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WO2012133783A1 - Method for producing benzylpyrazole derivative and production intermediate thereof - Google Patents

Method for producing benzylpyrazole derivative and production intermediate thereof Download PDF

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Publication number
WO2012133783A1
WO2012133783A1 PCT/JP2012/058604 JP2012058604W WO2012133783A1 WO 2012133783 A1 WO2012133783 A1 WO 2012133783A1 JP 2012058604 W JP2012058604 W JP 2012058604W WO 2012133783 A1 WO2012133783 A1 WO 2012133783A1
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Prior art keywords
group
alkoxy
halo
cycloalkyl
alkyl group
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French (fr)
Japanese (ja)
Inventor
孝幸 相内
雅周 小林
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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Priority to JP2013507792A priority Critical patent/JP5902671B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a method for producing a benzylpyrazole derivative useful as a pharmaceutical intermediate and a production intermediate thereof.
  • the glucopyranosyloxypyrazole derivative has been reported to be useful as a therapeutic agent for diabetes, for example (see, for example, Patent Documents 1 to 4).
  • Patent Document 4 in general formula (1):
  • Patent Document 4 (For the meaning of each symbol in the above formula, refer to the description in Patent Document 4) A method of producing a compound by condensing hydrazine and then alkylating and then hydrolyzing has been reported. Yes. Specifically, Patent Document 4 described above describes a production method of the general formula (1) using hydrazine, but no production method using isopropyl hydrazine has been reported.
  • Patent Document 5 describes general formula (3):
  • An object of the present invention is to provide an industrially superior production method as compared with a production intermediate of a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like, and a conventional production method of a benzylpyrazole derivative. is there.
  • R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 An alkylthio group or a halo C 1-6 alkoxy group, wherein R 5 is a C 1-6 alkyl group or a substituted C 7-11 aral
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group
  • R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C
  • R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 A method for producing a compound represented by an alkylthio group or a halo C 1-6 alkoxy group) or a salt thereof; (14) The production method according to (13),
  • Halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom.
  • C 1-6 alkyl group means methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group , A linear or branched alkyl group having 1 to 6 carbon atoms, such as a 1-methylbutyl group, a 2-methylbutyl group, and a hexyl group.
  • the halo C 1-6 alkyl group refers to the above C 1-6 alkyl group substituted with the above or different halogen atoms, such as a trifluoromethyl group, a 2,2,2-trifluoroethyl group, Examples include 2,2,2,1,1-pentafluoroethyl group and 2-fluoroethyl group.
  • the C 3-6 cycloalkyl group refers to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • C 1-6 alkoxy group means methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-butyloxy group
  • a straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as a group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, hexyloxy group and the like.
  • the halo C 1-6 alkoxy group refers to the above C 1-6 alkoxy group substituted with a different or the same halogen atom, and includes, for example, a trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2 2,2,1,1-pentafluoroethoxy group and the like.
  • the C 3-6 cycloalkyloxy group refers to a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • the C 3-6 cycloalkyl (C 1-6 alkoxy) group means the C 1-6 alkoxy group substituted with the C 3-6 cycloalkyl group.
  • the C 1-6 alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms such as a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, or a hexylthio group.
  • the optionally substituted C 7-11 aralkyl group, a substituent of heterologous or homologous have 1 to 3 means good C 7-11 aralkyl group, as a substituent in the substitutable C 7-11 aralkyl group Examples include a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a nitro group.
  • Examples of the replaceable C 7-11 aralkyl group include a benzyl group, a 4-methoxybenzyl group, a naphthylmethyl group, and the like.
  • the optionally substituted C 7-11 aralkyloxy group, a substituent of heterologous or homologous have 1 to 3 means which may C 7-11 aralkyloxy group, a substitutable C 7-11 aralkyloxy group
  • substituent include a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group, and the like.
  • replaceable C 7-11 aralkyloxy group include a benzyloxy group, a 4-methoxybenzyloxy group, a naphthylmethyloxy group, and the like.
  • the C 1-6 alkylene group means a divalent linear or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as —CH 2 —, —CH 2 CH 2 —, —CH. (CH 3 ) —, —CH (CH 3 ) CH 2 —, —CH 2 CH (CH 3 ) —, —C (CH 3 ) 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 C Examples include (CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, —C (CH 3 ) 2 CH 2 CH 2 —, —CH (CH 3 ) CH (CH 3 ) — and the like.
  • the salt includes, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt.
  • the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N ′ -dibenzylethylenediamine and the like.
  • Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like.
  • Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
  • a compound (B) By subjecting compound (A) to a carbonyl group protection reaction according to the method described in Protective Groups in Organic Synthesis (TWGreene et al., John Wiley & Sons, Inc., 1991, Second Edition) or a method analogous thereto.
  • a compound (B) can be obtained.
  • compound (B) can be obtained by subjecting compound (A) to a dehydration reaction with an alcohol in the presence of an acid in a solvent-free or inert solvent.
  • the inert solvent include hydrocarbon solvents such as cyclohexane, toluene, and xylene.
  • toluene and xylene are used.
  • Acids include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid and methanesulfonic acid, Lewis acids such as boron trifluoride diethyl ether complex, trimethylchlorosilane, and acids such as Amberlyst (registered trademark).
  • An ion exchange resin is mentioned.
  • Preferred are sulfonic acids such as sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and more preferred are p-toluenesulfonic acid and methanesulfonic acid.
  • the amount of the solvent can be used 5 to 10 times the amount of the compound (A).
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material and solvent used, the reaction temperature and the like.
  • the compound (C) can be obtained by subjecting the compound (B) to an ester hydrolysis reaction in the presence of a base in an inert solvent.
  • the inert solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof.
  • the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the amount of the base is preferably 1 to 3 equivalents relative to the compound (B).
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • R 5 is a substitutable C 7-11 aralkyl group
  • the compound (C) may be obtained by subjecting the compound (B) to a deprotection reaction according to a known method or a method analogous thereto. it can.
  • the compound (D) can be obtained by subjecting the compound (C) to an amidation reaction with isopropylhydrazine or a salt thereof in an inert solvent in the presence of a base and a condensing agent.
  • the inert solvent include ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, amide solvents such as dimethylformamide, or a mixed solvent thereof.
  • the base include triethylamine or pyridine.
  • the condensing agent examples include N, N′-dicyclohexylcarbodiimide, carbonyldiimidazole, and thionyldiimidazole, and carbonyldiimidazole and thionyldiimidazole are preferable.
  • a commercial item may be used for these condensing agents, and you may prepare and use at the time of reaction.
  • the amount of the base and the condensing agent is preferably 1 to 2 equivalents relative to the compound (C).
  • the reaction temperature is usually from 0 ° C. to the reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, etc.
  • the production intermediate (E) of a compound useful as a therapeutic agent for diabetes can be produced by the method shown in the following scheme 3 using the compound (D) obtained in the scheme 1.
  • Compound (E) can be obtained by subjecting compound (D) to a cyclization reaction in an inert solvent in the presence of an acid.
  • the inert solvent include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, amide solvents such as dimethylformamide, Water or a mixed solvent thereof can be used.
  • a mixed solvent of tetrahydrofuran, dimethylformamide, and water is used.
  • the acid examples include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and hydrochloric acid is preferable.
  • the amount of the solvent can be 5 to 20 times the amount of the compound (D).
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 35 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes can be produced from the compound (E) obtained in Scheme 2 according to the method described in Patent Document 1 or a method analogous thereto.
  • the compound (A) used as a starting material in the scheme 1 can be produced by the method shown in the following scheme 3, the method described in Patent Document 4, or a method analogous thereto.
  • Compound (I) is obtained by subjecting compound (G) to a condensation reaction with compound (H) in a solvent-free or inert solvent in the presence of a base or an acid and a base, if necessary, using a dehydrating agent.
  • a solvent-free or inert solvent examples include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, alcohol solvents such as ethanol, or These mixed solvents are mentioned, and it is preferable to react without solvent.
  • Examples of the acid include acetic acid, propionic acid, benzoic acid, sulfuric acid, p-toluenesulfonic acid, titanium chloride and the like, and acetic acid is preferable.
  • Examples of the base include organic amines such as piperidine, pyrrolidine, pyridine, diethylamine and triethylamine, and piperidine is preferable.
  • Examples of the dehydrating agent include molecular sieves.
  • the solvent can be used in an amount of 0 to 10 times that of the compound (G).
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 5 days, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.
  • Step 6 Compound (A) can be obtained by subjecting compound (I) to a reduction reaction.
  • an acid such as acetic acid in the presence of an acid such as acetic acid in an alcoholic solvent such as methanol or ethanol, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, or a mixed solvent thereof.
  • the compound (A) can be obtained by reduction using a metal catalyst such as palladium under a hydrogen atmosphere of 0.1 to 0.5 MPa, usually at room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, catalyst, reaction temperature, etc., but is usually 2 to 24 hours.
  • the compound having an unsaturated bond includes two geometric isomers, that is, a cis (Z) compound and a trans (E) compound.
  • a cis (Z) compound and a trans (E) compound.
  • any of these compounds may be used in the present invention, or a mixture thereof may be used.
  • the compound having an asymmetric carbon atom includes a compound having an R configuration and a compound having an S configuration for each asymmetric carbon. Any optical isomer may be used, and a mixture of these optical isomers may be used.
  • the production intermediate of the benzylpyrazole derivative (E) of the present invention may have various tautomers, and the compound of the present invention also includes those tautomers.
  • an isopropyl group can be introduced with high regioselectivity, and the compound (E), which is a pharmaceutical production intermediate, can be obtained in high yield and high purity. Furthermore, a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced using the compound (E).
  • Reference example 2 2- (4-Isopropoxybenzyl) -3-oxo-butanoic acid methyl ester
  • 2-propanol (80 g) and 10% palladium carbon powder (3.2 g) were added.
  • the mixture was stirred at room temperature for 6 hours.
  • the insoluble material was removed by filtration, and the insoluble material was washed with tert-butyl methyl ether (80 g).
  • the filtrate and washings were combined and concentrated under reduced pressure.
  • the obtained residue was dissolved in ethyl acetate (60 g), and water (60 g) was added to the mixture.
  • Example 1 Methyl 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoate
  • Ethylene glycol (18 g) and p-toluenesulfonic acid monohydrate (0.46 g) were added to a toluene (160 g) solution of methyl 2- (4-isopropoxybenzyl) -3-oxobutanoate (16.1 g). .
  • the mixture was heated to reflux for 8 hours while removing water.
  • the reaction mixture was cooled to room temperature and 5% aqueous sodium bicarbonate (80 g) was added.
  • Example 2 3- (4-Isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid To a solution of methyl 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoate (18.8 g) in methanol (19 g) was added 25 g / L aqueous sodium hydroxide solution ( 14 mL) was added. The mixture was stirred at 80 ° C. for 7 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (57 g) and tert-butyl methyl ether (95 g), and the aqueous layer was separated.
  • the aqueous layer was washed with tert-butyl methyl ether (95 g). To the aqueous layer were added tert-butyl methyl ether (95 g) and 2 mol / L hydrochloric acid (37 mL), and the organic layer was separated. The resulting organic layer was washed with 10% brine (57 g). The organic layer was dried over anhydrous magnesium sulfate, insolubles were removed by filtration, and the solvent was evaporated under reduced pressure to give 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolane-2 -Yl) propanoic acid (15.2 g) was obtained.
  • Example 3 N′-isopropyl-3- (p-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid hydrazide Pyridine (9.02 g) was added to a solution of imidazole (7.76 g) in tetrahydrofuran (150 g). To the obtained solution was added dropwise thionyl chloride (6.79 g) under ice cooling, and the mixture was stirred for 1 hour.
  • Example 4 1-isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1,2-dihydro-3H-pyrazol-3-one 6 mol / L hydrochloric acid (65 mL) was added to the solution B described in Example 3, and the mixture was stirred at 80 ° C. for 17 hours. The reaction mixture was cooled to room temperature, sodium bicarbonate (35 g) was added, and the organic layer was separated. The aqueous layer was extracted with toluene (72 g) and combined with the previous organic layer, and then the organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (36 g) at 80 ° C.
  • the compound (D) of the present invention is extremely useful as an intermediate for producing a pharmaceutical product, and a series of production methods via the compound (D) can regioselectively produce an isopropyl group on the pyrazole ring. Since it is a high yield and high purity, it turns out that it is very useful as an industrial manufacturing method.
  • a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced with high yield and high purity.

