WO2012133783A1 - Procédé de production de dérivés benzylpyrazole et intermédiaire de production de ceux-ci - Google Patents

Procédé de production de dérivés benzylpyrazole et intermédiaire de production de ceux-ci Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkoxy
halo
cycloalkyl
alkyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2012/058604
Other languages
English (en)
Japanese (ja)
Inventor
孝幸 相内
雅周 小林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP2013507792A priority Critical patent/JP5902671B2/ja
Publication of WO2012133783A1 publication Critical patent/WO2012133783A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un intermédiaire de production d'un dérivé glucopyranosyloxypyrazole représenté par la formule générale (E) (dans laquelle R3 et R4 sont tels que définis ci-dessous) qui est utile comme agent thérapeutique contre le diabète ou équivalent, et un procédé de production d'un dérivé benzylpyrazole, ledit procédé présentant industriellement plus d'avantages que les procédés conventionnels de production d'un dérivé benzylpyrazole, lequel peut être obtenu en faisant réagir un composé représenté par la formule générale (D) (dans laquelle chacun des R1 et R2 représente un groupe alkyle en C1 à C6 ou équivalent ; R3 représente un atome d'halogène, un groupe alcoxy en C1 à C6 ou équivalent ; et R4 représente un atome d'hydrogène, un atome d'halogène, un groupe alcoxy en C1 à C6, ou équivalent).
PCT/JP2012/058604 2011-03-31 2012-03-30 Procédé de production de dérivés benzylpyrazole et intermédiaire de production de ceux-ci Ceased WO2012133783A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2013507792A JP5902671B2 (ja) 2011-03-31 2012-03-30 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

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-079851 2011-03-31
JP2011079851 2011-03-31

Publications (1)

Publication Number Publication Date
WO2012133783A1 true WO2012133783A1 (fr) 2012-10-04

Family

ID=46931478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/058604 Ceased WO2012133783A1 (fr) 2011-03-31 2012-03-30 Procédé de production de dérivés benzylpyrazole et intermédiaire de production de ceux-ci

Country Status (2)

Country Link
JP (1) JP5902671B2 (fr)
WO (1) WO2012133783A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009502763A (ja) * 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 ピラゾール−ｏ−グリコシド誘導体の調製方法及び前記方法の新規中間体
WO2010076524A2 (fr) * 2008-12-29 2010-07-08 Sanofi-Aventis Derives de 2-pyridin-2-yl-pyrazol-3(2h)-one, leur preparation et leur application en therapeutique comme activateurs de hif

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 (ja) * 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 ピラゾール−ｏ−グリコシド誘導体の調製方法及び前記方法の新規中間体
WO2010076524A2 (fr) * 2008-12-29 2010-07-08 Sanofi-Aventis Derives de 2-pyridin-2-yl-pyrazol-3(2h)-one, leur preparation et leur application en therapeutique comme activateurs de hif

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 *

Also Published As

Publication number Publication date
JPWO2012133783A1 (ja) 2014-07-28
JP5902671B2 (ja) 2016-04-13

Similar Documents

Publication Publication Date Title
JP5545118B2 (ja) ニトリル化合物、カルボン酸化合物又はカルボン酸エステル化合物の製法
CN110627736B (zh) 一种1-苯基-5-羟基四氮唑的回收利用方法
EP2072503B1 (fr) Procédé de préparation de bosentan
JP5304818B2 (ja) ４−置換又は非置換テトラヒドロピラン−４−カルボン酸化合物又はそのエステル化合物の製法
US6806380B2 (en) Modified safe and efficient process for the environmentally friendly synthesis of imidoesters
JP5902671B2 (ja) 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
WO2015097850A1 (fr) Procédé de production de dérivé d'ester 2-aminonicotinate de benzyle
EP1611084A1 (fr) Procede de fabrication de n-alkoxalyl-alaninates
JP4727576B2 (ja) ジフルオロアセト酢酸のアルキルエステルを調製するための方法
US20040199002A1 (en) Process for producing(2-nitrophenyl)acetonitrile derivative and intermediate therefor
JPH04230674A (ja) 置換３−アミノアクリル酸エステルの製造法
US20080287693A1 (en) Process for the Preparation of 1-Naphthol Mixed Ethers and Intermediates of Crystalline Forms of (+) and (-)-Duloxetine
CZ299711B6 (cs) Zpusob prípravy 6-aryl-5,6-dioxohexanové kyseliny
KR101308227B1 (ko) 니코틴산 유도체 또는 그의 염의 제조 방법
US20090082579A1 (en) 2-alkenyl-3-aminothiophene derivative and process for producing thereof
CN100404516C (zh) 六氢哒嗪三羧酸酯的制备方法
JP5728027B2 (ja) ピロール誘導体及びその製造方法
US8124790B2 (en) Preparation process useful in synthesis of atorvastatin
JP5205971B2 (ja) テトラヒドロピラン化合物の製造方法
JP4561635B2 (ja) ４−アルコキシカルボニルテトラヒドロピラン又はテトラヒドロピラニル−４−カルボン酸の製法
US20070060630A1 (en) Alkoxy-(tetrazol-1-yl)benzaldehyde compound and process for producing the same
US20070149606A1 (en) Process for producing phenylacetic acid derivative
JP2003171359A (ja) （２−ニトロ−フェニル）アセトニトリル誘導体の製造方法及びその合成中間体
JP3952670B2 (ja) ２−（５−ハロゲノ−２−ニトロフェニル）−２−置換酢酸エステル誘導体の製法
JP2018087142A (ja) ３−ハロゲン化アルキルピラゾール誘導体の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12765658

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013507792

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12765658

Country of ref document: EP

Kind code of ref document: A1