present invention relates to a method for producing a 1,2,3,4-tetrahydronaphthalen-2-ol derivative and an epoxy derivative represented by the formula (EP-1). More specifically, exemplary embodiments of the present invention can be as described in [1] to [5] below.
〔１〕下記（Ｓｃｈｅｍｅ ７）中［（Ｓｃｈｅｍｅ ７）中、ｐ、Ｒ1、Ｙ、及び環Ａは、後述する本発明の第１の態様中に定義されている基と同じ基であり；各工程の反応条件は、後述する本発明の第１の態様中の各工程の反応条件と同じである］の、式（Ｉ）で表される化合物の製造方法。 [1] In the following (Scheme 7) [in (Scheme 7), p, R 1 , Y and ring A are the same groups as those defined in the first embodiment of the present invention described later]; The reaction conditions for each step are the same as the reaction conditions for each step in the first embodiment of the present invention, which will be described later.] A method for producing a compound represented by formula (I).
Figure JPOXMLDOC01-appb-I000029
Figure JPOXMLDOC01-appb-I000029
〔２〕下記（Ｓｃｈｅｍｅ ８）中［（Ｓｃｈｅｍｅ ８）中、ｐ及びＲ1は、後述する本発明の第２の態様中に定義されている基と同じ基であり；各工程の反応条件は、後述する本発明の第２の態様中の各工程の反応条件と同じである］の、式（ＡＭ－Ｘ）で表される化合物の製造方法。 [2] In the following (Scheme 8) [in (Scheme 8), p and R 1 are the same groups as those defined in the second embodiment of the present invention to be described later; , Which is the same as the reaction conditions for each step in the second embodiment of the present invention to be described later].
Figure JPOXMLDOC01-appb-I000030
Figure JPOXMLDOC01-appb-I000030
〔３〕下記（Ｓｃｈｅｍｅ ９）中［（Ｓｃｈｅｍｅ ９）中、ｐ、及びＲ1は、後述する本発明の第３の態様中に定義されている基と同じ基であり；各工程の反応条件は、後述する本発明の第３の態様中の各工程の反応条件と同じである］の、式（ＥＰ－１）で表される化合物の製造方法。 [3] In the following (Scheme 9) [in (Scheme 9), p and R 1 are the same groups as those defined in the third embodiment of the present invention described later; reaction conditions for each step Is the same as the reaction conditions in each step in the third embodiment of the present invention described later]. A method for producing a compound represented by the formula (EP-1)
Figure JPOXMLDOC01-appb-I000031
Figure JPOXMLDOC01-appb-I000031
〔４〕下記（Ｓｃｈｅｍｅ １０）中［（Ｓｃｈｅｍｅ １０）中、ｐ及びＲ1は、後述する本発明の第４の態様中に定義されている基と同じ基であり；各工程の反応条件は、後述する本発明の第４の態様中の各工程の反応条件と同じである］の、式（ＡＭ－Ｘ）で表される化合物の製造方法。 [4] In the following (Scheme 10) [in (Scheme 10), p and R 1 are the same groups as those defined in the fourth embodiment of the present invention to be described later; , Which is the same as the reaction conditions for each step in the fourth embodiment of the present invention to be described later].
Figure JPOXMLDOC01-appb-I000032
Figure JPOXMLDOC01-appb-I000032
〔５〕下記（Ｓｃｈｅｍｅ ４）中［（Ｓｃｈｅｍｅ ４）中、ｐ、Ｒ1、Ｙ及び環Ａは、後述する本発明の第５の態様中に定義されている基と同じ基であり；各工程の反応条件は、後述する本発明の第５の態様中の各工程の反応条件と同じである］の、式（Ｉ）で表される化合物の製造方法。 [5] In the following (Scheme 4) [in (Scheme 4), p, R 1 , Y and ring A are the same groups as those defined in the fifth embodiment of the present invention described later; The reaction conditions for the step are the same as the reaction conditions for each step in the fifth embodiment of the present invention described later]. A method for producing a compound represented by formula (I).
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000033
［本発明の態様］
　本発明の例示的な態様は、より具体的には、以下の態様［１］～［５］のとおりであり得る。
［１］本発明の第１の態様は、下記式（Ｉ）： [Aspect of the Invention]
More specifically, exemplary embodiments of the present invention may be as described in the following embodiments [1] to [5].
[1] A first aspect of the present invention is the following formula (I):
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-I000034
［式（Ｉ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表される化合物の製造方法であって、以下の工程：
（１）下記式（ＴＨ－１）： [In the formula (I), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group; C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di C 2- 7 a substituent selected from an alkanoylamino group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps:
(1) The following formula (TH-1):
Figure JPOXMLDOC01-appb-I000035
Figure JPOXMLDOC01-appb-I000035
［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物と、チタン触媒（例えば、四塩化チタン、四臭化チタン、チタンアルコキシド（チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド（Ti(OCH2CH2CH3)4）、チタンテトライソプロポキシド（Ti(OCH(CH3)2)4）、チタンテトラノルマルブトキシド（Ti(OCH2CH2CH2CH3)4）、チタンテトラターシャリーブトキシド（Ti(OC(CH3)3)4）、等）と、配位子としての下記式（ＬＧ－１）： [In the formula (TH-1), p and R 1 are as defined in the formula (I)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide, titanium Alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), titanium tetra Normal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 , etc.) and the following formula (LG-1) as a ligand ):
Figure JPOXMLDOC01-appb-I000036
Figure JPOXMLDOC01-appb-I000036
である、３，３’’－（（（（１Ｒ，２Ｒ）－シクロヘキサン－１，２－ジイル）ビス（アザネジル））ビス（メチレン））ビス（２’－メトキシ－［１，１’－ビフェニル］－２－オール）［ＣＡＳ番号：９２８７６９－１２－４］と、過酸化水素水（例えば、約３０～６０％濃度）と、緩衝液（例えば、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液、トリス（ヒドロキシメチル）アミノメタン（Ｔｒｉｓ）／ＨＣｌ緩衝液、ホウ酸／ＮａＯＨ緩衝液、ホウ酸Ｎａ／ＨＣｌ緩衝液、等）とを、溶媒（例えば、反応に関与しない溶媒、好ましくは有機溶媒、より好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等ニトリル系溶媒）中に加えて混合溶液（１）を得る工程、（２）前記混合溶液（１）を、反応温度（外温）３０℃～５０℃の範囲、好ましくは、３５～４５℃の範囲の温度で反応を行い、下記式（ＥＰ－１）： 3,3 ″-(((((1R, 2R) -cyclohexane-1,2-diyl) bis (azanezyl)) bis (methylene)) bis (2′-methoxy- [1,1′-biphenyl] -2-ol) [CAS number: 926769-12-4], hydrogen peroxide (for example, about 30 to 60% concentration), and buffer (for example, citric acid / NaOH buffer, citric acid / citrate). Sodium phosphate buffer, phosphate buffer, KH 2 PO 4 / NaOH buffer, tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ) And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.) A basic solvent, an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile) to obtain a mixed solution (1), (2) The mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
Figure JPOXMLDOC01-appb-I000037
Figure JPOXMLDOC01-appb-I000037
［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物を得る工程、（３）前記式（ＥＰ－１）で表される化合物をアンモニア水に加え、前記式（ＥＰ－１）で表される化合物とアンモニア水とを含む混合溶液（３）を得る工程、（４）前記混合溶液（３）を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＡＭ－Ｘ）： [In the formula (EP-1), p and R 1 are the same as defined in the formula (I)], (3) represented by the formula (EP-1) A step of obtaining a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia, and (4) the mixed solution (3) from 0 ° C. The reaction is performed at any temperature up to the temperature at which the mixed solution (3) is refluxed, and the following formula (AM-X):
Figure JPOXMLDOC01-appb-I000038
Figure JPOXMLDOC01-appb-I000038
［式（ＡＭ－Ｘ）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物を得る工程、
（５）下記式（ＡＭ－１）： [In the formula (AM-X), p and R 1 are as defined in the formula (I)] to obtain a compound represented by the formula:
(5) The following formula (AM-1):
Figure JPOXMLDOC01-appb-I000039
Figure JPOXMLDOC01-appb-I000039
［式（ＡＭ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表わされる化合物と、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、２，２，２－トリクロロエチルクロロホルメート、クロロギ酸フェニル、クロロギ酸ｐ－ニトロフェニル、クロロギ酸ｐ－トリル、Ｎ，Ｎ´－カルボニルジイミダゾール、及びＮ，Ｎ´－ジスクシンイミジルカルボナート等から選ばれるウレア化剤と、塩基とを、溶媒に加えて混合溶液（５）を得る工程、（６）前記混合溶液（５）を、０℃から前記混合溶液（５）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＣＢ－１）： [Wherein ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group], triphosgene, Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N ′ A step of adding a urea agent selected from disuccinimidyl carbonate and the like and a base to a solvent to obtain a mixed solution (5), (6) the mixed solution (5) from 0 ° C. to the mixed solution The reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
Figure JPOXMLDOC01-appb-I000040
Figure JPOXMLDOC01-appb-I000040
［式（ＣＢ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基であり；Ｙは、トリクロロメトキシ基、塩素原子、２，２，２－トリクロロエトキシ基、フェノキシ基、ｐ－ニトロフェノキシ基、ｐ－メチルフェノキシ基、イミダゾール－１－イル基、（２，５－ジオキソピロリジン－１－イル）オキシ基、等から選ばれる基である］で表わされる化合物を得る工程、（７）前記工程（４）で得られる式（ＡＭ－Ｘ）で表わされる化合物と、前記式（ＣＢ－１）で表わされる化合物と、塩基とを、溶媒に加えて混合溶液（７）を得る工程、及び
（８）前記混合溶液（７）を、０℃から前記混合溶液（７）が還流する温度までの間のいずれかの温度で反応を行い、式（Ｉ）で表される化合物を得る工程、を含む製造方法である。
　ここで、上記式（ＡＭ－１）は、以下に示す５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－アミンである。 [In Formula (CB-1), Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, (7) a compound represented by the formula (AM-X) obtained in the step (4), and a compound represented by the formula (CB-1). And a base are added to a solvent to obtain a mixed solution (7), and (8) the mixed solution (7) is any one of from 0 ° C. to a temperature at which the mixed solution (7) is refluxed. The reaction is carried out at a temperature of To obtain a compound, a production method including a.
Here, the formula (AM-1) is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine shown below.
Figure JPOXMLDOC01-appb-I000041
Figure JPOXMLDOC01-appb-I000041
［１－１－１］前記態様［１］の工程（１）において、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、好ましくは、１．５～１０等量の範囲であり；より好ましくは、１．５～５等量の範囲であり；特に好ましくは、１．５又は５．０等量である。ここで、「等量」とは、モル比で１：１であることを意味する。即ち、式（ＴＨ－１）１等量に対して、過酸化水素水の量が１．５～１０等量の場合は、過酸化水素水の量が、モル比で１：１．５～１：１０を意味する。 [1-1-1] In the step (1) of the embodiment [1], the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents. Here, “equivalent” means that the molar ratio is 1: 1. That is, when the amount of the hydrogen peroxide solution is 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1), the amount of the hydrogen peroxide solution is 1: 1.5 to 1 in molar ratio. It means 1:10.
［１－１－２］前記態様［１］の工程（１）において、過酸化水素水の濃度は、約３０％のものを用いることが好ましい。 [1-1-2] In the step (1) of the embodiment [1], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.
［１－２－１］前記態様［１］の工程（１）において、チタン触媒は、好ましくは、チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド、チタンテトライソプロポキシド、チタンテトラノルマルブトキシド、又はチタンテトラターシャリーブトキシドであり；より好ましくは、チタンテトライソプロポキシドである。 [1-2-1] In the step (1) of the embodiment [1], the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
［１－２－２］前記態様［１］の工程（１）において、チタン触媒の量は、好ましくは、式（ＴＨ－１）に対し０．１～１０ｍｏｌ％の範囲であり；より好ましくは１．０～５．０ｍｏｌ％の範囲であり；特に好ましくは、１．０、３．０、又は５．０ｍｏｌ％である。 [1-2-2] In the step (1) of the embodiment [1], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
［１－３］前記態様［１］の工程（１）において、配位子は、式（ＴＨ－１）に対して、好ましくは、０．１～１２ｍｏｌ％の範囲であり；より好ましくは１．２～６．０ｍｏｌ％の範囲であり；特に好ましくは、１．２、３．６、又は６．０ｍｏｌ％である。 [1-3] In the step (1) of the embodiment [1], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
［１－４］前記態様［１］の工程（１）において、溶媒は、好ましくは反応に関与しない溶媒であり、より好ましくは、有機溶媒であり、さらに好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒であり；より好ましくは、ジクロロメタンである。 [1-4] In the step (1) of the embodiment [1], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane. A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
［１－５］前記態様［１］の工程（１）において、溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、好ましくは、１～２０倍量の範囲であり；より好ましくは、５～２０倍量の範囲であり；特に好ましくは、５又は２０倍量である。 [1-5] In the step (1) of the embodiment [1], the amount of the solvent (the solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
［１－６－１］前記態様［１］の工程（１）において、緩衝液は、好ましくは、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、ホウ酸／ＮａＯＨ緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；より好ましくは、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；特に好ましくはリン酸緩衝液である。当該緩衝液によって、反応溶液等のｐＨを調製することができる。
［１－６－２］前記態様［１］の工程（１）において、反応溶液のｐＨは、好ましくは、ｐＨ＝７．４～８．０であり；より好ましくは、ｐＨ＝７．４、又はｐＨ＝８．０である。 [1-6-1] In the step (1) of the embodiment [1], the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus An acid buffer, KH 2 PO 4 / NaOH buffer; more preferably a phosphate buffer, KH 2 PO 4 / NaOH buffer; particularly preferably a phosphate buffer. The pH of the reaction solution can be adjusted with the buffer solution.
[1-6-2] In the step (1) of the embodiment [1], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably, pH = 7.4, Or pH = 8.0.
［１－７－１］前記態様［１］の工程（２）において、反応時間は、好ましくは、２０時間以下であり；より好ましくは４．０時間以下である。 [1-7-1] In the step (2) of the embodiment [1], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
［１－８－１］前記態様［１］の工程（４）の反応は、好ましくは、封管反応瓶を用いる封管反応である。 [1-8-1] The reaction in the step (4) of the embodiment [1] is preferably a sealed tube reaction using a sealed tube reaction bottle.
［１－８－２］前記態様［１－８－１］の封管反応の反応温度は、好ましくは、１００℃である。 [1-8-2] The reaction temperature of the sealed tube reaction of the embodiment [1-8-1] is preferably 100 ° C.
［１－８－３］前記態様［１－８－１］の封管反応の好ましい反応時間は２時間である。 [1-8-3] The preferred reaction time for the sealed tube reaction of the embodiment [1-8-1] is 2 hours.
［１－９］前記態様［１］の工程（５）において、ウレア化剤は、好ましくは、クロロギ酸フェニル、クロロギ酸ｐ－トリル、又は２，２，２－トリクロロエチルクロロホルメートであり；より好ましくは、２，２，２－トリクロロエチルクロロホルメートである。 [1-9] In the step (5) of the embodiment [1], the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
［１－１０］前記態様［１］の工程（５）において、塩基は、好ましくは、ピリジン、トリエチルアミン、又はＮ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、等の有機塩基、炭酸水素ナトリウム、炭酸ナトリウム、又は炭酸カリウム等の無機塩基、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、等の金属アルコキシド、水素化ナトリウム、水素化カリウム、又は水素化カルシウム等の水素化金属化合物、メチルリチウム、又はブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド、又はリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物等であり；より好ましくは、ピリジンである。 [1-10] In step (5) of the embodiment [1], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen A metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
［１－１１］前記態様［１］の工程（５）において、溶媒は、好ましくは、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチルピロリドン、又はアセトニトリル、等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン、又は１，４－ジオキサン等のエーテル系溶媒、酢酸エチル、又は酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム、又は１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒等であり；より好ましくは、１，２－ジクロロエタンである。 [1-11] In the step (5) of the embodiment [1], the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; 1,2-dichloroethane is more preferable.
［１－１２］前記態様［１］の工程（６）において、式（ＣＢ－１）中のＹは、好ましくは、フェノキシ基、ｐ－メチルフェノキシ基、又は２，２，２－トリクロロエトキシ基であり；より好ましくは、２，２，２－トリクロロエトキシ基である。 [1-12] In the step (6) of the embodiment [1], Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
［１－１３］前記態様［１］の工程（７）において、溶媒は、好ましくは、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチルピロリドン、又はアセトニトリル、等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン、又は１，４－ジオキサン等のエーテル系溶媒、酢酸エチル、又は酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム、又は１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒等であり；より好ましくは、Ｎ－メチルピロリドン及びジメチルスルホキシドである。 [1-13] In the step (7) of the embodiment [1], the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like N-methylpyrrolidone and dimethyl sulfoxide are more preferable.
［１－１４］前記態様［１］の工程（７）において、塩基は、好ましくは、ピリジン、トリエチルアミン、又はＮ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、等の有機塩基、炭酸水素ナトリウム、炭酸ナトリウム、又は炭酸カリウム等の無機塩基、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、等の金属アルコキシド、水素化ナトリウム、水素化カリウム、又は水素化カルシウム等の水素化金属化合物、メチルリチウム、又はブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド、又はリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物等であり；より好ましくは、トリエチルアミン及び１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）である。 [1-14] In the step (7) of the embodiment [1], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen A metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably triethylamine And 1,8-diazabicyclo 5.4.0] -7-undecene (DBU).
［１－１５］前記態様［１］の各式中において、ｐは、好ましくは、０または１の整数であり、より好ましくは０の整数である。 [1-15] In each formula of the embodiment [1], p is preferably an integer of 0 or 1, more preferably an integer of 0.
［１－１６］前記態様［１］の各式中において、Ｒ1は、好ましくは、ハロゲン原子、ヒドロキシＣ1-6アルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；より好ましくは、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり；更に好ましくは、水素原子、フッ素原子、臭素原子、又はメトキシメチル基から選ばれる置換基が１～２個置換しても良く；特に好ましくは、無置換である。 [1-16] In each formula of the above embodiment [1], R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
［１－１７］前記態様［１］の各式中において、Ｒ1の置換様式は、好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式（ＰＨ－１）ないし式（ＰＨ－４）で表わされる置換様式をとり；
Figure JPOXMLDOC01-appb-I000042
２個の置換基がＲ1によって置換する場合の部分構造式は、下記部分構造式（ＰＨ－５）ないし式（ＰＨ－１０））で表わされる置換様式をとり；
Figure JPOXMLDOC01-appb-I000043
より好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式：
Figure JPOXMLDOC01-appb-I000044
で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000045
から選ばれる置換様式をとる。
２個の置換基がＲ1によって置換する場合（ｐ＝２）は、下記部分構造式：
Figure JPOXMLDOC01-appb-I000046
で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000047
の置換様式をとる。 [1-17] In each formula of the embodiment [1], R 1 is preferably substituted in the following partial structural formula (p = 1) when one substituent is substituted by R 1 (p = 1): A substitution mode represented by PH-1) to formula (PH-4);
Figure JPOXMLDOC01-appb-I000042
The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
Figure JPOXMLDOC01-appb-I000043
More preferably, when one substituent is substituted by R 1 (p = 1), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000044
And a more specific combination with a substituent includes the following partial structural formula:
Figure JPOXMLDOC01-appb-I000045
Takes a substitution form selected from
When two substituents are substituted by R 1 (p = 2), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000046
Takes the substitution form represented by;
More specific combinations with substituents include the following partial structural formulas:
Figure JPOXMLDOC01-appb-I000047
Take the replacement form.
［１－１８］前記態様［１］の工程（１）において、好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、１．５～５等量の範囲であり；チタン触媒の量は、式（ＴＨ－１）に対して、１．０～５．０ｍｏｌ％の範囲であり；配位子は、式（ＴＨ－１）に対して、１．２～６．０ｍｏｌ％の範囲であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、５～２０倍量の範囲であり；反応溶液のｐＨは、ｐＨ＝７．４～８．０であり；反応時間は、２０時間以下である。 [1-18] In the step (1) of the embodiment [1], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1). The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (a solvent not involved in the reaction) is dichloromethane; the solvent (reaction) The amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; The time is 20 hours or less.
［１－１９］前記態様［１］の工程（１）において、より好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対し、１．５又は５．０等量であり；チタン触媒の量は式（ＴＨ－１）に対し、１．０又は３．０ｍｏｌ％であり；配位子は、式（ＴＨ－１）に対して、１．２又は３．６ｍｏｌ％であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、５倍量であり；反応溶液のｐＨは、ｐＨ＝７．４又はｐＨ＝８．０であり；反応時間は、４時間以下である。 [1-19] In the step (1) of the embodiment [1], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1) The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction). The amount is 5 times; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.
