WO2012165547A1 - Method for manufacturing pyrazole derivative - Google Patents

Method for manufacturing pyrazole derivative Download PDF

Info

Publication number
WO2012165547A1
WO2012165547A1 PCT/JP2012/064075 JP2012064075W WO2012165547A1 WO 2012165547 A1 WO2012165547 A1 WO 2012165547A1 JP 2012064075 W JP2012064075 W JP 2012064075W WO 2012165547 A1 WO2012165547 A1 WO 2012165547A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
salt
compound represented
chemical
compound
Prior art date
Application number
PCT/JP2012/064075
Other languages
French (fr)
Japanese (ja)
Inventor
文彦 赤星
伸治 桐原
Original Assignee
田辺三菱製薬株式会社
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 田辺三菱製薬株式会社 filed Critical 田辺三菱製薬株式会社
Priority to JP2013518161A priority Critical patent/JP5863789B2/en
Priority to CN201280027128.6A priority patent/CN103649055B/en
Publication of WO2012165547A1 publication Critical patent/WO2012165547A1/en

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
    • C07D231/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel method for producing a piperazinyl pyrazole compound useful as a pharmaceutical intermediate or the like.
  • the present invention also relates to a method for producing a proline amide compound useful as a therapeutic agent for diabetes, etc., using the novel method for producing the compound.
  • Proline amide compounds having a side chain containing a piperazinylpyrazole moiety show DPP-IV inhibitory activity and are reported to be useful in the treatment or prevention of diabetes and the like (see Patent Documents 1 and 2).
  • a target piperazinyl pyrazole compound is obtained by reacting a ⁇ -hydrazone amide compound produced from a ⁇ -ketoamide compound with phosphorus oxychloride in the presence of pyridine.
  • the piperazinyl pyrazole compound can be obtained only in a low yield, and further improvement has been desired for use as an industrial production method.
  • Patent Document 1 International Publication No. 2002/014271 Pamphlet
  • Patent Document 2 International Publication No. 2006/088129 Pamphlet
  • the present inventors have found that the target piperazinylpyrazole compound can be suitably produced in high yield by using phosphorus pentasulfide instead of phosphorus oxychloride, and completed the present invention. . That is, the present invention relates to the general formula (3):
  • the present invention provides a compound represented by the general formula (2) or a salt thereof by the above production method, and removes the amino-protecting group R 2 of the compound to obtain the general formula (6):
  • the carboxylate salt of the compound represented by the general formula (6) is a novel compound, and the compound is also included in the present invention. Moreover, this invention manufactures the compound represented by General formula (2), its salt, or the carboxylate of the compound represented by General formula (6) by the said manufacturing method, This is converted.
  • a piperazinylpyrazole compound represented by the general formula (2) or a salt thereof, and a carboxylate of the compound represented by the general formula (6) are efficiently and industrially produced. be able to.
  • the proline amide compound represented by the general formula (1) or a salt thereof useful as a pharmaceutical or the like can be produced efficiently and industrially advantageously.
  • the compound represented by the general formula (2) or a salt thereof can be obtained in high yield from the ⁇ -hydrazone amide compound represented by the general formula (3).
  • the compound represented by the general formula (6) is not crystallized, purification is difficult on a large scale.
  • the method of the present invention by converting the compound represented by the general formula (6) into its carboxylate, a crystal having high purity, excellent operability, storage stability, etc. can be obtained. , Advantageous for industrial production.
  • alkyl examples include linear or branched groups having 1 to 6 carbon atoms (C 1-6 ). Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl and n-hexyl.
  • cycloalkyl examples include cyclic groups having 3 to 8 carbon atoms (C 3-8 ). Specific examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl includes those having 1-2 alkyl substituents in the cyclic portion.
  • alkoxy examples include a group having 1 to 8 carbon atoms (C 1-8 ) in which the above alkyl or cycloalkyl and an oxygen atom are bonded. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, cyclopropoxy, and cyclobutoxy.
  • the alkyl or cycloalkyl represented by R 1 is preferably alkyl. More preferred is methyl, ethyl, n-propyl or isopropyl, and methyl is particularly preferred.
  • Examples of the aryl represented by Ar include a monocyclic aromatic hydrocarbon group having 6 carbon atoms and a bicyclic aromatic hydrocarbon group having 9 to 11 carbon atoms. Specific examples include phenyl, naphthyl, and indenyl.
  • the heteroaryl represented by Ar is a 5- to 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), 1 to 4 heteroatoms (oxygen, And an 8- to 10-membered bicyclic aromatic heterocyclic group containing sulfur or nitrogen).
  • Specific examples include imidazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolinyl, isoquinolyl or quinolyl.
  • aryl is preferable, specifically, phenyl or naphthyl is preferable, and phenyl is more preferable.
  • the protecting group for the amino group represented by R 2 and R 3 may be any protecting group that does not interfere with the reaction.
  • the protecting group for the amino group include alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, n- Propoxycarbonyl, t-butoxycarbonyl and the like) and substituted alkoxycarbonyl groups (benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl and the like) can be preferably used.
  • R 2 is preferably an alkoxycarbonyl group, and particularly preferably ethoxycarbonyl.
  • R 3 is preferably an alkoxycarbonyl group, and particularly preferably t-butoxycarbonyl.
  • Phosphorus pentasulfide is a compound represented by the molecular formula P 4 S 10 and is synonymous with phosphorous pentasulfide and phosphorous sulfide (V).
  • carboxylic acid examples include an optionally substituted linear or branched carboxylic acid having 1 to 7 carbon atoms (C 1-7 ).
  • C 1-7 formic acid, C 2-7 (C 2-7 ) alkyl carboxylic acid (such as acetic acid, propionic acid, butyric acid or isobutyric acid), C 2-7 (C 2-7 ) substitution Alkyl carboxylic acids (such as trifluoroacetic acid).
  • alkylcarboxylic acids are preferred, and acetic acid is particularly preferred.
  • the raw material compound can be easily obtained as a commercial product, can be produced by the production method shown below or a method known per se, or can be produced according to a method analogous thereto.
  • the compound used in each of the following reactions is an inorganic acid salt (for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate), organic acid salt (to the extent that does not interfere with the reaction)
  • organic acid salt for example, acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate
  • metal salt eg sodium salt, potassium salt, calcium salt, aluminum salt
  • a salt such as a salt with a base (for example, ethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt) may be formed.
  • the compound obtained in each of the following reactions may be used in the next reaction without being isolated from the reaction mixture or as a crude product.
  • the compound may be isolated from the reaction mixture according to a generally known method, or may be easily purified by a usual separation means such as recrystallization, distillation, chromatography or the like.
  • the compound may be isolated as a salt such as an inorganic acid salt, an organic acid salt, a metal salt, or a salt according to a generally known method.
  • the compound used in the present invention and the obtained compound, or a salt thereof include those solvates or hydrates.
  • the reaction (pyrazole ring formation reaction) between the compound represented by the general formula (3) ( ⁇ -hydrazone amide compound) and phosphorus pentasulfide can be carried out as follows. That is, the reaction of the compound represented by the general formula (3) and phosphorus pentasulfide can be performed in the presence or absence of a base, in a suitable solvent or without a solvent.
  • the amount of phosphorus pentasulfide used is, for example, 0.2 to 0.8 mol, preferably 0.25 to 0.35 mol of phosphorus pentasulfide with respect to 1 mol of the compound represented by the general formula (3). Is preferred.
  • This reaction is preferably performed in the presence of a base.
  • the base used include inorganic bases such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate, or organic bases such as pyridine, picoline, lutidine, triethylamine or N, N-diisopropylethylamine.
  • inorganic bases such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, are mentioned, More preferably, sodium carbonate is mentioned.
  • the base is generally used in an amount of 0.7 to 10 mol, preferably 0.8 to 2 mol, per 1 mol of the compound represented by the general formula (3).
  • This reaction is preferably performed in an appropriate reaction solvent.
  • the reaction solvent for example, tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, toluene, acetonitrile or propionitrile, or a mixed solvent thereof should be used.
  • THF tetrahydrofuran
  • 1,4-dioxane 1,2-dimethoxyethane
  • dichloromethane dichloromethane
  • chloroform chloroform
  • toluene acetonitrile or propionitrile
  • acetonitrile or propionitrile or a mixed solvent thereof
  • THF tetrahydrofuran
  • the reaction temperature can usually be arbitrarily selected from 0 to 110 ° C., and the reaction time is usually about 10 minutes to 2 days. Furthermore, this reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
  • the compound (piperazinylpyrazole compound) represented by the general formula (2) obtained as described above or a salt thereof is a carboxylic acid of the compound represented by the general formula (6) as follows. Can be converted to salt.
  • the compound represented by the general formula (2) or the amino group protecting group R 2 of the salt thereof is removed to produce the compound represented by the general formula (6), and then the compound is formed with a carboxylic acid.
  • the carboxylate of the compound represented by the general formula (6) can be produced.
  • deprotection can be performed by reacting with an acid in a suitable solvent or without a solvent.
  • the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, and the like, and preferably trifluoroacetic acid.
  • This reaction is preferably performed in an appropriate reaction solvent.
  • the reaction solvent for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene or water, or the above acid as a solvent, or a mixed solvent thereof may be used.
  • the acid can be used as a solvent.
  • deprotection can be performed by reacting with a base in a suitable solvent or without solvent.
  • a base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and preferably potassium hydroxide.
  • the concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L with respect to the reaction mixture.
  • This reaction is preferably performed in an appropriate reaction solvent.
  • the reaction solvent for example, methanol, ethanol, 2-propanol, THF, acetonitrile or water, or a mixed solvent thereof can be used, and preferably a mixed solvent of methanol and water can be used.
  • the reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
  • deprotection can be performed in a suitable solvent in a hydrogen atmosphere in the presence of a palladium carbon catalyst or a palladium hydroxide carbon catalyst.
  • deprotection can be performed by reacting with zinc powder in an appropriate solvent.
  • deprotection can be performed by reacting with pyrrolidine, piperidine or morpholine in a suitable solvent or without solvent.
  • a generally known method can be used for the salt formation treatment of the compound represented by the general formula (6) and the carboxylic acid. For example, it can be carried out by subjecting the compound represented by the general formula (6) and the carboxylic acid to salt formation in an appropriate solvent. Specifically, for example, 0.7 to 3 mol, preferably 0.9 to 1.1 mol of carboxylic acid is reacted with 1 mol of the compound represented by the general formula (6). A carboxylate salt of the compound represented by the formula (6) can be produced.
  • reaction solvent for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile or toluene, or a mixed solvent thereof can be used, and preferably toluene is used. be able to.
  • the reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 1 day.
  • the compound represented by the general formula (2) or a salt thereof obtained as described above, or the carboxylate of the compound represented by the general formula (6) is appropriately obtained by a known method or a combination thereof.
  • the compound can be converted into a compound represented by the general formula (1) (proline amide compound) or a salt thereof. Or it can convert suitably to the compound represented by General formula (1), or its salt by the method as described below.
  • R 3 represents an amino-protecting group, and the others are as defined above
  • reaction for the reductive amination reaction of the compound represented by the general formula (9) in the presence of the carboxylate salt of the compound represented by the general formula (6), a generally known method can be used. Specifically, the reaction can be performed by reacting the carboxylate of the compound represented by the general formula (6), the compound represented by the general formula (9), and a reducing agent in a suitable solvent.
  • sodium borohydride sodium triacetoxyborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, t-butylamine borane, N, N-diethylaniline borane or 2-picoline borane are preferable.
  • sodium triacetoxyborohydride sodium triacetoxyborohydride.
  • reaction solvent for example, dichloromethane, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene, dimethylformamide, or a mixed solvent thereof can be used, and preferably, toluene can be used.
  • the reaction temperature can usually be arbitrarily selected from ⁇ 20 to 100 ° C., and the reaction time is usually about 10 minutes to 1 day.
  • deprotection can be performed by reacting with an acid in a suitable solvent or without a solvent.
  • the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, and the like, and preferably hydrogen bromide.
  • the acid concentration is 0.01 to 10 mol / L, preferably 0.1 to 4 mol / L, based on the reaction mixture.
  • This reaction is preferably performed in an appropriate reaction solvent.
  • the reaction solvent for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene or water, or a mixed solvent thereof can be used, preferably 2- A mixed solvent of propanol and water can be used.
  • the reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
  • deprotection can be performed by reacting with a base in a suitable solvent or without solvent.
  • a base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and preferably potassium hydroxide.
  • the concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L with respect to the reaction mixture.
  • This reaction is preferably performed in an appropriate reaction solvent.
  • the reaction solvent for example, methanol, ethanol, 2-propanol, THF, acetonitrile or water, or a mixed solvent thereof can be used, and preferably a mixed solvent of methanol and water can be used.
  • the reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
  • deprotection can be performed in a suitable solvent in a hydrogen atmosphere in the presence of a palladium carbon catalyst or a palladium hydroxide carbon catalyst.
  • deprotection can be performed by reacting with zinc powder in an appropriate solvent.
  • deprotection can be performed by reacting with pyrrolidine, piperidine or morpholine in a suitable solvent or without solvent.
  • the salt formation treatment with an acid of the compound represented by the general formula (1) can be performed by treating with a corresponding acid according to a generally known method. For example, it can be carried out by subjecting the compound represented by the general formula (1) and the acid to salt formation in an appropriate solvent.
  • the acid examples include inorganic acids such as hydrogen chloride, hydrogen bromide or nitric acid, or p-toluenesulfonic acid, methanesulfonic acid, besylic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid Or organic acids, such as camphorsulfonic acid, are mentioned,
  • hydrogen bromide is mentioned.
  • 1 to 10 mol, preferably 2 to 5 mol of an acid is reacted with 1 mol of the compound represented by the general formula (1) to thereby represent the general formula (1). Salts of compounds can be produced.
  • reaction solvent for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene or water, or a mixed solvent thereof can be used, preferably a mixed solvent of 2-propanol and water. Can be used.
  • the reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
  • the compound represented by the general formula (3) as a raw material compound in the present invention can be appropriately produced by a known method or a combination thereof.
  • it can be suitably produced by the following method. it can.
  • the compound represented by the general formula (4) (piperazine compound) or a salt thereof is reacted with the ⁇ -ketocarboxylic acid represented by the general formula (a) or a reactive derivative thereof to give a general formula ( 5) is produced, and the compound is then reacted with a hydrazine compound represented by the formula Ar—NH—NH 2 or a salt thereof to produce a compound represented by the general formula (3).
  • a compound represented by the general formula (3) can be produced.
  • ⁇ -ketocarboxylic acid represented by the general formula (a) for example, alkyl esters or diketenes of ⁇ -ketocarboxylic acid represented by the general formula (a) can be used.
  • diketene is preferable.
  • the general formula (a) used is used as a method of reacting the compound represented by the general formula (4) or a salt thereof with the ⁇ -ketocarboxylic acid represented by the general formula (a) or a reactive derivative thereof.
  • a known method suitable for the ⁇ -ketocarboxylic acid represented by the formula (1) or a reactive derivative thereof can be appropriately used.
  • the reaction between the compound represented by the general formula (4) or a salt thereof and the ⁇ -ketocarboxylic acid represented by the general formula (a) uses a condensing agent in the presence of a base or In the absence, a condensation reaction carried out in a suitable solvent or without a solvent can be used. Examples of the condensation reaction include a method using carbodiimide and a mixed acid anhydride method.
  • Specific condensing agents include N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, dicyclohexylcarbodiimide, methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate. Etc.
  • alkyl ester of ⁇ -ketocarboxylic acid represented by general formula (a) When an alkyl ester of ⁇ -ketocarboxylic acid represented by general formula (a) is used as the reactive derivative of ⁇ -ketocarboxylic acid represented by general formula (a), the compound represented by general formula (4) Or a salt thereof and an alkyl ester of ⁇ -ketocarboxylic acid represented by the general formula (a) in the presence or absence of a suitable catalyst, in the presence or absence of a base, in a suitable solvent or It can be made to react with a solvent.
  • Specific examples of the alkyl ester of ⁇ -ketocarboxylic acid represented by general formula (a) include methyl ester of ⁇ -ketocarboxylic acid represented by general formula (a) and ⁇ -keto represented by general formula (a). Examples thereof include ethyl esters of ketocarboxylic acids and t-butyl esters of ⁇ -ketocarboxylic acids represented by the
  • diketene When diketene is used as the reactive derivative of ⁇ -ketocarboxylic acid represented by general formula (a), the compound represented by general formula (4) or a salt thereof and diketene are used in the presence or absence of a base.
  • the reaction can be carried out in a suitable solvent or without a solvent.
  • a generally known condensation reaction can be used as a method of reacting the compound represented by the general formula (5) with the hydrazine compound represented by the formula Ar—NH—NH 2 or a salt thereof.
  • a condensation reaction of the compound represented by the general formula (5) and the hydrazine compound or a salt thereof is performed in the presence or absence of an acid or a base in a suitable solvent or without a solvent. Can do.
  • the compound represented by the general formula (9) as a raw material compound in the present invention can be appropriately produced by a known method or a combination thereof. For example, it can be suitably produced by the following method. .
  • the condensation reaction of the compound represented by the general formula (8) or a salt thereof with thiazolidine can be carried out using a condensing agent, in the presence or absence of a base, in a suitable solvent or without solvent. .
  • condensation reaction examples include a mixed acid anhydride method and a method using a phosphonic anhydride derivative.
  • the condensing agent include chloroformic acid alkyl ester, substituted arylcarboxylic acid chloride, substituted arylcarboxylic acid anhydride or phosphonic anhydride cyclic trimer, preferably methyl chloroformate, ethyl chloroformate, chloroformic acid.
  • n-propylphosphonic anhydride More preferably, n-propylphosphonic anhydride (cyclic trimer) is used.
  • the base include pyridine, picoline, lutidine, triethylamine, N, N-diisopropylethylamine, and preferably N, N-diisopropylethylamine.
  • reaction solvent examples include THF, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, toluene, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, or propionitrile, or a mixed solvent thereof.
  • THF 1,4-dioxane
  • 1,2-dimethoxyethane 1,2-dimethoxyethane
  • dichloromethane chloroform
  • toluene methyl acetate
  • ethyl acetate propyl acetate
  • acetonitrile or propionitrile
  • the reaction temperature can usually be arbitrarily selected from ⁇ 20 to 110 ° C., and the reaction time is usually about 10 minutes to 2 days.
  • R 1 is alkyl (especially methyl, etc.)
  • R 2 is substituted or unsubstituted alkoxycarbonyl
  • R 3 is substituted or unsubstituted alkoxycarbonyl
  • Ar is aryl (especially phenyl, etc.)
  • alkylcarboxylic acid especially acetic acid etc.
  • a salt with the compound represented by the general formula (1) it is preferable to apply a salt of an inorganic acid (particularly a hydrobromide).
  • the compound represented by General formula (1), or its salt may form those solvates or hydrates.
  • Examples of the compound suitably produced by the production method of the present invention include 3- ⁇ (2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 -Yl] pyrrolidin-2-ylcarbonyl ⁇ thiazolidine, or a salt thereof.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Ph represents a phenyl group
  • Ac represents an acetyl group
  • t-Bu represents a tertiary butyl group.
  • w% represents wt%.
  • the obtained toluene layer was washed with 5 w% aqueous sodium bicarbonate (158 kg) and water (150 L) in this order, then concentrated under reduced pressure and evaporated to dryness. Solidified. To this residue was added 2-propanol (375 L), the temperature was raised, and 48 w% hydrobromic acid (42.14 kg) was added dropwise at 75 to 77 ° C., followed by refluxing for 2.5 hours. The reaction mixture was cooled, and seed crystals prepared by sampling the reaction mixture were inoculated at 58 ° C., then crystallized at 58 ° C. for 1 hour, then at 33-40 ° C. for 1 hour, and further at 17-25 ° C. for 1 hour. I left it overnight.
  • Ethanol (144 L) was added to the crude product (24.0 kg), heated and dissolved (73 ° C.), filtered while hot, and washed with ethanol (24 L). The filtrate and the washing solution were combined, water (3.4 L) was added at 67 ° C., and crystallization was performed at 49 to 55 ° C. for 2 hours and then at 19 to 25 ° C. for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol (24 L). The obtained crystals were dried under reduced pressure at 45 ° C. for 19 hours, and then dried with hot air at 50 ° C.
  • the obtained ethyl acetate layers were mixed and washed sequentially with a 10 w% aqueous diammonium hydrogen phosphate solution (600 kg) and water (300 kg). After the ethyl acetate layer was concentrated to a residual volume of 300 L, n-heptane (739 kg) was added at 23-25 ° C., and the mixture was stirred at 23-25 ° C. for 1 hour and 1-5 ° C. for 2 hours. The precipitated crystals were collected by filtration, washed with n-heptane (164 kg), and then dried under reduced pressure to give 3-[(2S) -1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine.
  • the target compound (compound 2b) is produced in a significantly higher yield as described in Example 1 when compared with the method using Lawson's reagent. I was able to.
  • a piperazinylpyrazole compound useful as a pharmaceutical intermediate or the like, or a salt thereof can be produced industrially and efficiently.
  • a proline amide compound or a salt thereof useful as a pharmaceutical or the like can be produced efficiently and industrially advantageously.

