WO2011074675A1 - スピロケタール誘導体の製造方法 - Google Patents
スピロケタール誘導体の製造方法 Download PDFInfo
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- WO2011074675A1 WO2011074675A1 PCT/JP2010/072791 JP2010072791W WO2011074675A1 WO 2011074675 A1 WO2011074675 A1 WO 2011074675A1 JP 2010072791 W JP2010072791 W JP 2010072791W WO 2011074675 A1 WO2011074675 A1 WO 2011074675A1
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- 0 C*CC(C(*)C(*)C1*)OC11OCc2c1cc(CC1=CC=CC(C)(*)C=C1)cc2 Chemical compound C*CC(C(*)C(*)C1*)OC11OCc2c1cc(CC1=CC=CC(C)(*)C=C1)cc2 0.000 description 3
- RTFQLDGGFXOOEO-UHFFFAOYSA-N CC1(C)C=C(CO)C=C(C(C(C2O)O)(OC3)OC(CO)C2O)C3=C1 Chemical compound CC1(C)C=C(CO)C=C(C(C(C2O)O)(OC3)OC(CO)C2O)C3=C1 RTFQLDGGFXOOEO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to a method for producing a spiroketal derivative and a synthetic intermediate useful for producing a spiroketal derivative.
- Patent Document 1 WO2006 / 080421
- Patent Document 1 discloses a method for producing a compound represented by the formula (A).
- Scheme 3 Patent Document 1, page 24
- a dibromobenzene derivative is allowed to act with alkyl lithium, and then a lactone is produced.
- Scheme 5 of this document describes a method for obtaining a target product by a coupling reaction with a halide.
- Patent Document 2 discloses a method for synthesizing a thioglucose derivative having a spiroketal structure.
- Patent Document 1 describes the formula (B):
- An object of the present invention is to provide an efficient and simple production method suitable for industrial production of a spiroketal derivative used as a raw material for pharmaceuticals, and a useful synthetic intermediate.
- the present inventors have found a method for efficiently producing the desired spiroketal derivative with a short process and a high yield, thereby completing the present invention.
- the present invention produces the desired spiroketal derivative without the use of toxic organotin compounds and purification operations for their removal and without going through labile intermediates such as, for example, benzyl halide.
- a method is provided.
- the introduction of the leaving group for the coupling reaction and the introduction of the protecting group can be performed in one step, and the product of the coupling reaction has good crystallinity, so effective purification without further conversion. Therefore, the production method of the present invention is efficient, and is suitable as a mass synthesis method, particularly as an industrial production method for pharmaceutical raw materials.
- R 1 and R 2 are each independently C 1-10 alkyl optionally substituted with one or more Ra, C 3-10 cycloalkyl optionally substituted with one or more Ra, one or more Ra good C 2-10 alkenyl optionally substituted by one or more optionally C 3-10 cycloalkenyl optionally substituted by Ra, one or more optionally C 2-10 alkynyl optionally substituted by Ra, 1 or more Aryl optionally substituted by Ra, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted by one or more Ra, cyano, halogen atom, nitro, mercapto, —OR 3 , —NR 4 R 5 , —S (O) p R 6 , —S (O) q NR 7 R 8 , —C ( ⁇ O) R 35 , —CR 36 ⁇ NOR 37 , —C ( ⁇ O) OR 9
- Rx is independently selected from C 1-6 alkyl, aryl, heteroaryl, C 1-6 alkoxy, aryloxy, and heteroaryloxy;
- R 41 is a group already defined as R 1 , provided that the group may have one or more protecting groups;
- n is as defined above.
- M is selected from B (R 100 ) 2 , ZnR 100 , and MgR 100 ;
- R 100 is independently selected from —OR 101 , Cl, Br, I, F, wherein R 101 is selected from a hydrogen atom and C 1-12 alkyl, or B (R 100 ) 2 is May form a 5- or 6-membered cyclic boronic ester, R 42 is a group already defined as R 2 , provided that the group may have one or more protecting groups, and m is as defined above.
- halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.
- C 1-10 alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s— Butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, Also included are 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, and the like, and cyclopropylmethyl, cyclohexylmethyl, etc. having a cyclic structure in part.
- C 1-10 alkyl further includes linear or branched C 1-6 alkyl and C 1-4 alkyl.
- C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s— Butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, Examples include 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, and the like, and cyclopropylmethyl, cyclopentylmethyl, and the like, which have a cyclic structure in part.
- C 1-6 alkyl further includes linear or branched C 1-5 alkyl, C 1-4 alkyl, and C 1-3 alkyl.
- C 3-10 cycloalkyl means a cyclic alkyl group having 3 to 10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl and the like.
- C 3-10 cycloalkyl further includes C 3-8 cycloalkyl, and C 3-7 cycloalkyl.
- C 2-10 alkenyl means a straight or branched alkenyl group having 2 to 10 carbon atoms, for example, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), propene-2 -Yl, 3-butenyl (homoallyl), 1,4-pentadien-3-yl and the like are included.
- C 2-10 alkenyl further includes linear or branched C 2-6 alkenyl, and C 2-4 alkenyl.
- C 3-10 cycloalkenyl means a cyclic alkenyl group having 3 to 10 carbon atoms, and includes, for example, cyclopentenyl, cyclohexenyl and the like, and C 5-10 cycloalkenyl and the like.
- C 2-10 alkynyl means a linear or branched alkynyl group having 2 to 10 carbon atoms, and includes, for example, ethynyl, 1-propynyl, 2-propynyl and the like. “C 2-10 alkynyl” further includes linear or branched C 2-6 alkynyl and C 2-4 alkynyl.
- C 1-10 alkoxy means an alkyloxy group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, for example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, 2-ethylbutoxy and the like are included.
- C 1-10 alkoxy further includes linear or branched C 1-6 alkoxy and C 1-4 alkoxy.
- C 1-6 alkoxy means an alkyloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms as the alkyl moiety, for example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, 2-ethylbutoxy and the like are included.
- C 1-6 alkoxy further includes linear or branched C 1-5 alkoxy, C 1-4 alkoxy, and C 1-3 alkoxy.
- C 1-10 alkylamino means an alkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, such as methylamino, ethylamino, n-propylamino. I-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino and the like.
- C 1-10 alkylamino further includes linear or branched C 1-6 alkylamino and C 1-4 alkylamino.
- di (C 1-10 alkyl) amino means a dialkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and the alkyl moieties may be the same.
- dimethylamino, diethylamino, di (n-propyl) amino, di (i-propyl) amino, di (n-butyl) amino, di (s-butyl) amino, di (i-butyl) ) Amino, di (t-butyl) amino, ethyl (methyl) amino, methyl (n-propyl) amino, methyl (i-propyl) amino, n-butyl (methyl) amino, s-butyl (methyl) amino, i -Butyl (methyl) amino, t-butyl (methyl) amino and the like are included.
- Di (C 1-10 alkyl) amino further includes linear or branched di (C 1-6 alkyl) amino and di (C 1-4 alkyl) amino.
- C 1-10 alkylthio means an alkylthio group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio and the like are included.
- C 1-10 alkylthio further includes linear or branched C 1-6 alkylthio and C 1-4 alkylthio.
- saturated, partially unsaturated, or unsaturated heterocyclyl includes, for example, saturated, partially unsaturated, including one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms.
- a saturated or unsaturated 4- to 10-membered heterocyclic group is meant.
- heterocyclyl examples include pyridyl, pyrimidyl, pyrazyl, triazinyl, quinolyl, quinoxalyl, quinazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl, morpholyl, tetrahydrofuranyl, and And pyranyl.
- aryl is not particularly limited, but means an aromatic carbocyclic group having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. .
- aryloxy is not particularly limited, but means an aryloxy group having the above aryl group as an aryl moiety, and includes, for example, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
- aralkyl is not particularly limited, and includes, for example, aryl C 1-6 alkyl.
- Aryl C 1-6 alkyl means a C 1-6 alkyl group substituted by an aromatic carbocyclic group having 6 to 14 carbon atoms, for example 6 to 10 carbon atoms, already defined as an aryl moiety, for example benzyl 1-naphthylmethyl, 2-naphthylmethyl and the like.
- heteroaryl means a 4- to 10-membered aromatic heterocyclic group containing, but not limited to, one or more heteroatoms selected from, for example, a nitrogen atom, an oxygen atom and a sulfur atom.
- heteroaryl include pyridyl, pyrimidyl, pyrazyl, triazinyl, quinolyl, quinoxalyl, quinazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and the like.
- heteroaryloxy includes, but is not limited to, a 4-10 membered aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms already defined as heteroaryl moieties.
- a heteroaryloxy group having a formula group, for example, pyridyloxy, pyrimidyloxy, pyrazyloxy, triazinyloxy, quinolyloxy, quinoxalyloxy, quinazolyloxy, furyloxy, thienyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy, and triayl Examples include zolyloxy.