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Abstract

A production intermediate of a glucopyranosyloxypyrazole derivative which is represented by general formula (E) (wherein R3 and R4 are as defined below) and is useful as a therapeutic agent for diabetes or the like, and a method for producing a benzylpyrazole derivative, said method being indistrially more advantageous than conventional methods for producing a benzylpyrazole derivative, can be provided by causing a reaction of a compound represented by general formula (D) (wherein each of R1 and R2 represents a C1-6 alkyl group or the like; R3 represents a halogen atom, a C1-6 alkoxy group or the like; and R4 represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or the like).

Description

ベンジルピラゾール誘導体の製造方法およびその製造中間体Process for producing benzylpyrazole derivative and production intermediate thereof

　本発明は、医薬品の製造中間体として有用なベンジルピラゾール誘導体の製造方法およびその製造中間体に関する。 The present invention relates to a method for producing a benzylpyrazole derivative useful as a pharmaceutical intermediate and a production intermediate thereof.

　グルコピラノシルオキシピラゾール誘導体は、例えば、糖尿病の治療薬等として有用であると報告されている（例えば、特許文献１～４参照）。 The glucopyranosyloxypyrazole derivative has been reported to be useful as a therapeutic agent for diabetes, for example (see, for example, Patent Documents 1 to 4).

　これまで、グルコピラノシルオキシピラゾール誘導体の製造中間体の製造方法は、特許文献４に、一般式（１）： So far, a method for producing an intermediate for producing a glucopyranosyloxypyrazole derivative is disclosed in Patent Document 4 in general formula (1):

Figure JPOXMLDOC01-appb-C000009
（上式中の各記号の意味については、特許文献４の記載を参照）を、一般式（２）：
Figure JPOXMLDOC01-appb-C000009
 (For the meaning of each symbol in the above formula, refer to the description of Patent Document 4), the general formula (2):

Figure JPOXMLDOC01-appb-C000010
（上式中の各記号の意味については、特許文献４の記載を参照）で表される化合物と、ヒドラジンを縮合させた後、アルキル化、次いで加水分解することにより製造する方法が報告されている。上述した特許文献４には、具体的にはヒドラジンを用いた一般式（１）の製造方法が記載されているが、イソプロピルヒドラジンを用いた製造方法は報告されていない。
Figure JPOXMLDOC01-appb-C000010
 (For the meaning of each symbol in the above formula, refer to the description in Patent Document 4) A method of producing a compound by condensing hydrazine and then alkylating and then hydrolyzing has been reported. Yes. Specifically, Patent Document 4 described above describes a production method of the general formula (1) using hydrazine, but no production method using isopropyl hydrazine has been reported.

　その他に、特許文献５には、一般式（３）： In addition, Patent Document 5 describes general formula (3):

Figure JPOXMLDOC01-appb-C000011
（上式中の各記号の意味については、特許文献５の記載を参照）で表される化合物の製造方法が報告されているが、具体的な反応例は記載されていない。
Figure JPOXMLDOC01-appb-C000011
 (For the meaning of each symbol in the above formula, a method for producing a compound represented by Patent Document 5) has been reported, but no specific reaction example is described.