Abstract

The present invention provides a prolinamide compound useful as a drug or the like and an industrially advantageous method for producing a piperazinyl pyrazole compound that is a production intermediate of the prolinamide compound. Specifically, the invention is a method for producing a compound represented by general formula (1) as represented by the following formula (where the symbols in the formula are the same as defined in the specification) or a salt thereof, wherein a compound represented by general formula (2) is produced, a pyrazole ring being formed via a reaction between a compound represented by general formula (3) and phosphorus pentasulfide; and, once the compound represented by general formula (2) is deprotected, a carboxylate of a compound represented by general formula (6) is produced, the compound obtained by forming a carboxylic acid and a salt.

Description

ピラゾール誘導体の製造方法Method for producing pyrazole derivative
　本発明は、医薬の合成中間体等として有用なピペラジニルピラゾール化合物の新規製造方法に関する。また、当該化合物の新規製造方法を利用して、糖尿病治療薬等として有用なプロリンアミド化合物を製造する方法に関する。 The present invention relates to a novel method for producing a piperazinyl pyrazole compound useful as a pharmaceutical intermediate or the like. The present invention also relates to a method for producing a proline amide compound useful as a therapeutic agent for diabetes, etc., using the novel method for producing the compound.
　ピペラジニルピラゾール部分を含んだ側鎖を有するプロリンアミド化合物（例えば、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジン等）は、ＤＰＰ－ＩＶ阻害活性を示し、糖尿病等の治療又は予防において有用であることが報告されている（特許文献１、２参照）。 Proline amide compounds having a side chain containing a piperazinylpyrazole moiety (eg 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine -L-yl] pyrrolidin-2-ylcarbonyl} thiazolidine etc.) show DPP-IV inhibitory activity and are reported to be useful in the treatment or prevention of diabetes and the like (see Patent Documents 1 and 2).
　また、かかるプロリンアミド化合物については、その製造方法及びその合成中間体であるピペラジニルピラゾール化合物の製造方法が開示されている（特許文献１参照）。 Further, for such proline amide compounds, a production method thereof and a production method of a piperazinyl pyrazole compound which is a synthetic intermediate thereof are disclosed (see Patent Document 1).
　当該製造方法は、ピリジン存在下に、β－ケトアミド化合物から製造したβ－ヒドラゾンアミド化合物と、オキシ塩化リンを反応させ、目的とするピペラジニルピラゾール化合物を得るものである。しかしながら、この製造方法では当該ピペラジニルピラゾール化合物は低収率でしか得られず、工業的製造方法として利用する上ではさらなる改良が望まれていた。 In this production method, a target piperazinyl pyrazole compound is obtained by reacting a β-hydrazone amide compound produced from a β-ketoamide compound with phosphorus oxychloride in the presence of pyridine. However, in this production method, the piperazinyl pyrazole compound can be obtained only in a low yield, and further improvement has been desired for use as an industrial production method.
　一般に、置換ピラゾール化合物を製造する方法としては、以下のような方法が知られている。例えば、β－ヒドラゾンアミド化合物とオキシ塩化リンを反応させ、ピラゾール化合物を製造する他の方法が報告されている（非特許文献１参照）が、当該報告におけるピラゾール化合物の収率は十分なものではない。 Generally, the following methods are known as methods for producing substituted pyrazole compounds. For example, other methods for producing a pyrazole compound by reacting a β-hydrazone amide compound with phosphorus oxychloride have been reported (see Non-Patent Document 1), but the yield of the pyrazole compound in the report is not sufficient. Absent.
　また、別の方法として、テトラヒドロフラン中、ピリジン存在下に、反応系内でβ－ケトアミド化合物とヒドラジン化合物から生成したβ－ヒドラゾンアミド化合物と、ローソン試薬（Ｌａｗｅｓｓｏｎ’ｓ ｒｅａｇｅｎｔ、２，４－ビス（４－メトキシフェニル）－１，３，２，４－ジチアジホスフェタン－２，４－ジスルフィド）を反応させて、５－（置換アミノ）ピラゾール化合物を製造する方法が報告されている（非特許文献２参照）。しかしながら、この報告における置換ピラゾール化合物の製造例は、いずれも数１０ｍｇ規模であり、この方法を工業的な規模においても利用できるかどうか不明である。 As another method, β-hydrazonamide compound produced from β-ketoamide compound and hydrazine compound in tetrahydrofuran in the presence of pyridine in the reaction system, Lawesson's reagent (Laesson's reagent, 2,4-bis ( 4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide) has been reported to produce a 5- (substituted amino) pyrazole compound (non- Patent Document 2). However, the production examples of substituted pyrazole compounds in this report are all on the scale of several tens of mg, and it is unclear whether this method can be used on an industrial scale.
特許文献１：国際公開第２００２／０１４２７１号パンフレット
特許文献２：国際公開第２００６／０８８１２９号パンフレット Patent Document 1: International Publication No. 2002/014271 Pamphlet Patent Document 2: International Publication No. 2006/088129 Pamphlet
　本発明の目的は、工業的な製造に適した効率的で優れたピペラジニルピラゾール化合物の製造方法を提供することにある。また、医薬等として有用なプロリンアミド化合物の工業的製造に適した効率的で優れた製造方法を提供することにある。 An object of the present invention is to provide an efficient and excellent method for producing a piperazinyl pyrazole compound suitable for industrial production. Another object of the present invention is to provide an efficient and excellent production method suitable for industrial production of prolinamide compounds useful as pharmaceuticals.
　前記の通り、ピペラジニルピラゾール化合物を製造するためにオキシ塩化リンを用いた場合、当該化合物は低収率でしか得られない。また、オキシ塩化リンに代えローソン試薬を用いても、十分な収率で当該化合物を得ることができず、工業的製造方法としては満足できるものではなかった。 As described above, when phosphorus oxychloride is used to produce a piperazinyl pyrazole compound, the compound can be obtained only in a low yield. Moreover, even if it used Lawson's reagent instead of phosphorus oxychloride, the said compound was not able to be obtained with sufficient yield, and it was not satisfactory as an industrial manufacturing method.
　本発明者等は、鋭意研究した結果、オキシ塩化リンに代えて五硫化リンを用いることで、目的とするピペラジニルピラゾール化合物が高い収率で好適に製造できることを見出し、本発明を完成した。
　すなわち、本発明は、一般式（３）： As a result of intensive studies, the present inventors have found that the target piperazinylpyrazole compound can be suitably produced in high yield by using phosphorus pentasulfide instead of phosphorus oxychloride, and completed the present invention. .
That is, the present invention relates to the general formula (3):
　　［化１］
Figure JPOXMLDOC01-appb-I000019
[Chemical 1]
Figure JPOXMLDOC01-appb-I000019
（式中、Ｒ１はアルキル又はシクロアルキルを示し、Ｒ２はアミノ基の保護基を示し、Ａｒはアリール又はヘテロアリールを示す）で表される化合物と五硫化リンとの反応によりピラゾール環を形成させることを特徴とする、一般式（２）： (Wherein R 1 represents alkyl or cycloalkyl, R 2 represents an amino-protecting group, Ar represents aryl or heteroaryl) and a reaction between the compound represented by phosphorus pentasulfide and the pyrazole ring. General formula (2) characterized in that it is formed:
　　［化２］
Figure JPOXMLDOC01-appb-I000020
[Chemical 2]
Figure JPOXMLDOC01-appb-I000020
（式中、各記号は前記と同義である）で表される化合物、又はその塩の製造方法である。 (Wherein each symbol has the same meaning as described above), or a salt production method thereof.
　また、本発明は、前記製造方法により一般式（２）で表される化合物、又はその塩を製造し、当該化合物のアミノ基の保護基Ｒ２を除去して、一般式（６）： In addition, the present invention provides a compound represented by the general formula (2) or a salt thereof by the above production method, and removes the amino-protecting group R 2 of the compound to obtain the general formula (6):
　　［化３］
Figure JPOXMLDOC01-appb-I000021
[Chemical formula 3]
Figure JPOXMLDOC01-appb-I000021
（式中、各記号は前記と同義である）で表される化合物とした後、該化合物をカルボン酸の塩とすることを特徴とする、一般式（６）で表される化合物のカルボン酸塩の製造方法である。 (Wherein each symbol has the same meaning as described above), and then the carboxylic acid salt of the compound represented by the general formula (6), wherein the compound is a carboxylic acid salt It is a manufacturing method of a salt.
　一般式（６）で表される化合物のカルボン酸塩は、新規な化合物であり、当該化合物もまた本願発明に包含される。
　また、本発明は、前記の製造方法により、一般式（２）で表される化合物、又はその塩、或いは、一般式（６）で表される化合物のカルボン酸塩を製造し、これを変換して一般式（１）： The carboxylate salt of the compound represented by the general formula (6) is a novel compound, and the compound is also included in the present invention.
Moreover, this invention manufactures the compound represented by General formula (2), its salt, or the carboxylate of the compound represented by General formula (6) by the said manufacturing method, This is converted. General formula (1):
　　［化４］
Figure JPOXMLDOC01-appb-I000022
[Chemical formula 4]
Figure JPOXMLDOC01-appb-I000022
（式中、各記号は前記と同義である）で表される化合物、又はその塩を得ることからなる、一般式（１）で表される化合物、又はその塩の製造方法である。 (Wherein each symbol has the same meaning as described above) or a salt thereof, which is a method for producing a compound represented by the general formula (1) or a salt thereof.
　本発明によれば、一般式（２）で表されるピペラジニルピラゾール化合物、又はその塩、及び一般式（６）で表される化合物のカルボン酸塩を工業的有利に効率的に製造することができる。また、医薬等として有用な一般式（１）で表されるプロリンアミド化合物、又はその塩を工業的有利に効率的に製造することができる。 According to the present invention, a piperazinylpyrazole compound represented by the general formula (2) or a salt thereof, and a carboxylate of the compound represented by the general formula (6) are efficiently and industrially produced. be able to. In addition, the proline amide compound represented by the general formula (1) or a salt thereof useful as a pharmaceutical or the like can be produced efficiently and industrially advantageously.
　本発明によれば、一般式（３）で表されるβ－ヒドラゾンアミド化合物から一般式（２）で表される化合物、又はその塩を高収率で得ることができる。
　また、一般式（６）で表される化合物は結晶化しないため、大量規模では精製に困難を伴うこととなる。しかし、本発明の方法によれば、一般式（６）で表される化合物をそのカルボン酸塩に変換することにより、高純度で、操作性、保存安定性等に優れた結晶が得られるので、工業的な生産に有利となる。 According to the present invention, the compound represented by the general formula (2) or a salt thereof can be obtained in high yield from the β-hydrazone amide compound represented by the general formula (3).
Moreover, since the compound represented by the general formula (6) is not crystallized, purification is difficult on a large scale. However, according to the method of the present invention, by converting the compound represented by the general formula (6) into its carboxylate, a crystal having high purity, excellent operability, storage stability, etc. can be obtained. , Advantageous for industrial production.
（定義） (Definition)
　本発明において、アルキルとしては、炭素数１～６（Ｃ１－６）の直鎖状又は分岐鎖状の基が挙げられる。具体的には、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、イソペンチル、ｎ－ヘキシルが挙げられる。 In the present invention, examples of alkyl include linear or branched groups having 1 to 6 carbon atoms (C 1-6 ). Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl and n-hexyl.
　シクロアルキルとしては、炭素数３～８（Ｃ３－８）の環状の基が挙げられる。該シクロアルキルとしては、具体的には、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルが挙げられる。シクロアルキルには、その環状部分において１～２個のアルキル置換基を有するものが含まれる。 Examples of cycloalkyl include cyclic groups having 3 to 8 carbon atoms (C 3-8 ). Specific examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl includes those having 1-2 alkyl substituents in the cyclic portion.
　アルコキシとしては、上記アルキル又は上記シクロアルキルと酸素原子が結合した炭素数１～８（Ｃ１－８）の基が挙げられる。具体的には、例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｔ－ブトキシ、シクロプロポキシ、シクロブトキシが挙げられる。 Examples of alkoxy include a group having 1 to 8 carbon atoms (C 1-8 ) in which the above alkyl or cycloalkyl and an oxygen atom are bonded. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, cyclopropoxy, and cyclobutoxy.
　Ｒ１で表されるアルキル又はシクロアルキルとしては、アルキルが好ましい。より好ましくは、メチル、エチル、ｎ－プロピル又はイソプロピルが挙げられ、とりわけメチルが好ましい。 The alkyl or cycloalkyl represented by R 1 is preferably alkyl. More preferred is methyl, ethyl, n-propyl or isopropyl, and methyl is particularly preferred.
　Ａｒで表されるアリールとしては、炭素数６の単環式の芳香族炭化水素基、炭素数９～１１の二環式の芳香族炭化水素基等が挙げられる。具体的には、例えば、フェニル、ナフチル又はインデニルが挙げられる。 Examples of the aryl represented by Ar include a monocyclic aromatic hydrocarbon group having 6 carbon atoms and a bicyclic aromatic hydrocarbon group having 9 to 11 carbon atoms. Specific examples include phenyl, naphthyl, and indenyl.
　Ａｒで表されるヘテロアリールとしては、１～４個のヘテロ原子（酸素、硫黄又は窒素）を含む５～６員の単環式芳香族複素環基、１～４個のヘテロ原子（酸素、硫黄又は窒素）を含む８～１０員の二環式芳香族複素環基等が挙げられる。具体的には、例えば、イミダゾリル、チアゾリル、ピラゾリル、ピリジル、ピリミジニル、ピリダジニル、インドリル、インドリニル、イソキノリル又はキノリルが挙げられる。 The heteroaryl represented by Ar is a 5- to 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), 1 to 4 heteroatoms (oxygen, And an 8- to 10-membered bicyclic aromatic heterocyclic group containing sulfur or nitrogen). Specific examples include imidazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indolinyl, isoquinolyl or quinolyl.