- heteroaryl C 1-6 alkyl includes, but is not limited to, 4-10 membered, including one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms, as previously defined as heteroaryl moieties Means a C 1-6 alkyl group substituted by an aromatic heterocyclic group of, Examples include pyrrolylmethyl, pyrazolylmethyl, imidazolylmethyl, and triazolylmethyl.
- C 1-6 alkoxy C 1-6 alkyl means, but not limited to, an alkyl group having 1 to 6 carbon atoms having the above C 1-6 alkoxy as an alkoxy moiety, such as methoxymethyl, Examples include ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl and the like.
- arylmethoxyC 1-6 alkyl is not particularly limited, but means arylmethoxyC 1-6 alkyl having the above aryl as an aryl moiety, and examples thereof include benzyloxymethyl and the like.
- C 1-6 alkylcarbonyl is not particularly limited, but means a carbonyl having the above C 1-6 alkyl as an alkyl moiety, and examples thereof include acetyl, propionyl, and pivaloyl.
- C 1-6 alkoxycarbonyl means, but is not limited to, a carbonyl having the above C 1-6 alkoxy as an alkoxy moiety, such as methoxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl Etc.
- arylselenyl is not particularly limited, but means arylselenyl having the aryl as an aryl moiety, and examples thereof include phenylselenyl (PhSe—).
- Ph means phenyl
- C 1-10 alkylene group means a linear or branched alkylene group having 1 to 10 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene, 3-methylbutylene, 2-methyl Methylbutylene, 1-methylbutylene, 1-ethylpropylene, hexylene, 4-methylpentylene, 3-methylpentylene, 2-methylpentylene, 1-methylpentylene, 3-ethylbutylene, 2-ethylbutylene, etc.
- cyclopropylmethylene having a cyclic structure in part, cyclohexylmethylene and the like are also included.
- C 1-10 alkylene further includes linear or branched C 1-6 alkylene, and C 1-4 alkylene.
- carrier as used herein is not particularly limited, and means a saturated, partially unsaturated, or unsaturated hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, For example, cyclohexane, benzene, naphthalene and the like are included.
- heterocycle as used herein is not particularly limited, but includes, for example, saturated, partially unsaturated, or unsaturated, including one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Of 4 to 10 membered heterocycles.
- heterocyclic ring examples include pyridine, piperidine, pyrimidine, pyrazine, piperazine, triazine, quinoline, quinoxaline, quinazoline, furan, tetrahydrofuran, thiophene, pyrrole, pyrazole, imidazole, and triazole.
- cyclic boronic ester used herein is not particularly limited as long as it is a cyclic boronic ester having 5 or 6 atoms in the ring. Examples thereof include cyclic boronic esters composed of carbon atoms, oxygen atoms and boron atoms. Examples of B (R 100 ) 2 include [1,3,2] dioxaborolanyl or [1,3,2] dioxaborinyl.
- the substituted silyl group specified by the formula —SiR 12 R 13 R 14 , the formula —SiR 23 R 24 R 25 , the formula —Si (R 53 ) 3 and the like is not particularly limited. , Triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, tert-butyldiphenylsilyl and the like.
- R 1 and R 2 defined in the present invention are not particularly limited.
- each of them is independently C 1-10 alkyl optionally substituted with one or more Ra, and substituted with one or more Ra.
- R 1 and R 2 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and —SiR 12 R 13 R 14 .
- R 1 and R 2 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and —SiR 12 R 13 R 14 .
- R 1 and R 2 when n and m are 0, R 1 and R 2 do not exist on the benzene ring, respectively.
- n and m are 0, R 1 and R 2 do not exist on the benzene ring, respectively.
- the halogen atom defined as R 1 and R 2 is preferably a fluorine atom or a chlorine atom.
- the groups defined as R 1 and R 2 when the groups defined as R 1 and R 2 have a group that can be protected, such as hydroxy, carboxy, carbonyl, amino, or mercapto, the group may be protected by a protecting group.
- a protecting group to be introduced into each group and the operation of introducing and removing the protecting group are described in, for example, “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(4th edition, John Wiley & Sons 2006)”. Can be done based on. Groups formed by introducing one or more protecting groups into groups defined as R 1 and R 2 are included in the definition of R 41 and R 42 .
- R 1 and / or R 2 examples include C 1-10 alkyl optionally substituted with one or more R 51 , and optionally substituted with one or more R 52 Groups such as good saturated, partially unsaturated, or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and —B (OR 55 ) 2 ;
- each R 51 is independently aryl optionally substituted by one or more R 56, C 1-10 alkoxy optionally substituted by one or more aryl, C 1-10 alkylthio, and aryl Selected from selenil;
- Each R 52 is independently selected from C 1-10 alkoxy;
- R 53 and R 55 are each independently selected from C 1-10 alkyl, and aryl;
- R 54 is a hydrogen atom, C 1-10 alkyl, aryl optionally substituted by one or more C 1-10 alkoxy, heteroaryl, amino optionally substituted by one or
- Preferred examples of the protecting group for hydroxy group include methyl, benzyl, 4-methoxybenzyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyranyl, 6-methoxytetrahydropyran-2-yl, Tetrahydrothiopyranyl, 6-methoxytetrahydrothiopyran-2-nyl, tetrahydrofuranyl, 5-methoxytetrahydrofuran-2-yl, tetrahydrothiofuranyl, 5-methoxytetrahydrothiofuran-2-nyl, 1-ethoxyethyl, 1 -Methoxy-1-methylethyl, tert-butyl, allyl, vinyl, triphenylmethyl (trityl), trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsily
- Examples of the protecting group when R 1 and / or R 2 include an amino group include C 1-10 alkyl optionally substituted with one or more R 51 , and substituted with one or more R 52 May be saturated, partially unsaturated, or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , or —C ( ⁇ O) R 54 , where R 51 to R 54. Is as already defined.
- Preferred examples of the amino-protecting group include benzyl and the like, and the primary amino group can be protected by being converted into a phthalimide group, a succinimide group, or a pyrrolidyl group.
- Examples of the protecting group for a carboxy group when R 1 and / or R 2 include a carboxy group include C 1-10 alkyl, C 2-10 alkenyl optionally substituted by one or more R 51 , — Ester-forming groups such as Si (R 53 ) 3 (where R 51 and R 53 are as previously defined), or amide-forming groups such as —NR 58 R 59 where R 58 and R 59 are Each independently selected from C 1-10 alkyl, C 2-10 alkenyl, and —Si (R 53 ) 3 optionally substituted by one or more R 51 , wherein R 51 and R 53 are As defined above).
- Preferable examples of conversion of carboxy by introduction of a protecting group include ethyl ester, benzyl ester, t-butyl ester and the like.
- the “protecting group” removed in the above step b is the group —C (O) —Rx contained in the compound of the formula (IV) and all or any of the protecting groups optionally contained in R 41 and R 42 Means.
- the step (step a) of obtaining the compound of formula (IV) by reacting the compound of formula (II) with the compound of formula (III) can be carried out in the presence of a suitable catalyst.
- a suitable catalyst include palladium catalysts such as PdCl 2 (dppf) ⁇ CH 2 Cl 2 , Pd (OAc) 2 , Pd (PPh 3 ) 4 , NiCl 2 (PPh 3 ) 2 , or NiCl 2 (dppf). Etc. can be used.
- the catalyst is used, for example, in an amount of 0.01 to 50 mol%, preferably 0.1 to 30 mol%, more preferably 1 to 10 mol%, based on the amount of the substrate.
- PdCl 2 (dppf) ⁇ CH 2 Cl 2 is N.P. E. Available for purchase from CHEMCAT.
- step a by adding a metal compound and a ligand to the reaction, the complex formed in the reaction system acts as a catalyst, and the target reaction proceeds.
- a reaction substrate in Step a a reagent such as a base, a solvent, and the like included in the reaction system may form a complex by acting on a metal compound.
- a reagent such as a base, a solvent, and the like included in the reaction system may form a complex by acting on a metal compound.
- the catalyst In the catalyst.
- metal compounds include [Pd ( ⁇ 3 -C 3 H 5 ) (cod)] BF 4 , PdBr 2 (cod), PdCl 2 (cod), Pd (OAc) 2 , Pd (dba) 2 , [ Pd ( ⁇ 3 -C 3 H 5 ) Cl] 2 , Pd 2 (dba) 3 and the like.
- ligands examples include triarylphosphine (eg, PPh 3 etc.), trialkylphosphine (eg P (t-Bu) 3 etc.), aryldialkylphosphine, alkyldiarylphosphine, (diphenylphosphino) ferrocene ( Abbreviations; dppf), Ph 2 P (CH 2 ) n PPh 2 (where n is 2 to 10), (oxydi-2,1-phenylene) bis (diphenylphosphine) ⁇ eg, DPEphos ⁇ , bis ( And diphenylphosphino) xanthene ⁇ eg, Xantphos ⁇ and bis (dialkylphosphino) xanthene ⁇ eg, Cy-Xantphos ⁇ .
- triarylphosphine eg, PPh 3 etc.
- trialkylphosphine eg P (t-Bu) 3 etc.