国際公開第０２／０５３５７３号International Publication No. 02/053573 国際公開第０１／１６１４７号International Publication No. 01/16147 国際公開第０２／０６８４３９号International Publication No. 02/068439 国際公開第２００７／０１００１５号International Publication No. 2007/010015 国際公開第２００４／０３１２０３号International Publication No. 2004/031203

　本発明者等が検討した結果、一般式（Ａ）で表される化合物とイソプロピルヒドラジンを反応させた場合、ベンジルピラゾール誘導体が効率的に得られないことがわかった（比較例参照）。更に、工業的製造において、改善する余地が残されていた。
　本発明の目的は、糖尿病の治療薬等として有用なグルコピラノシルオキシピラゾール誘導体の製造中間体、および従来のベンジルピラゾール誘導体の製造方法と比べ、工業的により優れた製造方法を提供することである。 As a result of investigations by the present inventors, it has been found that when the compound represented by the general formula (A) is reacted with isopropylhydrazine, a benzylpyrazole derivative cannot be obtained efficiently (see Comparative Example). Furthermore, there remains room for improvement in industrial production.
An object of the present invention is to provide an industrially superior production method as compared with a production intermediate of a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like, and a conventional production method of a benzylpyrazole derivative. is there.

　本発明者等は、上記課題を解決すべく鋭意研究を重ねた結果、医薬品の製造中間体である、一般式（Ｅ）： The present inventors have conducted extensive research to solve the above problems, and as a result, the general formula (E):

Figure JPOXMLDOC01-appb-C000012
（式中のＲ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩の新規な製造方法、ならびにその製造中間体を見出し、本発明を成すに至った。
　すなわち、本発明は、
Figure JPOXMLDOC01-appb-C000012
 (In the formula, R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group, R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 A novel method for producing a compound represented by the following formula: an alkylthio group or a halo C 1-6 alkoxy group, or a salt thereof, and a production intermediate thereof have been found, and the present invention has been accomplished.
That is, the present invention

（１）一般式（Ａ－１）： (1) General formula (A-1):

Figure JPOXMLDOC01-appb-C000013
（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ6は、ヒドロキシ基、Ｃ1-6アルコキシ基、置換可Ｃ7-11アラルキルオキシ基またはｉ－ＰｒＮＨＮＨ－基である）で表される化合物またはその塩；
（２）Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である、（１）記載の化合物またはその塩；
（３）Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である、（２）記載の化合物またはその塩；
（４）Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成する、（３）記載の化合物またはその塩；
（５）Ｒ6がヒドロキシ基またはｉ－ＰｒＮＨＮＨ－基である、（４）記載の化合物またはその塩；
（６）Ｒ6がｉ－ＰｒＮＨＮＨ－基である、（５）記載の化合物またはその塩；
（７）一般式（Ｃ）：
Figure JPOXMLDOC01-appb-C000013
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 alkoxy group, R 6 is hydroxy, C 1-6 alkoxy group, a substitutable C 7-11 aralkyloxy Or i-PrNHNH- compound represented by a group);
(2) The compound or salt thereof according to (1), wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom;
(3) The compound or salt thereof according to (2), wherein R 3 is an isopropyloxy group and R 4 is a hydrogen atom;
(4) The compound or salt thereof according to (3), wherein R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group;
(5) The compound or a salt thereof according to (4), wherein R 6 is a hydroxy group or an i-PrNHNH- group;
(6) The compound or a salt thereof according to (5), wherein R 6 is an i-PrNHNH— group;
(7) General formula (C):

Figure JPOXMLDOC01-appb-C000014
（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩をイソプロピルヒドラジンまたはその塩と反応することによる一般式（Ｄ）：
Figure JPOXMLDOC01-appb-C000014
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 ) or a salt thereof is the same as isopropyl hydrazine or a salt thereof. General formula (D) by responding:

Figure JPOXMLDOC01-appb-C000015

（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩の製造方法；
（８）Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である（７）記載の製造方法；
（９）Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である（８）記載の製造方法；
（１０）　工程１：
　一般式（Ａ）：
Figure JPOXMLDOC01-appb-C000015
(R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 is a alkoxy group) or a salt thereof;
(8) The production method according to (7), wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom;
(9) R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, and R 4 is a hydrogen atom. (8) The production method described in;
(10) Step 1:
Formula (A):

Figure JPOXMLDOC01-appb-C000016
（式中のＲ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ5はＣ1-6アルキル基または置換可Ｃ7-11アラルキル基である）で表される化合物のカルボニル基を保護することにより、一般式（Ｂ）：
Figure JPOXMLDOC01-appb-C000016
 (In the formula, R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group, R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 An alkylthio group or a halo C 1-6 alkoxy group, wherein R 5 is a C 1-6 alkyl group or a substituted C 7-11 aralkyl group). (B):

Figure JPOXMLDOC01-appb-C000017
（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ5はＣ1-6アルキル基または置換可Ｃ7-11アラルキル基である）で表される化合物を調製する工程；
　工程２：
　一般式（Ｂ）で表される化合物を、脱保護反応に付すことにより一般式（Ｃ）：
Figure JPOXMLDOC01-appb-C000017
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 is an alkoxy group, represented by R 5 is C 1-6 alkyl or optionally substituted C 7-11 aralkyl group) Preparing a compound;
Step 2:
By subjecting the compound represented by the general formula (B) to a deprotection reaction, the general formula (C):

Figure JPOXMLDOC01-appb-C000018
（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩を調製する工程；を包含する、（７）記載の製造方法；
（１１）Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である（１０）記載の製造方法；
（１２）Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子であり、Ｒ5がメチル基である（１１）記載の製造方法；
（１３）一般式（Ｄ）：
Figure JPOXMLDOC01-appb-C000018
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- (6 ) an alkoxy group), or a salt thereof. Production method;
(11) The production method according to (10), wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom;
(12) R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, and R 4 is a hydrogen atom. And the production method according to (11), wherein R 5 is a methyl group;
(13) General formula (D):

Figure JPOXMLDOC01-appb-C000019
（式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩を環化させることによる一般式（Ｅ）：
Figure JPOXMLDOC01-appb-C000019
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- A general formula (E) by cyclization of a compound represented by ( 6 alkoxy group) or a salt thereof:

Figure JPOXMLDOC01-appb-C000020
（式中のＲ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩の製造方法；
（１４）Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である、（１３）記載の製造方法；および
（１５）Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である、（１４）記載の製造方法；等を提供するものである。
Figure JPOXMLDOC01-appb-C000020
 (In the formula, R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group, R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 A method for producing a compound represented by an alkylthio group or a halo C 1-6 alkoxy group) or a salt thereof;
(14) The production method according to (13), wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom; and (15) R 1 and R 2 Are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, and R 4 is a hydrogen atom. And so on.

　本発明において以下の用語は、特に断らない限り、以下の意味を有する。 In the present invention, the following terms have the following meanings unless otherwise specified.

　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子をいう。 Halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom.

　Ｃ1-6アルキル基とは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、１－メチルブチル基、２－メチルブチル基、ヘキシル基等の炭素数１～６の直鎖状または枝分かれ状のアルキル基をいう。　 C 1-6 alkyl group means methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group , A linear or branched alkyl group having 1 to 6 carbon atoms, such as a 1-methylbutyl group, a 2-methylbutyl group, and a hexyl group.

　ハロＣ1-6アルキル基とは、異種または同種の上記ハロゲン原子で置換された、上記Ｃ1-6アルキル基をいい、例えば、トリフルオロメチル基、２，２，２－トリフルオロエチル基、２，２，２，１，１－ペンタフルオロエチル基、２－フルオロエチル基などが挙げられる。 The halo C 1-6 alkyl group refers to the above C 1-6 alkyl group substituted with the above or different halogen atoms, such as a trifluoromethyl group, a 2,2,2-trifluoroethyl group, Examples include 2,2,2,1,1-pentafluoroethyl group and 2-fluoroethyl group.

　Ｃ3-6シクロアルキル基とは、シクロプロピル基、シクロブチル基、シクロペンチル基およびシクロヘキシル基をいう。 The C 3-6 cycloalkyl group refers to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

　Ｃ1-6アルコキシ基とは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ネオペンチルオキシ基、ｔｅｒｔ－ブチルオキシ基、ｔｅｒｔ－ペンチルオキシ基、１－メチルブトキシ基、２－メチルブトキシ基、ヘキシルオキシ基等の炭素数１～６の直鎖状または枝分かれ状のアルコキシ基をいう。 C 1-6 alkoxy group means methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-butyloxy group A straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as a group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, hexyloxy group and the like.