［２］本発明の第２の態様は、下記式（ＡＭ－Ｘ）： [2] A second aspect of the present invention is the following formula (AM-X):
Figure JPOXMLDOC01-appb-I000048
Figure JPOXMLDOC01-appb-I000048
［式（ＡＭ－Ｘ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
（１）下記式（ＴＨ－１）： [In the formula (AM-X), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):
Figure JPOXMLDOC01-appb-I000049
Figure JPOXMLDOC01-appb-I000049
［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物と、チタン触媒（例えば、四塩化チタン、四臭化チタン、チタンアルコキシド（チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド（Ti(OCH2CH2CH3)4）、チタンテトライソプロポキシド（Ti(OCH(CH3)2)4）、チタンテトラノルマルブトキシド（Ti(OCH2CH2CH2CH3)4）、チタンテトラターシャリーブトキシド（Ti(OC(CH3)3)4）、等）と、配位子としての下記式（ＬＧ－１）： [In the formula (TH-1), p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
Figure JPOXMLDOC01-appb-I000050
Figure JPOXMLDOC01-appb-I000050
である、３，３’’－（（（（１Ｒ，２Ｒ）－シクロヘキサン－１，２－ジイル）ビス（アザネジル））ビス（メチレン））ビス（２’－メトキシ－［１，１’－ビフェニル］－２－オール）［ＣＡＳ番号：９２８７６９－１２－４］と、過酸化水素水（例えば、約３０～６０％濃度）と、緩衝液（例えば、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液、トリス（ヒドロキシメチル）アミノメタン（Ｔｒｉｓ）／ＨＣｌ緩衝液、ホウ酸／ＮａＯＨ緩衝液、ホウ酸Ｎａ／ＨＣｌ緩衝液、等）とを、溶媒（例えば、反応に関与しない溶媒、好ましくは有機溶媒、より好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等ニトリル系溶媒）中に加えて混合溶液（１）を得る工程、
（２）前記混合溶液（１）を、反応温度（外温）３０℃～５０℃の範囲、好ましくは、３５～４５℃の範囲の温度で反応を行い、下記式（ＥＰ－１）： 3,3 ″-(((((1R, 2R) -cyclohexane-1,2-diyl) bis (azanezyl)) bis (methylene)) bis (2′-methoxy- [1,1′-biphenyl] -2-ol) [CAS number: 926769-12-4], hydrogen peroxide (for example, about 30 to 60% concentration), and buffer (for example, citric acid / NaOH buffer, citric acid / citrate). Sodium phosphate buffer, phosphate buffer, KH 2 PO 4 / NaOH buffer, tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ) And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.) A basic solvent, an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile) to obtain a mixed solution (1),
(2) The mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
Figure JPOXMLDOC01-appb-I000051
Figure JPOXMLDOC01-appb-I000051
［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物を得る工程、
（３）前記式（ＥＰ－１）で表される化合物をアンモニア水に加え、前記式（ＥＰ－１）で表される化合物とアンモニア水とを含む混合溶液を得る工程、及び
（４）前記混合溶液を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、式（ＡＭ－Ｘ）で表される化合物を得る工程、を含む製造方法である。 [In the formula (EP-1), p and R 1 are as defined in the formula (AM-X)] to obtain a compound represented by the formula:
(3) adding a compound represented by the formula (EP-1) to aqueous ammonia to obtain a mixed solution containing the compound represented by the formula (EP-1) and aqueous ammonia; and (4) Reacting the mixed solution at any temperature between 0 ° C. and the temperature at which the mixed solution (3) is refluxed to obtain a compound represented by the formula (AM-X). is there.
［２－１－１］前記態様［２］の工程（１）において、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、好ましくは、１．５～１０等量の範囲であり；より好ましくは、１．５～５等量の範囲であり；特に好ましくは、１．５又は５．０等量である。 [2-1-1] In the step (1) of the embodiment [2], the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
［２－１－２］前記態様［２］の工程（１）において、過酸化水素水の濃度は、約３０％のものを用いることが好ましい。 [2-1-2] In the step (1) of the embodiment [2], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.
［２－２－１］前記態様［２］の工程（１）において、チタン触媒は、好ましくは、チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド、チタンテトライソプロポキシド、チタンテトラノルマルブトキシド、又はチタンテトラターシャリーブトキシドであり；より好ましくは、チタンテトライソプロポキシドである。 [2-2-1] In the step (1) of the embodiment [2], the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
［２－２－２］前記態様［２］の工程（１）において、チタン触媒の量は、好ましくは、式（ＴＨ－１）に対し０．１～１０ｍｏｌ％の範囲であり；より好ましくは１．０～５．０ｍｏｌ％の範囲であり；特に好ましくは、１．０、３．０、又は５．０ｍｏｌ％である。 [2-2-2] In the step (1) of the embodiment [2], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
［２－３］前記態様［２］の工程（１）において、配位子は、式（ＴＨ－１）に対して、好ましくは、０．１～１２ｍｏｌ％の範囲であり；より好ましくは１．２～６．０ｍｏｌ％の範囲であり；特に好ましくは、１．２、３．６、又は６．０ｍｏｌ％である。 [2-3] In the step (1) of the embodiment [2], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
［２－４］前記態様［２］の工程（１）において、溶媒は、好ましくは反応に関与しない溶媒であり、より好ましくは、有機溶媒であり、さらに好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒であり；より好ましくは、ジクロロメタンである。 [2-4] In step (1) of the embodiment [2], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane. A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
［２－５］前記態様［２］の工程（１）において、溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、好ましくは、１～２０倍量の範囲であり；より好ましくは、５～２０倍量の範囲であり；特に好ましくは、５又は２０倍量である。 [2-5] In the step (1) of the embodiment [2], the amount of the solvent (the solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
［２－６－１］前記態様［２］の工程（１）において、緩衝液は、好ましくは、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、ホウ酸／ＮａＯＨ緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；より好ましくは、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；特に好ましくはリン酸緩衝液である。当該緩衝液によって、反応溶液等のｐＨを調製することができる。 [2-6-1] In the step (1) of the embodiment [2], the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus An acid buffer, KH 2 PO 4 / NaOH buffer; more preferably a phosphate buffer, KH 2 PO 4 / NaOH buffer; particularly preferably a phosphate buffer. The pH of the reaction solution can be adjusted with the buffer solution.
［２－６－２］
前記態様［２］の工程（１）において、反応溶液のｐＨは、好ましくは、ｐＨ＝７．４～８．０であり；より好ましくは、ｐＨ＝７．４、又はｐＨ＝８．０である。 [2-6-2]
In step (1) of the embodiment [2], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably pH = 7.4 or pH = 8.0. is there.
［２－７］前記態様［２］の工程（２）において、反応時間は、好ましくは、２０時間以下であり；より好ましくは４．０時間以下である。 [2-7] In the step (2) of the embodiment [2], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
［２－８－１］前記態様［２］の工程（２）の反応は、好ましくは、封管反応瓶を用いる封管反応である。 [2-8-1] The reaction in the step (2) of the embodiment [2] is preferably a sealed tube reaction using a sealed tube reaction bottle.
［２－８－２］前記態様［２－８－１］の封管反応の反応温度は、好ましくは、１００℃である。 [2-8-2] The reaction temperature of the sealed tube reaction in the above embodiment [2-8-1] is preferably 100 ° C.
［２－８－３］前記態様［２－８－１］の封管反応の好ましい反応時間は２時間である。 [2-8-3] The preferred reaction time for the sealed tube reaction of the above embodiment [2-8-1] is 2 hours.
［２－９］前記態様［２］の各式中において、ｐは、好ましくは、０または１の整数であり、より好ましくは０の整数である。 [2-9] In each formula of the above embodiment [2], p is preferably an integer of 0 or 1, more preferably an integer of 0.
［２－１０］前記態様［２］の各式中において、Ｒ1は、好ましくは、ハロゲン原子、ヒドロキシＣ1-6アルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；より好ましくは、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり；更に好ましくは、水素原子、フッ素原子、臭素原子、又はメトキシメチル基から選ばれる置換基が１～２個置換しても良く；特に好ましくは、無置換である。 [2-10] In each formula of the embodiment [2], R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
［２－１１］前記態様［２］の各式中において、Ｒ1の置換様式は、好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式（ＰＨ－１）ないし式（ＰＨ－４）で表わされる置換様式をとり； [2-11] In each formula of the embodiment [2], the substitution pattern of R 1 is preferably the following partial structural formula (p = 1) when one substituent is substituted by R 1 (p = 1): A substitution mode represented by PH-1) to formula (PH-4);
Figure JPOXMLDOC01-appb-I000052
Figure JPOXMLDOC01-appb-I000052
２個の置換基がＲ1によって置換する場合の部分構造式は、下記部分構造式（ＰＨ－５）ないし式（ＰＨ－１０））で表わされる置換様式をとり； The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
Figure JPOXMLDOC01-appb-I000053
Figure JPOXMLDOC01-appb-I000053
より好ましくは、置換基が１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式： More preferably, when one substituent is substituted by R 1 (p = 1), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000054
Figure JPOXMLDOC01-appb-I000054
で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造
式： And a more specific combination with a substituent includes the following partial structural formula:
Figure JPOXMLDOC01-appb-I000055
Figure JPOXMLDOC01-appb-I000055
から選ばれる置換様式をとる。
２個の置換基がＲ1によって置換する場合（ｐ＝２）は、下記部分構造式： Takes a substitution form selected from
When two substituents are substituted by R 1 (p = 2), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000056
Figure JPOXMLDOC01-appb-I000056
で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式： Takes the substitution form represented by;
More specific combinations with substituents include the following partial structural formulas:
Figure JPOXMLDOC01-appb-I000057
の置換様式をとる。
Figure JPOXMLDOC01-appb-I000057
Take the replacement form.
［２－１２］前記態様［２］の工程（１）において、好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、１．５～５等量の範囲であり；チタン触媒の量は、式（ＴＨ－１）に対して、１．０～５．０ｍｏｌ％の範囲であり；配位子は、式（ＴＨ－１）に対して、１．２～６．０ｍｏｌ％の範囲であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、５～２０倍量の範囲であり；反応溶液のｐＨは、ｐＨ＝７．４～８．０であり；反応時間は、２０時間以下である。 [2-12] In the step (1) of the embodiment [2], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1). The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (a solvent not involved in the reaction) is dichloromethane; the solvent (reaction) The amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; The time is 20 hours or less.
［２－１３］前記態様［２］の工程（１）において、より好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対し、１．５又は５．０等量であり；チタン触媒の量は式（ＴＨ－１）に対し、１．０又は３．０ｍｏｌ％であり；配位子は、式（ＴＨ－１）に対して、１．２又は３．６ｍｏｌ％であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、５倍量であり；反応溶液のｐＨは、ｐＨ＝７．４又はｐＨ＝８．０であり；反応時間は、４時間以下である。 [2-13] In the step (1) of the embodiment [2], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1) The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction). The amount is 5 times; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.
［３］発明の第３の態様は、下記式（ＥＰ－１）： [3] A third aspect of the present invention is the following formula (EP-1):
Figure JPOXMLDOC01-appb-I000058
Figure JPOXMLDOC01-appb-I000058
［式（ＥＰ－１）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
（１）下記式（ＴＨ－１）： [In the formula (EP-1), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
(1) The following formula (TH-1):
Figure JPOXMLDOC01-appb-I000059
Figure JPOXMLDOC01-appb-I000059
［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物と、チタン触媒（例えば、四塩化チタン、四臭化チタン、チタンアルコキシド（チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド（Ti(OCH2CH2CH3)4）、チタンテトライソプロポキシド（Ti(OCH(CH3)2)4）、チタンテトラノルマルブトキシド（Ti(OCH2CH2CH2CH3)4）、チタンテトラターシャリーブトキシド（Ti(OC(CH3)3)4）、等）と、配位子としての下記式（ＬＧ－１）： [In the formula (TH-1), p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
Figure JPOXMLDOC01-appb-I000060
Figure JPOXMLDOC01-appb-I000060
である、３，３’’－（（（（１Ｒ，２Ｒ）－シクロヘキサン－１，２－ジイル）ビス（アザネジル））ビス（メチレン））ビス（２’－メトキシ－［１，１’－ビフェニル］－２－オール）［ＣＡＳ番号：９２８７６９－１２－４］と、過酸化水素水（例えば、約３０～６０％濃度）と、緩衝液（例えば、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液、トリス（ヒドロキシメチル）アミノメタン（Ｔｒｉｓ）／ＨＣｌ緩衝液、ホウ酸／ＮａＯＨ緩衝液、ホウ酸Ｎａ／ＨＣｌ緩衝液、等）とを、溶媒（例えば、反応に関与しない溶媒、好ましくは有機溶媒、より好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒、アセトニトリル等ニトリル系溶媒）中に加えて混合溶液（１）を得る工程、（２）前記混合溶液（１）を、反応温度（外温）３０℃～５０℃の範囲、好ましくは、３５～４５℃の範囲の温度で反応を行い、式（ＥＰ－１）で表される化合物を得る工程を含む製造方法である。 3,3 ″-(((((1R, 2R) -cyclohexane-1,2-diyl) bis (azanezyl)) bis (methylene)) bis (2′-methoxy- [1,1′-biphenyl] -2-ol) [CAS number: 926769-12-4], hydrogen peroxide (for example, about 30 to 60% concentration), and buffer (for example, citric acid / NaOH buffer, citric acid / citrate). Sodium phosphate buffer, phosphate buffer, KH 2 PO 4 / NaOH buffer, tris (hydroxymethyl) aminomethane (Tris) / HCl buffer, boric acid / NaOH buffer, Na borate / HCl buffer, etc. ) And a solvent (for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.) A basic solvent, an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile) to obtain a mixed solution (1), (2) The mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and represented by the formula (EP-1) A production method comprising a step of obtaining a compound.
［３－１－１］前記態様［３］の工程（１）において、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、好ましくは、１．５～１０等量の範囲であり；より好ましくは、１．５～５等量の範囲であり；特に好ましくは、１．５又は５．０等量である。 [3-1-1] In the step (1) of the embodiment [3], the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
［３－１－２］前記態様［３］の工程（１）において、過酸化水素水の濃度は、約３０％のものを用いることが好ましい。 [3-1-2] In the step (1) of the embodiment [3], it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.
［３－２－１］前記態様［３］の工程（１）において、チタン触媒は、好ましくは、チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド、チタンテトライソプロポキシド、チタンテトラノルマルブトキシド、又はチタンテトラターシャリーブトキシドであり；より好ましくは、チタンテトライソプロポキシドである。 [3-2-1] In the step (1) of the embodiment [3], the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
［３－２－２］前記態様［３］の工程（１）において、チタン触媒の量は、好ましくは、式（ＴＨ－１）に対し０．１～１０ｍｏｌ％の範囲であり；より好ましくは１．０～５．０ｍｏｌ％の範囲であり；特に好ましくは、１．０、３．０、又は５．０ｍｏｌ％である。 [3-2-2] In the step (1) of the embodiment [3], the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
［３－３］前記態様［３］の工程（１）において、配位子は、式（ＴＨ－１）に対して、好ましくは、０．１～１２ｍｏｌ％の範囲であり；より好ましくは１．２～６．０ｍｏｌ％の範囲であり；特に好ましくは、１．２、３．６、又は６．０ｍｏｌ％である。 [3-3] In the step (1) of the embodiment [3], the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
［３－４］前記態様［３］の工程（１）において、溶媒は、好ましくは反応に関与しない溶媒であり、より好ましくは、有機溶媒であり、さらに好ましくは、ジクロロメタン、１，２－ジクロロエタン、クロロベンゼン、フルオロベンゼン等のハロゲン化炭化水素系溶媒、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン等のエーテル系溶媒であり；より好ましくは、ジクロロメタンである。 [3-4] In the step (1) of the embodiment [3], the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and still more preferably dichloromethane, 1,2-dichloroethane. A halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
［３－５］前記態様［３］の工程（１）において、溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、好ましくは、１～２０倍量の範囲であり；より好ましくは、５～２０倍量の範囲であり；特に好ましくは、５又は２０倍量である。 [3-5] In the step (1) of the embodiment [3], the amount of the solvent (the solvent not involved in the reaction) is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
［３－６－１］前記態様［３］の工程（１）において、緩衝液は、好ましくは、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、ホウ酸／ＮａＯＨ緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；より好ましくは、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり；特に好ましくはリン酸緩衝液である。当該緩衝液によって、反応溶液等のｐＨを調製することができる。 [3-6-1] In the step (1) of the embodiment [3], the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus An acid buffer, KH 2 PO 4 / NaOH buffer; more preferably a phosphate buffer, KH 2 PO 4 / NaOH buffer; particularly preferably a phosphate buffer. The pH of the reaction solution can be adjusted with the buffer solution.
［３－６－２］前記態様［３］の工程（１）において、反応溶液のｐＨは、好ましくは、ｐＨ＝７．４～８．０であり；より好ましくは、ｐＨ＝７．４、又はｐＨ＝８．０である。 [3-6-2] In the step (1) of the embodiment [3], the pH of the reaction solution is preferably pH = 7.4 to 8.0; more preferably pH = 7.4, Or pH = 8.0.
［３－７］前記態様［３］の工程（２）において、反応時間は、好ましくは、２０時間以下であり；より好ましくは４．０時間以下である。 [3-7] In the step (2) of the embodiment [3], the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
［３－８］前記態様［３］の各式中において、ｐは、好ましくは、０または１の整数であり、より好ましくは０の整数である。 [3-8] In each formula of the above embodiment [3], p is preferably an integer of 0 or 1, more preferably an integer of 0.
［３－９］前記態様［３］の各式中において、Ｒ1は、好ましくは、ハロゲン原子、ヒドロキシＣ1-6アルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；より好ましくは、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり；更に好ましくは、水素原子、フッ素原子、臭素原子、又はメトキシメチル基から選ばれる置換基が１～２個置換しても良く；特に好ましくは、無置換である。 [3-9] In each formula of the above embodiment [3], R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
［３－１０］前記態様［３］の各式中において、Ｒ1の置換様式は、好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式（ＰＨ－１）ないし式（ＰＨ－４）で表わされる置換様式をとり； [3-10] In each formula of the embodiment [3], R 1 is preferably substituted in the following partial structural formula (p = 1) when one substituent is substituted by R 1 (p = 1): A substitution mode represented by PH-1) to formula (PH-4);
Figure JPOXMLDOC01-appb-I000061
Figure JPOXMLDOC01-appb-I000061
２個の置換基がＲ1によって置換する場合の部分構造式は、下記部分構造式（ＰＨ－５）ないし式（ＰＨ－１０））で表わされる置換様式をとり； The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
Figure JPOXMLDOC01-appb-I000062
Figure JPOXMLDOC01-appb-I000062
より好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式： More preferably, when one substituent is substituted by R 1 (p = 1), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000063
Figure JPOXMLDOC01-appb-I000063
で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造式： And a more specific combination with a substituent includes the following partial structural formula:
Figure JPOXMLDOC01-appb-I000064
Figure JPOXMLDOC01-appb-I000064
から選ばれる置換様式をとる。
２個の置換基がＲ1によって置換する場合（ｐ＝２）は、下記部分構造式： Takes a substitution form selected from
When two substituents are substituted by R 1 (p = 2), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000065
Figure JPOXMLDOC01-appb-I000065
で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000066
の置換様式をとる。 Takes the substitution form represented by;
More specific combinations with substituents include the following partial structural formulas:
Figure JPOXMLDOC01-appb-I000066
Take the replacement form.
［３－１１］前記態様［３］の工程（１）において、好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対して、１．５～５等量の範囲であり；チタン触媒の量は、式（ＴＨ－１）に対して、１．０～５．０ｍｏｌ％の範囲であり；配位子は、式（ＴＨ－１）に対して、１．２～６．０ｍｏｌ％の範囲であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、式（ＴＨ－１）の質量に対して、５～２０倍量の範囲であり；反応溶液のｐＨは、ｐＨ＝７．４～８．０であり；反応時間は、２０時間以下である。 [3-11] In the step (1) of the embodiment [3], the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1). The amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1). The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (a solvent not involved in the reaction) is dichloromethane; the solvent (reaction) The amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1); the pH of the reaction solution is pH = 7.4 to 8.0; The time is 20 hours or less.
［３－１２］前記態様［３］の工程（１）において、より好ましくは、過酸化水素水の量は、式（ＴＨ－１）１等量に対し、１．５又は５．０等量であり；チタン触媒の量は式（ＴＨ－１）に対し、１．０又は３．０ｍｏｌ％であり；配位子は、式（ＴＨ－１）に対して、１．２又は３．６ｍｏｌ％であり；チタン触媒は、チタンテトライソプロポキシドであり；緩衝液は、リン酸緩衝液であり；溶媒（反応に関与しない溶媒）は、ジクロロメタンであり；溶媒（反応に関与しない溶媒）の量は、５倍量であり；反応溶液のｐＨは、ｐＨ＝７．４又はｐＨ＝８．０であり；反応時間は、４時間以下である。 [3-12] In the step (1) of the embodiment [3], more preferably, the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1). The amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1) The titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction). The amount is 5 times; the pH of the reaction solution is pH = 7.4 or pH = 8.0; the reaction time is 4 hours or less.