- the metal compound is used, for example, in an amount of 0.01 to 50 mol%, preferably 0.1 to 30 mol%, more preferably 1 to 10 mol%, based on the amount of the substrate.
- the ligand is used, for example, in an amount of 0.01 to 200 mol%, preferably 0.01 to 120 mol%, more preferably 1 to 40 mol%, based on the amount of the substrate.
- Pd (dba) 2 is from Aldrich
- Pd (OAc) 2 is Aldrich or N.I. E.
- NiCl 2 (dppf) T. Hayashi et al., Chem. Lett. 1980, Vol. 6, pp. 767-768; PdBr 2 (cod): D. Drew et al., Inorg. Synth. 1972, 13, 47-55; [Pd ( ⁇ 3 -C 3 H 5 ) (cod)] BF 4 : D. A. White et al., Inorg. Synth. 1972, Vol. 13, p. 55.
- the above step is preferably performed in the presence of a base.
- bases used include carbonates (eg, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, and cesium carbonate), sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, phosphoric acid Salts (eg, potassium phosphate), fluorides (cesium fluoride), alkoxides (eg, sodium t-butoxide, potassium t-butoxide, and sodium t-pentoxide), amide salts (eg, lithium hexamethyldisilazide) And potassium hexamethyldisilazide).
- the base is used, for example, in an amount of 0.1 to 50 equivalents, preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents relative to the amount of the substrate.
- the reaction in step a can be performed in a solvent.
- solvents include alcohols (eg, C 1-10 alcohols such as methanol, ethanol, n-propanol, i-propanol, t-butanol, and t-amyl alcohol), ethers (eg, dioxane, tetrahydrofuran). , 1,2-dimethoxyethane, diisopropyl ether, and t-butyl methyl ether), amides (DMF, DMA, N-methylpyrrolidone, etc.), halogen compounds (chloroform, dichloromethane, etc.), hydrocarbons (hexane, And heptane).
- alcohols eg, C 1-10 alcohols such as methanol, ethanol, n-propanol, i-propanol, t-butanol, and t-amyl alcohol
- ethers eg, dioxane,
- the reaction temperature and reaction time in step a can be appropriately set based on the progress of the reaction and the like, and are not particularly limited, but the reaction is, for example, 20 to 300 ° C, preferably 30 to 120 ° C, more preferably 70 It is carried out in the range of ⁇ 90 ° C., for example, in the range of 0.1-24 hours, preferably 0.3-5 hours, more preferably 0.5-2 hours. From the viewpoint of improving the yield by maintaining the catalytic activity and reducing the cost, the reaction is preferably performed in an inert gas atmosphere such as nitrogen or argon, and is not contained in the reaction mixture in order to remove oxygen in the reaction system. It is desirable to start the reaction after bubbling the active gas.
- an inert gas atmosphere such as nitrogen or argon
- step a The reaction in step a is described in, for example, Kuwano et al., Organic Letters, 2005, Vol. 9, No. 5, pages 945-947; and Kuwano et al., Chem. Commun. 2005, pages 5899-5901 and the like.
- step b) can be carried out by selecting a method known in the art depending on the protecting group to be removed. For example, “Green and Wuts,“ Protective Groups in Organic Synthesis ”(4th edition, John Wiley & Sons). , 2006) "can be used.
- acids or Lewis acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, and boron tribromide; sodium hydroxide, lithium hydroxide, Bases such as potassium hydroxide and potassium carbonate; organometallic reagents such as butyl lithium and Grignard reagents; metal hydride reagents such as lithium aluminum hydride, lithium boron hydride and diisobutyl aluminum hydride; boron trifluoride diethyl ether Complex-ethanethiol, aluminum halide-sodium iodide, aluminum halide-thiol, and a combination of Lewis acid and nucleophile such as aluminum halide-sulfide; palladium on carbon, platinum, homogeneous palladium complex And hydrogenation using a homogeneous
- reaction removes the group —C (O) —Rx contained in the compound of formula (IV). Also, all or any of the protecting groups that may be included in R 41 and R 42 are removed.
- Rx is C 1-6 alkyl, aryl, heteroaryl, C 1-6 alkoxy, aryloxy, and heteroaryloxy, such as t-butyl, And methoxy.
- Rx in the said Formula (II) a methoxy is mentioned.
- Rx in the above formula (II) and formula (IV) represents the same group.
- Rx include t-butyl and methoxy.
- the compound of the formula (III) is not particularly limited as long as it is an organometallic reagent suitable for performing a cross-coupling reaction.
- the compound of formula (III) may form an art complex, for example, ArBF 3 K, and ArB (OR 101 ) 2 MeZnCl (wherein Ar represents a benzene ring moiety of formula (III)). .
- M is B (OH) 2 .
- Conversion of a compound of formula (V) to a compound of formula (II) is a compound of formula LC (O) Rx where L is a leaving group such as a halogen atom (such as a chlorine atom and a bromine atom). , Rx is as defined above), or is achieved by normal procedures using a reagent of the formula [RxC (O)] 2 O, wherein Rx is as defined above. be able to.
- Examples of preferred reagents include chloroformates (eg, methyl chloroformate, ethyl chloroformate, and isopropyl chloroformate), carbonyl chlorides (eg, acetyl chloride, etc.), dialkyl dicarbonates (eg, dimethyl dicarbonate, etc.), An acid anhydride (for example, acetic anhydride etc.) is mentioned.
- the reaction is preferably performed in the presence of a base.
- bases examples include organic bases (eg, triethylamine, pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, and morpholine), inorganic Bases such as potassium carbonate, sodium carbonate, sodium bicarbonate and the like.
- organic bases eg, triethylamine, pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, and morpholine
- inorganic Bases such as potassium carbonate, sodium carbonate, sodium bicarbonate and the like.
- the reaction in this step can be performed in a solvent.
- the solvent include nitriles (for example, acetonitrile), ethers (for example, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, diisopropyl ether, and t-butyl methyl ether), amides (DMF, DMA, And N-methylpyrrolidone), halogen compounds (such as chloroform and dichloromethane), hydrocarbons (such as hexane and heptane), and the like.
- the reaction temperature and reaction time in the step can be appropriately set based on the progress of the reaction and the like, and are not particularly limited. However, the reaction is performed within a range of, for example, ⁇ 20 to 50 ° C., preferably ⁇ 10 to 25 ° C. Also, for example, the reaction is performed for 1 to 10 hours, preferably 2 to 4 hours.
- X 1 is selected from a bromine atom and an iodine atom
- P 1 and P 2 are each independently selected from a metal ion, a hydrogen atom, or a protecting group for a hydroxy group
- R 41 and n are as defined above] Is treated with an organometallic reagent, followed by formula (VII):
- P 3 , P 4 , P 5 , and P 6 are each independently selected from hydroxy protecting groups; or P 3 and P 4 , P 4 and P 5 , and P 5 and P 6 may be each independently a divalent group that protects two hydroxy groups to form a ring.
- the metal ion defined in P 1 , P 2 , and X means a metal ion that becomes a counter ion of an alkoxide ion.
- alkali ions such as lithium ion, sodium ion, potassium ion, cesium ion, and magnesium ion are used.
- examples include metal ions, alkaline earth metal ions, and zinc ions, which may form complexes with other metals.
- the metal ions include, for example, metal ions (for example, lithium ions, magnesium ions, and zinc ions) generated by allowing the organometallic reagent used in the present invention to act on a hydroxy group.
- the “protecting group for hydroxy group” included in the definition of P 1 to P 6 is not particularly limited as long as it is a group usually used as a protecting group for hydroxy group.
- “Greene and Wuts,“ Protective Groups in Organic ” Included are protecting groups described in "Synthesis” (4th edition, John Wiley & Sons 2006).
- the protecting group for hydroxy group includes a protecting group as defined above, for example, C 1-10 alkyl optionally substituted by one or more R 51, saturated, partially unsaturated optionally substituted by one or more R 52.
- Groups such as saturated or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and —B (OR 55 ) 2 .
- protecting groups for hydroxy groups include methyl, benzyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxy Ethyl, 1-methoxy-1-methylethyl, tert-butyl, allyl, vinyl, triphenylmethyl (trityl), trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, tert-butyldiphenylsilyl, isobutyryl, pi
- a divalent group that protects two hydroxy groups to form a ring refers to a divalent group that connects the oxygen atoms of two hydroxy groups, eg, a C 1-10 alkylene.
- a group for example, methylene, methylmethylene, dimethylmethylene, etc.), a carbonyl group, and the like are meant.