　Ａｒで表されるアリール又はヘテロアリールとしては、アリールが好ましく、具体的には、フェニル又はナフチルが好ましく、フェニルがさらに好ましい。 As the aryl or heteroaryl represented by Ar, aryl is preferable, specifically, phenyl or naphthyl is preferable, and phenyl is more preferable.
　Ｒ２及びＲ３で表されるアミノ基の保護基は、反応を妨げない保護基であればよく、かかるアミノ基の保護基としては、例えば、アルコキシカルボニル基（メトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、ｔ－ブトキシカルボニル等）並びに置換アルコキシカルボニル基（ベンジルオキシカルボニル、２，２，２－トリクロロエトキシカルボニル、９－フルオレニルメトキシカルボニル等）が好適に使用できる。Ｒ２としては、これらのうち、アルコキシカルボニル基が好ましく、とりわけエトキシカルボニルが好ましい。また、Ｒ３としては、これらのうち、アルコキシカルボニル基が好ましく、とりわけｔ－ブトキシカルボニルが好ましい。 The protecting group for the amino group represented by R 2 and R 3 may be any protecting group that does not interfere with the reaction. Examples of the protecting group for the amino group include alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, n- Propoxycarbonyl, t-butoxycarbonyl and the like) and substituted alkoxycarbonyl groups (benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl and the like) can be preferably used. Among these, R 2 is preferably an alkoxycarbonyl group, and particularly preferably ethoxycarbonyl. Among these, R 3 is preferably an alkoxycarbonyl group, and particularly preferably t-butoxycarbonyl.
　五硫化リンとは、分子式Ｐ４Ｓ１０で表される化合物であり、五硫化二リン及び硫化リン（Ｖ）と同義である。 Phosphorus pentasulfide is a compound represented by the molecular formula P 4 S 10 and is synonymous with phosphorous pentasulfide and phosphorous sulfide (V).
　カルボン酸としては、置換されていてもよい直鎖状又は分岐鎖状の炭素数１～７（Ｃ１－７）のカルボン酸が挙げられる。具体的には、例えば、ギ酸、炭素数２～７（Ｃ２－７）のアルキルカルボン酸（酢酸、プロピオン酸、酪酸又はイソ酪酸等）、炭素数２～７（Ｃ２－７）の置換されたアルキルカルボン酸（トリフルオロ酢酸等）が挙げられる。これらのうち、アルキルカルボン酸が好ましく、とりわけ酢酸が好ましい。 Examples of the carboxylic acid include an optionally substituted linear or branched carboxylic acid having 1 to 7 carbon atoms (C 1-7 ). Specifically, for example, formic acid, C 2-7 (C 2-7 ) alkyl carboxylic acid (such as acetic acid, propionic acid, butyric acid or isobutyric acid), C 2-7 (C 2-7 ) substitution Alkyl carboxylic acids (such as trifluoroacetic acid). Of these, alkylcarboxylic acids are preferred, and acetic acid is particularly preferred.
（本発明の製造方法）
　以下、本発明の製造方法についてさらに詳細に説明する。 (Production method of the present invention)
Hereinafter, the production method of the present invention will be described in more detail.
　原料化合物は、市販品として容易に入手できるか、以下に示す製造方法若しくは自体公知の方法により製造することができるか、又はこれらに準ずる方法に従って製造することができる。 The raw material compound can be easily obtained as a commercial product, can be produced by the production method shown below or a method known per se, or can be produced according to a method analogous thereto.
　以下の各反応で用いられる化合物は、反応に支障を来たさない範囲において、無機酸塩（例えば、塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、リン酸塩）、有機酸塩（例えば、酢酸塩、酒石酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、トルエンスルホン酸塩、メタンスルホン酸塩）、金属塩（例えば、ナトリウム塩、カリウム塩、カルシウム塩、アルミニウム塩）、又は塩基との塩（例えば、エチルアミン塩、グアニジン塩、アンモニウム塩、ヒドラジン塩、キニーネ塩、シンコニン塩）等の塩を形成していてもよい。 The compound used in each of the following reactions is an inorganic acid salt (for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate), organic acid salt (to the extent that does not interfere with the reaction) For example, acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate), metal salt (eg sodium salt, potassium salt, calcium salt, aluminum salt), or A salt such as a salt with a base (for example, ethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt) may be formed.
　また、以下の各反応で得られた化合物は、反応混合物から単離せずに又は粗生成物として次の反応に用いられてもよい。あるいは、当該化合物は通常公知の方法に従って反応混合物から単離されてもよく、再結晶、蒸留、クロマトグラフィー等の通常の分離手段により容易に精製されてもよい。さらに、当該化合物は、通常公知の方法に従って、無機酸塩、有機酸塩、金属塩、又は塩基との塩等の塩として単離されてもよい。 In addition, the compound obtained in each of the following reactions may be used in the next reaction without being isolated from the reaction mixture or as a crude product. Alternatively, the compound may be isolated from the reaction mixture according to a generally known method, or may be easily purified by a usual separation means such as recrystallization, distillation, chromatography or the like. Furthermore, the compound may be isolated as a salt such as an inorganic acid salt, an organic acid salt, a metal salt, or a salt according to a generally known method.
　本発明に用いられる化合物及び得られた化合物、又はそれらの塩は、それらの溶媒和物、又は水和物を含むものである。 The compound used in the present invention and the obtained compound, or a salt thereof include those solvates or hydrates.
　本発明において、一般式（３）で表される化合物（β－ヒドラゾンアミド化合物）と五硫化リンとの反応（ピラゾール環形成反応）は、以下のようにして実施できる。すなわち、一般式（３）で表される化合物と五硫化リンとの反応は、塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で行なうことができる。
　五硫化リンの使用量は、例えば、一般式（３）で表される化合物１モルに対して五硫化リン０．２～０．８モル、好ましくは、０．２５～０．３５モルとするのが好適である。 In the present invention, the reaction (pyrazole ring formation reaction) between the compound represented by the general formula (3) (β-hydrazone amide compound) and phosphorus pentasulfide can be carried out as follows. That is, the reaction of the compound represented by the general formula (3) and phosphorus pentasulfide can be performed in the presence or absence of a base, in a suitable solvent or without a solvent.
The amount of phosphorus pentasulfide used is, for example, 0.2 to 0.8 mol, preferably 0.25 to 0.35 mol of phosphorus pentasulfide with respect to 1 mol of the compound represented by the general formula (3). Is preferred.
　本反応は、塩基の存在下に行なうことが好ましい。用いる塩基としては、炭酸カリウム、炭酸ナトリウム、炭酸リチウム、炭酸水素カリウム若しくは炭酸水素ナトリウム等の無機塩基、又は、ピリジン、ピコリン、ルチジン、トリエチルアミン若しくはＮ，Ｎ－ジイソプロピルエチルアミン等の有機塩基が挙げられ、好ましくは、炭酸カリウム、炭酸ナトリウム、炭酸リチウム、炭酸水素カリウム又は炭酸水素ナトリウム等の無機塩基が挙げられ、より好ましくは、炭酸ナトリウムが挙げられる。当該塩基は、一般式（３）で表される化合物１モルに対して、通常、０．７～１０モル、好ましくは、０．８～２モルを使用することができる。 This reaction is preferably performed in the presence of a base. Examples of the base used include inorganic bases such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate, or organic bases such as pyridine, picoline, lutidine, triethylamine or N, N-diisopropylethylamine. Preferably, inorganic bases, such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, are mentioned, More preferably, sodium carbonate is mentioned. The base is generally used in an amount of 0.7 to 10 mol, preferably 0.8 to 2 mol, per 1 mol of the compound represented by the general formula (3).
　本反応は、適当な反応溶媒中で行なうことが好ましい。反応溶媒としては、例えば、テトラヒドロフラン（以下、ＴＨＦと記す）、１，４－ジオキサン、１，２－ジメトキシエタン、ジクロロメタン、クロロホルム、トルエン、アセトニトリル若しくはプロピオニトリル、又はこれらの混合溶媒を使用することができ、好ましくは、ＴＨＦを使用することができる。 This reaction is preferably performed in an appropriate reaction solvent. As the reaction solvent, for example, tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, toluene, acetonitrile or propionitrile, or a mixed solvent thereof should be used. Preferably, THF can be used.
　反応温度としては、通常、０～１１０℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。さらに、本反応は、窒素やアルゴン等の不活性ガス雰囲気下で行うことが好ましい。 The reaction temperature can usually be arbitrarily selected from 0 to 110 ° C., and the reaction time is usually about 10 minutes to 2 days. Furthermore, this reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
　前記のようにして得られた一般式（２）で表される化合物（ピペラジニルピラゾール化合物）、又はその塩は、以下のようにして、一般式（６）で表される化合物のカルボン酸塩に変換することができる。 The compound (piperazinylpyrazole compound) represented by the general formula (2) obtained as described above or a salt thereof is a carboxylic acid of the compound represented by the general formula (6) as follows. Can be converted to salt.
　　［化５］
Figure JPOXMLDOC01-appb-I000023
[Chemical formula 5]
Figure JPOXMLDOC01-appb-I000023
（式中、各記号は前記と同義である） (Wherein each symbol has the same meaning as above)
　すなわち、一般式（２）で表される化合物、又はその塩のアミノ基の保護基Ｒ２を除去して一般式（６）で表される化合物を製造し、次いで同化合物をカルボン酸と造塩処理させることにより一般式（６）で表される化合物のカルボン酸塩を製造することができる。 That is, the compound represented by the general formula (2) or the amino group protecting group R 2 of the salt thereof is removed to produce the compound represented by the general formula (6), and then the compound is formed with a carboxylic acid. By carrying out the salt treatment, the carboxylate of the compound represented by the general formula (6) can be produced.
　一般式（２）で表される化合物、又はその塩のアミノ基の保護基Ｒ２を除去する方法としては、用いられた保護基に応じて適した公知の方法を適宜使用しうる。 As a method for removing the protecting group R 2 of the amino group of the compound represented by the general formula (2) or a salt thereof, a known method suitable for the protecting group used can be appropriately used.
　具体的には、例えば、保護基としてｔ－ブトキシカルボニルが用いられている場合は、適当な溶媒中又は無溶媒で、酸と反応させて脱保護を行うことができる。酸としては、トリフルオロ酢酸、塩化水素、臭化水素又は硫酸等が挙げられ、好ましくは、トリフルオロ酢酸が挙げられる。 Specifically, for example, when t-butoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with an acid in a suitable solvent or without a solvent. Examples of the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, and the like, and preferably trifluoroacetic acid.
　本反応は、適当な反応溶媒中で行なうことが好ましい。反応溶媒としては、例えば、ジクロロメタン、クロロホルム、メタノール、エタノール、２－プロパノール、ＴＨＦ、１，４－ジオキサン、アセトニトリル、トルエン若しくは水、若しくは、上記酸を溶媒として、又はこれらの混合溶媒を使用することができ、好ましくは、上記酸を溶媒として使用することができる。 This reaction is preferably performed in an appropriate reaction solvent. As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene or water, or the above acid as a solvent, or a mixed solvent thereof may be used. Preferably, the acid can be used as a solvent.
　保護基としてメトキシカルボニル、エトキシカルボニル又はｎ－プロポキシカルボニル等が用いられている場合は、適当な溶媒中又は無溶媒で、塩基と反応させて脱保護を行うことができる。塩基としては、水酸化リチウム、水酸化ナトリウム又は水酸化カリウム等が挙げられ、好ましくは、水酸化カリウムが挙げられる。当該塩基の濃度は反応混合物に対し、０．１～１００ｍｏｌ／Ｌ、好ましくは、１～１０ｍｏｌ／Ｌである。 When methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or the like is used as a protecting group, deprotection can be performed by reacting with a base in a suitable solvent or without solvent. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and preferably potassium hydroxide. The concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L with respect to the reaction mixture.
　本反応は、適当な反応溶媒中で行なうことが好ましい。反応溶媒としては、例えば、メタノール、エタノール、２－プロパノール、ＴＨＦ、アセトニトリル若しくは水、又はこれらの混合溶媒を使用することができ、好ましくは、メタノール及び水の混合溶媒を使用することができる。 This reaction is preferably performed in an appropriate reaction solvent. As the reaction solvent, for example, methanol, ethanol, 2-propanol, THF, acetonitrile or water, or a mixed solvent thereof can be used, and preferably a mixed solvent of methanol and water can be used.
　反応温度は、通常、０～１００℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。 The reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
　保護基として、ベンジルオキシカルボニルが用いられている場合は、適当な溶媒中、水素雰囲気下で、パラジウム炭素触媒又は水酸化パラジウム炭素触媒の存在下で脱保護を行なうことができる。 When benzyloxycarbonyl is used as a protecting group, deprotection can be performed in a suitable solvent in a hydrogen atmosphere in the presence of a palladium carbon catalyst or a palladium hydroxide carbon catalyst.
　保護基として、２，２，２－トリクロロエトキシカルボニルが用いられている場合は、適当な溶媒中で亜鉛粉末と反応させることで脱保護を行なうことができる。 When 2,2,2-trichloroethoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with zinc powder in an appropriate solvent.
　保護基として、９－フルオレニルメトキシカルボニルが用いられている場合は、適当な溶媒中又は無溶媒で、ピロリジン、ピペリジン又はモルホリンと反応させることで脱保護を行なうことができる。 When 9-fluorenylmethoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with pyrrolidine, piperidine or morpholine in a suitable solvent or without solvent.
　一般式（６）で表される化合物とカルボン酸との造塩処理は、通常公知の方法を使用できる。例えば、一般式（６）で表される化合物とカルボン酸を、適当な溶媒中、造塩処理させることにより実施できる。具体的には、例えば、一般式（６）で表される化合物１モルに対し、０．７～３モル、好ましくは、０．９～１．１モルのカルボン酸を反応させることで、一般式（６）で表される化合物のカルボン酸塩を製造することができる。 For the salt formation treatment of the compound represented by the general formula (6) and the carboxylic acid, a generally known method can be used. For example, it can be carried out by subjecting the compound represented by the general formula (6) and the carboxylic acid to salt formation in an appropriate solvent. Specifically, for example, 0.7 to 3 mol, preferably 0.9 to 1.1 mol of carboxylic acid is reacted with 1 mol of the compound represented by the general formula (6). A carboxylate salt of the compound represented by the formula (6) can be produced.
　反応溶媒としては、例えば、ジクロロメタン、クロロホルム、メタノール、エタノール、２－プロパノール、ＴＨＦ、１，４－ジオキサン、アセトニトリル若しくはトルエン、又はこれらの混合溶媒を使用することができ、好ましくは、トルエンを使用することができる。 As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile or toluene, or a mixed solvent thereof can be used, and preferably toluene is used. be able to.