［４］本発明の第４の態様は、下記式（ＡＭ－Ｘ）：
Figure JPOXMLDOC01-appb-I000067
[4] A fourth aspect of the present invention is the following formula (AM-X):
Figure JPOXMLDOC01-appb-I000067
［式（ＡＭ－Ｘ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
（３）下記式（ＥＰ－１）： [In the formula (AM-X), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
(3) The following formula (EP-1):
Figure JPOXMLDOC01-appb-I000068
Figure JPOXMLDOC01-appb-I000068
［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物をアンモニア水に加え、前記式（ＥＰ－１）で表される化合物とアンモニア水とを含む混合溶液（３）を得る工程、及び
（４）前記混合溶液（３）を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、式（ＡＭ－Ｘ）で表される化合物を得る工程、を含む製造方法である。 [In the formula (EP-1), p and R 1 are as defined in the formula (AM-X)] are added to aqueous ammonia, and the formula (EP-1) is used. A step of obtaining a mixed solution (3) containing the compound to be prepared and aqueous ammonia, and (4) any of the mixed solution (3) between 0 ° C. and a temperature at which the mixed solution (3) is refluxed And a step of obtaining a compound represented by the formula (AM-X) by reacting at a temperature.
［４－１－１］前記態様［４］の工程（４）の反応は、好ましくは、封管反応瓶を用いる封管反応である。 [4-1-1] The reaction in the step (4) of the embodiment [4] is preferably a sealed tube reaction using a sealed tube reaction bottle.
［４－１－２］前記態様［４－１－１］の封管反応の好ましい反応温度は１００℃である。 [4-1-2] A preferred reaction temperature for the sealed tube reaction of the embodiment [4-1-1] is 100 ° C.
［４－１－３］前記態様［４－１－１］の封管反応の好ましい反応時間は２時間である。 [4-1-3] The preferred reaction time for the sealed tube reaction of the embodiment [4-1-1] is 2 hours.
［４－２］前記態様［４］の各式中において、ｐは、好ましくは、０または１の整数であり、より好ましくは０の整数である。 [4-2] In each formula of the above embodiment [4], p is preferably an integer of 0 or 1, more preferably an integer of 0.
［４－３］前記態様［４］の各式中において、Ｒ1は、好ましくは、ハロゲン原子、ヒドロキシＣ1-6アルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；より好ましくは、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり；更に好ましくは、水素原子、フッ素原子、臭素原子、又はメトキシメチル基から選ばれる置換基が１～２個置換しても良く；特に好ましくは、無置換である。 [4-3] In each formula of the above embodiment [4], R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
［４－４］前記態様［４］の各式中において、Ｒ1の置換様式は、好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式（ＰＨ－１）ないし式（ＰＨ－４）で表わされる置換様式をとり； [4-4] In each formula of the embodiment [4], R 1 is preferably substituted in the following partial structural formula (p = 1) when one substituent is substituted by R 1 (p = 1): A substitution mode represented by PH-1) to formula (PH-4);
Figure JPOXMLDOC01-appb-I000069
Figure JPOXMLDOC01-appb-I000069
２個の置換基がＲ1によって置換する場合（ｐ＝２）の部分構造式は、下記部分構造式（ＰＨ－５）ないし式（ＰＨ－１０））で表わされる置換様式をとり； When two substituents are substituted by R 1 (p = 2), the partial structural formula takes the substitution mode represented by the following partial structural formula (PH-5) to (PH-10));
Figure JPOXMLDOC01-appb-I000070
Figure JPOXMLDOC01-appb-I000070
より好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式：
Figure JPOXMLDOC01-appb-I000071
More preferably, when one substituent is substituted by R 1 (p = 1), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000071
で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000072
And a more specific combination with a substituent includes the following partial structural formula:
Figure JPOXMLDOC01-appb-I000072
から選ばれる置換様式をとる。
２個の置換基がＲ1によって置換する場合（ｐ＝２）は、下記部分構造式： 
Figure JPOXMLDOC01-appb-I000073
Takes a substitution form selected from
When two substituents are substituted by R 1 (p = 2), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000073
で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000074
の置換様式をとる。 Takes the substitution form represented by;
More specific combinations with substituents include the following partial structural formulas:
Figure JPOXMLDOC01-appb-I000074
Take the replacement form.
［５］本発明の第５の態様は、下記式（Ｉ）：
Figure JPOXMLDOC01-appb-I000075
[5] A fifth aspect of the present invention is the following formula (I):
Figure JPOXMLDOC01-appb-I000075
［式（Ｉ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表される化合物の製造方法であって、以下の工程：
（５）下記式（ＡＭ－１）： [In the formula (I), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group; C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di C 2- 7 a substituent selected from an alkanoylamino group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps:
(5) The following formula (AM-1):
Figure JPOXMLDOC01-appb-I000076
Figure JPOXMLDOC01-appb-I000076
［式（ＡＭ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表わされる化合物と、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、２，２，２－トリクロロエチルクロロホルメート、クロロギ酸フェニル、クロロギ酸ｐ－ニトロフェニル、クロロギ酸ｐ－トリル、Ｎ，Ｎ´－カルボニルジイミダゾール、及びＮ，Ｎ´－ジスクシンイミジルカルボナート等から選ばれるウレア化剤と、塩基とを、溶媒に加えて混合溶液（５）を得る工程、（６）前記混合溶液（５）を、０℃から前記混合溶液（５）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＣＢ－１）： [Wherein ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group], triphosgene, Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N ′ A step of adding a urea agent selected from disuccinimidyl carbonate and the like and a base to a solvent to obtain a mixed solution (5), (6) the mixed solution (5) from 0 ° C. to the mixed solution The reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
Figure JPOXMLDOC01-appb-I000077
Figure JPOXMLDOC01-appb-I000077
［式（ＣＢ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基であり；Ｙは、トリクロロメトキシ基、塩素原子、２，２，２－トリクロロエトキシ基、フェノキシ基、ｐ－ニトロフェノキシ基、ｐ－メチルフェノキシ基、イミダゾール－１－イル基、（２，５－ジオキソピロリジン－１－イル）オキシ基、等から選ばれる基である］で表わされる化合物を得る工程、
前記式（ＣＢ－１）で表わされる化合物と、
下記式（ＡＭ－Ｘ）： [In Formula (CB-1), Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, A step of obtaining a compound represented by the formula:
A compound represented by the formula (CB-1);
The following formula (AM-X):
Figure JPOXMLDOC01-appb-I000078
Figure JPOXMLDOC01-appb-I000078
［式（ＡＭ－Ｘ）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物と、塩基とを、溶媒に加え混合溶液（７）を得る工程、及び
（８）前記混合溶液（７）を、０℃から前記混合溶液（７）が還流する温度までの間のいずれかの温度で反応を行い、式（Ｉ）で表される化合物を得る工程、を含む製造方法である。 [In the formula (AM-X), p and R 1 are as defined in the formula (I)] and a base are added to a solvent to obtain a mixed solution (7). And (8) reacting the mixed solution (7) at any temperature between 0 ° C. and a temperature at which the mixed solution (7) is refluxed to obtain a compound represented by the formula (I) A manufacturing method including a process.
［５－１］前記態様［５］の工程（５）において、ウレア化剤は、好ましくは、クロロギ酸フェニル、クロロギ酸ｐ－トリル、又は２，２，２－トリクロロエチルクロロホルメートであり；より好ましくは、２，２，２－トリクロロエチルクロロホルメートである。 [5-1] In the step (5) of the embodiment [5], the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
［５－２］前記態様［５］の工程（５）において、塩基は、好ましくは、ピリジン、トリエチルアミン、又はＮ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、等の有機塩基、炭酸水素ナトリウム、炭酸ナトリウム、又は炭酸カリウム等の無機塩基、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、等の金属アルコキシド、水素化ナトリウム、水素化カリウム、又は水素化カルシウム等の水素化金属化合物、メチルリチウム、又はブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド、又はリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物等であり；より好ましくは、ピリジンである。 [5-2] In the step (5) of the embodiment [5], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-. Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen A metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
［５－３］前記態様［５］の工程（５）において、溶媒は、好ましくは、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチルピロリドン、又はアセトニトリル、等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン、又は１，４－ジオキサン等のエーテル系溶媒、酢酸エチル、又は酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム、又は１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒等であり；より好ましくは、テトラヒドロフランである。 [5-3] In the step (5) of the above embodiment [5], the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably tetrahydrofuran.
［５－４］前記態様［５］の工程（５）において、式（ＣＢ－１）中のＹは、好ましくは、フェノキシ基、ｐ－メチルフェノキシ基、又は２，２，２－トリクロロエトキシ基であり；より好ましくは、２，２，２－トリクロロエトキシ基である。 [5-4] In the step (5) of the embodiment [5], Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
［５－５］前記態様［５］の工程（７）において、溶媒は、好ましくは、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチルピロリドン、又はアセトニトリル、等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン、又は１，４－ジオキサン等のエーテル系溶媒、酢酸エチル、又は酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム、又は１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒等であり；より好ましくは、Ｎ－メチルピロリドンである。 [5-5] In the step (7) of the above embodiment [5], the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably N-methylpyrrolidone.
［５－６］前記態様［５］の（７）において、塩基は、好ましくは、ピリジン、トリエチルアミン、又はＮ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、等の有機塩基、炭酸水素ナトリウム、炭酸ナトリウム、又は炭酸カリウム等の無機塩基、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、等の金属アルコキシド、水素化ナトリウム、水素化カリウム、又は水素化カルシウム等の水素化金属化合物、メチルリチウム、又はブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド、又はリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物等であり；より好ましくは、トリエチルアミンである。 [5-6] In (7) of the above embodiment [5], the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene. (DBU), organic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogenated A metal hydride compound such as calcium, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, triethylamine is there.
［５－７］前記態様［５］の各式中において、ｐは、好ましくは、０または１の整数であり、より好ましくは０の整数である。 [5-7] In each formula of the above embodiment [5], p is preferably an integer of 0 or 1, more preferably an integer of 0.
［５－８］前記態様［５］の各式中において、Ｒ1は、好ましくは、ハロゲン原子、ヒドロキシＣ1-6アルキル基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；より好ましくは、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり；更に好ましくは、水素原子、フッ素原子、臭素原子、又はメトキシメチル基から選ばれる置換基が１～２個置換しても良く；特に好ましくは、無置換である。 [5-8] In each formula of the above embodiment [5], R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
［５－９］前記態様［５］の各式中において、Ｒ1の置換様式は、好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式（ＰＨ－１）ないし式（ＰＨ－４）で表わされる置換様式をとり；
Figure JPOXMLDOC01-appb-I000079
[5-9] In each formula of the above embodiment [5], the substitution pattern of R 1 is preferably the following partial structural formula (p = 1) when one substituent is substituted by R 1 (p = 1): A substitution mode represented by PH-1) to formula (PH-4);
Figure JPOXMLDOC01-appb-I000079
２個の置換基がＲ1によって置換する場合の部分構造式は、下記部分構造式（ＰＨ－５）ないし式（ＰＨ－１０））で表わされる置換様式をとり；
Figure JPOXMLDOC01-appb-I000080
The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
Figure JPOXMLDOC01-appb-I000080
より好ましくは、１個の置換基がＲ1によって置換する場合（ｐ＝１）は、下記部分構造式：
Figure JPOXMLDOC01-appb-I000081
More preferably, when one substituent is substituted by R 1 (p = 1), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000081
で表わされる置換様式をとり；より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000082
And a more specific combination with a substituent includes the following partial structural formula:
Figure JPOXMLDOC01-appb-I000082
から選ばれる置換様式をとる。
２個の置換基がＲ1によって置換する場合（ｐ＝２）は、下記部分構造式：
Figure JPOXMLDOC01-appb-I000083
Takes a substitution form selected from
When two substituents are substituted by R 1 (p = 2), the following partial structural formula:
Figure JPOXMLDOC01-appb-I000083
で表わされる置換様式をとり；
より具体的な置換基との組み合わせとしては、下記部分構造式：
Figure JPOXMLDOC01-appb-I000084
の置換様式をとる。 Takes the substitution form represented by;
More specific combinations with substituents include the following partial structural formulas:
Figure JPOXMLDOC01-appb-I000084
Take the replacement form.
　以下に、本発明の態様［１］～［５］中の各置換基について具体的に説明する。本発明の化合物に関する説明において、例えば「Ｃ1-6」とは、構成炭素原子数が１から６であることを示し、特に断らない限り、直鎖、分枝鎖又は環状の基の総炭素原子数を表わす。鎖状の基と環状の基を含む基については「鎖と環の総炭素原子数」を意味する。 Hereinafter, each substituent in the embodiments [1] to [5] of the present invention will be specifically described. In the description of the compounds of the present invention, for example, “C 1-6 ” means that the number of carbon atoms constituting the compound is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms. For a group containing a chain group and a cyclic group, it means “total number of carbon atoms in the chain and ring”.
　本明細書中、特に断りのない限り、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、又はヨウ素原子等が挙げられる。
　本明細書中、特に断りのない限り、「ハロゲン化Ｃ1-6アルキル基」等における「ハロゲン化」とは、置換基として数個の、好ましくは１～５個の前記「ハロゲン原子」を有していてもよいことを意味する。
　本明細書中、特に断りのない限り、「シアノ化Ｃ1-6アルキル」等における「シアノ化」とは、置換基として数個の、好ましくは１～５個の「シアノ基」を有していてもよいことを意味する。 Unless otherwise specified, in this specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
In the present specification, unless otherwise specified, the “halogenation” in the “halogenated C 1-6 alkyl group” and the like refers to several, preferably 1 to 5, of the above “halogen atoms” as substituents. It means that you may have.
In this specification, unless otherwise specified, “cyanation” in “cyanated C 1-6 alkyl” and the like has several, preferably 1 to 5 “cyano groups” as substituents. It means that it may be.
　本明細書中、特に断りのない限り、「Ｃ1-6アルキル基」としては、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、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、又はヘキシル等の基が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Or groups, such as hexyl, are mentioned.
　本明細書中、特に断りのない限り、「ハロゲン化Ｃ1-6アルキル基」とは、前記「Ｃ1-6アルキル」が数個の、好ましくは１～５個のハロゲン原子で任意に置換されている基を意味し、例えば、フルオロメチル、ジフルオロメチル、トリフルオロメチル、２，２，２－トリフルオロエチル、１，１，２，２－テトラフルオロエチル、又はペンタフルオロエチル等の基が挙げられる。 In the present specification, unless otherwise specified, the “halogenated C 1-6 alkyl group” means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1 to 5 halogen atoms. A group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. Can be mentioned.
　本明細書中、特に断りのない限り、「ヒドロキシＣ1-6アルキル基」とは、前記「Ｃ1-6アルキル」が数個の、好ましくは１～５個の水酸基で任意に置換されている基を意味し、例えば、ヒドロキシメチル、２－ヒドロキシエチル、３－ヒドロキシプロピル、又は２，２－ジメチル－２－ヒドロキシエチル（＝２－ヒドロキシ－２－メチルプロピル）等の基が挙げられる。
　本明細書中、特に断りのない限り、「シアノ化Ｃ1-6アルキル基」とは、前記「Ｃ1-6アルキル」が数個の、好ましくは１～５個のシアノで任意に置換されている基を意味し、例えば、シアノメチル、１－シアノエチル、又は２－シアノエチル等の基が挙げられる。 In the present specification, unless otherwise specified, the “hydroxy C 1-6 alkyl group” means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1 to 5 hydroxyl groups. Groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, or 2,2-dimethyl-2-hydroxyethyl (= 2-hydroxy-2-methylpropyl).
In the present specification, unless otherwise specified, the “cyanated C 1-6 alkyl group” means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1-5 cyano. Groups such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and the like.
　本明細書中、特に断りのない限り、「Ｃ1-6アルコキシ基」とは、前記した「Ｃ1-6アルキル」が酸素原子に結合したアルコキシを表し、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、ｓｅｃ-ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、又はヘキシルオキシ等の基が挙げられる。
　本明細書中、特に断りのない限り、「ハロゲン化Ｃ1-6アルコキシ基」とは、前記した「ハロゲン化Ｃ1-6アルキル」が酸素原子に結合したハロゲン化アルコキシを表し、例えば、フルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、２，２，２－トリフルオロエトキシ、又は１，１，２，２－テトラフルオロエトキシ、ペンタフルオロエトキシ等の基が挙げられる。 In the present specification, unless otherwise specified, the “C 1-6 alkoxy group” means alkoxy in which the above-mentioned “C 1-6 alkyl” is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, iso Examples include groups such as propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or hexyloxy.
In the present specification, unless otherwise specified, the “halogenated C 1-6 alkoxy group” represents a halogenated alkoxy in which the above-mentioned “halogenated C 1-6 alkyl” is bonded to an oxygen atom. Examples include methoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy and the like.
　本明細書中、特に断りのない限り、「Ｃ1-6アルコキシＣ1-6アルキル基」とは、前記「Ｃ1-6アルコキシ」が前記「Ｃ1-6アルキル」に置換した基を意味する。本明細書中、特に断りのない限り、「Ｃ1-6アルコキシＣ1-6アルキル」としては、例えば、メトキシメチル、メトキシエチル、エトキシメチル、エトキシエチル、１，１－ジメトキシメチル、又は１，１－ジエトキシエチル等の基が挙げられる。 In the present specification, unless otherwise specified, the “C 1-6 alkoxy C 1-6 alkyl group” means a group in which the “C 1-6 alkoxy” is substituted with the “C 1-6 alkyl”. To do. Unless otherwise specified, in this specification, examples of the “C 1-6 alkoxy C 1-6 alkyl” include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl, or 1, Examples include groups such as 1-diethoxyethyl.
　本明細書中、特に断りのない限り、「モノ／ジＣ2-7アルカノイルアミノ基」とは、「アミノ基」の窒素原子上の一つ又は二つの水素原子が、後述する「Ｃ2-7アルカノイル基」で置換したアミノ基を意味し、例えば、アセトアミド、プロピオンアミド、ブチルアミド、イソブチルアミド、バレルアミド、イソバレルアミド、ピバルアミド、ヘキサンアミド、ヘプタンアミド、シクロプロパンカルボキサミド、シクロブタンカルボキサミド、シクロペンタンカルボキサミド、シクロヘキサンカルボキサミド、２－メチルシクロプロパンカルボキサミド、又はジアセトアミド等の基が挙げられる。
　本明細書中、特に断りのない限り、「Ｃ2-7アルカノイル基」とは、前記「Ｃ1-6アルキル基」にカルボニル基が結合した、「Ｃ1-6アルキルカルボニル基」を意味し、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、ヘプタノイル、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル、シクロプロピルメチルカルボニル、又は２－メチルシクロプロピルカルボニル等の基が挙げられる。 In the present specification, unless otherwise specified, the “mono / di C 2-7 alkanoylamino group” means that one or two hydrogen atoms on the nitrogen atom of the “amino group” are described later in “C 2− `` 7 alkanoyl group '' means an amino group substituted with, for example, acetamide, propionamide, butyramide, isobutyramide, valeramide, isovaleramide, pivalamide, hexaneamide, heptanamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, Examples include cyclohexanecarboxamide, 2-methylcyclopropanecarboxamide, or diacetamide.
In the present specification, unless otherwise specified, the “C 2-7 alkanoyl group” means a “C 1-6 alkylcarbonyl group” in which a carbonyl group is bonded to the “C 1-6 alkyl group”. A group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, or 2-methylcyclopropylcarbonyl Is mentioned.
　本明細書中、特に断りのない限り、「Ｃ1-6アルコキシカルボニル基」とは、「カルボキシ基（－ＣＯＯＨ）」の水素原子が前記「Ｃ1-6アルキル基」に置換した基、即ち「エステル基」を意味し、例えば、メトキシカルボニル（メチルエステル）、エトキシカルボニル（エチルエステル）、又はｔｅｒｔ－ブトキシカルボニル（ｔｅｒｔ－ブチルエステル）等の基が挙げられる。 In the present specification, unless otherwise specified, the “C 1-6 alkoxycarbonyl group” means a group in which a hydrogen atom of a “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”. “Ester group” means a group such as methoxycarbonyl (methyl ester), ethoxycarbonyl (ethyl ester), or tert-butoxycarbonyl (tert-butyl ester).
　本明細書前記態様中、特に断りのない限り、「ウレア化剤」としては、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、２，２，２－トリクロロエチルクロロホルメート、クロロギ酸フェニル、クロロギ酸ｐ－ニトロフェニル、クロロギ酸ｐ－トリル、Ｎ，Ｎ´－カルボニルジイミダゾール、又はＮ，Ｎ´－ジスクシンイミジルカルボナート等が挙げられる。但し、上記に記載したウレア化剤に必ずしも限定されるわけではない。 Unless otherwise specified, in this embodiment of the present specification, “urea agent” includes triphosgene, phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, chloroformate p- Examples thereof include nitrophenyl, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N′-disuccinimidyl carbonate. However, it is not necessarily limited to the urea agent described above.