- P 1 and P 2 are each independently lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion A zinc ion, a hydrogen atom, C 1-10 alkyl optionally substituted by one or more R 51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted by one or more R 52 , C Selected from 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and —B (OR 55 ) 2 ;
- P 3 , P 4 , P 5 , and P 6 are each independently C 1-10 alkyl optionally substituted with one or more R 51 , saturated optionally substituted with one or more R 52 , Selected from partially unsaturated or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and
- P 1 and P 2 are each independently lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion, Zinc ion, hydrogen atom, C 1-6 alkoxy C 1-6 alkyl, arylmethoxy C 1-6 alkyl, tetrahydropyranyl, tetrahydrofuranyl, group —Si (R 53 ) 3 , aralkyl, and group —B (OR 55 ) Selected from 2 ; P 3 , P 4 , P 5 , and P 6 are each independently C 1-6 alkoxy C 1-6 alkyl, arylmethoxy C 1-6 alkyl, tetrahydropyranyl, tetrahydrofuranyl, group —Si (R 53 ) 3 , aralkyl, group —B (OR 55 ) 2 , C 1-6 alkylcarbonyl, C
- R 53 and R 55 are each independently selected from C 1-10 alkyl, and aryl;
- X is a lithium ion, a sodium ion, a potassium ion, a cesium ion, a magnesium ion, a zinc ion, or a hydrogen atom.
- P 1 and P 2 are methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, tetrahydro Selected from pyranylpyranyl, tetrahydrofuranyl, or triphenylmethyl;
- P 3 , P 4 , P 5 , and P 6 are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, tetrahydropyranyl And tetrahydrofuranyl.
- the organometallic reagent used for the treatment of the compound of the formula (VI) is not particularly limited as long as it is an organometallic reagent suitable for performing a halogen metal exchange reaction on the benzene ring.
- an organometallic reagent suitable for performing a halogen metal exchange reaction on the benzene ring For example, C 1-10 alkyl lithium (Eg, n-butyllithium, s-butyllithium, and t-butyllithium), C 1-10 alkylmagnesium halides (eg, n-butylmagnesium chloride, isopropylmagnesium chloride, etc.), and di-C 1-10 Alkylmagnesium (eg, di-n-butylmagnesium) and the like are included.
- C 1-10 alkyl lithium Eg, n-butyllithium, s-butyllithium, and t-butyllithium
- the organometallic reagent is used in the presence of an inorganic salt or an organic salt (for example, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, and magnesium triflate). It may be used as a mixture with an inorganic salt or an organic salt.
- an inorganic salt or an organic salt for example, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, and magnesium triflate.
- organometallic reagents include mixtures or reaction products of the following reagents: butyl magnesium chloride and butyl lithium, isopropyl magnesium bromide and butyl lithium, dibutyl magnesium and butyl lithium, butyl magnesium bromide and butyl lithium, isopropyl magnesium.
- Bromide and lithium chloride dibutyl magnesium and ethoxy lithium, dibutyl magnesium and butoxy lithium, dibutyl magnesium and lithium hexamethyldisilazide, isopropyl magnesium bromide and butyl lithium and lithium chloride, butyl magnesium chloride and butyl lithium and ethoxy lithium, butyl magnesium chloride And butyl lithium and lithium hexamethyldisilazide, isopropyl magnesium Bromide and butyl lithium and ethoxy lithium.
- organometallic reagent examples include zinc chloride and butyl lithium, a mixture or reaction product of diethyl zinc and n-butyl lithium, and an organic zinc complex described in Japanese Patent Publication No. 2004-292328. It is done.
- n-butyllithium is used in the treatment of the compound of formula (VI) with an organometallic reagent.
- one or more additives may be further added.
- organolithium reagents eg, C 1-10 alkyllithiums such as n-butyllithium, s-butyllithium, and t-butyllithium
- Magnesium chloride for example, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride and the like; preferably MgBr 2 ⁇ OEt 2 and the like
- MgBr 2 ⁇ OEt 2 and the like may be further added.
- magnesium halide may be added after adding the organolithium reagent, and then reacted with the compound of formula (VII).
- MgBr 2 ⁇ OEt 2 is, for example, Boulder Scientific Co Inc. More purchased reagents can be used.
- the organometallic reagent is selected from C 1-10 alkyl lithium, C 1-10 alkyl magnesium halide, di-C 1-10 alkyl magnesium; or a combination of: Butyl magnesium chloride and butyl lithium; Isopropyl magnesium bromide and butyl lithium; Dibutyl magnesium and butyl lithium; Butyl magnesium bromide and butyl lithium; Isopropyl magnesium bromide and lithium chloride; Dibutyl magnesium and ethoxy lithium; Dibutyl magnesium and butoxy lithium; Dibutyl magnesium and lithium hexamethyldisilazide; Isopropyl magnesium bromide, butyl lithium and lithium chloride; Butyl magnesium chloride, butyl lithium and ethoxy lithium; Butyl magnesium chloride, butyl lithium and lithium hexamethyldisilazide; Isopropyl magnesium bromide, butyl lithium and lithium chloride; Butyl magnesium chloride, butyl lithium and ethoxy lithium
- the compound of formula (VI) is treated with an organolithium reagent and magnesium halide to react the compound of formula (VII).
- the magnesium halide is added after the organolithium reagent is added to the reaction system in the treatment of the compound of formula (VI) with the organometallic reagent.
- the organolithium reagent is selected from C 1-10 alkyllithium and the magnesium halide is selected from magnesium chloride, magnesium bromide, magnesium iodide, and magnesium fluoride.
- X 1 is, for example, a bromine atom.
- examples of P 1 and P 2 include, for example, lithium ions, hydrogen atoms, and, for example, C 1-6 alkoxy C 1-6 alkyl (for example, Methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl, etc.), arylmethoxy C 1-6 alkyl (eg benzyloxymethyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, group —Si (R 53 ) 3 (eg, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, tert-butyldiphenylsilyl, etc.), aralkyl (eg, benzyl, 4-methoxybenzyl, benzyl, 4-methoxybenzyl, benzyl, 4-me
- P 1 and P 2 are preferably protected groups such as C 1-6 alkoxy C 1-6 alkyl (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl, etc.) is there.
- C 1-6 alkoxy C 1-6 alkyl eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl, etc.
- the treatment of the compound of formula (VI) with an organometallic reagent can be performed using a solvent suitable for the halogen metal exchange reaction.
- the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, and dimethoxyethane), hydrocarbons (for example, pentane, Hexane, heptane, benzene, and toluene), N, N-tetramethylethylenediamine, N, N-tetramethylpropanediamine, and a mixed solvent containing two or more of the above-mentioned solvents.
- ethers for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl
- the organometallic reagent may use 0.5-1.5 equivalents, for example 0.8-1.1 equivalents, and P 1 and When one of P 2 is a hydrogen atom and the other is a metal ion or protecting group, the organometallic reagent is used in an amount of 1.5 to 3.0 equivalents, for example 1.8 to 2.2 equivalents. Alternatively, when both P 1 and P 2 are hydrogen atoms, the organometallic reagent may use 2.5 to 4.0 equivalents, for example 2.8 to 3.2 equivalents. Further, from the viewpoint of improving the regioselectivity of the reaction, the organometallic reagent may be added in portions.
- the organometallic reagent can be added little by little (for example, dropwise) into the system at a temperature of, for example, ⁇ 80 to 30 ° C., preferably ⁇ 60 to 25 ° C., particularly ⁇ 15 to 0 ° C.
- the reaction may be completed by stirring for a certain time (for example, 0.1 to 5 hours) at an appropriate temperature, for example, ⁇ 80 to 20 ° C., preferably ⁇ 15 to 10 ° C. .
- a halogen metal exchange reaction performed using C 1-10 alkyl lithium (eg, n-butyllithium, s-butyllithium, or t-butyllithium)
- another kind of organometallic reagent eg, n -Butylmagnesium chloride and n-butyllithium or dibutylmagnesium etc.
- the complex may be formed after stirring the reaction solution for 0.1 to 5 hours, preferably 0.5 to 2 hours.
- examples of P 3 , P 4 , P 5 , and P 6 include C 1-6 alkoxy C 1-6 alkyl (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, and 1-methoxy-1-methylethyl), arylmethoxy C 1-6 alkyl (eg, benzyloxymethyl), tetrahydropyranyl, tetrahydrofuranyl, —Si (R 53 ) 3 (eg, Trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, and tert-butyldiphenylsilyl), aralkyl (eg, benzyl, 4-methoxybenzyl, and triphenylmethyl), group -B (OR 55 ) 2 , C 1-6 alkylcarbonyl (eg , Acetyl),
- P 3 and P 4 , P 4 and P 5 , and P 5 and P 6 together are divalent groups that protect two hydroxy groups to form a ring (for example, —CH 2 —, -CH (CH 3 )-, -C (CH 3 ) 2- , and -CHPh-).
- P 3 , P 4 , P 5 , and P 6 are each independently a group —Si (R 53 ) 3 (eg, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, and tert- Butyldiphenylsilyl), pivaloyl, and 1-methoxy-1-methylethyl.
- Treatment of the compound of formula (VI) with an organometallic reagent and subsequent reaction with the compound of formula (VII) can be accomplished, for example, by treating a solution of the compound of formula (VI) treated with an organometallic reagent in a suitable solvent, At an appropriate temperature, for example at ⁇ 100 to 30 ° C., preferably at ⁇ 90 to ⁇ 10 ° C., in particular at ⁇ 80 to 0 ° C., containing a compound of formula (VII) (eg 1.0 to 1.1 equivalents) It can be carried out by adding the reaction solution little by little (for example, dropwise).