　ハロＣ1-6アルコキシ基とは、異種または同種の上記ハロゲン原子で置換された上記Ｃ1-6アルコキシ基をいい、例えば、トリフルオロメトキシ基、２，２，２－トリフルオロエトキシ基、２，２，２，１，１－ペンタフルオロエトキシ基等が挙げられる。 The halo C 1-6 alkoxy group refers to the above C 1-6 alkoxy group substituted with a different or the same halogen atom, and includes, for example, a trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2 2,2,1,1-pentafluoroethoxy group and the like.

　Ｃ3-6シクロアルキルオキシ基とは、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基およびシクロヘキシルオキシ基をいう。
　Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基とは、上記Ｃ3-6シクロアルキル基で置換された上記Ｃ1-6アルコキシ基を意味する。 The C 3-6 cycloalkyloxy group refers to a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
The C 3-6 cycloalkyl (C 1-6 alkoxy) group means the C 1-6 alkoxy group substituted with the C 3-6 cycloalkyl group.

　Ｃ1-6アルキルチオ基とは、メチルチオ基、エチルチオ基、プロピルチオ基、ブチルチオ基、ペンチルチオ基、ヘキシルチオ基等の炭素数１～６の直鎖状または枝分かれ状のアルキルチオ基をいう。 The C 1-6 alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms such as a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, or a hexylthio group.

　置換可Ｃ7-11アラルキル基とは、異種又は同種の置換基を１～３個有していてもよいＣ7-11アラルキル基を意味し、置換可Ｃ7-11アラルキル基の置換基としては、例えば、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ニトロ基等が挙げられる。置換可Ｃ7-11アラルキル基としては、例えば、ベンジル基、４-メトキシベンジル基、ナフチルメチル基等が挙げられる。 The optionally substituted C 7-11 aralkyl group, a substituent of heterologous or homologous have 1 to 3 means good C 7-11 aralkyl group, as a substituent in the substitutable C 7-11 aralkyl group Examples include a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a nitro group. Examples of the replaceable C 7-11 aralkyl group include a benzyl group, a 4-methoxybenzyl group, a naphthylmethyl group, and the like.

　置換可Ｃ7-11アラルキルオキシ基とは、異種又は同種の置換基を１～３個有していてもよいＣ7-11アラルキルオキシ基を意味し、置換可Ｃ7-11アラルキルオキシ基の置換基としては、例えば、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ニトロ基等が挙げられる。置換可Ｃ7-11アラルキルオキシ基としては、例えば、ベンジルオキシ基、４-メトキシベンジルオキシ基、ナフチルメチルオキシ基等が挙げられる。 The optionally substituted C 7-11 aralkyloxy group, a substituent of heterologous or homologous have 1 to 3 means which may C 7-11 aralkyloxy group, a substitutable C 7-11 aralkyloxy group Examples of the substituent include a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group, and the like. Examples of the replaceable C 7-11 aralkyloxy group include a benzyloxy group, a 4-methoxybenzyloxy group, a naphthylmethyloxy group, and the like.

　Ｃ1-6アルキレン基とは、炭素数１～６を有する２価の直鎖状または枝分かれ状の飽和炭化水素鎖を意味し、例えば、－ＣＨ2－、－ＣＨ2ＣＨ2－、－ＣＨ(ＣＨ3)－、－ＣＨ(ＣＨ3)ＣＨ2－、－ＣＨ2ＣＨ(ＣＨ3)－、－Ｃ (ＣＨ3)2－、－Ｃ (ＣＨ3)2ＣＨ2－、－ＣＨ2Ｃ (ＣＨ3)2－、－ＣＨ2ＣＨ2ＣＨ2－、－Ｃ (ＣＨ3)2ＣＨ2ＣＨ2－、－ＣＨ (ＣＨ3)ＣＨ(ＣＨ3)－などの基が挙げられる。 The C 1-6 alkylene group means a divalent linear or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as —CH 2 —, —CH 2 CH 2 —, —CH. (CH 3 ) —, —CH (CH 3 ) CH 2 —, —CH 2 CH (CH 3 ) —, —C (CH 3 ) 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 C Examples include (CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, —C (CH 3 ) 2 CH 2 CH 2 —, —CH (CH 3 ) CH (CH 3 ) — and the like.

　本発明において塩とは、例えば無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。無機塩基との塩の例としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩； カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。有機塩基との塩の例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、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、ジシクロヘキシルアミン、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。無機酸との塩の例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の例としては、例えばギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、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との塩が挙げられる。塩基性アミノ酸との塩の例としては、例えばアルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の例としては、例えばアスパラギン酸、グルタミン酸等との塩が挙げられる。 In the present invention, the salt includes, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. Examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N ′ -dibenzylethylenediamine and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

　以下、本発明の具体的製造方法を例示する。 Hereinafter, specific production methods of the present invention will be exemplified.

Figure JPOXMLDOC01-appb-C000021
（式中のＲ1、Ｒ2、Ｒ3、Ｒ4およびＲ5は前記と同じ意味をもつ）
Figure JPOXMLDOC01-appb-C000021
 (Wherein R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as described above)

（工程１）
　化合物（Ａ）を、Protective Groups in Organic Synthesis（T.W.Greene et al.，John Wiley & Sons, Inc.，1991年，Second Edition）に記載の方法若しくはそれに準ずる方法に従い、カルボニル基の保護反応に付すことにより、化合物（Ｂ）を得ることができる。例えば、化合物（Ａ）を無溶媒または不活性溶媒中、酸の存在下、アルコールと脱水反応することにより、化合物（Ｂ）を得ることができる。不活性溶媒としては、例えば、シクロヘキサン、トルエン、キシレン等の炭化水素系溶媒が挙げられる。好ましくは、トルエン、キシレンが挙げられる。酸としては、塩酸、硫酸等の鉱酸、ｐ－トルエンスルホン酸、メタンスルホン酸等の有機酸、三フッ化ホウ素ジエチルエーテル錯体、トリメチルクロロシラン等のルイス酸、アンバーリスト（登録商標）等の酸性イオン交換樹脂が挙げられる。好ましくは、硫酸、ｐ－トルエンスルホン酸、メタンスルホン酸等のスルホン酸が挙げられ、さらに好ましくはｐ－トルエンスルホン酸またはメタンスルホン酸が挙げられる。溶媒量は、前記化合物（Ａ）に対して５～１０倍量用いることができる。反応温度は通常室温～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常０．５～２０時間である。 (Process 1)
By subjecting compound (A) to a carbonyl group protection reaction according to the method described in Protective Groups in Organic Synthesis (TWGreene et al., John Wiley & Sons, Inc., 1991, Second Edition) or a method analogous thereto. A compound (B) can be obtained. For example, compound (B) can be obtained by subjecting compound (A) to a dehydration reaction with an alcohol in the presence of an acid in a solvent-free or inert solvent. Examples of the inert solvent include hydrocarbon solvents such as cyclohexane, toluene, and xylene. Preferably, toluene and xylene are used. Acids include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid and methanesulfonic acid, Lewis acids such as boron trifluoride diethyl ether complex, trimethylchlorosilane, and acids such as Amberlyst (registered trademark). An ion exchange resin is mentioned. Preferred are sulfonic acids such as sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and more preferred are p-toluenesulfonic acid and methanesulfonic acid. The amount of the solvent can be used 5 to 10 times the amount of the compound (A). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material and solvent used, the reaction temperature and the like.

（工程２）
　前記化合物（Ｂ）を、不活性溶媒中、塩基存在下、エステルの加水分解反応に付すことにより、前記化合物（Ｃ）を得ることができる。不活性溶媒としては、例えば、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン等のエーテル系溶媒、水またはそれらの混合溶媒が挙げられる。塩基としては水酸化ナトリウム、水酸化カリウム、水酸化リチウム等が挙げられる。塩基の量は、前記化合物（Ｂ）に対して１～３当量用いるのが好ましい。反応温度は通常室温～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常０．５時間～３日間である。
また、Ｒ5が置換可Ｃ7-11アラルキル基である場合は、公知の方法若しくはそれに準ずる方法に従い、前記化合物（Ｂ）を脱保護反応に付すことにより、前記化合物（Ｃ）を得ることもできる。 (Process 2)
The compound (C) can be obtained by subjecting the compound (B) to an ester hydrolysis reaction in the presence of a base in an inert solvent. Examples of the inert solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The amount of the base is preferably 1 to 3 equivalents relative to the compound (B). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
In addition, when R 5 is a substitutable C 7-11 aralkyl group, the compound (C) may be obtained by subjecting the compound (B) to a deprotection reaction according to a known method or a method analogous thereto. it can.