　本明細書前記態様中、特に断らない限り、「塩基」としては、例えば、ピリジン、トリエチルアミン、又はＮ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、２，６－ルチジン、イミダゾール、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン（ＤＭＡＰ）、Ｎ，Ｎ－ジメチルアニリン、１，５－ジアザビシクロ［４.３.０］－５－ノネン、１，４－ジアザビシクロ［２.２.２］オクタン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、又はＮ－メチルモルホリン等の有機塩基、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウム、リン酸三カリウム、酢酸ナトリウム、又はフッ化セシウム等の無機塩基、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、等の金属アルコキシド、水素化ナトリウム、水素化カリウム、水素化カルシウム、又はナトリウムアミド、等の水素化金属化合物、メチルリチウム、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、又はｔｅｒｔ－ブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド、又はリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物等が挙げられる。但し、上記に記載した塩基に必ずしも限定されるわけではない。これらの塩基は、単独で用いてもよく、又は適宜選択し二種以上の塩基を適宜の割合で混合して用いてもよい。 In the embodiments of the present specification, unless otherwise specified, examples of the “base” include pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). ), 2,6-lutidine, imidazole, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] -5-nonene, An organic base such as 1,4-diazabicyclo [2.2.2] octane, N-methylpiperidine, N-methylpyrrolidine, or N-methylmorpholine, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, Lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, hydrogen carbonate Inorganic bases such as thorium, tripotassium phosphate, sodium acetate or cesium fluoride, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, Metal hydride compounds such as calcium hydride or sodium amide, alkyllithium such as methyllithium, n-butyllithium, sec-butyllithium, or tert-butyllithium, lithium hexamethyldisilazide, or lithium diisopropylamide Lithium amide or a mixture thereof. However, it is not necessarily limited to the base described above. These bases may be used alone, or may be appropriately selected and two or more bases may be mixed and used at an appropriate ratio.
　本明細書前記態様中、「溶媒」若しくは「反応に関与しない溶媒」は、例えば、水、シクロヘキサン、ヘキサン、ベンゼン、クロロベンゼン、トルエン、キシレン、メタノール、エタノール、１－プロパノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン（ＮＭＰ）、ヘキサメチルホスホリックトリアミド、１，３‐ジメチル‐２‐イミダゾリジノン、ジメチルスルホキシド（ＤＭＳＯ）、アセトニトリル、プロピオニトリル、ジエチルエーテル、ジイソプロピルエーテル、ジフェニルエーテル、メチルｔｅｒｔ－ブチルエーテル（ＭＴＢＥ）、テトラヒドロフラン、２－メチルテトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、酢酸メチル、酢酸エチル、酢酸ブチル、アセトン、メチルエチルケトン、ジクロロメタン、クロロホルム、四塩化炭素、及び１，２－ジクロロエタン等から選ばれる当該反応に影響がでない溶媒が挙げられる。但し、上記に記載した溶媒に必ずしも限定されるわけではない。これらの溶媒は、溶媒は、一種の溶媒を単独で用いてもよく、又は適宜選択し二種以上の溶媒を適宜の割合で混合して用いてもよい。 In the embodiment of the present specification, “solvent” or “solvent not involved in the reaction” refers to, for example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert- Butyl alcohol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide ( DMSO), acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2 Dimethoxyethane, methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, and the solvent does not affect to the reaction selected from 1,2-dichloroethane and the like. However, it is not necessarily limited to the solvent described above. As these solvents, one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately mixed and used in an appropriate ratio.
本明細書において、化合物の構造式中に不斉炭素がある場合、当該不斉炭素の近傍に立体配置を示すＲ又はＳの記号を付す場合もある。例えば、下記式（ＡＭ－Ｘ）又は式（ＡＭ－Ｙ）では、１位及び２位が不斉炭素であり、各式において当該不斉炭素の近傍にＲ又はＳの記号を付している。
Figure JPOXMLDOC01-appb-I000085
In the present specification, when an asymmetric carbon is present in the structural formula of the compound, an R or S symbol indicating a configuration may be added in the vicinity of the asymmetric carbon. For example, in the following formula (AM-X) or formula (AM-Y), the 1-position and the 2-position are asymmetric carbons, and the symbol of R or S is attached in the vicinity of the asymmetric carbon in each formula. .
Figure JPOXMLDOC01-appb-I000085
　本明細書中の化合物（例えば、式（ＳＭ－２）、式（ＩＭ－６）、式（ＩＭ－７）、式（ＡＭ－１）、式（ＡＭ－Ｘ）、及び式（Ｉ）、等）は、置換基の種類によって、無機又は有機の酸との塩（酸付加塩）を形成する場合や、無機又は有機の塩基との塩を形成する場合がある。かかる塩としては、製薬学的に許容し得る塩であれば特に限定されないが、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性、又は酸性アミノ酸との塩などが挙げられる。 The compounds herein (eg, formula (SM-2), formula (IM-6), formula (IM-7), formula (AM-1), formula (AM-X), and formula (I)), Etc.) may form a salt with an inorganic or organic acid (acid addition salt) or a salt with an inorganic or organic base depending on the type of substituent. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basicity, Or the salt with an acidic amino acid etc. are mentioned.
　金属塩の好適な例としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩、アルミニウム塩などが挙げられる（例えば、モノ塩の他、二ナトリウム塩、二カリウム塩も含む）。有機塩基との塩の好適な例としては、例えば、メチルアミン、エチルアミン、ｔ－ブチルアミン、ｔ－オクチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、ジベンジルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ピペリジン、モルホリン、ピリジン、ピコリン、リシン、アルギニン、オルニチン、エチレンジアミン、Ｎ－メチルグルカミン、グルコサミン、フェニルグリシンアルキルエステル、グアニジン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、Ｎ，Ｎ'－ジベンジルエチレンジアミン等との塩が挙げられる。 Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included). Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N′-dibenzylethylenediamine and the like.
　無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、よう化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸等との塩、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、リンゴ酸、酒石酸等の脂肪族ジカルボン酸との塩、クエン酸等の脂肪族トリカルボン酸との塩、安息香酸、サリチル酸等の芳香族モノカルボン酸との塩、フタル酸等の芳香族ジカルボン酸の塩、桂皮酸、グリコール酸、ピルビン酸、オキシル酸、サリチル酸、Ｎ－アセチルシステイン等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩、アスパラギン酸、グルタミン酸等の酸性アミノ酸類との酸付加塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
　塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩（例、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩など）などの無機塩、アンモニウム塩など、又、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩、又は酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸などの有機酸との塩が挙げられる。 Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
　前記塩は、常法に従い、例えば、本明細書中の化合物と適量の酸もしくは塩基を含む溶液を混合することにより目的の塩を形成させた後に分別濾取するか、もしくは該混合溶媒を留去することにより得ることができる。又、本明細書中の化合物又はその塩は、水、エタノール、グリセロール等の溶媒と溶媒和物を形成し得る。塩に関する総説として、Handbook of Pharmaceutical Salts: Properties, Selection, and Use、Stahl&Wermuth(Wiley-VCH、2002)が出版されており、本書に詳細な記載がなされている。 According to a conventional method, the salt is formed by, for example, mixing the compound in the present specification with a solution containing an appropriate amount of acid or base to form a desired salt, and then fractionally filtering or removing the mixed solvent. It can be obtained by leaving. Moreover, the compound in this specification or its salt can form solvates with solvents, such as water, ethanol, and glycerol. As a review on salts, the Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) has been published and is described in detail in this document.
　本明細書中の化合物は、非溶媒和形態もしくは溶媒和形態で存在することがあり得る。本明細書において、「溶媒和物」は、本明細書中の化合物と１種または複数の薬学的に許容される溶媒分子（例えば、水、エタノール等）を含む分子複合体を意味する。前記溶媒分子が水であるとき、特に「水和物」と言う。 The compounds herein may exist in unsolvated or solvated forms. As used herein, “solvate” means a molecular complex comprising a compound herein and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
　本明細書中の化合物が、幾何異性体（ジオメトリカルアイソマー）、配置異性体（コンフィギュレーショナルアイソマー）、互変異性体（トウトメリックアイソマー）、光学異性体（オプティカルアイソマー）、立体異性体（ジアステレオマー）、位置異性体（レジオアイソマー）、回転異性体（ロテイショナルアイソマー）などの異性体を有する場合がある。 The compounds in the present specification are represented by geometric isomers (geometric isomers), configurational isomers (configurational isomers), tautomers (tortomeric isomers), optical isomers (optical isomers), stereoisomers (diastereomers). Isomers), positional isomers (regioisomers), rotational isomers (rotational isomers) and the like.
　本明細書中の化合物に、幾何異性体、配置異性体、立体異性体、配座異性体等が存在する場合には、公知の手段によりそれぞれを単離することができる。 In the case where geometric isomers, configuration isomers, stereoisomers, conformational isomers, and the like are present in the compounds in the present specification, they can be isolated by known means.
　本明細書中の化合物が、光学異性体、立体異性体、位置異性体、回転異性体、互変異性体を含有する場合には、自体公知の合成手法、分離手法により各々の異性体を単一の化合物として得ることができる。例えば、光学分割法としては、自体公知の方法、例えば、（１）分別再結晶法、（２）ジアステレオマー法、（３）キラルカラム法等が挙げられる。 When the compounds in the present specification contain optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is simply separated by a synthesis method or separation method known per se. It can be obtained as a single compound. For example, examples of the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
（１）分別再結晶法：ラセミ体に対して光学分割剤をイオン結合させることにより結晶性のジアステレオマーを得た後、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学的に純粋な化合物を得る方法である。光学分割剤としては、例えば、（＋）－マンデル酸、（－）－マンデル酸、（＋）－酒石酸、（－）－酒石酸、（＋）－１－フェネチルアミン、（－）－１－フェネチルアミン、シンコニン、（－）－シンコニジン、ブルシン等が挙げられる。 (1) Fractionation recrystallization method: After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, Examples include cinchonine, (−)-cinchonidine, brucine and the like.
（２）ジアステレオマー法：ラセミ体の混合物に光学分割剤を共有結合（反応）させ、ジアステレオマーの混合物とした後、これを通常の分離手段（例、分別再結晶、シリカゲルカラムクロマトグラフィー、ＨＰＬＣ（高速液体クロマトグラフィー）等）等を経て光学的に純粋なジアステレオマーへ分離した後、加水分解反応等の化学的な処理により、光学分割剤を除去することにより、光学的に純粋な光学異性体を得る方法である。例えば、本発明の化合物に分子内水酸基または１級、２級アミノ基を有する場合、該化合物と光学活性な有機酸（例、ＭＴＰＡ〔α－メトキシ－α－（トリフルオロメチル）フェニル酢酸〕、（－）－メントキシ酢酸等）等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、本発明の化合物にカルボキシ基が有る場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。上記の分離された各ジアステレオマーは、酸加水分解または塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 (2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining an optical isomer. For example, when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxy group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
（３）キラルカラム法：ラセミ体またはその塩をキラルカラム（光学異性体分離用カラム）でのクロマトグラフィーに付すことで、直接光学分割する方法である。例えば、高速液体クロマトグラフィー（Ｈｉｇｈ　ｐｅｒｆｏｒｍａｎｃｅ　ｌｉｑｕｉｄ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ：ＨＰＬＣ）の場合、ダイセル社製ＣＨＩＲＡＬシリーズ等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液（例、リン酸緩衝液）、有機溶媒（例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン）を単独で、または混合した溶液として用いて、展開させることにより、光学異性体を分離することができる。また、例えば、ガスクロマトグラフィーの場合、ＣＰ－Ｃｈｉｒａｓｉｌ－ＤｅＸ　ＣＢ（ジーエルサイエンス社製）等のキラルカラム使用して分離することができる。 (3) Chiral column method: This is a method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column). For example, in the case of high performance liquid chromatography (High performance liquid chromatography: HPLC), a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, water, various buffers (eg, phosphate buffer), Optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. In addition, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
　本明細書中の化合物は、結晶となり得る場合もある。結晶である場合、その結晶形が単一であっても結晶形混合物であっても良い。 The compound in the present specification may be a crystal. In the case of a crystal, the crystal form may be single or a crystal form mixture.
　本明細書中の化合物は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 The compound herein may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
　本明細書中の化合物には、同位元素（例えば、水素の同位体：2Ｈおよび3Ｈなど、炭素の同位体：11Ｃ、13Ｃ、および14Ｃなど、塩素の同位体：36Ｃｌなど、フッ素の同位体：18Ｆなど、ヨウ素の同位体：123Ｉおよび125Ｉなど、窒素の同位体：13Ｎおよび15Ｎなど、酸素の同位体：15Ｏ、17Ｏ、および18Ｏなど、リンの同位体：32Ｐなど、ならびに硫黄の同位体：35Ｓなど）で標識、又は置換された化合物も含まれる。 The compounds herein include isotopes (eg, hydrogen isotopes: 2 H and 3 H, carbon isotopes: 11 C, 13 C, and 14 C, chlorine isotopes: 36 Cl, etc. , Fluorine isotopes: 18 F, iodine isotopes: 123 I and 125 I, nitrogen isotopes: 13 N and 15 N, oxygen isotopes: 15 O, 17 O, and 18 O, etc. Also included are compounds labeled or substituted with phosphorus isotopes: 32 P, etc., and sulfur isotopes: 35 S, etc.
　ある種の同位元素（例えば、11Ｃ、18Ｆ、15Ｏ、および13Ｎなどの陽電子放出同位元素）で標識または置換された本発明の化合物は、例えば、陽電子断層法（Ｐｏｓｉｔｒｏｎ　Ｅｍｉｓｓｉｏｎ　Ｔｏｍｏｇｒａｐｈｙ；ＰＥＴ）において使用するトレーサー（ＰＥＴトレーサー）として用いることができ、医療診断などの分野において有用である。 Compounds of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N) can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
　ある種の同位体標識で標識または置換された本発明の化合物は、薬物および／または基質の組織分布研究において有用である。例えば、3Ｈおよび14Ｃは、それらの標識または置換が容易であり、かつ検出手段が容易である点から、該研究目的において有用である。 Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
　同位体標識された本発明の化合物は、当業者に知られている通常の技法によって、または後述の実施例に記載する合成方法に類似する方法によって得る事ができる。また、非標識化合物の代わりに、得られた同位体標識化合物を薬理実験に用いる事ができる。 The isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
　本明細書前記態様中又は本明細書中の製造方法において、「０℃から前記混合溶液・・・が還流する温度までの間のいずれかの温度」「０℃から溶媒が還流する温度までの間のいずれかの温度」等の記載が意味する処は、それぞれ、０℃から各混合溶液（溶媒）が還流する温度迄の範囲内の任意の温度（一定温度）を意味する。
　なお、本明細書において、特に断らない限り、「室温」とは、実験室、研究室等の温度の意味であり、通常約１℃から約３０℃、好ましくは通常約５℃から約３０℃、より好ましくは通常約１５℃から約２５℃、更に好ましくは２０±３℃の温度を示すものとする。 In the embodiment of the present specification or the production method in the present specification, “any temperature between 0 ° C. and the temperature at which the mixed solution is refluxed” “from 0 ° C. to the temperature at which the solvent is refluxed” The phrase “any temperature in between” means any temperature (constant temperature) within a range from 0 ° C. to the temperature at which each mixed solution (solvent) is refluxed.
In the present specification, unless otherwise specified, “room temperature” means a temperature in a laboratory, laboratory, etc., and is usually about 1 ° C. to about 30 ° C., preferably usually about 5 ° C. to about 30 ° C. More preferably, it usually exhibits a temperature of about 15 ° C. to about 25 ° C., more preferably 20 ± 3 ° C.
　本発明の製造方法において、使用する溶媒は、一種の溶媒を単独で用いてもよく、又は反応条件により適宜選択し二種以上の溶媒を適宜の割合で混合して用いてもよい。
　本発明の製造方法において、化合物の抽出、乾燥、精製等の工程は、周知の方法で適宜行い得る。
　本発明の製造方法において、各工程における反応時間は、特に断らない限り、反応が十分に進行する時間であればよく、適宜選択し得る。 In the production method of the present invention, as the solvent to be used, one kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio as appropriate depending on the reaction conditions.
In the production method of the present invention, steps such as compound extraction, drying, and purification can be appropriately performed by a known method.
In the production method of the present invention, the reaction time in each step may be appropriately selected as long as the reaction proceeds sufficiently unless otherwise specified.
［製造方法Ａ］本発明中の式(ＴＨ－１)で表される化合物の製造方法：
　以下に、本発明における、式(ＴＨ－１)［式（ＴＨ－１）中のｐ及びＲ1の定義は、態様［１］中の式（Ｉ）の定義と同じである］で表される化合物の製造方法について詳細に説明する。式(ＴＨ－１) で表される化合物及びその溶媒和物は、市販化合物又は市販化合物から文献公知の製造方法により容易に得ることが出来る化合物を出発原料若しくは合成中間体として、既知の一般的化学的な製造方法を組み合わせることで容易に製造することが可能であり、例えば、以下に示す代表的な製造方法に従い製造することができる。
　［製造方法Ａ］中、ＲAは、特に断らない限り、メチル基、エチル基、プロピル基、ｔｅｒｔ－ブチル基等のＣ1-6アルキル基、フェニル基、又はベンジル基である。 [Production Method A] A method for producing a compound represented by the formula (TH-1) in the present invention:
Hereinafter, in the present invention, the formula (TH-1) [the definitions of p and R 1 in the formula (TH-1) are the same as the definitions of the formula (I) in the embodiment [1]] The method for producing the compound will be described in detail. The compound represented by the formula (TH-1) and a solvate thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods.
In [Production Method A], R A is a C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, or a tert-butyl group, a phenyl group, or a benzyl group unless otherwise specified.
Figure JPOXMLDOC01-appb-I000086
Figure JPOXMLDOC01-appb-I000086
＜工程１＞　式（ＳＭ－１）［式（ＳＭ－１）の化合物は、市販化合物、又は市販化合物から文献公知の製造方法により製造できる化合物である］で表される化合物を用いて、文献公知の方法、例えば、『実験化学講座　第４版　２２　有機合成ＩＶ　酸・アミノ酸・ペプチド、１－８２頁、１９９２年、丸善』等に記載された方法に準じて、塩酸、硫酸、塩化チオニル、塩化アセチル等の酸性試薬存在下、メタノール、エタノール、２－プロパノール等の溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－１）で表される化合物を製造することができる。
　又、式（ＳＭ－１）で表される化合物を用い、文献公知の方法、例えば、『シンセッティク　コミュニケーションズ（Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ）、３１（１４）、２１７７－２１８３頁、２００１年』等に記載された方法に準じて、アルキルハライド剤（例えば、ヨウ化メチル、ヨウ化エチル等）存在下、炭酸カリウム、炭酸ナトリウム、水酸化カリウム、水酸化ナトリウム等の塩基存在下、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、Ｎ－メチルピロリドン等の極性溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－１）で表される化合物を製造することができる。 <Step 1> Using a compound represented by the formula (SM-1) [the compound of formula (SM-1) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature] In accordance with a known method such as “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-82, 1992, Maruzen”, etc., hydrochloric acid, sulfuric acid, thionyl chloride, In the presence of an acidic reagent such as acetyl chloride, the reaction is performed at a temperature between 0 ° C. and the temperature at which the solvent is refluxed using a solvent such as methanol, ethanol, 2-propanol, and the like (IM-1) The compound represented by these can be manufactured.
In addition, a method known in the literature using a compound represented by the formula (SM-1), for example, a method described in “Synthetic Communications, 31 (14), 2177-2183, 2001”, etc. In the presence of an alkyl halide agent (for example, methyl iodide, ethyl iodide, etc.), in the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, N, N-dimethylformamide, dimethyl sulfoxide Using a polar solvent such as N-methylpyrrolidone to produce a compound represented by the formula (IM-1) by carrying out the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed. it can.
　又、式（ＳＭ－１）で表される化合物を用い、文献公知の方法、例えば、『ケミカル　アンド　ファーマシューティカル　ブレティン　（Ｃｈｅｍｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ）、２９（５）、１４７５－１４７８頁、１９８１年』等に記載された方法に準じて、ジアゾメタン、トリメチルシリルジアゾメタン等のメチル化剤、エーテル、メタノール等の反応に関与しない溶媒、又はこれらの混合溶媒中、０℃から室温で反応を行い、式（ＩＭ－１）で表される化合物を製造することができる。　又、式（ＳＭ－１）で表わされる化合物及びアルコール（例えば、メタノール、エタノール、ベンジルアルコール等）を用い、文献公知の方法、例えば、『実験化学講座　第４版　２２　有機合成ＩＶ　酸・アミノ酸・ペプチド、１９１－３０９頁、１９９２年、丸善』等に記載された方法に準じて、１，３－ジシクロヘキシルカルボジイミド（ＤＣＣ）、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（ＷＳＣ・ＨＣｌ）、１－ヒドロキシベンゾトリアゾール（ＨＯＢＴ）、ベンゾトリアゾール－１－イロキシトリス（ジメチルアミノ）ホスホニウムヘキサフルオロホスフェイト（ＢＯＰ試薬）、ビス（２－オキソ－３－オキサゾリジニル）ホスフィニッククロリド（ＢＯＰ－Ｃｌ）、２－クロロ－１，３－ジメチルイミダゾリニウムヘキサフルオロホスフェイト（ＣＩＰ）、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（ＤＭＴＭＭ）、ポリリン酸（ＰＰＡ）、２－（１Ｈ－７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム　ヘキサフルオロホスフェート　メタンアミニウム（ＨＡＴＵ）、（１－シアノ－２－エトキシ－２－オキソエチリデンアミノオキシ）ジメチルアミノ－モルホリノ－カルベニウムヘキサフルオロホスフェート（ＣＯＭＵ）等の縮合剤の存在下、ジクロロメタン、クロロホルム、ジエチルエーテル、テトラヒドロフラン、トルエン、ベンゼン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン等反応に関与しない溶媒中、もしくはこれらの混合溶媒を用いて、トリエチルアミン、ピリジン等の塩基の存在下又は非存在下、０℃から溶媒が還流する温度までの間のいずれかの温度で反応させることにより、式（ＩＭ－１）で表わされる化合物を製造することができる。 Further, a method known in the literature using a compound represented by the formula (SM-1), for example, “Chemical & Pharmaceutical Bulletin, 29 (5), pp. 1475-1478, 1981” In accordance with the method described in the above, the reaction is carried out from 0 ° C. to room temperature in a methylating agent such as diazomethane or trimethylsilyldiazomethane, a solvent that does not participate in the reaction such as ether or methanol, or a mixed solvent thereof. The compound represented by -1) can be produced. Further, using a compound represented by the formula (SM-1) and an alcohol (for example, methanol, ethanol, benzyl alcohol, etc.), a method known in the literature, for example, “Experimental Chemistry Course, 4th Edition, 22. Organic Synthesis IV, Acid, Amino Acid, 1, 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (in accordance with the method described in Peptide, 191-309, 1992, Maruzen ”) WSC · HCl), 1-hydroxybenzotriazole (HOBT), benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP) -Cl), 2-chloro-1,3- Methylimidazolinium hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM), polyphosphoric acid (PPA) 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), (1-cyano-2-ethoxy-2- Oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) in the presence of a condensing agent, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene, benzene, N, N-dimethylformamide, N-methylpyrrolidone In a solvent that does not participate in the reaction Alternatively, by using these mixed solvents, the reaction is performed at any temperature between 0 ° C. and the temperature at which the solvent is refluxed in the presence or absence of a base such as triethylamine or pyridine. ) Can be produced.