- a compound of formula (VII) eg 1.0 to 1.1 equivalents
- Suitable solvents include ethers (eg, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, and dimethoxyethane), hydrocarbons (eg, , Hexane, heptane, benzene, toluene and the like), and a mixed solvent containing two or more of the above-mentioned solvents.
- the reaction may be completed by stirring at an appropriate temperature, for example, ⁇ 80 to 0 ° C. for a certain time (for example, 0.5 to 5 hours).
- This reaction can be worked up by a conventional method, and the resulting product can be purified by a conventional method to obtain the compound of formula (VIII).
- the production process is simplified and the solvent used From the viewpoint of suppressing the amount and manufacturing cost, it is preferable to perform the next step without performing post-treatment of this reaction.
- the compound of the formula (VIII) when P 1 is a protecting group for a hydroxy group, the compound is converted to a compound in which P 1 is a hydrogen atom by performing deprotection. In one embodiment of the present invention, the protecting group introduced as P 2 to P 6 is also removed by the deprotection.
- Deprotection can be performed by selecting methods known in the art, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, Acids or Lewis acids such as camphorsulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, and boron tribromide; bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, and potassium carbonate; butyl lithium, And organometallic reagents such as Grignard reagents; metal hydride reagents such as lithium aluminum hydride, boron boron hydride, and diisobutylaluminum hydride; boron trifluoride diethyl ether complex-ethanethiol, aluminum halide-sodium iodide,
- a spiro ring structure is formed by treating a compound of formula (VIII) wherein P 1 is a hydrogen atom under acidic conditions.
- This spiro ring structure formation reaction is carried out by using a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, dimethoxyethane, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetone.
- THF tetrahydrofuran
- methyltetrahydrofuran dimethoxyethane
- acetonitrile dimethyl sulfoxide
- N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone acetone.
- Acetate ester for example, ethyl acetate, methyl acetate, isopropyl acetate, etc.
- methylene chloride chloroform, dichloroethane, methanol, ethanol, isopropanol, water, or a mixed solvent containing two or more of the above solvents at an appropriate temperature, For example, it can be carried out at ⁇ 20 to 100 ° C., preferably 0 to 80 ° C., particularly 10 to 30 ° C.
- the reaction time can be appropriately set, and is, for example, about 0.5 to 10 hours, preferably about 1 to 6 hours.
- the acid that can be used is not particularly limited, and a Lewis acid may be used.
- hydrochloric acid sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, camphorsulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, and three.
- examples thereof include boron bromide.
- the compound of the above formula (VII) can be prepared by a known method, for example, by introducing a protecting group into D-(+)-glucono-1,5-lactone by a conventional method. .
- D-(+)-glucono-1,5-lactone can be obtained, for example, by purchasing from Tokyo Chemical Industry Co., Ltd. or Fuso Chemical Industry Co., Ltd.
- the compound of formula (VIII) is treated under acidic conditions to simultaneously remove the protecting groups introduced as P 1 to P 6 and form a spiro ring, thereby producing a compound of formula (V ) Can be obtained.
- Preferred examples of P 1 and P 2 include methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, triisopropylsilyl, tert-butyldiphenylsilyl, pivaloyl, aralkyl (eg, 4-methoxybenzyl , Triphenylmethyl, etc.), tetrahydropyranylpyranyl, and tetrahydrofuranyl, etc., more preferably methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, tetrahydropyranylpyranyl, tetrahydrofuranyl, and tri Phenylmethyl, particularly preferably 1-methoxy-1-methyle
- P 3 to P 6 include a group —Si (R 53 ) 3 (for example, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, and t-butyldiphenylsilyl), pivaloyl, 1-methoxy.
- Si (R 53 ) 3 for example, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, and t-butyldiphenylsilyl
- Usable acids include hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, camphorsulfonic acid, boron trifluoride diethyl ether complex, boron trichloride And boron tribromide.
- P 1 and P 2 are selected from methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, tetrahydropyranylpyranyl, tetrahydrofuranyl, and triphenylmethyl bulk
- P 3 -P 6 are trimethylsilyl Of the formula (VIII) selected from: triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, methoxymethyl, 2-methoxyethoxymethyl, 1-methoxy-1-methylethyl, tetrahydropyranylpyranyl, and tetrahydrofuranyl
- the compound of formula (VIII) is in the presence of an acid selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid. Is converted to the compound of formula (V).
- the step of converting the compound of formula (VIII) into the compound of formula (V) is performed in one pot.
- n is 0; or m is 1 and R 2 and R 42 are C 1-6 alkyl; or n is 0 and m is 0 or 1.
- a compound of formula (I) is prepared wherein R 2 and R 42 are C 1-6 alkyl.
- the compound of the formula (I) is represented by the formula (Ia):
- X 1 is selected from a bromine atom and an iodine atom
- P 1 and P 2 are each independently a lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion, zinc ion, hydrogen atom, C 1-10 alkyl optionally substituted by one or more R 51 , Saturated, partially unsaturated, or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and —B, optionally substituted by one or more R 52 (OR 55 ) 2 is selected from
- each R 51 is independently aryl optionally substituted by one or more R 56, C 1-10 alkoxy optionally substituted by one or more aryl, C 1-10 alkylthio, and aryl Selected from selenil
- Each R 52 is independently selected from C 1-10 alkoxy
- R 53 and R 55 are each independently selected from C 1-10 alkyl and aryl
- P 3 , P 4 , P 5 and P 6 are each independently C 1-10 alkyl optionally substituted with one or more R 51 , and substituted with one or more R 52. Selected from saturated, partially unsaturated, or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C ( ⁇ O) R 54 , and —B (OR 55 ) 2 ; or P 3 and P 4 , P 4 and P 5 , and P 5 and P 6 are each independently a divalent C 1-10 alkylene group that protects two hydroxy groups to form a ring. Or a carbonyl group;
- R 51 , R 52 , R 53 , R 54 , and R 55 are as already described.
- a solvent selected from water, alcohols, ethers, esters, amides, halogen compounds, hydrocarbons, acetone, acetonitrile, and dimethyl sulfoxide, or a mixture thereof is used.
- the method may further comprise purifying any of the compounds of formulas (II), (IV) and (V) by recrystallization.
- the compound of the formula (I) obtained by the production method of the present invention can also be further purified by recrystallization.
- the production method of the present invention can be carried out without performing a purification method such as column chromatography, which is complicated in operation and requires a large amount of a solvent and an adsorbent, and if necessary, a synthetic intermediate can be recrystallized. Therefore, it is useful from the viewpoint of increasing the efficiency of the manufacturing method and suppressing the manufacturing cost.
- a method for efficiently removing impurities from a compound used as a pharmaceutical is very important, and the production method of the present invention is useful for stably providing a safe pharmaceutical.
- R 41 , R 42 , n, and m are as defined in claim 1; Rx is C 1-6 alkoxy] are provided.
- the compounds of the above formulas (II) and (IV) are important synthetic intermediates for efficiently producing the compound of formula (I).
- the compound of formula (IX) is obtained as a crystal, for example a monohydrate.
- the monohydrate is not particularly limited as long as it is a crystal that stably retains one equivalent of moisture in an environment (temperature, relative humidity, etc.) in which a pharmaceutical is normally stored and used.
- Crystals of the compound of formula (IX) have a powder X-ray diffraction pattern of around 3.5 °, 6.9 °, and 13.8 °, specifically 3.5 °, 6.9 °, 13 .8 °, 16.0 °, 17.2 °, and around 18.4 °, more specifically 3.5 °, 6.9 °, 10.4 °, 13.8 °, 16.0 ° , 17.2 °, 18.4 °, 20.8 °, 21.4 °, and peaks at diffraction angles (2 ⁇ ) around 24.4 °.
- the powder X-ray diffraction pattern can be measured by a usual method.
- an error (for example, about ⁇ 0.2) is expected in the value of the diffraction angle of the powder X-ray diffraction peak of the crystal depending on the measurement conditions and the state of the sample.
- the monohydrate crystals of the compound of the formula (IX) are crystallized from a solvent such as water, a mixed solvent of methanol and water, a mixed solvent of acetone and water, and a mixed solvent of 1,2-dimethoxyethane and water. Can be obtained.
- the crystallization can be performed using, for example, a mixed solvent of acetone and water.
- the monohydrate crystals of the compound of formula (IX) have the property that the water content is almost constant under a certain range of relative humidity, the handling of the compound in the preparation process is easy, and good storage It is useful for producing a pharmaceutical preparation having stability.
- the crystal can be used to efficiently and highly purify the compound of formula (IX), and is also useful from the viewpoint of efficient production of a pharmaceutical product containing the compound.
- the compound of formula (IX) is provided as, for example, sodium acetate co-crystal or potassium acetate co-crystal.
