Method for producing 4-oxopyrrolidine-3-carboxamide derivatives

Abstract

To provide a novel method for producing pyrrolidine derivatives in fewer steps.SOLUTION: A method for producing 4-oxopyrrolidine-3-carboxamide derivatives represented by formula (1) includes a step A of obtaining a 4-oxopyrrolidine-3-carboxamide derivative represented by formula (1) by treating a compound represented by formula (2) and a compound represented by formula (3) by at least one base selected from alkali metal alkoxides, alkali metal hydrides and alkali metal amides in a solvent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing pyrrolidine derivatives, which can be used as intermediates in the production of antibacterial agents that are effective even against resistant bacteria. [Background technology]

[0002] Patent Document 1 discloses a method for producing a 4-oxopyrrolidine-3-carboxylic acid amide derivative, which is an intermediate for producing an optically active substance of (3R,4S)-3-alkylaminomethyl-4-fluoropyrrolidine or its enantiomer, which is useful as an intermediate for producing pharmaceuticals. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent No. 5844739 Summary of the Invention [Problem to be solved by the invention]

[0004] The production method disclosed in Patent Document 1 requires many steps and poses problems for industrial production. Therefore, an object of the present invention is to provide a novel method for producing a pyrrolidine derivative with fewer steps. [Means for solving the problem]

[0005] The present inventors have conducted extensive research into the above-mentioned problems and have found that pyrrolidine derivatives can be efficiently synthesized by successively carrying out an aza-Michael reaction and a Dieckmann cyclization, thereby arriving at the present invention.

[0006] The gist of the present invention is as follows. [1] Formula (1) [ka] [In formula (1), PG1 represents a protecting group for an amino group, and R 1 represents a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group, Process A: Formula (2) [ka] [In formula (2), PG 1 represents the above, and R 2 represents a C1 to C6 alkyl group.] and a compound represented by formula (3) [ka] [In formula (3), R 1 represents the same as above.] in a solvent with at least one base selected from alkali metal alkoxides, alkali metal hydrides and alkali metal amides to obtain a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by formula (1). [2] Process C: Formula (4) [ka] [In formula (4), R 2 represents a C1-C6 alkyl group. or a salt thereof, by protecting the amino group with a protecting group to obtain a compound represented by formula (2), Process B: Formula (5) [ka] [wherein X represents a leaving group] and a compound represented by formula (6) [ka] [In formula (6), R 1represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, to obtain a compound represented by formula (3), The production method according to [1], wherein the compound represented by formula (2) obtained in step C and the compound represented by formula (3) obtained in step B are subjected to step A. [3] The production method according to [1] or [2], wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide. [4] The production method according to [1] or [2], wherein in step A, the base is an alkali metal hydride. [5] The production method according to [1] or [2], wherein in step A, the base is an alkali metal amide. [6] The production method according to any one of [1] to [5], wherein in step A, the solvent is a cyclic ether. [7] The production method according to any one of [1] to [6], wherein in step A, the reaction temperature is 40 to 50°C. [8] PG 1 is an aralkoxycarbonyl group, and R 1 The method according to any one of [1] to [7], wherein the functional group represented by the formula: is a cyclopropyl group. [9] The production method according to any one of [1] to [3], wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide, and the solvent is a cyclic ether.

[10] The production method according to any one of [1] to [3], wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide, the solvent is a cyclic ether, and the reaction temperature is 40 to 50°C.

[11] In step A, the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide, the solvent is a cyclic ether, the reaction temperature is 40 to 50°C, and PG 1 is an aralkoxycarbonyl group, and R 1 The method according to any one of [1] to [3], wherein the functional group represented by the formula: is a cyclopropyl group. [Effects of the Invention]

[0007] According to the present invention, the pyrrolidine derivative represented by formula (1) can be obtained in fewer steps. DETAILED DESCRIPTION OF THE INVENTION

[0008] One embodiment of the present invention will be described in detail below.

[0009] The production method of this embodiment is shown in Scheme 1. TIFF2025114857000007.tif81162

[0010] In formulas (1) to (6), PG 1 represents a protecting group for an amino group. 1 represents a hydrogen atom, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group. 2 represents a C1 to C6 alkyl group, and is preferably a C1 to C4 alkyl group. In the formulas (1) to (6), X represents a leaving group, and is preferably a halogen atom. In this specification, "Cn to Cm" means a carbon number of n to m, where n and m are independent natural numbers, and m is a larger number than n. For example, "C1 to C6" means a carbon number of 1 to 6.