　又、式（ＳＭ－１）で表わされる化合物を、文献公知の方法、例えば、『ジャーナル・オブ・ザ・アメリカン・ケミカル・ソサエティ（Ｊｏｕｒｎａｌ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ）、１０９（２４）、ｐ７４８８－７４９４、１９８７年』等に記載された方法に準じて、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジメチルアミノピリジン等の塩基の存在もしくは非存在下、塩化チオニル、塩化オキサリル、塩化ホスホリル、塩化スルフリル、三塩化リン、五塩化リン、三臭化リン等のハロゲン化剤と、１，４－ジオキサン、テトラヒドロフラン、１，２－ジメトキシエタン、ベンゼン、トルエン、ジクロロメタン、１，２－ジクロロエタン、クロロホルム等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い酸ハライドに変換した後に、アルコール（例えば、メタノール、エタノール、ベンジルアルコール等）を用いて、文献公知の方法、例えば、『実験化学講座　第４版　２２　有機合成ＩＶ酸・アミノ酸・ペプチド、１４４－１４６頁、１９９２年、丸善』等に記載された方法に準じて、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン等の塩基の存在下、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、ジエチルエーテル、テトラドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、トルエン、ベンゼン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン等反応に関与しない溶媒中、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応させることにより、式（ＩＭ－１）で表わされる化合物を同様に製造することができる。 Further, the compound represented by the formula (SM-1) is converted into a method known in the literature, for example, “Journal of the American Chemical Society”, 109 (24), p7488-7494. In accordance with the method described in 1987, etc., in the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, thionyl chloride, oxalyl chloride, phosphoryl chloride, chloride Halogenating agents such as sulfuryl, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc. In response to Using an active solvent or a mixed solvent thereof, the reaction is carried out at any temperature between 0 ° C. and the temperature at which the solvent is refluxed, and then converted to an acid halide, followed by alcohol (eg, methanol, ethanol, benzyl alcohol). Etc.) according to methods known in the literature, for example, the method described in “Experimental Chemistry Course, 4th Edition, 22. Organic Synthetic IV Acids / Amino Acids / Peptides, 144-146, 1992, Maruzen” In the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetradrofuran, 1,4-dioxane, 1,2- Dimethoxyethane, toluene, benzene, N, N-dimethylformamide, N-me By reacting at any temperature between 0 ° C. and the temperature at which the solvent is refluxed in a solvent that does not participate in the reaction, such as lupyrrolidone, or a mixed solvent thereof, it is represented by the formula (IM-1) Compounds can be prepared similarly.
＜工程２＞［製造方法Ａ］＜工程１＞で得られる式（ＩＭ－１）で表される化合物を用いて、文献公知の方法、例えば、『実験化学講座　第４版　２５、有機合成ＶＩＩ、有機金属試薬による合成、１３－１９頁、５９－７２頁、１９９２年、丸善』等に記載された方法に準じて、Ｇｒｉｇｎａｒｄ試薬（例えば、メチルマグネシウムクロリド、メチルマグネシウムブロミド、エチルマグネシウムブロミド、等）、もしくはアルキル金属試薬（例えば、メチルリチウム、等）の存在下、ジエチルエーテル、１，４－ジオキサン、テトラヒドロフラン、２－メチルテトラヒドロフラン、１，２－ジメトキシエタン、ベンゼン、トルエン、キシレン等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－２）で表される化合物を製造することができる。 <Step 2> [Production Method A] Using the compound represented by the formula (IM-1) obtained in <Step 1>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 25, Organic Synthesis VII” In accordance with the method described in "Synthesis with organometallic reagents, pages 13-19, 59-72, 1992, Maruzen", etc., Grignard reagent (eg, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, etc. ), Or in the presence of an alkyl metal reagent (eg, methyllithium, etc.) for reactions such as diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, xylene, etc. The temperature at which the solvent is refluxed from −78 ° C. using an inert solvent or a mixed solvent thereof. The reaction was carried out at any temperature between at can be produced a compound represented by the formula (IM-2).
＜工程３＞　［製造方法Ａ］＜工程２＞で得られる式（ＩＭ－２）で表される化合物を用いて、文献公知の方法、例えば、『Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔｅｒｓ，５４（３２），ｐ４３３０－４３３２，２０１３年』等に記載された方法に準じて、酸として、トリフルオロメタンスルホン酸、五酸化二リン、五塩化リン、硫酸、リン酸、ビスマス（ＩＩＩ）トリフルオロメタンスルホネート等の酸試薬存在下、ジクロロメタン、クロロホルム、シクロヘキサン、ベンゼン、トルエン、キシレン、ジエチルエーテル、２－プロパノール、水等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－３）で表される化合物を製造することができる。 <Step 3> [Production Method A] Using the compound represented by the formula (IM-2) obtained in <Step 2>, a method known in the literature, for example, “Tetrahedron Letters, 54 (32), p4330-4332. In the presence of an acid reagent such as trifluoromethanesulfonic acid, diphosphorus pentoxide, phosphorous pentachloride, sulfuric acid, phosphoric acid, bismuth (III) trifluoromethanesulfonate, Using a solvent inert to the reaction, such as dichloromethane, chloroform, cyclohexane, benzene, toluene, xylene, diethyl ether, 2-propanol, water, or a mixed solvent thereof, the temperature between 0 ° C. and the temperature at which the solvent is refluxed. The reaction can be carried out at any temperature to produce the compound represented by the formula (IM-3).
＜工程４＞　［製造方法Ａ］＜工程３＞で得られる式（ＩＭ－３）で表される化合物を用いて、文献公知の方法、例えば、『Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ，７０（１０），ｐ１０４２－１０４３，２０１３年』等に記載された方法に準じて、オキソン（登録商標）（ＤｕＰｏｎｔ）、ｔｅｒｔ－ブチルヒドロペルオキシド（ＴＢＨＰ）、過マンガン酸カリウム、二酸化マンガン、クロム酸等の酸化剤存在下、ジクロロメタン、クロロホルム、四塩化炭素、ベンゼン、アセトニトリル、ｔｅｒｔ－ブチルアルコール、水等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－４）で表される化合物を製造することができる。 <Step 4> [Production Method A] Using the compound represented by the formula (IM-3) obtained in <Step 3>, a method known in the literature, for example, “Chemistry Letters, 70 (10), p1042-1043. In the presence of an oxidizing agent such as Oxone (registered trademark) (DuPont), tert-butyl hydroperoxide (TBHP), potassium permanganate, manganese dioxide, chromic acid, and the like. , Chloroform, carbon tetrachloride, benzene, acetonitrile, tert-butyl alcohol, water, or a solvent inert to the reaction, or a mixed solvent thereof. By reacting at a temperature, a compound represented by the formula (IM-4) can be produced.
＜工程５＞　［製造方法Ａ］＜工程４＞で得られる式（ＩＭ－４）で表される化合物を用いて、文献公知の方法、例えば、『実験化学講座　第４版　２６　有機合成ＶＩＩＩ　不斉合成・還元・糖・標識化合物、２３４－２４５頁、１９９２年、丸善』等に記載された方法に準じて、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ジイソブチルアルミニウム（ＤＩＢＡＨ）、水素化リチウムアルミニウム（ＬＡＨ）、ボラン－テトラヒドロフラン（ＢＨ3・ＴＨＦ）、ボラン－ジメチルスルフィド（ＢＨ3・Ｍｅ2Ｓ）等の還元剤存在下、ジエチルエーテル、テトラヒドロフラン、１，２－ジメトキシエタン、１，４－ジオキサン、メタノール、エタノール、２－プロパノール等の溶媒（反応に関与しない溶媒）、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－５）で表される化合物を製造することができる。 <Step 5> [Production Method A] Using the compound represented by the formula (IM-4) obtained in <Step 4>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII In accordance with the method described in “Synthetic Synthesis / Reduction / Sugar / Label Compound, pp. 234-245, 1992, Maruzen” etc., sodium borohydride, lithium borohydride, diisobutylaluminum hydride (DIBAH), hydrogenation In the presence of a reducing agent such as lithium aluminum (LAH), borane-tetrahydrofuran (BH 3 .THF), borane-dimethyl sulfide (BH 3 .Me 2 S), diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4 -Solvents such as dioxane, methanol, ethanol, 2-propanol (solvents that do not participate in the reaction), or a mixed solution thereof With conducting a reaction at any temperature between from 0 ℃ to a temperature at which the solvent refluxes, it is possible to produce a compound represented by the formula (IM-5).
＜工程６＞　［製造方法Ａ］＜工程５＞で得られる式（ＩＭ－５）で表される化合物を用いて、文献公知の方法、例えば、『国際公開２０１４／０７８４５４号パンフレット』等に記載された方法に準じて、酸として、ｐ－トルエンスルホン酸等の酸試薬存在下、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、ベンゼン、トルエン、キシレン、１，２－ジメトキシエタン等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＴＨ－１）で表される化合物を製造することができる。 <Step 6> [Production Method A] Using a compound represented by the formula (IM-5) obtained in <Step 5>, a method known in the literature, for example, described in “International Publication No. 2014/078454 Pamphlet”, etc. Inactive in the reaction of dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, 1,2-dimethoxyethane, etc. in the presence of an acid reagent such as p-toluenesulfonic acid, etc. A compound represented by the formula (TH-1) can be produced by performing a reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a suitable solvent or a mixed solvent thereof. .
［製造方法Ｂ］本発明中の式(ＡＭ－１)で表される化合物の製造方法：
　以下に、本発明における、式(ＡＭ－１)で表される化合物の製造方法について詳細に説明する。式(ＡＭ－１) で表される化合物及びその溶媒和物は、市販化合物又は市販化合物から文献公知の製造方法により容易に得ることが出来る化合物を出発原料若しくは合成中間体として、既知の一般的化学的な製造方法を組み合わせることで容易に製造することが可能であり、例えば、以下に示す代表的な製造方法に従い製造することができる。
　下記製造方法中、［Ｂ］は、ボロン酸、ボロン酸エステル、又はボロン酸Ｎ－メチルイミノ二酢酸（ＭＩＤＡ）エステル等である。 [Production Method B] A method for producing a compound represented by the formula (AM-1) in the present invention:
Hereinafter, the method for producing the compound represented by the formula (AM-1) in the present invention will be described in detail. The compound represented by the formula (AM-1) and a solvate thereof are known compounds that are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods.
In the following production method, [B] is boronic acid, boronic acid ester, boronic acid N-methyliminodiacetic acid (MIDA) ester or the like.
Figure JPOXMLDOC01-appb-I000087
Figure JPOXMLDOC01-appb-I000087
＜工程１＞式（ＳＭ－２）及び式（ＲＧ－１）［式（ＳＭ－２）及び式（ＲＧ－１）の化合物は、市販化合物、又は市販化合物から文献公知の製造方法により製造できる化合物である］で表わされる化合物を用いて、文献公知の方法、例えば、『実験化学講座　第５版　１８　有機化合物の合成　ＶＩ　－金属を用いる有機合成－、３２７‐３５２頁、２００４年、丸善』、及び『Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、４８（２０）、ｐ６３２６‐６３３９、２００５年』に記載された方法に準じて、酢酸パラジウム（ＩＩ）（Ｐｄ（ＯＡｃ）2）、テトラキストリフェニルホスフィンパラジウム（Ｐｄ（ＰＰｈ3）4）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド（Ｐｄ（ＰＰｈ3）2Ｃｌ2）、トリス（ジベンジリデンアセトン）ジパラジウム（Ｐｄ2（ｄｂａ）3）、ビス（ジベンジリデンアセトン）パラジウム（Ｐｄ（ｄｂａ）2）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（ＰｄＣｌ2（ｄｐｐｆ））等のパラジウム触媒、トリフェニルホスフィン、トリス（ｔｅｒｔ－ブチル）ホスフィン、トリス（ｏ－トリル）ホスフィン、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル等のホスフィン系試薬、及びトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、リン酸カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の有機又は無機塩基存在下、トルエン（トルエン／水）、キシレン、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－メチルピロリドン、１，２－ジメトキシエタン、アセトニトリル（アセトニトリル／水）、１，４－ジオキサン（１，４－ジオキサン／水）、テトラヒドロフラン（テトラヒドロフラン／水）、メタノール、エタノール（エタノール／水）、ジクロロメタン、１，２－ジクロロエタン、ジメトキシエタン（ジメトキシエタン／水）、水等の溶媒（反応に関与しない溶媒）、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－６）で表される化合物を製造することができる。又はホスフィン系試薬の替わりにテトラメチルアンモニウムクロリド、テトラブチルアンモニウムクロリド等を用いて、同様の方法にて製造することができる。 <Step 1> Formula (SM-2) and Formula (RG-1) [Formula (SM-2) and Formula (RG-1) are commercially available compounds or can be produced from commercially available compounds by known production methods in the literature. Using a compound represented by the above formula, a method known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” And palladium (II) acetate (Pd (OAc) 2 ), tetrakistriphenylphosphinepalladium (Pd (Pd (Pd (OAc) 2 )), and the method described in “Journal of Medicinal Chemistry, 48 (20), p6326-6339, 2005”. PPh 3) 4), bis (triphenylphosphine) palladium (II) chloride (Pd (PPh 3) 2 Cl 2), bets Scan (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3), bis (dibenzylideneacetone) palladium (Pd (dba) 2), [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II ) (PdCl 2 (dppf)), etc., palladium catalyst, triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2- Phosphine reagents such as dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate In the presence of toluene (toluene / water ), Xylene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, acetonitrile (acetonitrile / water), 1,4-dioxane (1,4-dioxane / water) ), Tetrahydrofuran (tetrahydrofuran / water), methanol, ethanol (ethanol / water), dichloromethane, 1,2-dichloroethane, dimethoxyethane (dimethoxyethane / water), water and other solvents (solvents not involved in the reaction), or these The compound represented by the formula (IM-6) can be produced by performing the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a mixed solvent. Alternatively, it can be produced by the same method using tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of the phosphine reagent.
＜工程２＞［製造方法Ｂ］＜工程１＞で得られる式（ＩＭ－６）の化合物、及びＮ－ブロモスクシンイミド（ＮＢＳ）を用いて、文献公知の方法、例えば、『国際公開２００９／０８８１０３号パンフレット』に記載された方法に準じて、Ｎ－メチルピロリドン、ジメチルホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、アセトニトリル等の溶媒（反応に関与しない溶媒）、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度までの間のいずれかの温度で反応を行い、式（ＩＭ－７）で表される化合物を製造することができる。
＜工程３＞［製造方法Ｂ］＜工程２＞で得られる式（ＩＭ－７）及び式（ＲＧ－２）［式（ＲＧ－２）の化合物は、市販化合物、又は市販化合物から文献公知の製造方法により製造できる化合物である］で表わされる化合物を用いて、上記［製造方法Ｂ］＜工程１＞に準じる反応を行い、式（ＡＭ－１）の化合物を製造することができる。 <Step 2> [Production Method B] Using the compound of formula (IM-6) obtained in <Step 1> and N-bromosuccinimide (NBS), methods known in the literature, for example, “International Publication 2009/088103” N-methylpyrrolidone, dimethylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and other solvents (solvents not involved in the reaction), or a mixture thereof The compound represented by the formula (IM-7) can be produced by performing the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a solvent.
<Step 3> [Production Method B] Formula (IM-7) and Formula (RG-2) obtained in <Step 2> [The compound of formula (RG-2) is a commercially available compound or a known compound from a commercially available compound. The compound of formula (AM-1) can be produced by carrying out a reaction according to the above [Production Method B] <Step 1> using the compound represented by [which is a compound that can be produced by the production method].
　上記、［製造方法Ａ］又は［製造方法Ｂ］において、式(ＳＭ－１)、式(ＳＭ－２)、式(ＩＭ－１)、式(ＩＭ－２)、式(ＩＭ－３)、式(ＩＭ－４)、式(ＩＭ－５)、式(ＩＭ－６)、及び式(ＩＭ－７)の化合物は、塩を形成していてもよく、かかる塩としては、製薬学的に許容し得る塩であれば特に限定されないが、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性、又は酸性アミノ酸との塩などが挙げられる。金属塩の好適な例としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩、アルミニウム塩などが挙げられる（例えば、モノ塩の他、二ナトリウム塩、二カリウム塩も含む）。有機塩基との塩の好適な例としては、例えば、メチルアミン、エチルアミン、ｔ－ブチルアミン、ｔ－オクチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、ジベンジルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ピペリジン、モルホリン、ピリジン、ピコリン、リシン、アルギニン、オルニチン、エチレンジアミン、Ｎ－メチルグルカミン、グルコサミン、フェニルグリシンアルキルエステル、グアニジン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、Ｎ，Ｎ'－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、よう化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸等との塩、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、リンゴ酸、酒石酸等の脂肪族ジカルボン酸との塩、クエン酸等の脂肪族トリカルボン酸との塩、安息香酸、サリチル酸等の芳香族モノカルボン酸との塩、フタル酸等の芳香族ジカルボン酸の塩、桂皮酸、グリコール酸、ピルビン酸、オキシル酸、サリチル酸、Ｎ－アセチルシステイン等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩、アスパラギン酸、グルタミン酸等の酸性アミノ酸類との酸付加塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩（例、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩など）などの無機塩、アンモニウム塩など、又、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸など無機酸との塩、又は酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸などの有機酸との塩が挙げられる。 In the above [Production Method A] or [Production Method B], Formula (SM-1), Formula (SM-2), Formula (IM-1), Formula (IM-2), Formula (IM-3), The compounds of formula (IM-4), formula (IM-5), formula (IM-6), and formula (IM-7) may form a salt, and as such a salt, pharmaceutically Although it is not particularly limited as long as it is an acceptable salt, examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic salts, and salts with acidic amino acids. It is done. Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included). Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
　また、上記、［製造方法Ａ］又は［製造方法Ｂ］において、式(ＩＭ－１)、式(ＩＭ－２)、式(ＩＭ－３)、式(ＩＭ－４)、式(ＩＭ－５)、式(ＩＭ－６)、及び式(ＩＭ－７)の化合物は、反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、それ自体が公知の手段、例えば、抽出、濃縮、中和、濾過、蒸留、再結晶、クロマトグラフィーなどの分離手段により容易に精製することができる。 In addition, in the above [Production Method A] or [Production Method B], the formula (IM-1), the formula (IM-2), the formula (IM-3), the formula (IM-4), the formula (IM-5) ), The formula (IM-6), and the compound of the formula (IM-7) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. It can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
　上記、［製造方法Ａ］又は［製造方法Ｂ］において、製造方法中の反応条件については、特に断らない限り、以下の如きとする。反応温度は、－７８℃から溶媒が還流する温度の範囲であれば、限定されない。又、反応時間は、特に断らない限り、反応が十分に進行する時間であれば、限定されない。
　前記反応温度における、「－７８℃から溶媒が還流する温度の範囲」の意味する処は、－７８℃から反応に用いる溶媒（又は混合溶媒）が還流する温度迄の範囲内の温度を意味する。例えば、溶媒にメタノールを用いる場合、「－７８℃から溶媒が還流する温度で」とは、－７８℃からメタノールが還流する温度迄の範囲内の温度を意味する。また、同様に「－７８℃から反応溶液が還流する温度で」とは、－７８℃から反応溶液が還流する温度迄の範囲内の任意の温度を意味する。 In the above [Production Method A] or [Production Method B], the reaction conditions in the production method are as follows unless otherwise specified. The reaction temperature is not limited as long as it is in the range from −78 ° C. to the temperature at which the solvent is refluxed. The reaction time is not limited as long as the reaction is sufficiently advanced unless otherwise specified.
The term “range of the temperature at which the solvent refluxes from −78 ° C.” in the reaction temperature means a temperature within the range from −78 ° C. to the temperature at which the solvent (or mixed solvent) used in the reaction refluxes. . For example, when methanol is used as the solvent, “at a temperature at which the solvent is refluxed from −78 ° C.” means a temperature within a range from −78 ° C. to a temperature at which the methanol is refluxed. Similarly, “at a temperature at which the reaction solution is refluxed from −78 ° C.” means any temperature within a range from −78 ° C. to a temperature at which the reaction solution is refluxed.