- the sodium acetate co-crystal of the present invention has a powder X-ray diffraction pattern in the vicinity of 4.9 °, 14.7 °, 16.0 °, 17.1 °, and 19.6 °, more specifically 4.9. °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 It has a peak at a diffraction angle (2 ⁇ ) in the vicinity of ° and 22.0 °.
- the potassium acetate co-crystal of the present invention has a vicinity of 5.0 °, 15.1 °, 19.0 °, 20.1 ° and 25.2 °, more specifically 5.0 °. Diffraction angles around 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 °, and 25.2 ° It has a peak at (2 ⁇ ).
- the powder X-ray diffraction pattern can be measured by a usual method.
- an error (for example, about ⁇ 0.2) is expected in the value of the diffraction angle of the powder X-ray diffraction peak of the crystal depending on the measurement conditions and the state of the sample.
- Sodium acetate co-crystals of the compound of formula (IX) are, for example, methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, propyl acetate, hexyl acetate, 2-butanone, 2-heptanone, n-propylbenzene, hexylbenzene, And from a solvent selected from 1-chlorohexane or from a mixed solvent of two or more such solvents, preferably from a mixed solvent of methanol and isopropanol.
- the potassium acetate co-crystal of the compound of formula (IX) is, for example, from a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, N, N-dibutylformamide, acetone, and diisopropyl ether, or two or more It can be obtained from a mixed solvent of the above solvent, preferably from a mixed solvent of methanol and isopropanol.
- the sodium acetate co-crystal and potassium acetate co-crystal of the compound of formula (IX) are useful for producing a pharmaceutical preparation having good storage stability. Moreover, it can be used in order to efficiently and highly purify the compound of the formula (IX), and is also useful from the viewpoint of efficient production of a pharmaceutical containing the compound.
- the method for producing the compound of formula (I) provided by the present invention is an efficient production method with a short process and a high yield, and is suitable as an industrial production method.
- the intermediate compound provided by the present invention is a very useful compound in the efficient production of the compound of formula (I).
- NMR nuclear magnetic resonance apparatus JEOL JNM-EX-270 (270 MHz), JEOL JNM-ECP-500 (500 MHz), or Varian Mercury 300 (300 MHz).
- Mass spectrometry was measured using LCT Premier XE (manufactured by Waters). For high performance liquid chromatography, Waters 2690/2996 (detector) was used. When the product was used in the next step without purification, a part of the product was taken or a product separately prepared by the same technique was appropriately purified, and then NMR was measured.
- Step 2 Preparation of 2-bromo-1,4-bis (1-methoxy-1-methyl-ethoxymethyl) benzene
- Step 3 Preparation of (3R, 4S, 5R, 6R) -3,4,5-tris (trimethylsilyloxy) -6-trimethylsilyloxymethyl-tetrahydropyran-2-one
- Step 4 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-6,6′-bis (hydroxymethyl) -spiro [ Preparation of isobenzofuran-1 (3H), 2 ′-[2H] pyran] -3 ′, 4 ′, 5′-triol
- P-Toluenesulfonic acid monohydrate (1.4 kg, 7.4 mol) was added to the mixture and stirred at 20 ° C. for 1 hour. After cooling to 0 ° C. and stirring for 1 hour, the obtained crystals were centrifuged, washed with methanol (25 kg), dried at 40 ° C. under reduced pressure for 8 hours, and the title compound (5.47 kg, collected). 50%).
- Step 5 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6-[(methoxycarbonyloxy) methyl] -3 ′, 4 ′, 5 ′, 6′-tetrahydro-3 ′ , 4 ′, 5′-Tris (methoxycarbonyloxy) -6 ′-[(methoxycarbonyloxy) methyl] -spiro [isobenzofuran-1 (3H), 2 ′-[2H] pyran]
- Step 6 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6-[(4-Ethylphenyl) methyl] -3 ′, 4 ′, 5 ′, 6′-tetrahydro-3
- the resulting solid was centrifuged and washed twice with a mixture of ethanol (55 kg) and water (35 kg).
- the obtained wet powder (10.21 kg) was dissolved again in ethanol (77 kg) at 70 ° C., water (9.7 kg) was added, and the mixture was cooled to 60 ° C. and stirred for 1 hour. After confirming solid precipitation, the mixture was cooled from 60 ° C. to 0 ° C. over 2.5 hours and further stirred at 5 ° C. or less for 1 hour or more.
- Step 7 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6-[(4-Ethylphenyl) methyl] -3 ′, 4 ′, 5 ′, 6′-tetrahydro-6
- -6-[(4-Ethylphenyl) methyl] -3 ′, 4 ′, 5 ′, 6′-tetrahydro-6 Preparation of '-(hydroxymethyl) -spiro [isobenzofuran-1 (3H), 2'-[2H] pyran] -3 ', 4', 5'-triol
- ⁇ HPLC measurement conditions Column: YMC-Pack ODS-A 6.0 ⁇ 150 mm, 5 ⁇ m Mobile phase: 0.1 volume% TFA / MeCN (5 volume%) + 0.1 volume% TFA / H 2 O (95 volume%) to 0.1 volume% TFA / MeCN (100 volume%) 20 minute gradient And then elution for 5 minutes under the same conditions (0.1 vol% TFA / MeCN (100 vol%)) Flow rate: 1.5 ml / min Column temperature: room temperature Detection conditions: Total plot of all wavelengths from 230 to 400 nm.
- Step 3 Preparation of 2-bromo-1,4-bis [(1-methoxy-1-methyl) ethoxymethyl] benzene
- Step 4 (3′R, 4 ′S, 5′R, 6′R) -2- [2,5- [bis (1-methoxy-1-methyl) ethoxymethyl] phenyl] -3,4,5 -Tris (trimethylsilyloxy) -6-trimethylsilyloxymethyl-tetrahydropyran-2-ol
- Step 5 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-6,6′-bis (hydroxymethyl) -spiro [ Preparation of isobenzofuran-1 (3H), 2 ′-[2H] pyran] -3 ′, 4 ′, 5′-triol
- Methyl tert-butyl ether (108.7 kg) was added to the reaction mixture, and the mixture was cooled to 10 ° C. and stirred for 1 hour. The precipitated solid was collected by filtration and washed with methanol (104 kg) to obtain a white wet powder (24.08 kg). This powder was suspended in methanol (42.9 kg), heated to 48 ° C. over 30 minutes, and stirred at 48 ° C. for 1 hour. Subsequently, it cooled to 10 degreeC and stirred for 1 hour. The suspension was filtered to collect a solid, and washed with methanol (10.0 kg) and methyl tert-butyl ether (10.0 kg) to obtain a wet powder (19.78 kg). The powder was dried at 40 ° C. under reduced pressure to give the title compound (14.71 kg, yield of 2 steps 63.4%) as white crystals.