（工程３）
　前記化合物（Ｃ）を、不活性溶媒中、塩基及び縮合剤の存在下、イソプロピルヒドラジンまたはその塩とのアミド化反応に付すことにより、前記化合物（Ｄ）を得ることができる。不活性溶媒としては、例えば、テトラヒドロフラン等のエーテル系溶媒、酢酸エチル等のエステル系溶媒、ジメチルホルムアミド等のアミド系溶媒またはそれらの混合溶媒が挙げられる。塩基としてはトリエチルアミンまたはピリジン等が挙げられる。縮合剤としては、Ｎ、Ｎ’－ジシクロヘキシルカルボジイミド、カルボニルジイミダゾールまたはチオニルジイミダゾール等が挙げられ、カルボニルジイミダゾール、チオニルジイミダゾールが好ましい。これらの縮合剤は、市販品を用いてもよく、反応時に調製して用いてもよい。塩基および縮合剤の量は、前記化合物（Ｃ）に対して1～２当量用いるのが好ましい。反応温度は通常０℃～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常０．５～２０時間である。 (Process 3)
The compound (D) can be obtained by subjecting the compound (C) to an amidation reaction with isopropylhydrazine or a salt thereof in an inert solvent in the presence of a base and a condensing agent. Examples of the inert solvent include ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, amide solvents such as dimethylformamide, or a mixed solvent thereof. Examples of the base include triethylamine or pyridine. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, carbonyldiimidazole, and thionyldiimidazole, and carbonyldiimidazole and thionyldiimidazole are preferable. A commercial item may be used for these condensing agents, and you may prepare and use at the time of reaction. The amount of the base and the condensing agent is preferably 1 to 2 equivalents relative to the compound (C). The reaction temperature is usually from 0 ° C. to the reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, etc.

　前記スキーム１で得られた化合物（Ｄ）を用いて、下記スキーム３に示す方法により糖尿病の治療薬等として有用な化合物の製造中間体(Ｅ)を製造することができる。 The production intermediate (E) of a compound useful as a therapeutic agent for diabetes can be produced by the method shown in the following scheme 3 using the compound (D) obtained in the scheme 1.

Figure JPOXMLDOC01-appb-C000022
（式中のＲ1、Ｒ2、Ｒ3およびＲ4は前記と同じ意味をもつ）
Figure JPOXMLDOC01-appb-C000022
 (Wherein R 1 , R 2 , R 3 and R 4 have the same meaning as described above)

（工程４）
　前記化合物（Ｄ）を不活性溶媒中、酸の存在下、環化反応に付すことにより、化合物（Ｅ）を得ることができる。不活性溶媒としては、アセトニトリル等のニトリル系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン、ｔｅｒｔ－ブチルメチルエーテル等のエーテル系溶媒、トルエン等の炭化水素系溶媒、ジメチルホルムアミド等のアミド系溶媒、水、またはそれらの混合溶媒が挙げられる。好ましくは、テトラヒドロフラン、ジメチルホルムアミド、水の混合溶媒が挙げられる。酸としては、塩酸、硫酸、ｐ－トルエンスルホン酸またはメタンスルホン酸等が挙げられ、塩酸が好ましい。溶媒量は、前記化合物（Ｄ）に対して５～２０倍量用いることができる。反応温度は通常室温～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常０．５～３５時間である。 (Process 4)
Compound (E) can be obtained by subjecting compound (D) to a cyclization reaction in an inert solvent in the presence of an acid. Examples of the inert solvent include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, amide solvents such as dimethylformamide, Water or a mixed solvent thereof can be used. Preferably, a mixed solvent of tetrahydrofuran, dimethylformamide, and water is used. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and hydrochloric acid is preferable. The amount of the solvent can be 5 to 20 times the amount of the compound (D). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 35 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

　前記スキーム２で得られた化合物（Ｅ）を、特許文献１記載の方法若しくはそれに準ずる方法に従い、糖尿病の治療薬等として有用なグルコピラノシルオキシピラゾール誘導体を製造することができる。 A glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes can be produced from the compound (E) obtained in Scheme 2 according to the method described in Patent Document 1 or a method analogous thereto.

　前記スキーム１で出発原料として用いられる化合物（Ａ）は、下記スキーム３に示す方法または特許文献４に記載された方法若しくはそれに準じた方法により製造することができる。 The compound (A) used as a starting material in the scheme 1 can be produced by the method shown in the following scheme 3, the method described in Patent Document 4, or a method analogous thereto.

Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023

（工程５）
　化合物（Ｇ）を無溶媒または不活性溶媒中、塩基または酸および塩基の存在下、必要に応じ脱水剤を用いて、化合物（Ｈ）との縮合反応に付すことにより、化合物（Ｉ）を得ることができる。不活性溶媒としては、アセトニトリル等のニトリル系溶媒、酢酸エチル等のエステル系溶媒、テトラヒドロフラン、ｔｅｒｔ－ブチルメチルエーテル等のエーテル系溶媒、トルエン等の炭化水素系溶媒、エタノール等のアルコール系溶媒、またはそれらの混合溶媒が挙げられ、無溶媒で反応することが好ましい。酸としては酢酸、プロピオン酸、安息香酸、硫酸、ｐ－トルエンスルホン酸、塩化チタン等が挙げられ、酢酸が好ましい。塩基としては、ピペリジン、ピロリジン、ピリジン、ジエチルアミン、トリエチルアミン等の有機アミン等が挙げられ、ピペリジンが好ましい。脱水剤としては、モレキュラシーブス等が挙げられる。溶媒量は、前記化合物（Ｇ）に対して０～１０倍量用いることができる。反応温度は通常室温～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常０．５時間～５日間である。 (Process 5)
Compound (I) is obtained by subjecting compound (G) to a condensation reaction with compound (H) in a solvent-free or inert solvent in the presence of a base or an acid and a base, if necessary, using a dehydrating agent. be able to. Examples of the inert solvent include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, alcohol solvents such as ethanol, or These mixed solvents are mentioned, and it is preferable to react without solvent. Examples of the acid include acetic acid, propionic acid, benzoic acid, sulfuric acid, p-toluenesulfonic acid, titanium chloride and the like, and acetic acid is preferable. Examples of the base include organic amines such as piperidine, pyrrolidine, pyridine, diethylamine and triethylamine, and piperidine is preferable. Examples of the dehydrating agent include molecular sieves. The solvent can be used in an amount of 0 to 10 times that of the compound (G). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 5 days, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

（工程６）
　化合物（Ｉ）を、還元反応に付すことにより、化合物（Ａ）を得ることができる。例えば、化合物（Ｉ）を、メタノールまたはエタノール等のアルコール系溶媒、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、またはそれらの混合溶媒中、酢酸等の酸の存在下または非存在下、パラジウム等の金属触媒を用いて、０．１～０．５ＭＰａの水素雰囲気下で、通常室温～還流温度で還元することにより、化合物（Ａ）を得ることができる。反応時間は使用する原料物質や溶媒、触媒、反応温度などにより異なるが、通常２～２４時間である。 (Step 6)
Compound (A) can be obtained by subjecting compound (I) to a reduction reaction. For example, in the presence or absence of an acid such as acetic acid in the presence of an acid such as acetic acid in an alcoholic solvent such as methanol or ethanol, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, or a mixed solvent thereof. The compound (A) can be obtained by reduction using a metal catalyst such as palladium under a hydrogen atmosphere of 0.1 to 0.5 MPa, usually at room temperature to reflux temperature. The reaction time varies depending on the raw material used, solvent, catalyst, reaction temperature, etc., but is usually 2 to 24 hours.