　また、上記、［製造方法Ａ］又は［製造方法Ｂ］の各工程は、無溶媒、あるいは反応前に原料化合物を適当な溶媒に溶解又は懸濁して行うことができる。前記溶媒としては、反応に関与しない溶媒が好ましく、例えば、水、シクロヘキサン、ヘキサン、ベンゼン、クロロベンゼン、トルエン、キシレン、メタノール、エタノール、１－プロパノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン（ＮＭＰ）、ヘキサメチルホスホリックトリアミド、１，３‐ジメチル‐２‐イミダゾリジノン、ジメチルスルホキシド、アセトニトリル、プロピオニトリル、ジエチルエーテル、ジイソプロピルエーテル、ジフェニルエーテル、メチルｔｅｒｔ－ブチルエーテル（ＭＴＢＥ）、テトラヒドロフラン、２－メチルテトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、酢酸メチル、酢酸エチル、酢酸ブチル、アセトン、メチルエチルケトン、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、ルチジン、無水酢酸、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、メタンスルホン酸、塩酸、及び硫酸等が挙げられる。これらの溶媒は、単独で用いることも可能であり、又は反応条件により適宜選択し二種以上の溶媒を適宜の割合で混合して用いることも可能である。これらの溶媒は、反応条件に応じて適宜選択される。
　本明細書の製造方法中、特に断らない限り、「溶媒」、「反応に関与しない溶媒」又は「反応に不活性な溶媒」と記載した場合、使用する溶媒は、一種の溶媒を単独で用いてもよく、又は反応条件により適宜選択し二種以上の溶媒を適宜の割合で混合して用いてもよいことを意味する。 Each step of [Production Method A] or [Production Method B] can be performed without solvent or by dissolving or suspending the raw material compound in an appropriate solvent before the reaction. The solvent is preferably a solvent that does not participate in the reaction. For example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N, N— Dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, diethyl Ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl acetate , Ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, acetic anhydride, formic acid, acetic acid, propionic acid, trifluoro Examples include acetic acid, methanesulfonic acid, hydrochloric acid, and sulfuric acid. These solvents can be used alone, or can be appropriately selected depending on the reaction conditions, and two or more solvents can be mixed and used at an appropriate ratio. These solvents are appropriately selected according to the reaction conditions.
Unless otherwise specified, in the production method of the present specification, when “solvent”, “solvent not involved in the reaction” or “solvent inert to the reaction” is described, the solvent to be used is a single solvent. Alternatively, it may be selected as appropriate depending on the reaction conditions, and two or more solvents may be mixed and used at an appropriate ratio.
　上記、［製造方法Ａ］又は［製造方法Ｂ］の各工程で用いられる塩基（又は脱酸剤）としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸カルシウム、炭酸水素ナトリウム、リン酸三カリウム、酢酸ナトリウム、フッ化セシウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、４－ジメチルアミノピリジン（ＤＭＡＰ）、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン、１，５－ジアザビシクロ［４.３.０］－５－ノネン、１，４－ジアザビシクロ［２.２.２］オクタン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン（ＤＢＵ）、イミダゾール、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、水素化ナトリウム、水素化カリウム、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、メチルリチウム、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム等が挙げられる。但し、上記に記載したものに必ずしも限定されるわけではない。これらの塩基は、反応条件に応じて適宜選択される。 Examples of the base (or deoxidizing agent) used in each step of [Production Method A] or [Production Method B] include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, Sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4- Dimethylaminopyridine (DMAP), N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4- Diazabicyclo [2.2.2] octane, 1,8-dia Zabicyclo [5.4.0] -7-undecene (DBU), imidazole, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide Lithium hexamethyldisilazide, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and the like. However, it is not necessarily limited to those described above. These bases are appropriately selected depending on the reaction conditions.
　上記［製造方法Ａ］又は［製造方法Ｂ］の各工程で用いられる酸、又は酸触媒は、例えば、塩酸、硫酸、硝酸、臭化水素酸、リン酸、酢酸、トリフルオロ酢酸、シュウ酸、フタル酸、フマル酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸、１０－カンファースルホン酸、三フッ化ホウ素エーテル錯体、ヨウ化亜鉛、無水塩化アルミニウム、無水塩化亜鉛、無水塩化鉄等が挙げられる。但し、上記に記載したものに必ずしも限定されるわけではない。これらの酸又は酸触媒は、反応条件に応じて適宜選択される。 Examples of the acid or acid catalyst used in each step of [Production Method A] or [Production Method B] include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, Phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous chloride Examples include zinc and anhydrous iron chloride. However, it is not necessarily limited to those described above. These acids or acid catalysts are appropriately selected according to the reaction conditions.
　次に、本発明をさらに詳細に説明するために実施例をあげるが、これらの例は単なる実施であって、本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 Next, examples will be given to describe the present invention in more detail. However, these examples are merely implementations, do not limit the present invention, and are changed without departing from the scope of the present invention. May be.
　核磁気共鳴スペクトル（ＮＭＲ）の測定には、ＪＥＯＬ　ＪＮＭ－ＥＣＸ４００　ＦＴ－ＮＭＲ又はＪＥＯＬ ＪＮＭ－ＥＣＸ３００ ＦＴ－ＮＭＲ（日本電子）を用いた。実施例中の1Ｈ－ＮＭＲデータにおいて1Ｈ－ＮＭＲ(#)と記載した場合、ＪＥＯＬ　ＪＮＭ－ＥＣＸ３００　ＦＴ－ＮＭＲ（日本電子）を用いて測定をしたことを意味する。液体クロマトグラフィー－質量分析スペクトル（ＬＣ－Ｍａｓｓ）は以下の方法で測定した。［ＵＰＬＣ］Ｗａｔｅｒｓ　ＡＱＵＩＴＹ　ＵＰＬＣシステム及びＢＥＨ　Ｃ１８カラム（２．１ｍｍ×５０ｍｍ、１．７μｍ）（Ｗａｔｅｒｓ）を用い、参考例ではアセトニトリル：０．０５％トリフルオロ酢酸水溶液＝５：９５（０分）～９５：５（１．０分）～９５：５（１．６分）～５：９５（２．０分）の移動相及びグラジエント条件を、実施例ではアセトニトリル：１０ｍＭ重炭酸アンモニウム水溶液（５％アセトニトリル）＝５：９５（０．５分）～１００：０（７．０分）～１００：０（７．５分）～５：９５（７．５１分）の移動相およびグラジエント条件を用いた。超臨界流体液体クロマトグラフィー（ＳＦＣ）による光学純度分析はＷａｔｅｒｓ　ＳＦＣ　ＵＰＣ２および対応するキラルカラムを用いて実施した。 For the measurement of nuclear magnetic resonance spectrum (NMR), JEOL JNM-ECX400 FT-NMR or JEOL JNM-ECX300 FT-NMR (JEOL) was used. When 1 H-NMR (#) is described in the 1 H-NMR data in the examples, it means that measurement was performed using JEOL JNM-ECX300 FT-NMR (JEOL). The liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method. [UPLC] Waters AQUITY UPLC system and BEH C18 column (2.1 mm × 50 mm, 1.7 μm) (Waters) were used, and in the reference example, acetonitrile: 0.05% trifluoroacetic acid aqueous solution = 5: 95 (0 min) to The mobile phase and gradient conditions from 95: 5 (1.0 min) to 95: 5 (1.6 min) to 5:95 (2.0 min) were used in the examples: acetonitrile: 10 mM aqueous ammonium bicarbonate (5% Acetonitrile) = 5: 95 (0.5 min) to 100: 0 (7.0 min) to 100: 0 (7.5 min) to 5:95 (7.51 min) mobile phase and gradient conditions were used. It was. Optical purity analysis by supercritical fluid liquid chromatography (SFC) was performed using Waters SFC UPC2 and the corresponding chiral column.
　1Ｈ－ＮＭＲデータ中、ＮＭＲシグナルのパターンで、ｓはシングレット、ｄはダブレット、ｔはトリプレット、ｑはカルテット、ｍはマルチプレット、ｂｒはブロード、Ｊはカップリング定数、Ｈｚはヘルツ、ＣＤＣｌ3は重クロロホルム、ＤＭＳＯ－Ｄ6は重ジメチルスルホキシド、ＣＤ3ＯＤは重メタノールを意味する。1Ｈ－ＮＭＲデータ中、水酸基（ＯＨ）、アミノ基（ＮＨ2）、カルボキシル基（ＣＯＯＨ）のプロトン等、ブロードバンドであるため確認ができないシグナルについては、データに記載していない。 1 H-NMR data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is Hertz, CDCl 3 Represents deuterated chloroform, DMSO-D 6 represents deuterated dimethyl sulfoxide, and CD 3 OD represents deuterated methanol. In 1 H-NMR data, signals that cannot be confirmed due to broadband such as hydroxyl (OH), amino group (NH 2 ), and carboxyl group (COOH) protons are not described in the data.
　ＬＣ－Ｍａｓｓデータ中、Ｍは分子量、ＲＴは保持時間、［Ｍ＋Ｈ］+，［Ｍ＋Ｎａ］+は分子イオンピークを意味する。
　参考例、実施例、及び実験例中のＬＣ－Ｍａｓｓ測定条件は、Ｗａｔｅｒｓ　ＡＱＵＩＴＹ　ＵＰＬＣシステムおよびＢＥＨ　Ｃ１８カラム（２．１ｍｍ×５０ｍｍ、１．７μｍ）（Ｗａｔｅｒｓ）を用い、アセトニトリル：０．０５％トリフルオロ酢酸水溶液＝５：９５（０分）～９５：５（１．０分）～９５：５（１．６分）～５：９５（２．０分）の移動相およびグラジエントである。 In LC-Mass data, M means molecular weight, RT means retention time, and [M + H] + and [M + Na] + mean molecular ion peaks.
The LC-Mass measurement conditions in the Reference Examples, Examples, and Experimental Examples were as follows: a Waters AQUITY UPLC system and a BEH C18 column (2.1 mm × 50 mm, 1.7 μm) (Waters), acetonitrile: 0.05% Aqueous fluoroacetic acid = mobile phase and gradient from 5:95 (0 min) to 95: 5 (1.0 min) to 95: 5 (1.6 min) to 5:95 (2.0 min).
　参考例及び実施例中の「室温」は、通常約２０～２５℃の温度を示すものとする。
　（実施例２）の表中の溶媒の欄のＤＣＭは、ジクロロメタン、ＤＣＥは、１，２－ジクロロエタンを意味する。 The “room temperature” in the reference examples and examples usually indicates a temperature of about 20 to 25 ° C.
DCM in the column of solvent in the table of (Example 2) means dichloromethane, DCE means 1,2-dichloroethane.
（参考例１）１，１－ジメチル－１，２－ジヒドロナフタレン（式（ＴＨ－１）においてｐ＝０の化合物）の合成法：
Figure JPOXMLDOC01-appb-I000088
(Reference Example 1) Synthesis method of 1,1-dimethyl-1,2-dihydronaphthalene (compound with p = 0 in formula (TH-1)):
Figure JPOXMLDOC01-appb-I000088
＜工程１＞　４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－１－オールの合成：
　市販の４，４－ジメチル－３，４－ジヒドロナフタレン－１（２Ｈ）－オン（ＣＡＳ番号：２９７９－６９－３）（１．０ｇ）のメタノール（１０ｍＬ）溶液に、氷水冷下、水素化ホウ素ナトリウム（０．２４ｇ）を２回に分けて加え、室温で１時間攪拌した。減圧下にてメタノールを除去し、得られた残渣に１規定水酸化ナトリウム水溶液（３０ｍＬ）と酢酸エチル（４０ｍＬ）を加えて分配した。有機層を飽和食塩水（２５ｍＬ）で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮することにより標記化合物（１．０ｇ）を淡黄色油状物として得た。 <Step 1> Synthesis of 4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol:
Hydrogenation of a commercially available 4,4-dimethyl-3,4-dihydronaphthalen-1 (2H) -one (CAS number: 2979-69-3) (1.0 g) in methanol (10 mL) under ice water cooling Sodium boron (0.24 g) was added in two portions and stirred at room temperature for 1 hour. Methanol was removed under reduced pressure, and 1N aqueous sodium hydroxide solution (30 mL) and ethyl acetate (40 mL) were added to the resulting residue for partitioning. The organic layer was washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.0 g) as a pale yellow oil.
1Ｈ－ＮＭＲデータ(δ:ppm)<300MHz>:(CDCl3) δ:7.43(1H,dd,J=8,2Hz),7.35(1H,dd,J=8,2Hz),7.30-7.17(2H,m),4.82-4.69(1H,m),2.16-2.04(1H,m),1.97-1.83(2H,m),1.74-1.54(1H,m),1.35(3H,s),1.26(3H,s).
MS-ESI(m/z)[M+H]+=159(-OH)、保持時間=1.04(分)。 1 H-NMR data (δ: ppm) <300 MHz>: (CDCl 3 ) δ: 7.43 (1H, dd, J = 8, 2 Hz), 7.35 (1H, dd, J = 8, 2 Hz), 7.30-7.17 ( 2H, m), 4.82-4.69 (1H, m), 2.16-2.04 (1H, m), 1.97-1.83 (2H, m), 1.74-1.54 (1H, m), 1.35 (3H, s), 1.26 ( 3H, s).
MS-ESI (m / z) [M + H] + = 159 (-OH), retention time = 1.04 (min).
＜工程２＞１，１－ジメチル－１，２－ジヒドロナフタレンの合成：
（参考例１）＜工程１＞で得られた化合物（１．０ｇ）とｐ－トルエンスルホン酸・１水和物（０．０５ｇ）のトルエン（１０ｍＬ）溶液を９０℃で１．５時間攪拌した。室温まで放冷後、酢酸エチル（４０ｍＬ）と飽和炭酸水素化ナトリウム水溶液（３０ｍＬ）を加えて分配した。有機層を飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥した後、乾燥した有機層をろ過後、得られた酢酸エチルを減圧下にて濃縮することにより標記化合物（０．８６ｇ）を黄色油状物として得た。 <Step 2> Synthesis of 1,1-dimethyl-1,2-dihydronaphthalene:
(Reference Example 1) A toluene (10 mL) solution of the compound (1.0 g) obtained in <Step 1> and p-toluenesulfonic acid monohydrate (0.05 g) was stirred at 90 ° C. for 1.5 hours. did. After cooling to room temperature, ethyl acetate (40 mL) and saturated aqueous sodium hydrogencarbonate (30 mL) were added and partitioned. The organic layer was washed with saturated brine, the organic layer was dried over sodium sulfate, the dried organic layer was filtered, and the resulting ethyl acetate was concentrated under reduced pressure to give the title compound (0.86 g). Obtained as a yellow oil.
1Ｈ－ＮＭＲデータ(δ:ppm)<400MHz>:(CDCl3)δ:7.30(1H,d,J=7Hz),7.22-7.12(2H,m),7.04(1H,dd,J=7,2Hz),6.48-6.43(1H,m),5.97-5.91(1H,m), 2.26(2H,dd,J=4,2Hz),1.28(6H,s).
MS-ESI(m/z)[M+H]+=159、保持時間=1.25(分)。 1 H-NMR data (δ: ppm) <400 MHz>: (CDCl 3 ) δ: 7.30 (1H, d, J = 7 Hz), 7.22-7.12 (2H, m), 7.04 (1H, dd, J = 7, 2Hz), 6.48-6.43 (1H, m), 5.97-5.91 (1H, m), 2.26 (2H, dd, J = 4,2Hz), 1.28 (6H, s).
MS-ESI (m / z) [M + H] + = 159, retention time = 1.25 (min).
（参考例２）５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－アミン（式（ＡＭ－１））の合成法：
Figure JPOXMLDOC01-appb-I000089
Reference Example 2 Synthesis method of 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine (formula (AM-1)):
Figure JPOXMLDOC01-appb-I000089
＜工程１＞　５－メチル－２－フェニルピリジン－３－アミンの合成：
　市販の２－クロロ－５－メチル－３－ピリジンアミン（ＣＡＳ番号：３４５５２－１３－１）（１．０ｇ）、フェニルボロニックアシッド（０．８６ｇ）およびテトラキストリフェニルホスフィンパラジウム（０．８１ｇ）を、エタノール（１５ｍＬ）、トルエン（３５ｍＬ）、および２規定炭酸カリウム水溶液（１１ｍＬ）の混合溶媒に加え、窒素雰囲気下、１００℃で１８時間攪拌した。放冷後、撹拌して得られた反応液に酢酸エチルと水を加えて分配し、有機層を飽和食塩水で洗浄、硫酸ナトリウムで乾燥した。乾燥した有機層をろ過後、得られた酢酸エチルを減圧下にて留去し、得られた残渣をヘプタン／酢酸エチルの混合溶媒に溶解し、シリカゲルカラムクロマトグラフィー（移動相：ヘプタン／酢酸エチル＝７０：３０－６５：３５－６０：４０）を通して得られた溶液を減圧下にて留去することで、標記化合物（１．２ｇ）を無色固体として得た。 <Step 1> Synthesis of 5-methyl-2-phenylpyridin-3-amine:
Commercially available 2-chloro-5-methyl-3-pyridinamine (CAS number: 34552-13-1) (1.0 g), phenylboronic acid (0.86 g) and tetrakistriphenylphosphine palladium (0.81 g) Was added to a mixed solvent of ethanol (15 mL), toluene (35 mL), and 2N aqueous potassium carbonate solution (11 mL), and the mixture was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. After allowing to cool, ethyl acetate and water were added to the reaction mixture obtained by stirring, and the mixture was partitioned. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtering the dried organic layer, the obtained ethyl acetate was distilled off under reduced pressure, and the resulting residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (mobile phase: heptane / ethyl acetate). = 70: 30-65: 35-60: 40), and the resulting solution was distilled off under reduced pressure to obtain the title compound (1.2 g) as a colorless solid.
1Ｈ－ＮＭＲデータ(δ:ppm)<400MHz>:(CDCl3)δ:7.97(1H,s),7.69-7.63(2H,m),7.50-7.43(2H,m),7.42-7.33(1H,m),6.87(1H,s),3.79(2H,br s),2.29(3H,s)。
MS-ESI(m/z)[M+H]+=185、保持時間=0.58(分)。 1 H-NMR data (δ: ppm) <400 MHz>: (CDCl 3 ) δ: 7.97 (1H, s), 7.69-7.63 (2H, m), 7.50-7.43 (2H, m), 7.42-7.33 (1H m), 6.87 (1H, s), 3.79 (2H, br s), 2.29 (3H, s).
MS-ESI (m / z) [M + H] + = 185, retention time = 0.58 (min).
＜工程２＞　６－ブロモ－５－メチル－２－フェニルピリジン－３－アミンの合成：
　（参考例２）＜工程１＞で得られた化合物（０．１９ｇ）のＮ－メチルピロリドン（２．０ｍＬ）溶液にＮ－ブロモスクシンイミド（０．２１ｇ）を加え、室温で２時間攪拌した。反応液に水（２．０ｍＬ）を加え、ｔｅｒｔ－ブチルメチルエーテルで二回抽出、有機層を水で洗浄した。得られたｔｅｒｔ－ブチルメチルエーテルを減圧下にて留去し、得られた残渣を、ヘプタン／酢酸エチルの混合溶媒に溶解し、シリカゲルカラムクロマトグラフィー（固定相：アミノ－シリカゲル、移動相：ヘプタン／酢酸エチル＝９０：１０～３０：１０）を通して得られた溶液を減圧下にて留去することで、標記化合物（０．２０ｇ）を褐色固体として得た。 <Step 2> Synthesis of 6-bromo-5-methyl-2-phenylpyridin-3-amine:
(Reference Example 2) N-bromosuccinimide (0.21 g) was added to a solution of the compound (0.19 g) obtained in <Step 1> in N-methylpyrrolidone (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Water (2.0 mL) was added to the reaction solution, extracted twice with tert-butyl methyl ether, and the organic layer was washed with water. The obtained tert-butyl methyl ether was distilled off under reduced pressure, and the obtained residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane) / Ethyl acetate = 90: 10 to 30:10) was distilled off under reduced pressure to obtain the title compound (0.20 g) as a brown solid.
1Ｈ－ＮＭＲデータ(δ:ppm)<300MHz>:(CDCl3)δ:7.67-7.61(2H,m),7.50-7.42(2H,m),7.41-7.34(1H,m),6.93(1H,d,J=1Hz),3.81(2H,br s),2.34(3H,s)。
MS-ESI(m/z)[M+H]+=263,265、保持時間=1.02(分)。 1 H-NMR data (δ: ppm) <300 MHz>: (CDCl 3 ) δ: 7.67-7.61 (2H, m), 7.50-7.42 (2H, m), 7.41-7.34 (1H, m), 6.93 (1H , d, J = 1 Hz), 3.81 (2H, br s), 2.34 (3H, s).
MS-ESI (m / z) [M + H] + = 263,265, retention time = 1.02 (min).