　反応温度は、通常、０～１００℃から任意に選択することができ、反応時間は、通常、１０分～１日程度である。 The reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 1 day.
　前記のようにして得られる一般式（２）で表される化合物若しくはその塩、又は一般式（６）で表される化合物のカルボン酸塩は、適宜、既知の方法又はそれらを組み合わせることにより、一般式（１）で表される化合物（プロリンアミド化合物）、又はその塩に変換することができる。或いは、以下に記載の方法により、一般式（１）で表される化合物、又はその塩へと好適に変換することができる。 The compound represented by the general formula (2) or a salt thereof obtained as described above, or the carboxylate of the compound represented by the general formula (6) is appropriately obtained by a known method or a combination thereof. The compound can be converted into a compound represented by the general formula (1) (proline amide compound) or a salt thereof. Or it can convert suitably to the compound represented by General formula (1), or its salt by the method as described below.
　　［化６］
Figure JPOXMLDOC01-appb-I000024
[Chemical 6]
Figure JPOXMLDOC01-appb-I000024
（式中、Ｒ３はアミノ基の保護基を示し、他は前記と同義である） (Wherein R 3 represents an amino-protecting group, and the others are as defined above)
　すなわち、一般式（６）で表される化合物のカルボン酸塩存在下、一般式（９）で表される化合物（４－オキソプロリンアミド化合物）を還元的アミノ化反応に付すことにより、一般式（１０）で表される化合物、又はその塩を製造し、次いで同化合物のアミノ基の保護基Ｒ３を除去して一般式（１）で表される化合物（ピペラジニルプロリンアミド化合物）を製造できる。さらに所望によりこれを酸による造塩処理に付すことにより、その塩に変換できる。 That is, by subjecting the compound represented by the general formula (9) (4-oxoprolinamide compound) to a reductive amination reaction in the presence of the carboxylate of the compound represented by the general formula (6), A compound represented by (10) or a salt thereof is produced, and then the amino-protecting group R 3 of the compound is removed to obtain a compound represented by the general formula (1) (piperazinylprolinamide compound). Can be manufactured. If desired, it can be converted to a salt thereof by subjecting it to a salt formation treatment with an acid.
　一般式（６）で表される化合物のカルボン酸塩存在下での、一般式（９）で表される化合物の還元的アミノ化反応には、通常公知の方法を使用しうる。具体的には、適当な溶媒中、一般式（６）で表される化合物のカルボン酸塩、一般式（９）で表される化合物及び還元剤を反応させることにより行なうことができる。 For the reductive amination reaction of the compound represented by the general formula (9) in the presence of the carboxylate salt of the compound represented by the general formula (6), a generally known method can be used. Specifically, the reaction can be performed by reacting the carboxylate of the compound represented by the general formula (6), the compound represented by the general formula (9), and a reducing agent in a suitable solvent.
　例えば、還元剤としては、水素化ホウ素ナトリウム、ナトリウムトリアセトキシボロヒドリド、ジメチルアミンボラン、トリエチルアミンボラン、トリメチルアミンボラン、ｔ－ブチルアミンボラン、Ｎ，Ｎ－ジエチルアニリンボラン又は２－ピコリンボランが挙げられ、好ましくは、ナトリウムトリアセトキシボロヒドリドが挙げられる。 For example, as the reducing agent, sodium borohydride, sodium triacetoxyborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, t-butylamine borane, N, N-diethylaniline borane or 2-picoline borane are preferable. Includes sodium triacetoxyborohydride.
　反応溶媒としては、例えば、ジクロロメタン、メタノール、エタノール、２－プロパノール、ＴＨＦ、アセトニトリル、トルエン若しくはジメチルホルムアミド、又はこれらの混合溶媒を使用することができ、好ましくは、トルエンを使用することができる。 As the reaction solvent, for example, dichloromethane, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene, dimethylformamide, or a mixed solvent thereof can be used, and preferably, toluene can be used.
　反応温度は、通常、－２０～１００℃から任意に選択することができ、反応時間は、通常、１０分～１日程度である。 The reaction temperature can usually be arbitrarily selected from −20 to 100 ° C., and the reaction time is usually about 10 minutes to 1 day.
　一般式（１０）で表される化合物、又はその塩のアミノ基の保護基Ｒ３を除去する方法としては、用いられた保護基に応じて適した公知の方法を適宜使用しうる。 As a method for removing the protecting group R 3 of the amino group of the compound represented by the general formula (10) or a salt thereof, a known method suitable for the protecting group used can be appropriately used.
　具体的には、例えば、保護基としてｔ－ブトキシカルボニルが用いられている場合は、適当な溶媒中又は無溶媒で、酸と反応させて脱保護を行うことができる。酸としては、トリフルオロ酢酸、塩化水素、臭化水素又は硫酸等が挙げられ、好ましくは、臭化水素が挙げられる。当該酸の濃度は反応混合物に対し０．０１～１０ｍｏｌ／Ｌ、好ましくは、０．１～４ｍｏｌ／Ｌである。 Specifically, for example, when t-butoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with an acid in a suitable solvent or without a solvent. Examples of the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, and the like, and preferably hydrogen bromide. The acid concentration is 0.01 to 10 mol / L, preferably 0.1 to 4 mol / L, based on the reaction mixture.
　本反応は、適当な反応溶媒中で行なうことが好ましい。反応溶媒としては、例えば、ジクロロメタン、クロロホルム、メタノール、エタノール、２－プロパノール、ＴＨＦ、１，４－ジオキサン、アセトニトリル、トルエン若しくは水、又はこれらの混合溶媒を使用することができ、好ましくは、２－プロパノール及び水の混合溶媒を使用することができる。 This reaction is preferably performed in an appropriate reaction solvent. As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene or water, or a mixed solvent thereof can be used, preferably 2- A mixed solvent of propanol and water can be used.
　反応温度は、通常、０～１００℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。 The reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
　保護基としてメトキシカルボニル、エトキシカルボニル又はｎ－プロポキシカルボニル等が用いられている場合は、適当な溶媒中又は無溶媒で、塩基と反応させて脱保護を行うことができる。塩基としては、水酸化リチウム、水酸化ナトリウム又は水酸化カリウム等が挙げられ、好ましくは、水酸化カリウムが挙げられる。当該塩基の濃度は反応混合物に対し、０．１～１００ｍｏｌ／Ｌ、好ましくは、１～１０ｍｏｌ／Ｌである。 When methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or the like is used as a protecting group, deprotection can be performed by reacting with a base in a suitable solvent or without solvent. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and preferably potassium hydroxide. The concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L with respect to the reaction mixture.
　本反応は、適当な反応溶媒中で行なうことが好ましい。反応溶媒としては、例えば、メタノール、エタノール、２－プロパノール、ＴＨＦ、アセトニトリル若しくは水、又はこれらの混合溶媒を使用することができ、好ましくは、メタノール及び水の混合溶媒を使用することができる。 This reaction is preferably performed in an appropriate reaction solvent. As the reaction solvent, for example, methanol, ethanol, 2-propanol, THF, acetonitrile or water, or a mixed solvent thereof can be used, and preferably a mixed solvent of methanol and water can be used.
　反応温度は、通常、０～１００℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。 The reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
　保護基として、ベンジルオキシカルボニルが用いられている場合は、適当な溶媒中、水素雰囲気下で、パラジウム炭素触媒又は水酸化パラジウム炭素触媒の存在下で脱保護を行なうことができる。 When benzyloxycarbonyl is used as a protecting group, deprotection can be performed in a suitable solvent in a hydrogen atmosphere in the presence of a palladium carbon catalyst or a palladium hydroxide carbon catalyst.
　保護基として、２，２，２－トリクロロエトキシカルボニルが用いられている場合は、適当な溶媒中で亜鉛粉末と反応させることで脱保護を行なうことができる。 When 2,2,2-trichloroethoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with zinc powder in an appropriate solvent.
　保護基として、９－フルオレニルメトキシカルボニルが用いられている場合は、適当な溶媒中又は無溶媒で、ピロリジン、ピペリジン又はモルホリンと反応させることで脱保護を行なうことができる。 When 9-fluorenylmethoxycarbonyl is used as a protecting group, deprotection can be performed by reacting with pyrrolidine, piperidine or morpholine in a suitable solvent or without solvent.
　一般式（１）で表される化合物の酸による造塩処理は、通常公知の方法に従って対応する酸と処理することで行うことができる。例えば、一般式（１）で表される化合物と酸を、適当な溶媒中、造塩処理させることにより行なうことができる。 The salt formation treatment with an acid of the compound represented by the general formula (1) can be performed by treating with a corresponding acid according to a generally known method. For example, it can be carried out by subjecting the compound represented by the general formula (1) and the acid to salt formation in an appropriate solvent.
　酸としては、例えば、塩化水素、臭化水素若しくは硝酸等の無機酸、又は、ｐ－トルエンスルホン酸、メタンスルホン酸、ベシル酸、ナフタレン－１－スルホン酸、ナフタレン－２－スルホン酸、没食子酸若しくはカンファースルホン酸等の有機酸が挙げられ、好ましくは、臭化水素が挙げられる。具体的には、一般式（１）で表される化合物１モルに対して、１～１０モル、好ましくは、２～５モルの酸を反応させることで、一般式（１）で表される化合物の塩を製造することができる。 Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide or nitric acid, or p-toluenesulfonic acid, methanesulfonic acid, besylic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid Or organic acids, such as camphorsulfonic acid, are mentioned, Preferably, hydrogen bromide is mentioned. Specifically, 1 to 10 mol, preferably 2 to 5 mol of an acid is reacted with 1 mol of the compound represented by the general formula (1) to thereby represent the general formula (1). Salts of compounds can be produced.
　反応溶媒としては、例えば、ジクロロメタン、クロロホルム、メタノール、エタノール、２－プロパノール、ＴＨＦ、アセトニトリル、トルエン若しくは水、又はこれらの混合溶媒を使用することができ、好ましくは、２－プロパノール及び水の混合溶媒を使用することができる。 As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene or water, or a mixed solvent thereof can be used, preferably a mixed solvent of 2-propanol and water. Can be used.
　反応温度は、通常、０～１００℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。 The reaction temperature can usually be arbitrarily selected from 0 to 100 ° C., and the reaction time is usually about 10 minutes to 2 days.
　一般式（１）で表される化合物の酸との塩を製造する場合においては、一般式（１０）で表される化合物、又はその塩のアミノ基の保護基Ｒ３としてｔ－ブトキシカルボニル等の酸で除去できる保護基を用いると、保護基Ｒ３の除去反応と次の造塩処理とを同時に行うことができるので、より好ましい。 In the case of producing a salt of the compound represented by the general formula (1) with the acid, the compound represented by the general formula (10), or t-butoxycarbonyl as the amino protecting group R 3 of the salt, etc. It is more preferable to use a protecting group that can be removed with an acid, since the removal reaction of the protecting group R 3 and the subsequent salt formation treatment can be carried out simultaneously.
　本発明において原料化合物となる一般式（３）で表される化合物は、適宜、既知の方法、又はそれらを組み合わせることにより製造することができるが、例えば、以下の方法により好適に製造することができる。 The compound represented by the general formula (3) as a raw material compound in the present invention can be appropriately produced by a known method or a combination thereof. For example, it can be suitably produced by the following method. it can.
　　［化７］
Figure JPOXMLDOC01-appb-I000025
[Chemical 7]
Figure JPOXMLDOC01-appb-I000025
（式中、各記号は前記と同義である） (Wherein each symbol has the same meaning as above)
　すなわち、一般式（４）で表される化合物（ピペラジン化合物）、又はその塩と、一般式（ａ）で表されるβ－ケトカルボン酸、又はその反応性誘導体とを反応させて、一般式（５）で表される化合物（β－ケトアミド化合物）を製造し、次いで同化合物を式Ａｒ－ＮＨ－ＮＨ２で表されるヒドラジン化合物、又はその塩と反応させることにより一般式（３）で表される化合物を製造することができる。 That is, the compound represented by the general formula (4) (piperazine compound) or a salt thereof is reacted with the β-ketocarboxylic acid represented by the general formula (a) or a reactive derivative thereof to give a general formula ( 5) is produced, and the compound is then reacted with a hydrazine compound represented by the formula Ar—NH—NH 2 or a salt thereof to produce a compound represented by the general formula (3). Can be produced.
　一般式（ａ）で表されるβ－ケトカルボン酸の反応性誘導体としては、例えば、一般式（ａ）で表されるβ－ケトカルボン酸のアルキルエステルやジケテンを用いることができる。 As the reactive derivative of β-ketocarboxylic acid represented by the general formula (a), for example, alkyl esters or diketenes of β-ketocarboxylic acid represented by the general formula (a) can be used.
　一般式（ａ）で表されるβ－ケトカルボン酸、又はその反応性誘導体としては、ジケテンが好ましい。 As the β-ketocarboxylic acid represented by the general formula (a) or a reactive derivative thereof, diketene is preferable.
　一般式（４）で表される化合物、又はその塩と、一般式（ａ）で表されるβ－ケトカルボン酸、又はその反応性誘導体とを反応させる方法としては、用いられる一般式（ａ）で表されるβ－ケトカルボン酸、又はその反応性誘導体に応じて適した公知の方法を適宜使用しうる。 As a method of reacting the compound represented by the general formula (4) or a salt thereof with the β-ketocarboxylic acid represented by the general formula (a) or a reactive derivative thereof, the general formula (a) used is used. A known method suitable for the β-ketocarboxylic acid represented by the formula (1) or a reactive derivative thereof can be appropriately used.
　具体的には、一般式（４）で表される化合物、又はその塩と、一般式（ａ）で表されるβ－ケトカルボン酸との反応としては、縮合剤を用い、塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で行なう、縮合反応を使用できる。縮合反応としては、例えば、カルボジイミドを用いる方法及び混合酸無水物法が挙げられる。具体的な縮合剤としては、Ｎ－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド、ジシクロヘキシルカルボジイミド、クロロギ酸メチル、クロロギ酸エチル、クロロギ酸プロピル、クロロギ酸イソプロピル、クロロギ酸ブチル、クロロギ酸イソブチル等が挙げられる。 Specifically, the reaction between the compound represented by the general formula (4) or a salt thereof and the β-ketocarboxylic acid represented by the general formula (a) uses a condensing agent in the presence of a base or In the absence, a condensation reaction carried out in a suitable solvent or without a solvent can be used. Examples of the condensation reaction include a method using carbodiimide and a mixed acid anhydride method. Specific condensing agents include N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, dicyclohexylcarbodiimide, methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate. Etc.