　本発明のベンジルピラゾール誘導体（Ｅ）の製造中間体の中、不飽和結合を有する化合物には、２つの幾何異性体である、シス（Ｚ）体の化合物及びトランス（Ｅ）体の化合物が存在するが、本発明においてはそのいずれの化合物を使用してもよく、それらの混合物であっても構わない。 Among the intermediates for producing the benzylpyrazole derivative (E) of the present invention, the compound having an unsaturated bond includes two geometric isomers, that is, a cis (Z) compound and a trans (E) compound. However, any of these compounds may be used in the present invention, or a mixture thereof may be used.

　本発明のベンジルピラゾール誘導体（Ｅ）の製造中間体の中、不斉炭素原子を有する化合物には、１つの不斉炭素につきそれぞれＲ配置の化合物及びＳ配置の化合物が存在するが、本発明においてはいずれの光学異性体を使用してもよく、それらの光学異性体の混合物であっても構わない。 Among the production intermediates of the benzylpyrazole derivative (E) of the present invention, the compound having an asymmetric carbon atom includes a compound having an R configuration and a compound having an S configuration for each asymmetric carbon. Any optical isomer may be used, and a mixture of these optical isomers may be used.

　本発明のベンジルピラゾール誘導体（Ｅ）の製造中間体には、種々の互変異性体が存在することがあるが、本発明の化合物にはそれらの互変異性体も含まれる。 The production intermediate of the benzylpyrazole derivative (E) of the present invention may have various tautomers, and the compound of the present invention also includes those tautomers.

　本発明の製造方法により、イソプロピル基の導入を高位置選択的に行うことができ、医薬品の製造中間体である前記化合物（Ｅ）を高収率および高純度で得ることができる。さらに、前記化合物（Ｅ）を用いて、糖尿病の治療薬等として有用なグルコピラノシルオキシピラゾール誘導体を製造することができる。 By the production method of the present invention, an isopropyl group can be introduced with high regioselectivity, and the compound (E), which is a pharmaceutical production intermediate, can be obtained in high yield and high purity. Furthermore, a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced using the compound (E).

本発明の内容を以下の実施例により更に詳細に説明するが、本発明はその内容に限定されるものではない。 The content of the present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the content.

参考例１
２－[（４－イソプロポキシフェニル）メチリデン]－３－オキソ－ブタン酸メチル
　４－イソプロポキシベンズアルデヒド（１０．０ｇ）、アセト酢酸メチル（１４ｇ）、酢酸（５．０ｇ）の溶液にピペリジン（１．６ｇ）を加え、その混合物を室温で１１５時間撹拌した。この反応混合物は精製する事なく次工程に用いた（溶液Ａ）。 Reference example 1
Methyl 2-[(4-isopropoxyphenyl) methylidene] -3-oxo-butanoate Piperidine (1 g) was added to a solution of 4-isopropoxybenzaldehyde (10.0 g), methyl acetoacetate (14 g), and acetic acid (5.0 g). .6 g) was added and the mixture was stirred at room temperature for 115 hours. This reaction mixture was used in the next step without purification (solution A).

参考例２
２－（４－イソプロポキシベンジル）－３－オキソ－ブタン酸メチル
　参考例1記載の溶液Ａに２－プロパノール（８０ｇ）、及び１０％パラジウム炭素末（３．２ｇ）を加え、この混合物を水素雰囲気下室温にて６時間撹拌した。不溶物をろ去し、不溶物をｔｅｒｔ－ブチルメチルエーテル（８０ｇ）で洗浄した。ろ液と洗液を合わせ減圧下濃縮した。得られた残渣を酢酸エチル（６０ｇ）に溶解させた後、その混合物に、水（６０ｇ）を加えた。分離した有機層を５％重曹水（６０ｇ）、１０％塩水（６０ｇ）で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し、不溶物をろ去した後、ろ液を減圧下濃縮し、２－（４－イソプロポキシベンジル）－３－オキソ－ブタン酸メチル（１９．１ｇ）を得た。
1H-NMR (CDCl3) δ ppm:
1.31 (6H, d, J=6.0Hz), 2.17 (3H, s), 3.09 (2H, d, J=8.0Hz), 3.69 (3H, s), 3.75 (1H, t, J=7.6Hz), 4.44-4.56 (1H, m), 6.75-6.83 (2H, m), 7.02-7.10 (2H, m) Reference example 2
2- (4-Isopropoxybenzyl) -3-oxo-butanoic acid methyl ester To solution A described in Reference Example 1, 2-propanol (80 g) and 10% palladium carbon powder (3.2 g) were added. The mixture was stirred at room temperature for 6 hours. The insoluble material was removed by filtration, and the insoluble material was washed with tert-butyl methyl ether (80 g). The filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (60 g), and water (60 g) was added to the mixture. The separated organic layer was washed sequentially with 5% aqueous sodium bicarbonate (60 g) and 10% brine (60 g). The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give methyl 2- (4-isopropoxybenzyl) -3-oxo-butanoate (19.1 g). It was.
1 H-NMR (CDCl 3 ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 2.17 (3H, s), 3.09 (2H, d, J = 8.0Hz), 3.69 (3H, s), 3.75 (1H, t, J = 7.6Hz), 4.44-4.56 (1H, m), 6.75-6.83 (2H, m), 7.02-7.10 (2H, m)

実施例１
３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸メチル

Figure JPOXMLDOC01-appb-C000024
　２－（４－イソプロポキシベンジル）－３－オキソブタン酸メチル（１６．１ｇ）のトルエン（１６０ｇ）溶液にエチレングリコール（１８ｇ）、ｐ－トルエンスルホン酸一水和物（０．４６ｇ）を加えた。この混合物を水の除去をしながら8時間加熱還流した。この反応混合物を室温まで冷却し、５％重曹水（８０ｇ）を加えた。分離した有機層を水（４０ｇ）で洗浄した後、溶媒を減圧下留去し、３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸メチル（２３．０ｇ）を得た。
1H-NMR (CDCl3) δ ppm:
1.31 (6H, d, J=6.0Hz), 1.46 (3H, s), 2.84-3.03 (3H, m), 3.56 (3H, s), 3.95-4.07 (4H, m), 4.42-4.58 (1H, m), 6.73-6.83 (2H, m), 7.00-7.10 (2H, m) Example 1
Methyl 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoate
Figure JPOXMLDOC01-appb-C000024
 Ethylene glycol (18 g) and p-toluenesulfonic acid monohydrate (0.46 g) were added to a toluene (160 g) solution of methyl 2- (4-isopropoxybenzyl) -3-oxobutanoate (16.1 g). . The mixture was heated to reflux for 8 hours while removing water. The reaction mixture was cooled to room temperature and 5% aqueous sodium bicarbonate (80 g) was added. The separated organic layer was washed with water (40 g), and the solvent was evaporated under reduced pressure to give 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propane. Methyl acid (23.0 g) was obtained.
1 H-NMR (CDCl 3 ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 1.46 (3H, s), 2.84-3.03 (3H, m), 3.56 (3H, s), 3.95-4.07 (4H, m), 4.42-4.58 (1H, m), 6.73-6.83 (2H, m), 7.00-7.10 (2H, m)