Abstract
Description
R1およびR2は、それぞれ独立に、1以上のRaにより置換されていてもよいC1-10アルキル、1以上のRaにより置換されていてもよいC3-10シクロアルキル、1以上のRaにより置換されていてもよいC2-10アルケニル、1以上のRaにより置換されていてもよいC3-10シクロアルケニル、1以上のRaにより置換されていてもよいC2-10アルキニル、1以上のRaにより置換されていてもよいアリール、1以上のRaにより置換されていてもよい飽和、部分不飽和、または不飽和のへテロシクリル、シアノ、ハロゲン原子、ニトロ、メルカプト、-OR3、-NR4R5、-S(O)pR6、-S(O)qNR7R8、-C(=O)R35、-CR36=NOR37、-C(=O)OR9、-C(=O)NR10R11、および-SiR12R13R14から選択され;nが2以上の場合、R1はそれぞれ同一であっても、異なっていてもよく;mが2以上の場合、R2はそれぞれ同一であっても、異なっていてもよく;または、隣接する炭素原子上に存在する2つのR1は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;隣接する炭素原子上に存在する2つのR2は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;
pは、0~2から選択される整数であり;qは、1および2から選択される整数であり;
R3は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R4およびR5は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R6は、C1-10アルキル、C3-10シクロアルキル、アリール、またはヘテロアリールであり、ただし、pが0の場合、R6はさらに-SiR12R13R14、または-C(=O)R15であってもよく;
R7、R8、R10およびR11は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R9は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、または-SiR12R13R14であり;
Raは、それぞれ独立に、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、ヒドロキシ、ハロゲン原子、-NR21R22、-OR38、-SR26、-S(O)2R27、-SiR23R24R25、カルボキシ、-C(O)NR28R29、-C(=O)R30、-CR31=NOR32、シアノ、および-S(O)rNR33R34から選択され;
rは、1および2から選択される整数であり;
R12、R13、R14、R23、R24、およびR25は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R15およびR30は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、C1-10アルキルアミノ、ジ(C1-10アルキル)アミノ、C1-10アルキルチオ、アリール、およびヘテロアリールから選択され;
R21、R22、R28、R29、R33およびR34は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR23R24R25、および-C(=O)R30から選択され;
R26は、水素原子、C1-10アルキル、C1-10アルコキシ、C3-10シクロアルキルオキシ、アリールオキシ、C3-10シクロアルキル、アリール、ヘテロアリール、-C(=O)R30、または-SiR23R24R25であり;
R27は、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R31は、水素原子、C1-10アルキル、またはC3-10シクロアルキルであり;
R32は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R35は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、またはヘテロアリールであり;
R36は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、またはC2-10アルキニルであり;
R37は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R38は、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30である]
の化合物を製造する方法であって;
工程a)式(II):
R41は、R1として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく;nは既に定義したとおりである]
の化合物を、式(III):
R100は、独立に、-OR101、Cl、Br、I、Fから選択され、ここで、R101は水素原子およびC1-12アルキルから選択され、または、B(R100)2は、5または6員環の環状ボロン酸エステルを形成していてもよく、
R42は、R2として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく、mは既に定義したとおりである]
の化合物と反応させて、式(IV):
の化合物を得る工程;および
工程b)保護基を除去することにより、式(IV)の化合物を式(I)の化合物に変換する工程;
を含み、さらに、上記工程中、および/またはその前後の任意の段階において、保護基を導入する工程、および/または保護基を除去する工程を含んでいてもよい、前記製造方法が提供される。
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキル、およびアリールから選択される。
P1およびP2は、それぞれ独立して、金属イオン、水素原子、またはヒドロキシ基の保護基から選択され;
R41およびnは既に定義したとおりである]
の化合物を有機金属試薬で処理し、その後、式(VII):
を反応させて、式(VIII):
Xは、金属イオン、または水素原子である]
の化合物を得る工程;および
式(VIII)の化合物を、上記式(V)の化合物に変換する工程;
をさらに含む製造方法が提供される。
P3、P4、P5、およびP6は、それぞれ独立に、1以上のR51により置換されていてもよいC1-10アルキル、1以上のR52により置換されていてもよい飽和、部分不飽和、または不飽和のヘテロシクリル、C2-10アルケニル、-Si(R53)3、-C(=O)R54、および-B(OR55)2から選択され;またはP3およびP4、P4およびP5、ならびにP5およびP6は一緒になって、それぞれ独立に、それぞれ2つのヒドロキシ基を保護して環を形成する2価のC1-10アルキレン基、またはカルボニル基であってもよく;
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
Xは、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である。
P3、P4、P5、およびP6は、それぞれ独立に、C1-6アルコキシC1-6アルキル、アリールメトキシC1-6アルキル、テトラヒドロピラニル、テトラヒドロフラニル、基-Si(R53)3、アラルキル、基-B(OR55)2、C1-6アルキルカルボニル、C1-6アルコキシカルボニル、およびtert-ブチルから選択され;または、P3およびP4、P4およびP5、ならびにP5およびP6は一緒になって、-CH2-、-CH(CH3)-、-C(CH3)2-、および-CHPh-から選択される2つのヒドロキシ基を保護して環を形成する2価の基を表してもよく;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
Xは、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である。
P3、P4、P5、およびP6が、トリメチルシリル、トリエチルシリル、t-ブチルジメチルシリル、トリイソプロピルシリル、メトキシメチル、2-メトキシエトキシメチル、1-メトキシ-1-メチルエチル、テトラヒドロピラニル、およびテトラヒドロフラニルから選択される。
ブチルマグネシウムクロリドとブチルリチウム;
イソプロピルマグネシウムブロミドとブチルリチウム;
ジブチルマグネシウムとブチルリチウム;
ブチルマグネシウムブロミドとブチルリチウム;
イソプロピルマグネシウムブロミドとリチウムクロリド;
ジブチルマグネシウムとエトキシリチウム;
ジブチルマグネシウムとブトキシリチウム;
ジブチルマグネシウムとリチウムヘキサメチルジシラジド;
イソプロピルマグネシウムブロミドとブチルリチウムとリチウムクロリド;
ブチルマグネシウムクロリドとブチルリチウムとエトキシリチウム;
ブチルマグネシウムクロリドとブチルリチウムとリチウムヘキサメチルジシラジド;
イソプロピルマグネシウムブロミドとブチルリチウムとエトキシリチウム;
塩化亜鉛とブチルリチウム;および
ジエチル亜鉛とn-ブチルリチウム;
から選ばれる試薬の混合物または反応生成物である。
P1およびP2は、それぞれ独立に、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、水素原子、1以上のR51により置換されていてもよいC1-10アルキル、1以上のR52により置換されていてもよい飽和、部分不飽和、または不飽和のヘテロシクリル、C2-10アルケニル、-Si(R53)3、-C(=O)R54、および-B(OR55)2から選択され、
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキルおよびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキルおよびアリールから選択される]
の化合物を有機金属試薬で処理し、その後、式(VII):
ここで、R51、R52、R53、R54、R55は既に述べたとおりである]
を反応させて、式(VIIIb):
Xはリチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である]
の化合物を得る工程;および
式(VIIIb)の化合物を、式(Vb):
の化合物を得る工程;および
保護基を除去することにより、式(IVb)の化合物を式(Ib)の化合物に変換する工程;
を含む前記製造方法が提供される。式(I)の化合物の製造方法に関して本明細書で述べた態様は全て式(Ib)の化合物の製造方法に適用されうる。
Rxは、C1-6アルコキシである]
の化合物が提供される。上記式(II)および(IV)の化合物は、式(I)の化合物を効率的に製造する上での重要な合成中間体である。
工程1:(2-ブロモ-4-ヒドロキシメチルフェニル)メタノールの調製
MS(ESI+):362[M+2]+。
MS(ESI+):589[M+1]+、606[M+18]+。
MS(ESI+):619[M+1]+、636[M+18]+。
分析法:電量滴定法
KF分析装置:微量水分測定装置 三菱化学社製 型式KF-100
陽極液:アクアミクロンAX(三菱化学製)
陰極液:アクアミクロンCXU(三菱化学製)
MS(ESI+):387[M+1]+。
工程1:2-ブロモテレフタル酸ジメチルエステルの調製
HPLC保持時間:17.59分。
カラム:YMC-Pack ODS-A 6.0×150mm、5μm
移動相:10mM AcONH4/MeOH(5容積%)+10mM AcONH4/H2O(95容積%)から10mM AcONH4/MeOH(100容積%)まで20分間のグラジエントをかけ、その後同条件(10mM AcONH4/MeOH(100容積%))で5分間溶出
流速:1.5ml/分
カラム温度:室温
検出条件:230~400nmの全波長の合計プロット。
HPLC保持時間:7.48分。
カラム:YMC-Pack ODS-A 6.0×150mm、5μm
移動相:0.1容積%TFA/MeCN(5容積%)+0.1容積%TFA/H2O(95容積%)から0.1容積%TFA/MeCN(100容積%)まで20分間のグラジエントをかけ、その後同条件(0.1容積%TFA/MeCN(100容積%))で5分間溶出
流速:1.5ml/分
カラム温度:室温
検出条件:230~400nmの全波長の合計プロット。
MS(ESI+):299[M+1]+
HPLC保持時間:5.68分。
カラム:YMC-Pack ODS-A 6.0×150mm、5μm
移動相:10mM AcONH4/MeOH(5容積%)+10mM AcONH4/H2O(95容積%)から10mM AcONH4/MeOH(100容積%)まで20分間のグラジエントをかけ、その後同条件(10mM AcONH4/MeOH(100容積%))で5分間溶出
流速:1.5ml/分
カラム温度:室温
検出条件:230~400nmの全波長の合計プロット。
Claims (24)
- 式(I):