　一般式（ａ）で表されるβ－ケトカルボン酸の反応性誘導体として、一般式（ａ）で表されるβ－ケトカルボン酸のアルキルエステルを用いる場合は、一般式（４）で表される化合物、又はその塩と、一般式（ａ）で表されるβ－ケトカルボン酸のアルキルエステルを、適当な触媒の存在下又は非存在下、塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で反応させることができる。具体的な一般式（ａ）で表されるβ－ケトカルボン酸のアルキルエステルとしては、一般式（ａ）で表されるβ－ケトカルボン酸のメチルエステル、一般式（ａ）で表されるβ－ケトカルボン酸のエチルエステル、一般式（ａ）で表されるβ－ケトカルボン酸のｔ－ブチルエステル等が挙げられる。 When an alkyl ester of β-ketocarboxylic acid represented by general formula (a) is used as the reactive derivative of β-ketocarboxylic acid represented by general formula (a), the compound represented by general formula (4) Or a salt thereof and an alkyl ester of β-ketocarboxylic acid represented by the general formula (a) in the presence or absence of a suitable catalyst, in the presence or absence of a base, in a suitable solvent or It can be made to react with a solvent. Specific examples of the alkyl ester of β-ketocarboxylic acid represented by general formula (a) include methyl ester of β-ketocarboxylic acid represented by general formula (a) and β-keto represented by general formula (a). Examples thereof include ethyl esters of ketocarboxylic acids and t-butyl esters of β-ketocarboxylic acids represented by the general formula (a).
　一般式（ａ）で表されるβ－ケトカルボン酸の反応性誘導体としてジケテンを用いる場合は、一般式（４）で表される化合物、又はその塩と、ジケテンを、塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で反応させることができる。 When diketene is used as the reactive derivative of β-ketocarboxylic acid represented by general formula (a), the compound represented by general formula (4) or a salt thereof and diketene are used in the presence or absence of a base. The reaction can be carried out in a suitable solvent or without a solvent.
　一般式（５）で表される化合物と、式Ａｒ－ＮＨ－ＮＨ２で表されるヒドラジン化合物、又はその塩とを反応させる方法としては、通常公知の縮合反応を使用しうる。具体的には、一般式（５）で表される化合物と、ヒドラジン化合物、又はその塩の縮合反応は、酸又は塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で実施することができる。 As a method of reacting the compound represented by the general formula (5) with the hydrazine compound represented by the formula Ar—NH—NH 2 or a salt thereof, a generally known condensation reaction can be used. Specifically, the condensation reaction of the compound represented by the general formula (5) and the hydrazine compound or a salt thereof is performed in the presence or absence of an acid or a base in a suitable solvent or without a solvent. Can do.
　本発明において原料化合物となる一般式（９）で表される化合物は、適宜、既知の方法又はそれらを組み合わせることにより製造することができるが、例えば、以下の方法により好適に製造することができる。 The compound represented by the general formula (9) as a raw material compound in the present invention can be appropriately produced by a known method or a combination thereof. For example, it can be suitably produced by the following method. .
　　［化８］
Figure JPOXMLDOC01-appb-I000026
[Chemical 8]
Figure JPOXMLDOC01-appb-I000026
（式中、記号は前記と同義である） (Wherein the symbols are as defined above)
　すなわち、一般式（８）で表される化合物、又はその塩と、チアゾリジンとを縮合させることにより好適に製造することができる。 That is, it can be suitably produced by condensing the compound represented by the general formula (8) or a salt thereof with thiazolidine.
　一般式（８）で表される化合物、又はその塩と、チアゾリジンとの縮合反応は、縮合剤を用い、塩基の存在下又は非存在下、適当な溶媒中又は無溶媒で実施することができる。 The condensation reaction of the compound represented by the general formula (8) or a salt thereof with thiazolidine can be carried out using a condensing agent, in the presence or absence of a base, in a suitable solvent or without solvent. .
　かかる縮合反応としては、例えば、混合酸無水物法及び無水ホスホン酸誘導体を用いる方法が挙げられる。具体的な縮合剤としては、クロロギ酸アルキルエステル、置換アリールカルボン酸クロリド、置換アリールカルボン酸無水物又は無水ホスホン酸環状三量体が挙げられ、好ましくは、クロロギ酸メチル、クロロギ酸エチル、クロロギ酸プロピル、クロロギ酸イソプロピル、クロロギ酸ブチル、クロロギ酸イソブチル、２，４，６－トリクロロベンゾイルクロリド、２－メチル－６－ニトロ安息香酸無水物又はｎ－プロピルホスホン酸無水物（環状三量体）が挙げられ、より好ましくは、ｎ－プロピルホスホン酸無水物（環状三量体）が挙げられる。塩基としては、ピリジン、ピコリン、ルチジン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等が挙げられ、好ましくは、Ｎ，Ｎ－ジイソプロピルエチルアミンが挙げられる。 Examples of such a condensation reaction include a mixed acid anhydride method and a method using a phosphonic anhydride derivative. Specific examples of the condensing agent include chloroformic acid alkyl ester, substituted arylcarboxylic acid chloride, substituted arylcarboxylic acid anhydride or phosphonic anhydride cyclic trimer, preferably methyl chloroformate, ethyl chloroformate, chloroformic acid. Propyl, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, 2,4,6-trichlorobenzoyl chloride, 2-methyl-6-nitrobenzoic anhydride or n-propylphosphonic anhydride (cyclic trimer) More preferably, n-propylphosphonic anhydride (cyclic trimer) is used. Examples of the base include pyridine, picoline, lutidine, triethylamine, N, N-diisopropylethylamine, and preferably N, N-diisopropylethylamine.
　また、反応溶媒としては、例えば、ＴＨＦ、１，４－ジオキサン、１，２－ジメトキシエタン、ジクロロメタン、クロロホルム、トルエン、酢酸メチル、酢酸エチル、酢酸プロピル、アセトニトリル若しくはプロピオニトリル、又はこれらの混合溶媒を使用することができ、好ましくは、酢酸エチルを使用することができる。 Examples of the reaction solvent include THF, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, toluene, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, or propionitrile, or a mixed solvent thereof. Can be used, preferably ethyl acetate can be used.
　反応温度は、通常、－２０～１１０℃から任意に選択することができ、反応時間は、通常、１０分～２日程度である。 The reaction temperature can usually be arbitrarily selected from −20 to 110 ° C., and the reaction time is usually about 10 minutes to 2 days.
　本発明においては、Ｒ１がアルキル（特にメチル等）であり、Ｒ２が置換又は無置換のアルコキシカルボニルであり、Ｒ３が置換又は無置換のアルコキシカルボニルであり、Ａｒがアリール（特にフェニル等）であるような各化合物を用いることにより本発明の製法をより好適に実施することができる。また、一般式（６）で表される化合物との塩を製造するカルボン酸としてはアルキルカルボン酸（特に酢酸等）を適用することが好ましい。さらにまた、一般式（１）で表される化合物との塩としては無機酸の塩（特に臭化水素酸塩など）を適用することが好ましい。なお、一般式（１）で表される化合物、又はその塩は、それらの溶媒和物又は水和物を形成していてもよい。 In the present invention, R 1 is alkyl (especially methyl, etc.), R 2 is substituted or unsubstituted alkoxycarbonyl, R 3 is substituted or unsubstituted alkoxycarbonyl, and Ar is aryl (especially phenyl, etc.) ), The production method of the present invention can be more suitably carried out. Moreover, it is preferable to apply alkylcarboxylic acid (especially acetic acid etc.) as carboxylic acid which manufactures a salt with the compound represented by General formula (6). Furthermore, as a salt with the compound represented by the general formula (1), it is preferable to apply a salt of an inorganic acid (particularly a hydrobromide). In addition, the compound represented by General formula (1), or its salt may form those solvates or hydrates.
　本発明の製法により好適に製造される化合物としては、例えば、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジン、又はその塩が挙げられる。 Examples of the compound suitably produced by the production method of the present invention include 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 -Yl] pyrrolidin-2-ylcarbonyl} thiazolidine, or a salt thereof.
　かかる化合物として、より詳細には、例えば、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの２．５臭化水素酸塩が挙げられる。さらに詳細には、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの２．５臭化水素酸塩の１～２水和物が挙げられる。 As such a compound, more specifically, for example, 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidine- 2-ylcarbonyl} thiazolidine 2.5 hydrobromide. More particularly, 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine And 2.5 hydrobromide monohydrate or dihydrate.
　本明細書中、略号、「Ｍｅ」はメチル基、「Ｅｔ」はエチル基、「Ｐｈ」はフェニル基、「Ａｃ」はアセチル基、「ｔ－Ｂｕ」は第三級ブチル基を、各々表す。 In this specification, the abbreviation, “Me” represents a methyl group, “Et” represents an ethyl group, “Ph” represents a phenyl group, “Ac” represents an acetyl group, and “t-Bu” represents a tertiary butyl group. .
　以下に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。実施例中、「ｗ％」とは、重量％を表す。 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto. In the examples, “w%” represents wt%.
実施例１
５－（４－ｔ－ブトキシカルボニルピペラジン－１－イル）－３－メチル－１－フェニルピラゾールの製造 Example 1
Preparation of 5- (4-t-butoxycarbonylpiperazin-1-yl) -3-methyl-1-phenylpyrazole
　　［化９］
Figure JPOXMLDOC01-appb-I000027
[Chemical 9]
Figure JPOXMLDOC01-appb-I000027
　４－ｔ－ブトキシカルボニル－１－［３－（２－フェニルヒドラゾノ）ブチリル］ピペラジン（化合物３ｂ）（７２１ｍｇ）と炭酸ナトリウム（２５４ｍｇ）のＴＨＦ（１０ｍＬ）溶液に、五硫化リン（２６７ｍｇ）を加え、３０分間加熱還流した。減圧下で溶媒を留去し、残渣にジエチルエーテル（３０ｍＬ）を加え、濾過した。濾液に水（２０ｍＬ）を加え分液した。得られた有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥し、濾過した。この濾液を減圧下で濃縮することにより５－（４－ｔ－ブトキシカルボニルピペラジン－１－イル）－３－メチル－１－フェニルピラゾール（化合物２ｂ）を５８０ｍｇ得た。（収率８５％）
１Ｈ－ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ－ｄ６）δ１．３９（９Ｈ，ｓ），２．１５（３Ｈ，ｓ），２．７３（４Ｈ，ｍ），３．３７（４Ｈ，ｍ），５．８３（１Ｈ，ｓ），７．２８（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．４６（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）． To a solution of 4-t-butoxycarbonyl-1- [3- (2-phenylhydrazono) butyryl] piperazine (Compound 3b) (721 mg) and sodium carbonate (254 mg) in THF (10 mL) was added phosphorus pentasulfide (267 mg). In addition, the mixture was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, and diethyl ether (30 mL) was added to the residue, followed by filtration. Water (20 mL) was added to the filtrate for liquid separation. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 580 mg of 5- (4-t-butoxycarbonylpiperazin-1-yl) -3-methyl-1-phenylpyrazole (Compound 2b). (Yield 85%)
1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.39 (9H, s), 2.15 (3H, s), 2.73 (4H, m), 3.37 (4H, m), 5. 83 (1H, s), 7.28 (1H, t, J = 7.4 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.76 (2H, d, J = 7.4 Hz) ).
実施例２
３－メチル－１－フェニル－５－（１－ピペラジニル）ピラゾール酢酸塩の製造 Example 2
Preparation of 3-methyl-1-phenyl-5- (1-piperazinyl) pyrazole acetate
　　［化１０］
Figure JPOXMLDOC01-appb-I000028
[Chemical Formula 10]
Figure JPOXMLDOC01-appb-I000028
　ＴＨＦ（５５０Ｌ）に１－エトキシカルボニルピペラジン（化合物４ａ）（３７．５ｋｇ）を溶解した。この溶液を冷却し、０～７℃でジケテン（１９．９ｋｇ）を滴下後、１～５℃で１．５時間攪拌した。この反応混合物にフェニルヒドラジン（２５．６ｋｇ）のＴＨＦ（１０Ｌ）溶液を滴下し、２０～２６℃で７時間攪拌させた。反応混合物を残量が１００Ｌとなるまで減圧下で濃縮し、残った反応混合物にＴＨＦ（２６０Ｌ）を加えた。この反応混合物に炭酸ナトリウム（２５．１ｋｇ）及び五硫化リン（２６．３ｋｇ）を加えた後、３６～４４℃で１．５時間、４５～５２℃で３時間撹拌した。反応混合物を冷却し、五硫化リン（５．３ｋｇ）を追加し、４５～５１℃で１時間攪拌し、反応混合物を冷却した。この反応混合物にトルエン（３７５Ｌ）、水（３７５Ｌ）を加え分液した。得られた有機層を水（３７５Ｌ）で洗浄し、減圧濃縮した後、残渣にメタノール（１９０Ｌ）を加え、減圧濃縮した。この残渣にメタノール（２６０Ｌ）、水（１１０Ｌ）を加え、冷却下で水酸化カリウム（１１２．６ｋｇ）を投入した。反応混合物を２．５時間還流後、５１℃まで冷却し、トルエン（２６０Ｌ）、水（５５Ｌ）を加えて分液した。得られた有機層を２０ｗ％食塩水（７５ｋｇ）で３回、水（３８Ｌ）で１回それぞれ洗浄した。有機層を常圧下で濃縮し、溶媒を２１０Ｌ留去した。残った反応混合物に、５５℃で酢酸（１０．７ｋｇ）を滴下し、５１～５６℃で１時間、次いで１７～２５℃で１．５時間晶析した。析出した結晶を濾取し、トルエン（４０Ｌ）で洗浄した。得られた結晶を１５時間温風乾燥（４０～４６℃）し、３－メチル－１－フェニル－５－（１－ピペラジニル）ピラゾールの酢酸塩（化合物７ａ）を４７．４ｋｇ得た。（収率６６％）
１Ｈ－ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ－ｄ６）δ１．９０（３Ｈ，ｓ），２．１４（３Ｈ，ｓ），２．７０（８Ｈ，ｍ），５．７７（１Ｈ，ｓ），７．３７（１Ｈ，ｔ），７．４５（２Ｈ，ｔ），７．７５（２Ｈ，ｄ）． 1-Ethoxycarbonylpiperazine (Compound 4a) (37.5 kg) was dissolved in THF (550 L). The solution was cooled, diketene (19.9 kg) was added dropwise at 0-7 ° C., and the mixture was stirred at 1-5 ° C. for 1.5 hours. To this reaction mixture, a solution of phenylhydrazine (25.6 kg) in THF (10 L) was added dropwise and stirred at 20 to 26 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure until the remaining amount was 100 L, and THF (260 L) was added to the remaining reaction mixture. Sodium carbonate (25.1 kg) and phosphorus pentasulfide (26.3 kg) were added to the reaction mixture, followed by stirring at 36 to 44 ° C. for 1.5 hours and at 45 to 52 ° C. for 3 hours. The reaction mixture was cooled, phosphorus pentasulfide (5.3 kg) was added, and the mixture was stirred at 45-51 ° C. for 1 hour to cool the reaction mixture. Toluene (375 L) and water (375 L) were added to the reaction mixture for liquid separation. The obtained organic layer was washed with water (375 L) and concentrated under reduced pressure, methanol (190 L) was added to the residue, and the mixture was concentrated under reduced pressure. Methanol (260 L) and water (110 L) were added to this residue, and potassium hydroxide (112.6 kg) was added under cooling. The reaction mixture was refluxed for 2.5 hours, cooled to 51 ° C., and separated by adding toluene (260 L) and water (55 L). The obtained organic layer was washed 3 times with 20 w% saline (75 kg) and once with water (38 L). The organic layer was concentrated under normal pressure, and 210 L of the solvent was distilled off. Acetic acid (10.7 kg) was added dropwise to the remaining reaction mixture at 55 ° C., and crystallization was performed at 51 to 56 ° C. for 1 hour and then at 17 to 25 ° C. for 1.5 hours. The precipitated crystals were collected by filtration and washed with toluene (40 L). The obtained crystals were dried in warm air (40-46 ° C.) for 15 hours to obtain 47.4 kg of acetate (compound 7a) of 3-methyl-1-phenyl-5- (1-piperazinyl) pyrazole. (Yield 66%)