実施例２
３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸

Figure JPOXMLDOC01-appb-C000025
　３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸メチル（１８．８ｇ）のメタノール（１９ｇ）溶液に２５ｇ／L水酸化ナトリウム水溶液（１４ｍL）を加えた。この混合物を８０℃で７時間撹拌した後、反応混合物を減圧下濃縮した。残渣を水（５７ｇ）、ｔｅｒｔ－ブチルメチルエーテル（９５ｇ）に溶解させ、水層を分離した。水層をｔｅｒｔ－ブチルメチルエーテル（９５ｇ）で洗浄した。水層にｔｅｒｔ－ブチルメチルエーテル（９５ｇ）及び２ｍｏｌ／Ｌ塩酸（３７ｍL）を加え、有機層を分離した。得られた有機層を１０％塩水（５７ｇ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、不溶物をろ去した後、溶媒を減圧下留去し、３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸（１５．２ｇ）を得た。
1H-NMR (CDCl3) δ ppm:
1.31 (6H, d, J=6.0Hz), 1.47 (3H, s), 2.85-3.02 (3H, m), 3.93-4.13 (4H, m), 4.42-4.56 (1H, m), 6.74-6.84 (2H, m), 7.04-7.12 (2H, m), 8.00-12.00 (1H, br) Example 2
3- (4-Isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid
Figure JPOXMLDOC01-appb-C000025
 To a solution of methyl 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoate (18.8 g) in methanol (19 g) was added 25 g / L aqueous sodium hydroxide solution ( 14 mL) was added. The mixture was stirred at 80 ° C. for 7 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (57 g) and tert-butyl methyl ether (95 g), and the aqueous layer was separated. The aqueous layer was washed with tert-butyl methyl ether (95 g). To the aqueous layer were added tert-butyl methyl ether (95 g) and 2 mol / L hydrochloric acid (37 mL), and the organic layer was separated. The resulting organic layer was washed with 10% brine (57 g). The organic layer was dried over anhydrous magnesium sulfate, insolubles were removed by filtration, and the solvent was evaporated under reduced pressure to give 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolane-2 -Yl) propanoic acid (15.2 g) was obtained.
1 H-NMR (CDCl 3 ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 1.47 (3H, s), 2.85-3.02 (3H, m), 3.93-4.13 (4H, m), 4.42-4.56 (1H, m), 6.74-6.84 ( 2H, m), 7.04-7.12 (2H, m), 8.00-12.00 (1H, br)

実施例３
Ｎ’－イソプロピル－３－（ｐ－イソプロポキシフェニル）－２－(２－メチル－１，３－ジオキソラン－２－イル)プロパン酸ヒドラジド

Figure JPOXMLDOC01-appb-C000026
　イミダゾール（７．７６ｇ）のテトラヒドロフラン（１５０ｇ）溶液にピリジン（９．０２ｇ）を加えた。得られた溶液に、氷冷下、塩化チオニル（６．７９ｇ）を滴下した後、この混合物を１時間撹拌した。反応混合物を室温まで加熱し、３－（４－イソプロポキシフェニル）－２－（２－メチル－１，３－ジオキソラン－２－イル）プロパン酸（１５．２ｇ）のテトラヒドロフラン（６０ｇ）溶液を加え、この混合物を１時間撹拌した。更に、この混合物にＮ，Ｎ－ジメチルホルムアミド（３１ｇ）、トリエチルアミン（１０．５ｇ）、イソプロピルヒドラジン塩酸塩（８．６１ｇ）を順次加え、この混合物を８０℃で６時間撹拌した。この反応混合物は精製する事なく次工程に用いた（溶液Ｂ）。
1H-NMR (CDCl３) δ ppm:
0.86 (3H, d, J=6.4Hz), 0.96 (3H, d, J=6.4Hz), 1.30 (6H, d, J=6.0Hz), 1.42 (3H, s), 2.54 (1H, dd, J=3.2, 11.2Hz), 2.84-3.07(3H, m), 3.90-4.10 (4H, m), 4.40-4.70 (1H, br), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.02-7.15 (3H, m)  Example 3
N′-isopropyl-3- (p-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid hydrazide
Figure JPOXMLDOC01-appb-C000026
 Pyridine (9.02 g) was added to a solution of imidazole (7.76 g) in tetrahydrofuran (150 g). To the obtained solution was added dropwise thionyl chloride (6.79 g) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was heated to room temperature and a solution of 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid (15.2 g) in tetrahydrofuran (60 g) was added. The mixture was stirred for 1 hour. Further, N, N-dimethylformamide (31 g), triethylamine (10.5 g) and isopropyl hydrazine hydrochloride (8.61 g) were sequentially added to the mixture, and the mixture was stirred at 80 ° C. for 6 hours. This reaction mixture was used in the next step without purification (solution B).
1 H-NMR (CDCl 3 ) δ ppm:
0.86 (3H, d, J = 6.4Hz), 0.96 (3H, d, J = 6.4Hz), 1.30 (6H, d, J = 6.0Hz), 1.42 (3H, s), 2.54 (1H, dd, J = 3.2, 11.2Hz), 2.84-3.07 (3H, m), 3.90-4.10 (4H, m), 4.40-4.70 (1H, br), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m ), 7.02-7.15 (3H, m)

実施例４
１－イソプロピル－４－（４－イソプロポキシベンジル）－５－メチル－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン

Figure JPOXMLDOC01-appb-C000027
　実施例３記載の溶液Ｂに６ｍｏｌ／Ｌ塩酸（６５ｍＬ）を加え、この混合物を８０℃で１７時間撹拌した。反応混合物を室温まで冷却し、重曹（３５ｇ）を加え、有機層を分離した。水層をトルエン（７２ｇ）で抽出し、先の有機層と合わせた後、その有機層を減圧下濃縮した。残渣を８０℃でアセトニトリル（３６ｇ）に溶解させた。この混合物を６０℃まで冷却した後、水（３６ｇ）を滴下し、結晶を析出させた。得られた懸濁液を室温まで冷却し、水（１８ｇ）を滴下した後、この懸濁液を３時間撹拌した。析出物をろ取し、アセトニトリル（９ｇ）、水（９ｇ）の混合溶液で２回洗浄した後、減圧乾燥し、１－イソプロピル－４－（４－イソプロポキシベンジル）－５－メチル－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン（１１．３ｇ、純度：９９．３％）を得た。
1H-NMR (CDCl3) δ ppm:
1.30 (6H, d, J=6.0Hz), 1.39 (6H, d, J=6.8Hz), 2.05 (3H, s), 3.62 (1H, s), 4.18-4.32 (1H, m), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.10-7.18 (2H, m), 10.00-13.00 (1H, br) Example 4
1-isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1,2-dihydro-3H-pyrazol-3-one
Figure JPOXMLDOC01-appb-C000027
 6 mol / L hydrochloric acid (65 mL) was added to the solution B described in Example 3, and the mixture was stirred at 80 ° C. for 17 hours. The reaction mixture was cooled to room temperature, sodium bicarbonate (35 g) was added, and the organic layer was separated. The aqueous layer was extracted with toluene (72 g) and combined with the previous organic layer, and then the organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (36 g) at 80 ° C. After cooling this mixture to 60 ° C., water (36 g) was added dropwise to precipitate crystals. The obtained suspension was cooled to room temperature, water (18 g) was added dropwise, and the suspension was stirred for 3 hours. The precipitate was collected by filtration, washed twice with a mixed solution of acetonitrile (9 g) and water (9 g), and then dried under reduced pressure to give 1-isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1, 2-Dihydro-3H-pyrazol-3-one (11.3 g, purity: 99.3%) was obtained.
1 H-NMR (CDCl 3 ) δ ppm:
1.30 (6H, d, J = 6.0Hz), 1.39 (6H, d, J = 6.8Hz), 2.05 (3H, s), 3.62 (1H, s), 4.18-4.32 (1H, m), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.10-7.18 (2H, m), 10.00-13.00 (1H, br)

比較例
１－イソプロピル－４－（４－イソプロポキシベンジル）－５－メチル－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン
　イソプロピルヒドラジン塩酸塩（１．６７ｇ）のエタノール（３ｍＬ）懸濁液に、トリエチルアミン（２．６８ｇ）を加えた。この混合物を室温で1時間撹拌した。反応混合物に２－（４－イソプロポキシベンジル）－３－オキソブタン酸メチル（１．０５ｇ）のトルエン溶液を室温で加え、この混合物を４０℃で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｔｅｒｔ－ブチルメチルエーテル／ｎ－ヘキサン＝１／３）にて精製し、１－イソプロピル－４－（４－イソプロポキシベンジル）－５－メチル－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン（０．０８ｇ）を得た。 Comparative Example 1 Isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1,2-dihydro-3H-pyrazol-3-one Isopropylhydrazine hydrochloride (1.67 g) in ethanol (3 mL) suspension To this was added triethylamine (2.68 g). The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a toluene solution of methyl 2- (4-isopropoxybenzyl) -3-oxobutanoate (1.05 g) at room temperature, and the mixture was stirred at 40 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: tert-butyl methyl ether / n-hexane = 1/3) to give 1-isopropyl-4- (4-isopropoxybenzyl) -5-Methyl-1,2-dihydro-3H-pyrazol-3-one (0.08 g) was obtained.