＜工程３＞５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－アミンの合成：
　（参考例２）＜工程２＞で得られた化合物（０．４０ｇ）の１，２－ジメトキシエタン（１０ｍＬ）と水（２．０ｍＬ）の混合溶液に、２－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）ピリミジン（０．４４ｇ）、炭酸セシウム（１．５ｇ）およびジクロロ［１，１‘ビス（ジフェニルホスフィノ）フェロセン］パラジウム　ジクロロメタン付加物（０．１２ｇ）を加え８０℃で４時間攪拌した。放冷後、反応液に水を加えた。反応液及び水の混合溶液中の不溶物をセライトパッドで濾別し、酢酸エチルで洗浄した。得られた濾液から有機層を分離し、水、飽和食塩水で順次洗浄し、硫酸ナトリウムで乾燥した。乾燥した有機層をろ過後、得られた酢酸エチルを減圧下にて留去し、得られた残渣をヘプタン／酢酸エチルの混合溶媒に溶解し、シリカゲルカラムクロマトグラフィー（固定相：アミノ－シリカゲル、移動相：ヘプタン／酢酸エチル＝１００：０～５０：５０）を通して得られた溶液を減圧下にて留去することで、標記化合物（０．３１ｇ）を得た。 <Step 3> Synthesis of 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine:
Reference Example 2 To a mixed solution of the compound obtained in <Step 2> (0.40 g) in 1,2-dimethoxyethane (10 mL) and water (2.0 mL) was added 2-methyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (0.44 g), cesium carbonate (1.5 g) and dichloro [1,1′bis (diphenylphosphino) ferrocene] Palladium dichloromethane adduct (0.12 g) was added and stirred at 80 ° C. for 4 hours. After allowing to cool, water was added to the reaction solution. Insoluble matter in the mixed solution of the reaction solution and water was filtered off through a celite pad and washed with ethyl acetate. The organic layer was separated from the obtained filtrate, washed successively with water and saturated brine, and dried over sodium sulfate. After filtering the dried organic layer, the obtained ethyl acetate was distilled off under reduced pressure, and the resulting residue was dissolved in a mixed solvent of heptane / ethyl acetate, and silica gel column chromatography (stationary phase: amino-silica gel, Mobile phase: heptane / ethyl acetate = 100: 0 to 50:50), and the resulting solution was distilled off under reduced pressure to obtain the title compound (0.31 g).
1Ｈ－ＮＭＲデータ(δ:ppm)<300MHz>:(CDCl3)δ:8.96(2H,s),7.74-7.69(2H,m),7.53-7.46(2H,m),7.44-7.38(1H,m),7.02(1H,s),3.99(2H,br s),2.41(3H,s),1.64(3H,s)。
MS-ESI(m/z)[M+H]+=277(-OH)、保持時間=0.66(分)。 1 H-NMR data (δ: ppm) <300 MHz>: (CDCl 3 ) δ: 8.96 (2H, s), 7.74-7.69 (2H, m), 7.53-7.46 (2H, m), 7.44-7.38 (1H , m), 7.02 (1H, s), 3.99 (2H, br s), 2.41 (3H, s), 1.64 (3H, s).
MS-ESI (m / z) [M + H] + = 277 (-OH), retention time = 0.66 (min).
（実施例１）
２，２，２－トリクロロエチル　（５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル）カルバメート（式（ＣＢ－１）においてＹ＝２，２，２－トリクロロエトキシ基の化合物）の合成（前記態様中の工程（５）（６））： 
Figure JPOXMLDOC01-appb-I000090
Example 1
2,2,2-trichloroethyl (5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl) carbamate (in formula (CB-1) Y = 2,2, Synthesis of 2-trichloroethoxy group compound (steps (5) and (6) in the above embodiment):
Figure JPOXMLDOC01-appb-I000090
（参考例２）で得られた化合物（０．３０ｇ）の１，２－ジクロロエタン（１００ｍＬ）溶液にピリジン（０．２２ｍＬ）および２，２，２－トリクロロエチルクロロホルメート（０．３６ｍＬ）を室温で加え、同温にて１時間攪拌した。撹拌して得られた反応液に炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、得られた有機層を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（固定相：アミノ－シリカゲル、移動相：ヘプタン／酢酸エチル＝２：１）で精製し、標記化合物（０．４１ｇ）を白色固体として得た。
1H-NMR(#)(CDCl3) δ: 8.89 (2H, s), 8.41 (1H, br s), 7.67-7.61 (2H, m), 7.60-7.47 (3H, m), 7.06 (1H, br s), 4.86 (2H, s), 2.81 (3H, s), 2.50 (3H, s).
LCMS m/z [M+H]+=451、453、455.UPLC保持時間:1.12分 To a 1,2-dichloroethane (100 mL) solution of the compound (0.30 g) obtained in (Reference Example 2), pyridine (0.22 mL) and 2,2,2-trichloroethyl chloroformate (0.36 mL) were added. It added at room temperature and stirred at the same temperature for 1 hour. A sodium bicarbonate aqueous solution was added to the reaction solution obtained by stirring, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the obtained organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane / ethyl acetate = 2: 1) to give the title compound (0.41 g) as a white solid Got as.
1 H-NMR (#) (CDCl 3 ) δ: 8.89 (2H, s), 8.41 (1H, br s), 7.67-7.61 (2H, m), 7.60-7.47 (3H, m), 7.06 (1H, br s), 4.86 (2H, s), 2.81 (3H, s), 2.50 (3H, s).
LCMS m / z [M + H] + = 451, 453, 455.UPLC retention time: 1.12 minutes
（実施例２）
（１ａＲ，７ｂＳ）－３，３－ジメチル－１ａ，２，３，７ｂ－テトラヒドロナフト［１，２－ｂ］オキシレン（式（ＥＰ－１）においてｐ＝０の化合物）の合成（前記態様中の工程（１）（２））：
Figure JPOXMLDOC01-appb-I000091
(Example 2)
Synthesis of (1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxylene (compound of formula (EP-1) with p = 0) Step (1) (2)):
Figure JPOXMLDOC01-appb-I000091
　文献公知、例えば『国際公開第２００６／０８７８７４号パンフレット』に記載された方法に準じて合成した配位子の、３，３’’－（（（（１Ｒ，２Ｒ）－シクロヘキサン－１，２－ジイル）ビス（アザネジル））ビス（メチレン））ビス（２’－メトキシ－［１，１’－ビフェニル］－２－オール）：（ＣＡＳ番号：９２８７６９－１２－４） を、ジクロロメタン又は１，２－ジクロロエタンに溶解させた後、チタン触媒であるチタンテトライソプロポキシドを加え、１５℃～２５℃で１時間撹拌した。撹拌した混合溶液に、（参考例１）で得られた化合物（式（ＴＨ－１）においてｐ＝０の化合物）及びリン酸緩衝液を加えた。（以下、ｉ室温反応する場合、又はii加熱反応する場合の条件に分けて記載する）。
［ｉ室温反応する場合］その後、前記反応溶液に３０％過酸化水素水を加え、室温で撹拌した。反応後、室温下にて飽和チオ硫酸ナトリウム水溶液を加え有機層と水層を分離し、水層をジクロロメタンで抽出した。有機層と抽出溶液の混合溶液を減圧下濃縮し、標記化合物の粗生成体を褐色油状物質として得た。
［ii加熱反応する場合］その後、当該反応溶液が還流する温度（ジクロロメタンの場合：外温が４０℃±５℃、１，２－ジクロロエタンの場合：外温が６０℃±５℃）に昇温させ、前記反応溶液に３０％過酸化水素水を加え、更に反応溶液が還流する温度（ジクロロメタンの場合：外温が４０℃±５℃、１，２－ジクロロエタンの場合：外温が６０℃±５℃）で撹拌した。反応後、室温下にて飽和チオ硫酸ナトリウム水溶液を加え有機層と水層を分離し、水層をジクロロメタンで抽出した。有機層と抽出溶液の混合溶液を減圧下濃縮し、標記化合物の粗生成体を褐色油状物質として得た。 3,3 ″-(((((1R, 2R) -cyclohexane-1,2-) of a ligand synthesized according to a method known in the literature, for example, described in “Pamphlet of International Publication No. 2006/087874”. Diyl) bis (azanezyl)) bis (methylene)) bis (2′-methoxy- [1,1′-biphenyl] -2-ol): (CAS number: 926769-12-4) in dichloromethane or 1,2 -After dissolving in dichloroethane, titanium tetraisopropoxide as a titanium catalyst was added and stirred at 15 to 25 ° C for 1 hour. To the stirred mixed solution, the compound obtained in (Reference Example 1) (compound with p = 0 in formula (TH-1)) and a phosphate buffer were added. (Hereinafter, the conditions are described separately for i reaction at room temperature or ii heating reaction).
[When reacting at room temperature] Thereafter, 30% aqueous hydrogen peroxide was added to the reaction solution, and the mixture was stirred at room temperature. After the reaction, a saturated aqueous sodium thiosulfate solution was added at room temperature to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with dichloromethane. The mixed solution of the organic layer and the extraction solution was concentrated under reduced pressure to obtain a crude product of the title compound as a brown oily substance.
[In the case of heating reaction] Thereafter, the temperature is raised to a temperature at which the reaction solution refluxes (in the case of dichloromethane: external temperature is 40 ° C. ± 5 ° C., in the case of 1,2-dichloroethane: the external temperature is 60 ° C. ± 5 ° C.) 30% hydrogen peroxide solution is added to the reaction solution, and the reaction solution is refluxed (in the case of dichloromethane: external temperature is 40 ° C. ± 5 ° C., in the case of 1,2-dichloroethane: the external temperature is 60 ° C. ± (5 ° C.). After the reaction, a saturated aqueous sodium thiosulfate solution was added at room temperature to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with dichloromethane. The mixed solution of the organic layer and the extraction solution was concentrated under reduced pressure to obtain a crude product of the title compound as a brown oily substance.
上記反応を、下表の各種条件にて実施した（実施例2A～2D；参考例2a～2c）。
表Ａ
Figure JPOXMLDOC01-appb-I000092
　なお、表Ａ中の溶媒のDCEは１，２－ジクロロエタンを意味し、DCMはジクロロメタンを意味する。 The above reaction was carried out under the various conditions shown in the following table (Examples 2A to 2D; Reference Examples 2a to 2c).
Table A
Figure JPOXMLDOC01-appb-I000092
In Table A, the solvent DCE means 1,2-dichloroethane, and DCM means dichloromethane.
表Ｂ
Figure JPOXMLDOC01-appb-I000093
　なお、表Ｂ中の溶媒のDCEは１，２－ジクロロエタンを意味し、DCMはジクロロメタンを意味する。
　参考例2aは、Synlett,20,p3545-3547,2006年（非特許文献３）に記載の反応条件下での反応であり、参考例2bは、Synlett,15,p2445-2447,2007年（非特許文献４）に記載の反応条件下での反応である。 Table B
Figure JPOXMLDOC01-appb-I000093
In Table B, DCE as a solvent means 1,2-dichloroethane, and DCM means dichloromethane.
Reference Example 2a is a reaction under the reaction conditions described in Synlett, 20, p3545-3547, 2006 (Non-patent Document 3), and Reference Example 2b is Synlett, 15, p2445-2447, 2007 (non-patent document 3). This is a reaction under the reaction conditions described in Patent Document 4).
　上記表中の転化率は、反応により消失した反応物質（出発物質）の供給量に対する割合を意味する。即ち、転化率が高いほど、反応物質（出発物質）が消失しており、反応が進行していると解することができる。転嫁率の測定は、ＵＰＬＣの２２０ｎｍＵＶスペクトル強度から算出した。又、測定収率は、ＮＭＲから内部標準物質（テレフタル酸ジメチル）との比較により算出した。 The conversion rate in the above table means the ratio to the supply amount of the reaction material (starting material) disappeared by the reaction. That is, it can be understood that the higher the conversion rate, the more the reaction material (starting material) disappears and the reaction proceeds. The pass-through rate was calculated from the UPLC 220 nm UV spectrum intensity. The measurement yield was calculated by comparison with an internal standard substance (dimethyl terephthalate) from NMR.
［（１ａＲ，７ｂＳ）－３，３－ジメチル－１ａ，２，３，７ｂ－テトラヒドロナフト［１，２－ｂ］オキシレンのデータ］；
1H-NMR (CDCl3) δ: 7.42 (1H, dd, J = 8.0, 1.2 Hz), 7.37-7.30 (2H, m), 7.20 (1H, td, J = 7.2, 1.2 Hz), 3.86 (1H, d, J = 4.1 Hz), 3.73-3.71 (1H, m), 2.21 (1H, dd, J = 15.2, 2.8 Hz), 1.84 (1H, d, J = 15.2 Hz), 1.36 (3H, s), 1.31 (3H, s).
LCMS m/z [M+H]+=175、UPLC保持時間: 4.08分 
光学純度分析:1% イソプロパノール (0.1%ジエチルアミン含有), 3.0mL/分, CHIRALCEL OD-H(4.6mm×150mm、5.0μm)(daicel), major 2.35, minor 2.20. [Data for (1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxylene];
1 H-NMR (CDCl 3 ) δ: 7.42 (1H, dd, J = 8.0, 1.2 Hz), 7.37-7.30 (2H, m), 7.20 (1H, td, J = 7.2, 1.2 Hz), 3.86 (1H , d, J = 4.1 Hz), 3.73-3.71 (1H, m), 2.21 (1H, dd, J = 15.2, 2.8 Hz), 1.84 (1H, d, J = 15.2 Hz), 1.36 (3H, s) , 1.31 (3H, s).
LCMS m / z [M + H] + = 175, UPLC retention time: 4.08 minutes
Optical purity analysis: 1% isopropanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm x 150 mm, 5.0 μm) (daicel), major 2.35, minor 2.20.
（実施例３）
（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オール（式（ＡＭ－Ｘ）においてｐ＝０の化合物）の合成（前記態様中の工程（３）（４））：
Figure JPOXMLDOC01-appb-I000094
Example 3
Synthesis of (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol (compound with formula p = 0 in formula (AM-X)) Step (3) (4)):
Figure JPOXMLDOC01-appb-I000094
　（実施例２ｊ）の方法で得られた（１ａＲ，７ｂＳ）－３，３－ジメチル－１ａ，２，３，７ｂ－テトラヒドロナフト［１，２－ｂ］オキシレン（２．０ｇ，　５１％純度）のエタノール（５．１ｍＬ）溶液中に、２５％アンモニア水（５．１ｍＬ）を加え、封管中１００℃で２時間攪拌した。放冷後、反応液に水と飽和食塩水を加え、酢酸エチルで２回抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、濾過後に減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（固定相：アミノ－シリカゲル、移動相：ヘプタン／酢酸エチル＝１００：０～０：１００）で精製し、標記化合物（０．７６ｇ）を得た。
［（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オールのデータ］；
1H-NMR (DMSO-D6) δ: 7.62-7.60 (1H, m), 7.29-7.26 (1H, m), 7.17-7.10 (2H, m), 4.79 (1H, d, J = 4.0 Hz) 3.49-3.40 (2H, m), 1.85 (2H, br s), 1.78 (1H, dd, J = 13.2, 2.8 Hz), 1.28 (3H, s), 1.23 (3H, s).
LCMS m/z [M+H]+=192、UPLC保持時間: 2.39分
光学純度分析:10% メタノール (0.1%ジエチルアミン含有), 3.0mL/分, CHIRALCEL OD-H(4.6mm×150mm、5.0μm)(daicel), major 1.90分, minor 2.32分. 鏡像体過剰率99%.
　得られた、（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オールは、下記（実験例１）に示すように有機酸との付加塩・水和物を形成できる。 (1aR, 7bS) -3,3-dimethyl-1a, 2,3,7b-tetrahydronaphtho [1,2-b] oxylene (2.0 g, 51% purity) obtained by the method of Example 2j 25% aqueous ammonia (5.1 mL) was added to an ethanol (5.1 mL) solution, and the mixture was stirred at 100 ° C. for 2 hours in a sealed tube. After allowing to cool, water and saturated brine were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (stationary phase: amino-silica gel, mobile phase: heptane / ethyl acetate = 100: 0 to 0: 100) to obtain the title compound (0.76 g).
[Data for (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol];
1 H-NMR (DMSO-D 6 ) δ: 7.62-7.60 (1H, m), 7.29-7.26 (1H, m), 7.17-7.10 (2H, m), 4.79 (1H, d, J = 4.0 Hz) 3.49-3.40 (2H, m), 1.85 (2H, br s), 1.78 (1H, dd, J = 13.2, 2.8 Hz), 1.28 (3H, s), 1.23 (3H, s).
LCMS m / z [M + H] + = 192, UPLC retention time: 2.39 min Optical purity analysis: 10% methanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm x 150 mm, 5.0 μm ) (daicel), major 1.90min, minor 2.32min. Enantiomeric excess rate 99%.
The obtained (1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol is obtained with an organic acid as shown below (Experimental Example 1). Can form addition salts and hydrates.
（実験例１）（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オール （２Ｓ，３Ｓ）－２，３－ジヒドロスクシネート １水和物の合成
（実施例３）の方法で得られた化合物（９．５ｇ）とＤ－（-）－酒石酸（７．４　ｇ）をアセトニトリル（１１３ｍＬ）と水（１２．５ｍＬ）の混合溶媒に溶解し、７５℃で１時間加熱還流した。反応液を冷却し、室温で２時間撹拌後、析出した白色固体を濾取し、水とアセトニトリルの混合溶液で洗浄することで標記化合物（１２ｇ）を得た。
［（１Ｒ，２Ｒ）－１－アミノ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－２－オール （２Ｓ，３Ｓ）－２，３－ジヒドロスクシネート １水和物のデータ］；
1H-NMR (DMSO-D6) δ: 7.48 (1H, d, J = 7.4 Hz), 7.44 (1H, dd, J = 7.6, 1.0 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.27 (1H, td, J = 7.4, 1.0 Hz), 4.06 (1H, d, J = 9.0 Hz), 3.96 (2H, s), 1.89 (1H, dd, J = 12.8, 3.4 Hz), 1.72 (1H, t, J = 12.8 Hz), 1.32 (3H, s), 1.27 (3H, s).
LCMS m/z [M+H]+= 192、ＵＰＬＣ保持時間: 2.43分 
光学純度分析:１０％ メタノール (０．１％ジエチルアミン含有), 3.0mL/分, CHIRALCEL OD-H(4.6mm×150mm、5.0μm)(daicel), major 1.89分, minor 2.38分. 鏡像体過剰率100%. Experimental Example 1 (1R, 2R) -1-Amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol (2S, 3S) -2,3-dihydrosuccinate 1 Synthesis of Hydrate Compound (9.5 g) obtained by the method of Example 3 and D-(−)-tartaric acid (7.4 g) were mixed with acetonitrile (113 mL) and water (12.5 mL). It melt | dissolved in the solvent and heated and refluxed at 75 degreeC for 1 hour. The reaction mixture was cooled and stirred at room temperature for 2 hours. The precipitated white solid was collected by filtration and washed with a mixed solution of water and acetonitrile to obtain the title compound (12 g).
[(1R, 2R) -1-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol (2S, 3S) -2,3-dihydrosuccinate monohydrate data];
1H-NMR (DMSO-D6) δ: 7.48 (1H, d, J = 7.4 Hz), 7.44 (1H, dd, J = 7.6, 1.0 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.27 ( 1H, td, J = 7.4, 1.0 Hz), 4.06 (1H, d, J = 9.0 Hz), 3.96 (2H, s), 1.89 (1H, dd, J = 12.8, 3.4 Hz), 1.72 (1H, t , J = 12.8 Hz), 1.32 (3H, s), 1.27 (3H, s).
LCMS m / z [M + H] + = 192, UPLC retention time: 2.43 minutes
Optical purity analysis: 10% methanol (containing 0.1% diethylamine), 3.0 mL / min, CHIRALCEL OD-H (4.6 mm x 150 mm, 5.0 μm) (daicel), major 1.89 min, minor 2.38 min. Enantiomeric excess 100%.
（実施例４）
１－（（１Ｒ，２Ｒ）－２－ヒドロキシ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－１－イル）－３－（５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル）ウレア（式（Ｉ）においてｐ＝０の化合物）の合成（前記態様中の工程（７）（８））： Example 4
1-((1R, 2R) -2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -3- (5-methyl-6- (2-methylpyrimidine- Synthesis of 5-yl) -2-phenylpyridin-3-yl) urea (compound with p = 0 in formula (I)) (steps (7) and (8) in the above embodiment):
Figure JPOXMLDOC01-appb-I000095
Figure JPOXMLDOC01-appb-I000095
　（実施例３）で得られた化合物（０．７５ｇ）と（実施例１）で得られた化合物（１．７７ｇ）のジメチルスルホキシド（１０ｍＬ）溶液に、ジアザビシクロウンデセン（０．５９ｍＬ）を加えて室温で一夜攪拌した。撹拌して得られた反応液に水（１０ｍＬ）とエタノール（１０ｍＬ）を加え、５５℃で１時間攪拌した。撹拌して得られた反応液を冷却し、室温で３時間攪拌後、析出した沈殿を濾取し、水とエタノールの混合溶液で洗浄、減圧乾燥することにより標記化合物（１．５９ｇ、８２％）を得た。
［１－（（１Ｒ，２Ｒ）－２－ヒドロキシ－４，４－ジメチル－１，２，３，４－テトラヒドロナフタレン－１－イル）－３－（５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル）ウレアのデータ］；
1H-NMR (DMSO-D6) δ: 8.94 (2H, s), 8.42 (1H, s), 7.79 (1H, br s), 7.65 (2H, d, J = 6.8 Hz), 7.52-7.43 (3H, m), 7.32 (1H, d, J = 6.8 Hz), 7.21-7.16 (4H, m), 4.94 (1H, d, J = 4.4 Hz), 4.58 (1H, t, J = 8.8 Hz), 3.75-3.68 (1H, m), 2.68 (3H, s), 2.43 (3H, s), 1.84 (1H, dd, J = 12.8, 3.6 Hz), 1.70 (1H, t, J = 12.0 Hz), 1.31 (3H, s), 1.23 (3H, s).