[0011] The "amino-protecting group" referred to in the present specification is not particularly limited as long as it is a protecting group commonly known as a protecting group for an amino group, and examples thereof include aralkyl groups such as benzyl and p-methoxybenzyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, and tert-butyloxycarbonyl; aralkoxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl; 1-(alkoxy)alkyl groups such as methoxymethyl, methoxyethoxymethyl, 1-(ethoxy)ethyl, and methoxyisopropyl; and acyl groups such as acetyl, trifluoroacetyl, propionyl, butyryl, pivaloyl, benzoyl, and methylbenzoyl.

[0012] Among these, the protecting group for the amino group is preferably an aralkoxycarbonyl group or an alkoxycarbonyl group, more preferably an aralkoxycarbonyl group, and even more preferably a benzyloxycarbonyl group.

[0013] The term "optionally substituted C1-C6 alkyl group" used herein means a C1-C6 alkyl group having 1 to 5 identical or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an optionally substituted aryloxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a C4-C9 cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an optionally substituted arylsulfonylamino group, or an unsubstituted C1-C6 alkyl group.

[0014] The above-mentioned "C1 to C6 alkyl group" means a linear or branched alkyl group. Examples of the C1 to C6 alkyl group include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropan-1-yl group, a tert-butyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a butyl group, and a hexyl group. Among these, an ethyl group or a tert-butyl group is preferred as the C1 to C6 alkyl group.

[0015] The term "optionally substituted C3-C8 cycloalkyl group" used herein means a C3-C8 cycloalkyl group having 1 to 5 identical or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an optionally substituted aryloxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a C4-C9 cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an optionally substituted arylsulfonylamino group, or an unsubstituted C3-C8 cycloalkyl group.

[0016] The above-mentioned "C3 to C8 cycloalkyl group" means an alkyl group having a cycloalkyl ring. Examples of C3 to C8 cycloalkyl groups include cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. The C3 to C8 cycloalkyl group is preferably a cyclopropyl group.

[0017] Examples of the above-mentioned "C1 to C6 alkoxy group" include a methoxy group, an ethoxy group, a butoxy group, and a hexyloxy group.

[0018] The above-mentioned "optionally substituted aryloxy group" means an aryloxy group having 1 to 5 identical or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, and a C1 to C6 alkylthio group, or an unsubstituted aryloxy group.

[0019] Examples of the above-mentioned "aryloxy group" include a phenoxy group and a naphthyloxy group.

[0020] Examples of the above-mentioned "C1 to C6 alkylcarbonyl group" include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a hexanoyl group.

[0021] Examples of the above-mentioned "C1 to C6 alkoxycarbonyl group" include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.

[0022] Examples of the above-mentioned "C1 to C6 alkylthio group" include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.

[0023] The above-mentioned "mono- or di-substituted C1-C6 alkylamino group" means a C1-C6 alkylamino group having 1 to 2 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, an amino group, a C4-C9 cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkylsulfonylamino group, and an optionally substituted arylsulfonylamino group.

[0024] Examples of the above-mentioned "C1 to C6 alkylamino group" include a methylamino group, an ethylamino group, an n-propylamino group, an n-butylamino group, a sec-butylamino group, an n-pentylamino group, and an n-hexylamino group.

[0025] The above-mentioned "C4 to C9 cyclic amino group optionally containing 1 to 3 heteroatoms" refers to a cyclic amino group containing one to three nitrogen atoms in the ring, and optionally containing oxygen atoms and sulfur atoms in the ring in such a range that the total number of oxygen atoms and sulfur atoms, together with the nitrogen atoms, is 3 or less. Examples of C4 to C9 cyclic amino groups include aziridyl, pyrrolidyl, piperidyl, morpholyl, oxazolyl, azabicycloheptyl, and azabicyclooctyl groups.

[0026] Examples of the above-mentioned "C1 to C6 alkylcarbonylamino group" include an acetylamino group, a propionylamino group, and a butyrylamino group.