　本発明の前記化合物（Ｄ）は医薬品の製造中間体として極めて有用であり、また、化合物（Ｄ）を経由する一連の製造方法は、ピラゾール環上のイソプロピル基を位置選択的に製造でき、更に高収率および高純度であるため、工業的製造方法として極めて有用であることがわかる。 The compound (D) of the present invention is extremely useful as an intermediate for producing a pharmaceutical product, and a series of production methods via the compound (D) can regioselectively produce an isopropyl group on the pyrazole ring. Since it is a high yield and high purity, it turns out that it is very useful as an industrial manufacturing method.

　本発明により、糖尿病の治療薬等として有用なグルコピラノシルオキシピラゾール誘導体を高収率かつ高純度で製造することができる。

　 According to the present invention, a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced with high yield and high purity.

Claims (15)

一般式（Ａ－１）：
Figure JPOXMLDOC01-appb-C000001
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ6は、ヒドロキシ基、Ｃ1-6アルコキシ基、置換可Ｃ7-11アラルキルオキシ基またはｉ－ＰｒＮＨＮＨ－基である）で表される化合物またはその塩。 Formula (A-1):
Figure JPOXMLDOC01-appb-C000001
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 alkoxy group, R 6 is hydroxy, C 1-6 alkoxy group, a substitutable C 7-11 aralkyloxy Or i-PrNHNH- compound represented by a is) group. Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である、請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom. Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である、請求項２記載の化合物またはその塩。 The compound or a salt thereof according to claim 2, wherein R 3 is an isopropyloxy group and R 4 is a hydrogen atom. Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成する、請求項３記載の化合物またはその塩。 The compound or a salt thereof according to claim 3, wherein R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group. Ｒ6がヒドロキシ基またはｉ－ＰｒＮＨＮＨ－基である、請求項４記載の化合物またはその塩。 The compound or a salt thereof according to claim 4, wherein R 6 is a hydroxy group or an i-PrNHNH- group. Ｒ6がｉ－ＰｒＮＨＮＨ－基である、請求項５記載の化合物またはその塩。 The compound or a salt thereof according to claim 5, wherein R 6 is an i-PrNHNH- group. 一般式（Ｃ）：
Figure JPOXMLDOC01-appb-C000002
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩をイソプロピルヒドラジンまたはその塩と反応することによる一般式（Ｄ）：
Figure JPOXMLDOC01-appb-C000003
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩の製造方法。 Formula (C):
Figure JPOXMLDOC01-appb-C000002
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 ) or a salt thereof is the same as isopropyl hydrazine or a salt thereof. General formula (D) by responding:
Figure JPOXMLDOC01-appb-C000003
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 is an alkoxy group) or a salt thereof. Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である請求項７記載の製造方法。 The process according to claim 7, wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom. Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である請求項８記載の製造方法。 9. R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, and R 4 is a hydrogen atom. The manufacturing method as described. 　工程１：
　一般式（Ａ）：
Figure JPOXMLDOC01-appb-C000004
 （式中のＲ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ5はＣ1-6アルキル基または置換可Ｃ7-11アラルキル基である）で表される化合物のカルボニル基を保護することにより、一般式（Ｂ）：
Figure JPOXMLDOC01-appb-C000005
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ5はＣ1-6アルキル基または置換可Ｃ7-11アラルキル基である）で表される化合物を調製する工程；
　工程２：
　一般式（Ｂ）で表される化合物を、脱保護反応に付すことにより一般式（Ｃ）：
Figure JPOXMLDOC01-appb-C000006
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩を調製する工程；を包含する、請求項７記載の製造方法。 Step 1:
Formula (A):
Figure JPOXMLDOC01-appb-C000004
 (In the formula, R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group, R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 An alkylthio group or a halo C 1-6 alkoxy group, wherein R 5 is a C 1-6 alkyl group or a substituted C 7-11 aralkyl group). (B):
Figure JPOXMLDOC01-appb-C000005
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 is an alkoxy group, represented by R 5 is C 1-6 alkyl or optionally substituted C 7-11 aralkyl group) Preparing a compound;
Step 2:
By subjecting the compound represented by the general formula (B) to a deprotection reaction, the general formula (C):
Figure JPOXMLDOC01-appb-C000006
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- A compound represented by ( 6 ) alkoxy group) or a salt thereof. Manufacturing method. Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である請求項１０記載の製造方法。 The production method according to claim 10, wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom. Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子であり、Ｒ5がメチル基である請求項１１記載の製造方法。 R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, R 4 is a hydrogen atom, R 5 The production method according to claim 11, wherein is a methyl group. 一般式（Ｄ）：
Figure JPOXMLDOC01-appb-C000007
 （式中のＲ1およびＲ2は同一あるいは異なっていてもよく、それぞれＣ1-6アルキル基を示すか、またはそれらが結合しＣ1-6アルキレン基を形成してもよく、Ｒ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩を環化させることにより一般式（Ｅ）：
Figure JPOXMLDOC01-appb-C000008
 （式中のＲ3は、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基であり、Ｒ4は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルキルオキシ基、Ｃ3-6シクロアルキル（Ｃ1-6アルコキシ）基、Ｃ1-6アルコキシ基、Ｃ1-6アルキルチオ基またはハロＣ1-6アルコキシ基である）で表される化合物またはその塩の製造方法。 Formula (D):
Figure JPOXMLDOC01-appb-C000007
 (R 1 and R 2 in the formula may be the same or different, or show a C 1-6 alkyl group, respectively, or may form them bonded C 1-6 alkylene group, R 3 is , Halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group A C 1-6 alkoxy group, a C 1-6 alkylthio group or a halo C 1-6 alkoxy group, wherein R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group, or halo C 1- 6 ) or a salt thereof is cyclized to form a compound represented by the general formula (E):
Figure JPOXMLDOC01-appb-C000008
 (In the formula, R 3 represents a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyloxy group, a C 3-6 cycloalkyl ( C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 alkylthio group or halo C 1-6 alkoxy group, R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyloxy group, C 3-6 cycloalkyl (C 1-6 alkoxy) group, C 1-6 alkoxy group, C 1-6 A method for producing a compound represented by the following formula: an alkylthio group or a halo C 1-6 alkoxy group. Ｒ3がＣ1-6アルキル基またはＣ1-6アルコキシ基であり、Ｒ4が水素原子またはハロゲン原子である、請求項１３記載の製造方法。 The production method according to claim 13, wherein R 3 is a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 4 is a hydrogen atom or a halogen atom. Ｒ1およびＲ2が互いに結合して、－ＣＨ2ＣＨ2－または－ＣＨ2ＣＨ2ＣＨ2－基を形成し、Ｒ3がイソプロピルオキシ基であり、Ｒ4が水素原子である、請求項１４記載の製造方法。 R 1 and R 2 are bonded to each other to form a —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — group, R 3 is an isopropyloxy group, and R 4 is a hydrogen atom. 14. The production method according to 14.
PCT/JP2012/058604 2011-03-31 2012-03-30 Method for producing benzylpyrazole derivative and production intermediate thereof Ceased WO2012133783A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009502763A (en) * 2005-07-22 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Process for the preparation of pyrazole-O-glycoside derivatives and novel intermediates of said process
WO2010076524A2 (en) * 2008-12-29 2010-07-08 Sanofi-Aventis Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998092A (en) * 1998-05-27 1999-12-07 Clariant International, Ltd. Water soluble negative-working photoresist composition

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009502763A (en) * 2005-07-22 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Process for the preparation of pyrazole-O-glycoside derivatives and novel intermediates of said process
WO2010076524A2 (en) * 2008-12-29 2010-07-08 Sanofi-Aventis Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GUILLOU,S. ET AL.: "N-arylation of 3-alkoxypyrazoles, the case of the pyridines", TETRAHEDRON, vol. 66, no. 14, 2010, pages 2654 - 2663, XP026941250, DOI: doi:10.1016/j.tet.2010.02.032 *
MARTIN,V.A. ET AL.: "Chemistry of aldolate dianions. Effects of p-heteroatom substituents on ketone enolization", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 112, no. 19, 1990, pages 6965 - 6978 *

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