LCMS m/z [M+H]+=494.UPLC保持時間: 3.75分
光学純度分析:30% エタノール, 3.0mL/分, CHIRALPAK IC(4.6mm×150mm、5.0μm)(daicel), major 3.34分, minor 2.83分. 鏡像体過剰率100%. Diazabicycloundecene (0.59 mL) was added to a solution of the compound (0.75 g) obtained in (Example 3) and the compound (1.77 g) obtained in (Example 1) in dimethyl sulfoxide (10 mL). And stirred at room temperature overnight. Water (10 mL) and ethanol (10 mL) were added to the reaction solution obtained by stirring, and the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture obtained by stirring was cooled and stirred at room temperature for 3 hours. The deposited precipitate was collected by filtration, washed with a mixed solution of water and ethanol, and dried under reduced pressure to give the title compound (1.59 g, 82% )
[1-((1R, 2R) -2-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -3- (5-methyl-6- (2-methylpyrimidine -5-yl) -2-phenylpyridin-3-yl) urea data];
1 H-NMR (DMSO-D 6 ) δ: 8.94 (2H, s), 8.42 (1H, s), 7.79 (1H, br s), 7.65 (2H, d, J = 6.8 Hz), 7.52-7.43 ( 3H, m), 7.32 (1H, d, J = 6.8 Hz), 7.21-7.16 (4H, m), 4.94 (1H, d, J = 4.4 Hz), 4.58 (1H, t, J = 8.8 Hz), 3.75-3.68 (1H, m), 2.68 (3H, s), 2.43 (3H, s), 1.84 (1H, dd, J = 12.8, 3.6 Hz), 1.70 (1H, t, J = 12.0 Hz), 1.31 (3H, s), 1.23 (3H, s).
LCMS m / z [M + H] + = 494.UPLC retention time: 3.75 min Optical purity analysis: 30% ethanol, 3.0 mL / min, CHIRALPAK IC (4.6 mm x 150 mm, 5.0 μm) (daicel), major 3.34 min , minor 2.83 min. Enantiomeric excess 100%.
　本発明によれば、式（Ｉ）で表される化合物を、短工程、かつ工業的生産に適した製造方法が提供される。また、式（Ｉ）で表される化合物の製造の為の中間体である式（ＡＭ－Ｘ）で表される化合物の有用な製造方法が提供される。 According to the present invention, there is provided a production method suitable for industrial production of the compound represented by formula (I) in a short process. In addition, a useful process for producing a compound represented by the formula (AM-X), which is an intermediate for the production of the compound represented by the formula (I), is provided.

Claims (12)

  1. 下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-I000001
    ［式（Ｉ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表される化合物の製造方法であって、以下の工程：
    （１）下記式（ＴＨ－１）：
    Figure JPOXMLDOC01-appb-I000002
    ［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物と、チタン触媒と、下記式（ＬＧ－１）：
    Figure JPOXMLDOC01-appb-I000003
    で表わされる配位子と、過酸化水素水と、緩衝液とを、溶媒中に加えて混合溶液（１）を得る工程、
    （２）前記混合溶液（１）を、外温３０℃～５０℃の範囲の温度で反応を行い、下記式（ＥＰ－１）：
    Figure JPOXMLDOC01-appb-I000004
    ［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物を得る工程、
    （３）前記式（ＥＰ－１）で表される化合物とアンモニア水とを含む混合溶液（３）を得る工程、
    （４）前記混合溶液（３）を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＡＭ－Ｘ）：
    Figure JPOXMLDOC01-appb-I000005
    ［式（ＡＭ－Ｘ）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物を得る工程、
    （５）下記式（ＡＭ－１）：
    Figure JPOXMLDOC01-appb-I000006
    ［式（ＡＭ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表わされる化合物と、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、２，２，２－トリクロロエチルクロロホルメート、クロロギ酸フェニル、クロロギ酸ｐ－ニトロフェニル、クロロギ酸ｐ－トリル、Ｎ，Ｎ´－カルボニルジイミダゾール、及びＮ，Ｎ´－ジスクシンイミジルカルボナートから選ばれるウレア化剤と、塩基とを、溶媒に加えて混合溶液（５）を得る工程、
    （６）前記混合溶液（５）を、０℃から前記混合溶液（５）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＣＢ－１）：
    Figure JPOXMLDOC01-appb-I000007
    ［式（ＣＢ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基であり；Ｙは、トリクロロメトキシ基、塩素原子、２，２，２－トリクロロエトキシ基、フェノキシ基、ｐ－ニトロフェノキシ基、ｐ－メチルフェノキシ基、イミダゾール－１－イル基、又は（２，５－ジオキソピロリジン－１－イル）オキシ基から選ばれる基である］で表わされる化合物を得る工程、
    （７）前記式（ＡＭ－Ｘ）で表わされる化合物と、前記式（ＣＢ－１）で表わされる化合物と、塩基とを、溶媒に加えて混合溶液（７）を得る工程、及び
    （８）前記混合溶液（７）を、０℃から前記混合溶液（７）が還流する温度までの間のいずれかの温度で反応を行い、式（Ｉ）で表される化合物を得る工程、
    を含むことを特徴とする、製造方法。     The following formula (I):
    Figure JPOXMLDOC01-appb-I000001
    [In the formula (I), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group; C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di C 2- 7 a substituent selected from an alkanoylamino group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps:
    (1) The following formula (TH-1):
    Figure JPOXMLDOC01-appb-I000002
    [In the formula (TH-1), p and R 1 are as defined in the formula (I)], a titanium catalyst, and the following formula (LG-1):
    Figure JPOXMLDOC01-appb-I000003
    A step of obtaining a mixed solution (1) by adding a ligand represented by the formula: hydrogen peroxide solution and a buffer solution to a solvent;
    (2) The mixed solution (1) is reacted at an external temperature ranging from 30 ° C. to 50 ° C., and the following formula (EP-1):
    Figure JPOXMLDOC01-appb-I000004
    [In the formula (EP-1), p and R 1 are as defined in the formula (I)] to obtain a compound represented by the formula:
    (3) obtaining a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia;
    (4) The mixed solution (3) is reacted at any temperature between 0 ° C. and a temperature at which the mixed solution (3) is refluxed, and the following formula (AM-X):
    Figure JPOXMLDOC01-appb-I000005
    [In the formula (AM-X), p and R 1 are as defined in the formula (I)] to obtain a compound represented by the formula:
    (5) The following formula (AM-1):
    Figure JPOXMLDOC01-appb-I000006
    [Wherein ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group], triphosgene, Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N ′ -Adding a urea agent selected from disuccinimidyl carbonate and a base to a solvent to obtain a mixed solution (5);
    (6) The mixed solution (5) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (5) is refluxed, and the following formula (CB-1):
    Figure JPOXMLDOC01-appb-I000007
    [In Formula (CB-1), Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, or (2,5-dioxopyrrolidin-1-yl) oxy group A compound represented by the following formula:
    (7) adding the compound represented by the formula (AM-X), the compound represented by the formula (CB-1), and a base to a solvent to obtain a mixed solution (7); and (8) Reacting the mixed solution (7) at any temperature between 0 ° C. and a temperature at which the mixed solution (7) is refluxed to obtain a compound represented by the formula (I);
    The manufacturing method characterized by including.
  2. 式（Ｉ）中、ｐは０又は１であり、
    Ｒ1は、ハロゲン原子、又はＣ1-6アルコキシＣ1-6アルキル基であり、
    工程（１）中のチタン触媒は、チタンテトラメトキシド、チタンテトラエトキシド、チタンテトラノルマルプロポキシド、チタンテトライソプロポキシド、チタンテトラノルマルブトキシド、又はチタンテトラターシャリーブトキシドであり、
    工程（１）中の溶媒は、有機溶媒であり、
    工程（１）中の緩衝液は、クエン酸／ＮａＯＨ緩衝液、クエン酸／クエン酸ナトリウム緩衝液、ホウ酸／ＮａＯＨ緩衝液、リン酸緩衝液、ＫＨ2ＰＯ4／ＮａＯＨ緩衝液であり、
    工程（５）中のウレア化剤は、クロロギ酸フェニル、クロロギ酸ｐ－トリル、又は２，２，２－トリクロロエチルクロロホルメートであり、
    工程（５）中の塩基は、有機塩基であり、
    工程（５）中の溶媒は、非プロトン性極性溶媒であり、
    式（ＣＢ－１）中のＹは、フェノキシ基、ｐ－メチルフェノキシ基、又は２，２，２－トリクロロエトキシ基であり、
    工程（７）中の塩基は、有機塩基であり、
    工程（７）中の溶媒は、非プロトン性極性溶媒である、
    請求項１に記載の製造方法。     In formula (I), p is 0 or 1,
    R 1 is a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group,
    The titanium catalyst in step (1) is titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetranormal butoxide, or titanium tetratertiary butoxide.
    The solvent in step (1) is an organic solvent,
    Buffers in step (1) are citrate / NaOH buffer, citrate / sodium citrate buffer, borate / NaOH buffer, phosphate buffer, KH 2 PO 4 / NaOH buffer,
    The ureating agent in step (5) is phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate,
    The base in step (5) is an organic base,
    The solvent in step (5) is an aprotic polar solvent,
    Y in the formula (CB-1) is a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group,
    The base in step (7) is an organic base,
    The solvent in step (7) is an aprotic polar solvent.
    The manufacturing method according to claim 1.
  3. 式（Ｉ）中、ｐは０であり、
    工程（１）中のチタン触媒は、チタンテトライソプロポキシドであり、
    工程（１）の溶媒は、ジクロロメタンであり、
    工程（１）中の緩衝液は、リン酸緩衝液であり、
    工程（５）中のウレア化剤は、２，２，２－トリクロロエチルクロロホルメートであり、
    工程（５）中の塩基は、ピリジンであり、
    工程（５）中の溶媒は、１，２－ジクロロエタンであり、
    式（ＣＢ－１）中のＹは、２，２，２－トリクロロエトキシ基であり、
    工程（７）中の塩基は、ジアザビシクロウンデセンであり、
    工程（７）中の溶媒は、ジメチルスルホキシドである、
    請求項１に記載の製造方法。     In formula (I), p is 0,
    The titanium catalyst in step (1) is titanium tetraisopropoxide,
    The solvent in step (1) is dichloromethane,
    The buffer in step (1) is a phosphate buffer,
    The urea agent in step (5) is 2,2,2-trichloroethyl chloroformate,
    The base in step (5) is pyridine;
    The solvent in step (5) is 1,2-dichloroethane,
    Y in the formula (CB-1) is a 2,2,2-trichloroethoxy group,
    The base in step (7) is diazabicycloundecene,
    The solvent in step (7) is dimethyl sulfoxide.
    The manufacturing method according to claim 1.
  4. 工程（１）において、過酸化水素水の量が、式（ＴＨ－１）１等量に対して、１．５～１０等量の範囲であり、かつ、チタン触媒の量が、式（ＴＨ－１）に対し０．１～１０ｍｏｌ％の範囲である、請求項１～３のいずれかに記載の製造方法。 In step (1), the amount of hydrogen peroxide water is in the range of 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1), and the amount of titanium catalyst is the formula (TH The production method according to any one of claims 1 to 3, wherein the content is in the range of 0.1 to 10 mol% relative to -1).
  5. 工程（１）において、反応溶液のｐＨが、ｐＨ＝７．４～８．０である、請求項１～４のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 4, wherein in the step (1), the pH of the reaction solution is pH = 7.4 to 8.0.
  6. 工程（１）において、溶媒の量が、式（ＴＨ－１）の質量に対して、５～２０倍量の範囲である、請求項１～５のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 5, wherein in step (1), the amount of the solvent is in the range of 5 to 20 times the mass of the formula (TH-1).
  7. 工程（１）において、反応温度（外温）が３５～４５℃の範囲である、請求項１～６のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein in step (1), the reaction temperature (external temperature) is in the range of 35 to 45 ° C.
  8. 工程（４）の反応が、封管反応瓶を用いる封管反応である、請求項１～７のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 7, wherein the reaction in the step (4) is a sealed tube reaction using a sealed tube reaction bottle.
  9. 下記式（ＡＭ－Ｘ）：
    Figure JPOXMLDOC01-appb-I000008
    ［式（ＡＭ－Ｘ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
    （１）下記式（ＴＨ－１）：
    Figure JPOXMLDOC01-appb-I000009
    ［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物と、チタン触媒と、下記式（ＬＧ－１）：
    Figure JPOXMLDOC01-appb-I000010
    で表わされる配位子と、過酸化水素水と、緩衝液とを、溶媒中に加えて混合溶液（１）を得る工程、
    （２）前記混合溶液（１）を、外温３０℃～５０℃の範囲の温度で反応を行い、下記式（ＥＰ－１）：
    Figure JPOXMLDOC01-appb-I000011
    ［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物を得る工程、
    （３）前記式（ＥＰ－１）で表される化合物とアンモニア水とを含む混合溶液（３）を得る工程、及び
    （４）前記混合溶液（３）を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、前記式（ＡＭ－Ｘ）で表される化合物を得る工程、
    を含むことを特徴とする、製造方法。     The following formula (AM-X):
    Figure JPOXMLDOC01-appb-I000008
    [In the formula (AM-X), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
    (1) The following formula (TH-1):
    Figure JPOXMLDOC01-appb-I000009
    [In the formula (TH-1), p and R 1 are as defined in the formula (AM-X)], a titanium catalyst, and the following formula (LG-1):
    Figure JPOXMLDOC01-appb-I000010
    A step of obtaining a mixed solution (1) by adding a ligand represented by the formula: hydrogen peroxide solution and a buffer solution to a solvent;
    (2) The mixed solution (1) is reacted at an external temperature ranging from 30 ° C. to 50 ° C., and the following formula (EP-1):
    Figure JPOXMLDOC01-appb-I000011
    [In the formula (EP-1), p and R 1 are as defined in the formula (AM-X)] to obtain a compound represented by the formula:
    (3) a step of obtaining a mixed solution (3) containing the compound represented by the formula (EP-1) and aqueous ammonia, and (4) the mixed solution (3) from 0 ° C. to the mixed solution (3 ) Reacting at any temperature up to the reflux temperature to obtain a compound represented by the formula (AM-X),
    The manufacturing method characterized by including.
  10. 下記式（ＥＰ－１）：
    Figure JPOXMLDOC01-appb-I000012
    ［式（ＥＰ－１）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
    （１）下記式（ＴＨ－１）：
    Figure JPOXMLDOC01-appb-I000013
    ［式（ＴＨ－１）中、ｐ及びＲ1は、前記式（ＥＰ－１）中の定義と同じである］で表される化合物と、チタン触媒と、下記式（ＬＧ－１）：
    Figure JPOXMLDOC01-appb-I000014
    で表わされる配位子と、過酸化水素水と、緩衝液とを、溶媒中に加えて混合溶液（１）を得る工程、及び
    （２）前記混合溶液（１）を、外温３０℃～５０℃の範囲の温度で反応を行い、前記式（ＥＰ－１）で表される化合物を得る工程、
    を含むことを特徴とする、製造方法。     Formula (EP-1) below:
    Figure JPOXMLDOC01-appb-I000012
    [In the formula (EP-1), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
    (1) The following formula (TH-1):
    Figure JPOXMLDOC01-appb-I000013
    [In the formula (TH-1), p and R 1 are as defined in the formula (EP-1)], a titanium catalyst, and the following formula (LG-1):
    Figure JPOXMLDOC01-appb-I000014
    And a step of adding a hydrogen peroxide solution and a buffer solution to a solvent to obtain a mixed solution (1), and (2) the mixed solution (1) having an external temperature of 30 ° C. to Carrying out the reaction at a temperature in the range of 50 ° C. to obtain a compound represented by the formula (EP-1);
    The manufacturing method characterized by including.
  11. 下記式（ＡＭ－Ｘ）：
    Figure JPOXMLDOC01-appb-I000015
    ［式（ＡＭ－Ｘ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基である］で表される化合物の製造方法であって、以下の工程：
    （３）下記式（ＥＰ－１）：
    Figure JPOXMLDOC01-appb-I000016
    ［式（ＥＰ－１）中、ｐ及びＲ1は、前記式（ＡＭ－Ｘ）中の定義と同じである］で表される化合物とアンモニア水とを含む混合溶液（３）を得る工程、及び
    （４）前記混合溶液（３）を、０℃から前記混合溶液（３）が還流する温度までの間のいずれかの温度で反応を行い、前記式（ＡＭ－Ｘ）で表される化合物を得る工程、
    を含むことを特徴とする、製造方法。     The following formula (AM-X):
    Figure JPOXMLDOC01-appb-I000015
    [In the formula (AM-X), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps:
    (3) The following formula (EP-1):
    Figure JPOXMLDOC01-appb-I000016
    [In the formula (EP-1), p and R 1 are the same as defined in the formula (AM-X)] to obtain a mixed solution (3) containing ammonia water, And (4) reacting the mixed solution (3) at any temperature between 0 ° C. and the temperature at which the mixed solution (3) is refluxed, and the compound represented by the formula (AM-X) Obtaining a step,
    The manufacturing method characterized by including.
  12. 下記式（Ｉ）：
    Figure JPOXMLDOC01-appb-I000017
    ［式（Ｉ）中、ｐは、０、１、及び２から選ばれる整数であり；Ｒ1は、ハロゲン原子、シアノ基、Ｃ1-6アルキル基、ハロゲン化Ｃ1-6アルキル基、ヒドロキシＣ1-6アルキル基、シアノ化Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ハロゲン化Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、モノ／ジＣ2-7アルカノイルアミノ基、カルボキサミド基、及びＣ1-6アルコキシカルボニル基から選ばれる置換基であり；環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表される化合物の製造方法であって、以下の工程：
    （５）下記式（ＡＭ－１）：
    Figure JPOXMLDOC01-appb-I000018
    ［式（ＡＭ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基である］で表わされる化合物と、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、２，２，２－トリクロロエチルクロロホルメート、クロロギ酸フェニル、クロロギ酸ｐ－ニトロフェニル、クロロギ酸ｐ－トリル、Ｎ，Ｎ´－カルボニルジイミダゾール、及びＮ，Ｎ´－ジスクシンイミジルカルボナートから選ばれるウレア化剤と、塩基とを、溶媒に加えて混合溶液（５）を得る工程、
    （６）前記混合溶液（５）を、０℃から前記混合溶液（５）が還流する温度までの間のいずれかの温度で反応を行い、下記式（ＣＢ－１）：
    Figure JPOXMLDOC01-appb-I000019
    ［式（ＣＢ－１）中、環Ａは、５－メチル－６－（２－メチルピリミジン－５－イル）－２－フェニルピリジン－３－イル基であり；Ｙは、トリクロロメトキシ基、塩素原子、２，２，２－トリクロロエトキシ基、フェノキシ基、ｐ－ニトロフェノキシ基、ｐ－メチルフェノキシ基、イミダゾール－１－イル基、（２，５－ジオキソピロリジン－１－イル）オキシ基、等から選ばれる基である］で表わされる化合物を得る工程、
    （７）下記式（ＡＭ－Ｘ）：
    Figure JPOXMLDOC01-appb-I000020
    ［式（ＡＭ－Ｘ）中、ｐ及びＲ1は、前記式（Ｉ）中の定義と同じである］で表される化合物と、前記式（ＣＢ－１）で表わされる化合物と、塩基とを、溶媒に加えて混合溶液（７）を得る工程、及び
    （８）前記混合溶液（７）を、０℃から前記混合溶液（７）が還流する温度までの間のいずれかの温度で反応を行い、式（Ｉ）で表される化合物を得る工程、
    を含むことを特徴とする、製造方法。     The following formula (I):
    Figure JPOXMLDOC01-appb-I000017
    [In the formula (I), p is an integer selected from 0, 1, and 2; R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group; C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di C 2- 7 a substituent selected from an alkanoylamino group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps:
    (5) The following formula (AM-1):
    Figure JPOXMLDOC01-appb-I000018
    [Wherein ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group], triphosgene, Phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N ′ -Adding a urea agent selected from disuccinimidyl carbonate and a base to a solvent to obtain a mixed solution (5);
    (6) The mixed solution (5) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (5) is refluxed, and the following formula (CB-1):
    Figure JPOXMLDOC01-appb-I000019
    [In Formula (CB-1), Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, A step of obtaining a compound represented by the formula:
    (7) The following formula (AM-X):
    Figure JPOXMLDOC01-appb-I000020
    [In the formula (AM-X), p and R 1 are as defined in the formula (I)], a compound represented by the formula (CB-1), a base, Is added to a solvent to obtain a mixed solution (7), and (8) the mixed solution (7) is reacted at any temperature between 0 ° C. and the temperature at which the mixed solution (7) is refluxed. A step of obtaining a compound represented by formula (I),
    The manufacturing method characterized by including.
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