1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.90 (3H, s), 2.14 (3H, s), 2.70 (8H, m), 5.77 (1H, s), 7. 37 (1H, t), 7.45 (2H, t), 7.75 (2H, d).
実施例３
４－ｔ－ブトキシカルボニル－１－［３－（２－フェニルヒドラゾノ）ブチリル］ピペラジンの合成 Example 3
Synthesis of 4-t-butoxycarbonyl-1- [3- (2-phenylhydrazono) butyryl] piperazine
　　［化１１］
Figure JPOXMLDOC01-appb-I000029
[Chemical 11]
Figure JPOXMLDOC01-appb-I000029
　１－ｔ－ブトキシカルボニルピペラジン（化合物４ｂ）（８０ｇ）のＮ，Ｎ－ジメチルホルムアミド（２５６ｍＬ）溶液に氷冷下でジケテン（３４．７ｍＬ）を滴下し、室温で１時間攪拌した。この反応混合物にフェニルヒドラジン（４８．７ｇ）のエタノール（１９２ｍＬ）及び水（１９２ｍＬ）の混合溶液を水冷下で滴下し、室温で１時間攪拌した。この反応混合物に水（３２０ｍＬ）を滴下し、室温で１時間攪拌した。析出物を濾取し、メタノールと水の１：１の混合液で洗浄し、真空下で乾燥し、４－ｔ－ブトキシカルボニル－１－［３－（２－フェニルヒドラゾノ）ブチリル］ピペラジン（化合物３ｂ）を１４９ｇ得た。（収率９７％、幾何異性体比１：１）
１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ１．４６，１．４８（９Ｈ，ｓ），１．９５（１．５Ｈ，ｓ），２．１１（１．５Ｈ，ｓ），２．８８（０．５Ｈ，ｓ），２．９６（０．５Ｈ，ｓ），３．３５－３．６４（１０Ｈ，ｍ），６．８０－７．３２（５Ｈ，ｍ）． Diketene (34.7 mL) was added dropwise to a solution of 1-t-butoxycarbonylpiperazine (Compound 4b) (80 g) in N, N-dimethylformamide (256 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. To this reaction mixture, a mixed solution of phenylhydrazine (48.7 g) in ethanol (192 mL) and water (192 mL) was added dropwise under water cooling, and the mixture was stirred at room temperature for 1 hour. Water (320 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with a 1: 1 mixture of methanol and water, dried under vacuum, and 4-t-butoxycarbonyl-1- [3- (2-phenylhydrazono) butyryl] piperazine ( 149 g of compound 3b) were obtained. (Yield 97%, geometric isomer ratio 1: 1)
1 H-NMR (300 MHz, CDCl 3 ) δ 1.46, 1.48 (9H, s), 1.95 (1.5H, s), 2.11 (1.5H, s), 2.88 (0 .5H, s), 2.96 (0.5H, s), 3.35-3.64 (10H, m), 6.80-7.32 (5H, m).
実施例４
３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジン化合物の製造 Example 4
Preparation of 3-{(2S, 4S) -4- [4- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine compounds
　　［化１２］
Figure JPOXMLDOC01-appb-I000030
[Chemical 12]
Figure JPOXMLDOC01-appb-I000030
（式中、Ｙは１～２を示す） (In the formula, Y represents 1-2)
　３－メチル－１－フェニル－５－（１－ピペラジニル）ピラゾールの酢酸塩（化合物７ａ）（２５．２ｋｇ）、３－［（２Ｓ）－１－ｔ－ブトキシカルボニル－４－オキソピロリジン－２－イルカルボニル］チアゾリジン（化合物９ａ）（２５．０ｋｇ）にトルエン（４２５Ｌ）を加え、更にナトリウムトリアセトキシボロヒドリド（２３．０ｋｇ）のトルエン（７５Ｌ）スラリーを８℃で加えた後、２０～２８℃で３時間撹拌した。この反応混合物に、水（１５０Ｌ）を加え、分液した。得られたトルエン層を５ｗ％重曹水（１５８ｋｇ）、水（１５０Ｌ）の順で洗浄後、減圧濃縮、乾固し、得られた残渣に２－プロパノール（１２５Ｌ）を加えて再度減圧濃縮、乾固した。この残渣に２－プロパノール（３７５Ｌ）を加え、昇温し、４８ｗ％臭化水素酸（４２．１４ｋｇ）を７５～７７℃で滴下後、２．５時間還流した。反応混合物を冷却し、反応混合物をサンプリングして作成した種晶を５８℃で接種後、５８℃で１時間、次いで３３～４０℃で１時間、更に１７～２５℃で１時間晶析し、一夜静置した。析出した結晶を濾取し、２－プロパノール（５０Ｌ）で結晶を洗浄した。得られた結晶を１８時間温風乾燥（４０～４７℃）し、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの臭化水素酸塩（５０．０ｋｇ）を粗生成物として得た。 3-methyl-1-phenyl-5- (1-piperazinyl) pyrazole acetate (compound 7a) (25.2 kg), 3-[(2S) -1-t-butoxycarbonyl-4-oxopyrrolidine-2- Toluene (425 L) was added to [Ilcarbonyl] thiazolidine (Compound 9a) (25.0 kg), and a toluene (75 L) slurry of sodium triacetoxyborohydride (23.0 kg) was added at 8 ° C., followed by 20 to 28 ° C. For 3 hours. Water (150 L) was added to the reaction mixture and the layers were separated. The obtained toluene layer was washed with 5 w% aqueous sodium bicarbonate (158 kg) and water (150 L) in this order, then concentrated under reduced pressure and evaporated to dryness. Solidified. To this residue was added 2-propanol (375 L), the temperature was raised, and 48 w% hydrobromic acid (42.14 kg) was added dropwise at 75 to 77 ° C., followed by refluxing for 2.5 hours. The reaction mixture was cooled, and seed crystals prepared by sampling the reaction mixture were inoculated at 58 ° C., then crystallized at 58 ° C. for 1 hour, then at 33-40 ° C. for 1 hour, and further at 17-25 ° C. for 1 hour. I left it overnight. The precipitated crystals were collected by filtration and washed with 2-propanol (50 L). The obtained crystals were dried with hot air (40-47 ° C.) for 18 hours to give 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine. -1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine hydrobromide (50.0 kg) was obtained as a crude product.
　当該粗生成物（２４．０ｋｇ）にエタノール（１４４Ｌ）を加え、加熱溶解（７３℃）後、熱時濾過し、エタノール（２４Ｌ）で洗浄した。この濾液及び洗液を合わせ、６７℃で水（３．４Ｌ）を加えた後、４９～５５℃で２時間、次いで１９～２５℃で１時間晶析した。析出した結晶を濾取し、エタノール（２４Ｌ）で洗浄した。得られた結晶を４５℃で１９時間減圧乾燥した後、５０℃で１８時間温風乾燥することにより、精製物として、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの２．５臭化水素酸塩の１～２水和物（化合物１１ａ）を２０．９ｋｇ得た。（収率７９％、収率は２水和物とみなして計算した値）
１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｃ５Ｄ５Ｎ）δ２．０２－２．１４（１Ｈ，ｍ），２．３３（３Ｈ，ｍ），２．４６－２．５６（４Ｈ，ｍ），２．８７（４Ｈ，ｍ），２．９１－３．１２（３Ｈ，ｍ），３．４５－３．５１（１Ｈ，ｍ），３．６３－３．６７（１Ｈ，ｍ），３．８０－３．９０（１．４Ｈ，ｍ），４．０８（０．６Ｈ，ｍ），４．１１－４．１６（１Ｈ，ｍ），４．６８（０．６Ｈ，ｄ，Ｊ＝１０．１Ｈｚ），４．７２（０．６Ｈ，ｄ，Ｊ＝１０．１Ｈｚ），４．８０（０．４Ｈ，ｄ，Ｊ＝８．８Ｈｚ），４．９６（０．４Ｈ，ｄ，Ｊ＝８．８Ｈｚ），５．４２（０．６Ｈ，ｄｄ，Ｊ＝８．８，８．８Ｈｚ），５．５２（０．４Ｈ，ｄｄ，Ｊ＝８．８，８．８Ｈｚ），５．７６（０．４Ｈ，ｓ），５．７７（０．６Ｈ，ｓ），７．３２（１Ｈ，ｔ＝７．８Ｈｚ），７．５３（２Ｈ，ｄｄ，Ｊ＝８．８，７．８Ｈｚ），８．０７（２Ｈ，ｄ＝８．８Ｈｚ）． Ethanol (144 L) was added to the crude product (24.0 kg), heated and dissolved (73 ° C.), filtered while hot, and washed with ethanol (24 L). The filtrate and the washing solution were combined, water (3.4 L) was added at 67 ° C., and crystallization was performed at 49 to 55 ° C. for 2 hours and then at 19 to 25 ° C. for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol (24 L). The obtained crystals were dried under reduced pressure at 45 ° C. for 19 hours, and then dried with hot air at 50 ° C. for 18 hours to give a purified product as 3-{(2S, 4S) -4- [4- (3-methyl- 1-Phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine 2.5 hydrobromide monohydrate or dihydrate (Compound 11a) 20.9 kg Obtained. (Yield 79%, Yield calculated as dihydrate)
1 H-NMR (400 MHz, C 5 D 5 N) δ 2.02-2.14 (1H, m), 2.33 (3H, m), 2.46-2.56 (4H, m), 2. 87 (4H, m), 2.91-3.12 (3H, m), 3.45-3.51 (1H, m), 3.63-3.67 (1H, m), 3.80- 3.90 (1.4 H, m), 4.08 (0.6 H, m), 4.11-4.16 (1 H, m), 4.68 (0.6 H, d, J = 10.1 Hz) ), 4.72 (0.6 H, d, J = 10.1 Hz), 4.80 (0.4 H, d, J = 8.8 Hz), 4.96 (0.4 H, d, J = 8. 8 Hz), 5.42 (0.6 H, dd, J = 8.8, 8.8 Hz), 5.52 (0.4 H, dd, J = 8.8, 8.8 Hz), 5.76 (0 .4H, s), 5.77 (0.6H, s ), 7.32 (1H, t = 7.8 Hz), 7.53 (2H, dd, J = 8.8, 7.8 Hz), 8.07 (2H, d = 8.8 Hz).
実施例５
３－［（２Ｓ）－１－ｔ－ブトキシカルボニル－４－オキソピロリジン－２－イルカルボニル］チアゾリジン化合物の製造 Example 5
Preparation of 3-[(2S) -1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine compound
　　［化１３］
Figure JPOXMLDOC01-appb-I000031
[Chemical 13]
Figure JPOXMLDOC01-appb-I000031
　（２Ｓ）－１－ｔ－ブトキシカルボニル－４－オキソピロリジン－２－カルボン酸（化合物８ａ）（６０．０ｋｇ）、チアゾリジン（３０．３ｋｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（１１８ｋｇ）の酢酸エチル（５９５ｋｇ）溶液に、２８ｗ％プロピルホスホン酸無水物（環状三量体）酢酸エチル溶液（４４６ｋｇ）を２～７℃で加えた後、反応混合物を２～４℃で２時間撹拌した。この反応混合物に、１５ｗ％クエン酸水溶液（６００ｋｇ）を加え分液し、水層を酢酸エチル（２７１ｋｇ）で抽出した。得られた酢酸エチル層を混合し、１０ｗ％リン酸水素二アンモニウム水溶液（６００ｋｇ）と水（３００ｋｇ）で順次洗浄した。酢酸エチル層を濃縮し残量を３００Ｌにした後、ｎ－ヘプタン（７３９ｋｇ）を２３～２５℃で添加し、混合物を２３～２５℃で１時間、１～５℃で２時間撹拌した。析出した結晶を濾取し、ｎ－ヘプタン（１６４ｋｇ）で洗浄した後、減圧乾燥することにより、３－［（２Ｓ）－１－ｔ－ブトキシカルボニル－４－オキソピロリジン－２－イルカルボニル］チアゾリジン（化合物９ａ）を６７．８ｋｇ得た。（収率８６％）
１Ｈ－ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ－ｄ６）δ１．３６，１．４０（９Ｈ，ｓ），２．３６－２．４５（１Ｈ，ｍ），２．９７－３．１２（３Ｈ，ｍ），３．６２－３．７１（２Ｈ，ｍ），３．７４－３．９４（２Ｈ，ｍ），４．３３－４．８０（２Ｈ，ｍ），４．９１－５．０４（１Ｈ，ｍ）． (2S) -1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 8a) (60.0 kg), thiazolidine (30.3 kg), N, N-diisopropylethylamine (118 kg) in ethyl acetate ( To the 595 kg) solution was added 28 w% propylphosphonic anhydride (cyclic trimer) ethyl acetate solution (446 kg) at 2-7 ° C., and the reaction mixture was stirred at 2-4 ° C. for 2 hours. To this reaction mixture, 15 w% aqueous citric acid solution (600 kg) was added for liquid separation, and the aqueous layer was extracted with ethyl acetate (271 kg). The obtained ethyl acetate layers were mixed and washed sequentially with a 10 w% aqueous diammonium hydrogen phosphate solution (600 kg) and water (300 kg). After the ethyl acetate layer was concentrated to a residual volume of 300 L, n-heptane (739 kg) was added at 23-25 ° C., and the mixture was stirred at 23-25 ° C. for 1 hour and 1-5 ° C. for 2 hours. The precipitated crystals were collected by filtration, washed with n-heptane (164 kg), and then dried under reduced pressure to give 3-[(2S) -1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine. 67.8 kg of (Compound 9a) was obtained. (Yield 86%)
1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.36, 1.40 (9H, s), 2.36-2.45 (1H, m), 2.97-3.12 (3H, m) , 3.62-3.71 (2H, m), 3.74-3.94 (2H, m), 4.33-4.80 (2H, m), 4.91-5.04 (1H, m).
比較例１
ローソン試薬を用いた５－（４－ｔ－ブトキシカルボニルピペラジン－１－イル）－３－メチル－１－フェニルピラゾールの製造 Comparative Example 1
Production of 5- (4-t-butoxycarbonylpiperazin-1-yl) -3-methyl-1-phenylpyrazole using Lawesson's reagent
　　［化１４］
Figure JPOXMLDOC01-appb-I000032
[Chemical 14]
Figure JPOXMLDOC01-appb-I000032
　４－ｔ－ブトキシカルボニル－１－［３－（２－フェニルヒドラゾノ）ブチリル］ピペラジン（化合物３ｂ）（１．００ｇ）のトルエン（１８ｍＬ）溶液に、ローソン試薬（６７４ｍｇ）を加え、８０℃で１．５時間加熱した。原料の消失を確認した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィーにて精製することにより５－（４－ｔ－ブトキシカルボニルピペラジン－１－イル）－３－メチル－１－フェニルピラゾール（化合物２ｂ）を５５１ｍｇ得た。（収率５８％）
１Ｈ－ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ－ｄ６）δ１．３９（９Ｈ，ｓ），２．１５（３Ｈ，ｓ），２．７３（４Ｈ，ｍ），３．３７（４Ｈ，ｍ），５．８３（１Ｈ，ｓ），７．２８（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．４６（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）． To a solution of 4-t-butoxycarbonyl-1- [3- (2-phenylhydrazono) butyryl] piperazine (Compound 3b) (1.00 g) in toluene (18 mL) was added Lawesson's reagent (674 mg) at 80 ° C. Heated for 1.5 hours. After confirming disappearance of the raw material, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 5- (4-t-butoxycarbonylpiperazin-1-yl) -3-methyl-1-phenyl. 551 mg of pyrazole (Compound 2b) was obtained. (Yield 58%)
1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.39 (9H, s), 2.15 (3H, s), 2.73 (4H, m), 3.37 (4H, m), 5. 83 (1H, s), 7.28 (1H, t, J = 7.4 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.76 (2H, d, J = 7.4 Hz) ).
　このようにローソン試薬を用いる方法と比較して、本発明の方法を用いて製造した場合には、前記実施例１に記載の通り、顕著に高い収率で目的化合物（化合物２ｂ）を製造することができた。 As described in Example 1, the target compound (compound 2b) is produced in a significantly higher yield as described in Example 1 when compared with the method using Lawson's reagent. I was able to.
　本発明の製造方法によれば、医薬の合成中間体等として有用なピペラジニルピラゾール化合物、又はその塩を工業的有利に効率的に製造することができる。また、医薬等として有用なプロリンアミド化合物、又はその塩を工業的有利に効率的に製造することができる。 According to the production method of the present invention, a piperazinylpyrazole compound useful as a pharmaceutical intermediate or the like, or a salt thereof can be produced industrially and efficiently. In addition, a proline amide compound or a salt thereof useful as a pharmaceutical or the like can be produced efficiently and industrially advantageously.
　以上、本発明の具体的な態様のいくつかを詳細に説明したが、当業者であれば示された特定の態様には、本発明の教示と利点から実質的に逸脱しない範囲で様々な修正と変更をなすことは可能である。従って、そのような修正および変更も、すべて特許請求の範囲で請求される本発明の精神と範囲内に含まれるものである。 Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed.
　本出願は、特願２０１１－１２３８１９を基礎としており、その内容は本明細書に全て包含されるものである。
  This application is based on patent application No. 2011-123819, the contents of which are incorporated in full herein.