R1およびR2は、それぞれ独立に、1以上のRaにより置換されていてもよいC1-10アルキル、1以上のRaにより置換されていてもよいC3-10シクロアルキル、1以上のRaにより置換されていてもよいC2-10アルケニル、1以上のRaにより置換されていてもよいC3-10シクロアルケニル、1以上のRaにより置換されていてもよいC2-10アルキニル、1以上のRaにより置換されていてもよいアリール、1以上のRaにより置換されていてもよい飽和、部分不飽和、または不飽和のへテロシクリル、シアノ、ハロゲン原子、ニトロ、メルカプト、-OR3、-NR4R5、-S(O)pR6、-S(O)qNR7R8、-C(=O)R35、-CR36=NOR37、-C(=O)OR9、-C(=O)NR10R11、および-SiR12R13R14から選択され;nが2以上の場合、R1はそれぞれ同一であっても、異なっていてもよく;mが2以上の場合、R2はそれぞれ同一であっても、異なっていてもよく;または、隣接する炭素原子上に存在する2つのR1は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;隣接する炭素原子上に存在する2つのR2は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;
pは、0~2から選択される整数であり;qは、1および2から選択される整数であり;
R3は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R4およびR5は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R6は、C1-10アルキル、C3-10シクロアルキル、アリール、またはヘテロアリールであり、ただし、pが0の場合、R6はさらに-SiR12R13R14、または-C(=O)R15であってもよく;
R7、R8、R10およびR11は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R9は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、または-SiR12R13R14であり;
Raは、それぞれ独立に、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、ヒドロキシ、ハロゲン原子、-NR21R22、-OR38、-SR26、-S(O)2R27、-SiR23R24R25、カルボキシ、-C(O)NR28R29、-C(=O)R30、-CR31=NOR32、シアノ、および-S(O)rNR33R34から選択され;
rは、1および2から選択される整数であり;
R12、R13、R14、R23、R24、およびR25は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R15およびR30は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、C1-10アルキルアミノ、ジ(C1-10アルキル)アミノ、C1-10アルキルチオ、アリール、およびヘテロアリールから選択され;
R21、R22、R28、R29、R33およびR34は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR23R24R25、および-C(=O)R30から選択され;
R26は、水素原子、C1-10アルキル、C1-10アルコキシ、C3-10シクロアルキルオキシ、アリールオキシ、C3-10シクロアルキル、アリール、ヘテロアリール、-C(=O)R30、または-SiR23R24R25であり;
R27は、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R31は、水素原子、C1-10アルキル、またはC3-10シクロアルキルであり;
R32は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R35は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、またはヘテロアリールであり;
R36は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、またはC2-10アルキニルであり;
R37は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R38は、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30である]
の化合物を製造する方法であって;
工程a)式(II):
R41は、R1として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく;nは既に定義したとおりである]
の化合物を、式(III):
R100は、独立に、-OR101、Cl、Br、I、Fから選択され、ここで、R101は水素原子、およびC1-12アルキルから選択され、または、B(R100)2は、5また6員環の環状ボロン酸エステルを形成していてもよく、
R42は、R2として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく、mは既に定義したとおりである]
の化合物と反応させて、式(IV):
の化合物を得る工程;および
工程b)保護基を除去することにより、式(IV)の化合物を式(I)の化合物に変換する工程;
を含み、さらに、上記工程中、および/またはその前後の任意の段階において、保護基を導入する工程、および/または保護基を除去する工程を含んでいてもよい、前記製造方法。 - 式(II)および式(IV)におけるRxが同一の基を表す、請求項1に記載の製造方法。
- 式(II)および式(IV)におけるRxがt-ブチルまたはメトキシである、請求項2に記載の製造方法。
- 式(VI):
P1およびP2は、それぞれ独立して、金属イオン、水素原子、またはヒドロキシ基の保護基から選択され;
R41およびnは請求項1において定義したとおりである]
の化合物を有機金属試薬で処理し、その後、式(VII):
を反応させて、式(VIII):
Xは、金属イオン、または水素原子である]
の化合物を得る工程;および
式(VIII)の化合物を、請求項4に定義した式(V)の化合物に変換する工程;
をさらに含む、請求項1~4のいずれか1項に記載の製造方法。 - 式(VI)、式(VII)、および式(VIII)において、
P1およびP2は、それぞれ独立に、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、水素原子、1以上のR51により置換されていてもよいC1-10アルキル、1以上のR52により置換されていてもよい飽和、部分不飽和、または不飽和のヘテロシクリル、C2-10アルケニル、-Si(R53)3、-C(=O)R54、および-B(OR55)2から選択され;
P3、P4、P5、およびP6は、それぞれ独立に、1以上のR51により置換されていてもよいC1-10アルキル、1以上のR52により置換されていてもよい飽和、部分不飽和、または不飽和のヘテロシクリル、C2-10アルケニル、-Si(R53)3、-C(=O)R54、および-B(OR55)2から選択され;またはP3およびP4、P4およびP5、ならびにP5およびP6は一緒になって、それぞれ独立に、それぞれ2つのヒドロキシ基を保護して環を形成する2価のC1-10アルキレン基、またはカルボニル基であってもよく;
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
Xは、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である、請求項5に記載の製造方法。 - 式(VI)、式(VII)、式(VIII)において、
P1およびP2は、それぞれ独立に、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、水素原子、C1-6アルコキシC1-6アルキル、アリールメトキシC1-6アルキル、テトラヒドロピラニル、テトラヒドロフラニル、基-Si(R53)3、アラルキル、および基-B(OR55)2から選択され;
P3、P4、P5、およびP6は、それぞれ独立に、C1-6アルコキシC1-6アルキル、アリールメトキシC1-6アルキル、テトラヒドロピラニル、テトラヒドロフラニル、基-Si(R53)3、アラルキル、基-B(OR55)2、C1-6アルキルカルボニル、C1-6アルコキシカルボニル、およびtert-ブチルから選択され;または、P3およびP4、P4およびP5、ならびにP5およびP6は一緒になって、-CH2-、-CH(CH3)-、-C(CH3)2-、および-CHPh-から選択される2つのヒドロキシ基を保護して環を形成する2価の基を表してもよく;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
Xは、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である、請求項5に記載の製造方法。 - 式(VI)、式(VII)、式(VIII)において、
P1およびP2が、メトキシメチル、2-メトキシエトキシメチル、1-メトキシ-1-メチルエチル、テトラヒドロピラニルピラニル、テトラヒドロフラニル、およびトリフェニルメチルから選択され;
P3、P4、P5、およびP6が、トリメチルシリル、トリエチルシリル、t-ブチルジメチルシリル、トリイソプロピルシリル、メトキシメチル、2-メトキシエトキシメチル、1-メトキシ-1-メチルエチル、テトラヒドロピラニル、およびテトラヒドロフラニルから選択される、請求項5に記載の製造方法。 - 式(VIII)の化合物を、塩酸、硫酸、酢酸、トリフルオロ酢酸、p-トルエンスルホン酸、メタンスルホン酸、およびカンファースルホン酸から選択される酸の存在下で処理することにより、式(V)の化合物に変換する、請求項8に記載の製造方法。
- 式(VIII)の化合物を式(V)の化合物に変換する工程をワンポットで行う、請求項9に記載の製造方法。
- 式(VI)の化合物を有機リチウム試薬とハロゲン化マグネシウムにより処理し、式(VII)の化合物を反応させる、請求項5~10のいずれか1項に記載の製造方法。
- 式(VI)の化合物の有機金属試薬による処理において、有機リチウム試薬を添加した後にハロゲン化マグネシウムを加える、請求項11に記載の製造方法。
- 有機リチウム試薬がC1-10アルキルリチウムから選択され、ハロゲン化マグネシウムが塩化マグネシウム、臭化マグネシウム、ヨウ化マグネシウム、およびフッ化マグネシウムから選択される、請求項11または12に記載の製造方法。
- nが0である、請求項1~13のいずれか1項に記載の製造方法。
- mが1であり、R2およびR42がC1-6アルキルである、請求項1~14のいずれか1項に記載の製造方法。
- 式(Ib):
の化合物を製造する方法であって;
式(VIb)
P1およびP2は、それぞれ独立に、リチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、水素原子、1以上のR51により置換されていてもよいC1-10アルキル、1以上のR52により置換されていてもよい飽和、部分不飽和、または不飽和のヘテロシクリル、C2-10アルケニル、-Si(R53)3、-C(=O)R54、および-B(OR55)2から選択され、
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキルおよびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキル、およびアリールから選択される]
の化合物を有機金属試薬で処理し、その後、式(VII):
ここで、R51、R52、R53、R54、およびR55は既に定義したとおりである]
を反応させて、式(VIIIb):
Xはリチウムイオン、ナトリウムイオン、カリウムイオン、セシウムイオン、マグネシウムイオン、亜鉛イオン、または水素原子である]
の化合物を得る工程;
式(VIIIb)の化合物を、式(Vb):
式(Vb)の化合物を、式(IIb):
の化合物に変換する工程;
式(IIb)の化合物を式(IIIb):
の化合物と反応させて、式(IVb):
の化合物を得る工程;および
保護基を除去することにより、式(IVb)の化合物を式(Ib)の化合物に変換する工程;
を含む前記製造方法。 - P1およびP2が、メトキシメチル、2-メトキシエトキシメチル、1-メトキシ-1-メチルエチル、テトラヒドロピラニルピラニル、テトラヒドロフラニル、およびトリフェニルメチルから選択され;P3、P4、P5、およびP6が、トリメチルシリル、トリエチルシリル、t-ブチルジメチルシリル、トリイソプロピルシリル、メトキシメチル、2-メトキシエトキシメチル、1-メトキシ-1-メチルエチル、テトラヒドロピラニルピラニル、およびテトラヒドロフラニルから選択される、請求項17に記載の製造方法。
- 式(VIIIb)の化合物を、塩酸、硫酸、酢酸、トリフルオロ酢酸、p-トルエンスルホン酸、メタンスルホン酸、およびカンファースルホン酸から選択される酸の存在下で処理することにより、式(Vb)の化合物に変換する、請求項18に記載の製造方法。
- 式(VIIIb)の化合物を式(Vb)の化合物に変換する工程をワンポットで行う、請求項19に記載の製造方法。
- nが0であり、Rxが、t-ブチル、またはメトキシである請求項21に記載の式(II)の化合物。
- nが0、mが1、R42がC1-6アルキルである、請求項23に記載の式(IV)の化合物。
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