Claims (15)

  1. 一般式（３）：
    　　［化１］
    Figure JPOXMLDOC01-appb-I000001
    （式中、Ｒ１はアルキル又はシクロアルキルを示し、Ｒ２はアミノ基の保護基を示し、Ａｒはアリール又はヘテロアリールを示す）で表される化合物と五硫化リンとの反応によりピラゾール環を形成させることを特徴とする、一般式（２）：
    　　［化２］
    Figure JPOXMLDOC01-appb-I000002
    （式中、各記号は前記と同義である）で表される化合物、又はその塩の製造方法。     General formula (3):
    [Chemical 1]
    Figure JPOXMLDOC01-appb-I000001
    (Wherein R 1 represents alkyl or cycloalkyl, R 2 represents an amino-protecting group, Ar represents aryl or heteroaryl) and a reaction between the compound represented by phosphorus pentasulfide and the pyrazole ring. General formula (2) characterized in that it is formed:
    [Chemical 2]
    Figure JPOXMLDOC01-appb-I000002
    (Wherein each symbol is as defined above), or a method for producing a salt thereof.
  2. 請求項１に記載の製造方法により一般式（２）：
    　　［化３］
    Figure JPOXMLDOC01-appb-I000003
    （式中、各記号は請求項１と同義である）で表される化合物、又はその塩を製造し、当該化合物のアミノ基の保護基Ｒ２を除去して、一般式（６）：
    　　［化４］
    Figure JPOXMLDOC01-appb-I000004
    （式中、各記号は前記と同義である）で表される化合物とした後、該化合物をカルボン酸の塩とすることを特徴とする、
    一般式（６）で表される化合物のカルボン酸塩の製造方法。     According to the production method of claim 1, the general formula (2):
    [Chemical formula 3]
    Figure JPOXMLDOC01-appb-I000003
    (Wherein each symbol is as defined in claim 1) a compound represented by, or salt thereof, by removal of the protecting group R 2 of the amino group of the compound of the general formula (6):
    [Chemical formula 4]
    Figure JPOXMLDOC01-appb-I000004
    (Wherein each symbol has the same meaning as described above), and then the compound is converted to a carboxylic acid salt.
    The manufacturing method of the carboxylate of the compound represented by General formula (6).
  3. 請求項１に記載の製造方法により一般式（２）：
    　　［化５］
    Figure JPOXMLDOC01-appb-I000005
    （式中、各記号は請求項１と同義である）で表される化合物、又はその塩を製造し、これを変換して一般式（１）：
    　　［化６］
    Figure JPOXMLDOC01-appb-I000006
    （式中、各記号は前記と同義である）で表される化合物、又はその塩を得ることからなる、一般式（１）で表される化合物、又はその塩の製造方法。     According to the production method of claim 1, the general formula (2):
    [Chemical formula 5]
    Figure JPOXMLDOC01-appb-I000005
    (Wherein each symbol has the same meaning as in claim 1) or a salt thereof is produced and converted to general formula (1):
    [Chemical 6]
    Figure JPOXMLDOC01-appb-I000006
    (Wherein each symbol has the same meaning as described above), or a method for producing the compound represented by the general formula (1), or a salt thereof.
  4. 請求項２に記載の製造方法により一般式（６）：
    　　［化７］
    Figure JPOXMLDOC01-appb-I000007
    （式中、各記号は請求項２と同義である）で表される化合物のカルボン酸塩を製造し、これを変換して一般式（１）：
    　　［化８］
    Figure JPOXMLDOC01-appb-I000008
    （式中、各記号は前記と同義である）で表される化合物、又はその塩を得ることからなる、一般式（１）で表される化合物、又はその塩の製造方法。     According to the production method of claim 2, the general formula (6):
    [Chemical 7]
    Figure JPOXMLDOC01-appb-I000007
    (Wherein each symbol has the same meaning as in claim 2), a carboxylate of the compound represented by formula (1):
    [Chemical 8]
    Figure JPOXMLDOC01-appb-I000008
    (Wherein each symbol has the same meaning as described above), or a method for producing the compound represented by the general formula (1), or a salt thereof.
  5. 請求項２に記載の製造方法により一般式（６）：
    　　［化９］
    Figure JPOXMLDOC01-appb-I000009
    （式中、各記号は請求項２と同義である）で表される化合物のカルボン酸塩を製造し、当該カルボン酸塩存在下、一般式（９）：
    　　［化１０］
    Figure JPOXMLDOC01-appb-I000010
    （式中、Ｒ３はアミノ基の保護基を示す）で表される化合物を還元的アミノ化反応に付すことにより、一般式（１０）：
    　　［化１１］
    Figure JPOXMLDOC01-appb-I000011
    （式中、各記号は前記と同義である）で表される化合物、又はその塩を製造し、次いで一般式（１０）で表される化合物、又はその塩のアミノ基の保護基Ｒ３を除去することからなる、
    一般式（１）：
    　　［化１２］
    Figure JPOXMLDOC01-appb-I000012
    （式中、各記号は前記と同義である）で表される化合物、又はその塩の製造方法。     According to the production method of claim 2, the general formula (6):
    [Chemical 9]
    Figure JPOXMLDOC01-appb-I000009
    (Wherein each symbol has the same meaning as in claim 2), and in the presence of the carboxylate, general formula (9):
    [Chemical Formula 10]
    Figure JPOXMLDOC01-appb-I000010
    (Wherein R 3 represents a protecting group for an amino group) is subjected to a reductive amination reaction to give a general formula (10):
    [Chemical 11]
    Figure JPOXMLDOC01-appb-I000011
    (Wherein each symbol is as defined above), or a salt thereof, and then the amino group protecting group R 3 of the compound represented by the general formula (10) or a salt thereof is prepared. Consisting of removing,
    General formula (1):
    [Chemical 12]
    Figure JPOXMLDOC01-appb-I000012
    (Wherein each symbol is as defined above), or a method for producing a salt thereof.
  6. 請求項５に記載の製造方法により一般式（１）：
    　　［化１３］
    Figure JPOXMLDOC01-appb-I000013
    （式中、各記号は請求項５と同義である）で表される化合物を製造し、次いで酸による造塩処理に付すことからなる、一般式（１）で表される化合物の塩の製造方法。     According to the production method of claim 5, the general formula (1):
    [Chemical 13]
    Figure JPOXMLDOC01-appb-I000013
    (Wherein each symbol has the same meaning as in claim 5), and then subjecting to a salt formation treatment with an acid, production of a salt of the compound represented by general formula (1) Method.
  7. 下記一般式（６）：
    　　［化１４］
    Figure JPOXMLDOC01-appb-I000014
    （式中、各記号は請求項１と同義である）で表される化合物のカルボン酸塩。     The following general formula (6):
    [Chemical 14]
    Figure JPOXMLDOC01-appb-I000014
    (Wherein each symbol has the same meaning as in claim 1).
  8. 一般式（３）で表される化合物が、
    一般式（４）：
    　　［化１５］
    Figure JPOXMLDOC01-appb-I000015
    （式中、Ｒ２は請求項１と同義である）で表される化合物、又はその塩と、一般式（ａ）：
    　　［化１６］
    　
    Figure JPOXMLDOC01-appb-I000016
    （式中、Ｒ１は請求項１と同義である）で表されるβ－ケトカルボン酸、又はその反応性誘導体とを反応させて、一般式（５）：
    　　［化１７］
    Figure JPOXMLDOC01-appb-I000017
    （式中、各記号は前記と同義である）
    で表される化合物を製造し、次いで該化合物を、式：
    　　［化１８］
    Ａｒ－ＮＨ－ＮＨ２
    （式中、Ａｒは請求項１と同義である）で表されるヒドラジン化合物、又はその塩と反応させることにより製造されたものである、請求項１又は２に記載の製造方法。     The compound represented by the general formula (3) is
    General formula (4):
    [Chemical 15]
    Figure JPOXMLDOC01-appb-I000015
    (Wherein R 2 has the same meaning as in claim 1), or a salt thereof, and general formula (a):
    [Chemical 16]

    Figure JPOXMLDOC01-appb-I000016
    (Wherein R 1 has the same meaning as in claim 1), and a reactive derivative thereof is reacted with general formula (5):
    [Chemical Formula 17]
    Figure JPOXMLDOC01-appb-I000017
    (Wherein each symbol has the same meaning as above)
    And then the compound is represented by the formula:
    [Chemical Formula 18]
    Ar-NH-NH 2
    The manufacturing method of Claim 1 or 2 which is manufactured by making it react with the hydrazine compound represented by (In formula, Ar is synonymous with Claim 1), or its salt.
  9. 一般式（９）で表される化合物が、
    一般式（８）：
    　　［化１９］
    Figure JPOXMLDOC01-appb-I000018
    （式中、Ｒ３は請求項５と同義である）で表される化合物、又はその塩と、チアゾリジンとを縮合させることにより製造されたものである、請求項５に記載の製造方法。     The compound represented by the general formula (9) is
    General formula (8):
    [Chemical formula 19]
    Figure JPOXMLDOC01-appb-I000018
    (Wherein, R 3 is a is defined in claim 5) in which a compound represented by or a salt thereof, prepared by condensation of thiazolidine process according to claim 5.
  10. Ｒ１がメチルであり、Ｒ２が置換又は無置換のアルコキシカルボニルであり、Ａｒがフェニルである請求項１又は２に記載の製造方法。 The production method according to claim 1 or 2, wherein R 1 is methyl, R 2 is substituted or unsubstituted alkoxycarbonyl, and Ar is phenyl.
  11. Ｒ１がメチルであり、Ｒ３が置換又は無置換のアルコキシカルボニルであり、Ａｒがフェニルである請求項５又は６に記載の製造方法。 The production method according to claim 5 or 6, wherein R 1 is methyl, R 3 is substituted or unsubstituted alkoxycarbonyl, and Ar is phenyl.
  12. 一般式（１）で表される化合物、又はその塩が、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの塩である請求項３～６のいずれか１項に記載の製造方法。 The compound represented by the general formula (1) or a salt thereof is 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 The production method according to any one of claims 3 to 6, which is a salt of -yl] pyrrolidin-2-ylcarbonyl} thiazolidine.
  13. 一般式（１）で表される化合物、又はその塩が、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの２．５臭化水素酸塩である請求項３～６のいずれか１項に記載の製造方法。 The compound represented by the general formula (1) or a salt thereof is 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 The production method according to any one of claims 3 to 6, which is 2.5 hydrobromide of -yl] pyrrolidin-2-ylcarbonyl} thiazolidine.
  14. 一般式（１）で表される化合物、又はその塩が、３－｛（２Ｓ，４Ｓ）－４－［４－（３－メチル－１－フェニル－１Ｈ－ピラゾール－５－イル）ピペラジン－１－イル］ピロリジン－２－イルカルボニル｝チアゾリジンの２．５臭化水素酸塩・水和物である請求項３～６のいずれか１項に記載の製造方法。 The compound represented by the general formula (1) or a salt thereof is 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 The production method according to any one of claims 3 to 6, which is 2.5 hydrobromide salt / hydrate of -yl] pyrrolidin-2-ylcarbonyl} thiazolidine.
  15. Ｒ１がメチルであり、Ａｒがフェニルであり、且つカルボン酸が酢酸である請求項７記載の化合物。 The compound according to claim 7, wherein R 1 is methyl, Ar is phenyl, and the carboxylic acid is acetic acid.
PCT/JP2012/064075 2011-06-01 2012-05-31 Method for manufacturing pyrazole derivative WO2012165547A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2013518161A JP5863789B2 (en) 2011-06-01 2012-05-31 Method for producing pyrazole derivative
CN201280027128.6A CN103649055B (en) 2011-06-01 2012-05-31 For the preparation of the method for pyrazole derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-123819 2011-06-01
JP2011123819 2011-06-01

Publications (1)

Publication Number Publication Date
WO2012165547A1 true WO2012165547A1 (en) 2012-12-06

Family

ID=47259399

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/064075 WO2012165547A1 (en) 2011-06-01 2012-05-31 Method for manufacturing pyrazole derivative

Country Status (3)

Country Link
JP (1) JP5863789B2 (en)
CN (1) CN103649055B (en)
WO (1) WO2012165547A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275010A (en) * 2013-05-30 2013-09-04 上海皓元生物医药科技有限公司 Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazolyl-5-yl)piperazine
CN104177295A (en) * 2013-05-24 2014-12-03 南京华威医药科技开发有限公司 Teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method
WO2015019238A1 (en) * 2013-08-06 2015-02-12 Ranbaxy Laboratories Limited Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one
JP2019147763A (en) * 2018-02-27 2019-09-05 田辺三菱製薬株式会社 Manufacturing method of proline amide compound

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294673B (en) * 2014-06-18 2018-04-13 四川科伦药物研究院有限公司 A kind of hydrobromic acid replaces the synthetic method of Ge Lieting
CN105085510B (en) * 2015-09-11 2018-03-02 沧州那瑞化学科技有限公司 A kind of preparation method of the carboxylic acid tert-butyl ester of (S) 4 oxo 2 (carbonyl of thiazolidine 3) pyrrolidines 1
CN108727364A (en) * 2017-04-18 2018-11-02 乳源东阳光药业有限公司 A kind of hydrobromic acid is unformed and preparation method thereof for Ge Lieting
WO2019205021A1 (en) * 2018-04-25 2019-10-31 乳源东阳光药业有限公司 Amorphous teneligliptin hydrobromide and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014271A1 (en) * 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Proline derivatives and use thereof as drugs
WO2003024942A1 (en) * 2001-09-14 2003-03-27 Mitsubishi Pharma Corporation Thiazolidine derivative and medicinal use thereof
WO2006088129A1 (en) * 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
JP2012102092A (en) * 2010-10-15 2012-05-31 Dainippon Sumitomo Pharma Co Ltd Method for producing 5-di-substituted aminopyrazol-3-carboxylic acid ester

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1227235C (en) * 1999-12-09 2005-11-16 辛根塔参与股份公司 Pyrazolecarboxamide and pyrazolethioamide as fungioide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014271A1 (en) * 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Proline derivatives and use thereof as drugs
WO2003024942A1 (en) * 2001-09-14 2003-03-27 Mitsubishi Pharma Corporation Thiazolidine derivative and medicinal use thereof
WO2006088129A1 (en) * 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
JP2012102092A (en) * 2010-10-15 2012-05-31 Dainippon Sumitomo Pharma Co Ltd Method for producing 5-di-substituted aminopyrazol-3-carboxylic acid ester

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOUILLON JEAN-PHILIPPE ET AL.: "Trifluoromethylated Heterocycles from Beta-Trifluoroacetyl-Lactams and -Benzolactams", TETRAHEDRON LETTERS, vol. 34, no. 32, 1993, pages 5075 - 5078 *
DIMITROWA K. ET AL.: "Biphenyl- and terphenylanaloge 1,3,4-Thiadiazole", J.PRAKT. CHEM., vol. 322, no. 6, 1980, pages 933 - 944 *
DODD DHARMPAL S. ET AL.: "One-pot synthesis of 5-(substituted-amino)pyrazoles", TETRAHEDRON LETTERS, vol. 45, no. 22, 2004, pages 4265 - 4267 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177295A (en) * 2013-05-24 2014-12-03 南京华威医药科技开发有限公司 Teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method
CN104177295B (en) * 2013-05-24 2016-08-17 南京华威医药科技开发有限公司 Preparation method for Ge Lieting key intermediate 1-(3-methyl isophthalic acid-phenyl-5-pyrazolyl) piperazine
CN103275010A (en) * 2013-05-30 2013-09-04 上海皓元生物医药科技有限公司 Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazolyl-5-yl)piperazine
WO2015019238A1 (en) * 2013-08-06 2015-02-12 Ranbaxy Laboratories Limited Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one
JP2019147763A (en) * 2018-02-27 2019-09-05 田辺三菱製薬株式会社 Manufacturing method of proline amide compound

Also Published As

Publication number Publication date
CN103649055B (en) 2016-04-13
JPWO2012165547A1 (en) 2015-02-23
CN103649055A (en) 2014-03-19
JP5863789B2 (en) 2016-02-17

Similar Documents

Publication Publication Date Title
JP5863789B2 (en) Method for producing pyrazole derivative
AU2015414743B2 (en) Process for the preparation of kinase inhibitors and intermediates thereof
US20170204065A1 (en) Process for the preparation of kinase inhibitors and intermediates thereof
EP2346850A1 (en) A method for the preparation of dabigatran and its intermediates
JP6985179B2 (en) Method for producing proline amide compound
EP2608791B1 (en) A process for the preparation of imatinib base
CA2787427C (en) Process for the preparation of 2-(cyclohexylmethyl)-n-{2-[(2s)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
JP7373241B2 (en) Method for producing pyrimidinyl bipyridine compounds and intermediates therefor
AU775413B2 (en) Process for preparing (S-(R*,S*)) -beta -(((1-(1-oxo-3- (4-piperidinyl) propyl) -3-piperidinyl) carbonyl) amino) -3- pyridinepropanoic acid and derivatives
HU231050B1 (en) Process for the preparation of a pharmaceutical active ingredient
JPWO2006123767A1 (en) Preparation of asymmetric tetrasubstituted carbon atom-containing compounds
JP7252978B2 (en) Process for preparing 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid
JP7279134B2 (en) Method for producing prolinamide compound
JP2023100917A (en) Method for producing prolinamide compound
JP4768109B2 (en) Process for producing 1H-2-substituted-4 (5) -amino-5 (4) -carboxamide-imidazole
WO2019098551A1 (en) Method for preparing intermediate compound for synthesizing pharmaceutical
WO2022180416A1 (en) Process for obtaining avapritinib and its intermediates
JP5080050B2 (en) Method for producing optically active piperazine compound
EP1324983A1 (en) Process for preparing distamycin derivatives
WO2002008184A1 (en) Process for preparing distamycin derivatives
KR20110048337A (en) 6-Amino-N-hydroxyhexanamide compounds having inhibitory activity against histone deacetylase, and method for preparation thereof

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: 12792664

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013518161

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: 12792664

Country of ref document: EP

Kind code of ref document: A1