[0027] Examples of the above-mentioned "C1 to C6 alkoxycarbonylamino group" include a methoxycarbonylamino group, an ethoxycarbonylamino group, a tert-butoxycarbonylamino group, and a hexyloxycarbonylamino group.

[0028] Examples of the above-mentioned "C1 to C6 alkylsulfonylamino group" include a methylsulfonylamino group and an ethylsulfonylamino group.

[0029] The above-mentioned "optionally substituted arylsulfonylamino group" means an arylsulfonylamino group having 1 to 5 identical or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, and a C1 to C6 alkylthio group, or an unsubstituted arylsulfonylamino group.

[0030] Examples of the above-mentioned "arylsulfonylamino group" include a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, and a naphthylsulfonylamino group.

[0031] In this specification, the term "C1-C4 alkyl group" refers to a straight-chain or branched alkyl group. Examples of the "C1-C4 alkyl group" include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropan-1-yl group, a tert-butyl group, and a butyl group. Among these, the C1-C4 alkyl group is preferably a methyl group or an ethyl group, and more preferably an ethyl group.

[0032] As used herein, the term "alkali metal" includes, for example, lithium, sodium, and potassium.

[0033] Examples of the "leaving group" referred to in this specification include a halogen atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, etc. Among these, a halogen atom is preferred as the leaving group.

[0034] The "halogen atom" referred to in this specification includes an iodine atom, a bromine atom, a chlorine atom, and a fluorine atom. Among these, a chlorine atom is preferred as the halogen atom.

[0035] Examples of the "cyclic ethers" referred to herein include 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydropyran, etc. Among these, tetrahydrofuran is preferred as the cyclic ether.

[0036] The reaction in step C is a step in which a protecting group is introduced into the compound represented by formula (4) to obtain the compound represented by formula (2). The type and introduction of the protecting group used in the reaction of step C can be determined, for example, by the method described in "Greene's Protective Groups in Organic Synthesis," edited by Theodra W. Green & Peter GM Wuts, fourth edition, Wiley-Interscience, 2006.

[0037] Among these, protection with a benzyloxycarbonyl group is preferred, and in this case, the compound can be produced using benzyl chloroformate, a base, and a solvent. The amount of benzyl chloroformate relative to the compound represented by formula (4) is not particularly limited, but typically 1 to 5 equivalents is preferred, more preferably 1 to 2 equivalents, and most preferably 1.05 equivalents. Any base that does not inhibit the reaction, such as sodium bicarbonate, can be used. Typically, 1 to 5 equivalents is preferred, more preferably 2 to 3 equivalents, and most preferably 2.2 equivalents. Examples of solvents include esters such as ethyl acetate, butyl acetate, and isopropyl acetate; ethers such as 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tert-butyl methyl ether (TBME), dimethoxyethane (DME), and diglyme; water; and mixtures thereof. The reaction temperature is usually preferably in the range of -20°C to the boiling point of the solvent used, more preferably in the range of 0°C to the boiling point of the solvent, and even more preferably 30 to 50°C.

[0038] In step B, a compound represented by formula (5) and an amine compound represented by formula (6) are condensed in the presence of a base to obtain a compound represented by formula (3). The condensation reaction can be carried out under commonly used condensation conditions.

[0039] The amount of the amine represented by formula (6) used is not particularly limited, but is usually preferably 1 to 3 equivalents, more preferably 1.0 to 1.5 equivalents, relative to the compound represented by formula (5).

[0040] Any base may be used as long as it does not inhibit the reaction, and examples thereof include organic bases such as triethylamine, trimethylamine, tripropylamine, diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, N-methylpyrrolidine, and 4-dimethylaminopyridine.

[0041] Among these, N-methylmorpholine, N-methylpyrrolidine or triethylamine is preferred as the base in step B, and triethylamine is more preferred.

[0042] It is usually preferable to use a solvent for the reaction in step B. Examples of the solvent include esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene, and xylene, hydrocarbons such as hexane, heptane, and cyclohexane, cyclic ethers such as 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and tetrahydropyran, ethers such as tert-butyl methyl ether (TBME), dimethoxyethane (DME), and diglyme, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and N-methylpyrrolidone, and mixtures thereof.

[0043] Among these, preferred solvents for use in step B include esters such as ethyl acetate and butyl acetate, tetrahydrofuran, a mixed solvent of tetrahydrofuran and N,N-dimethylformamide, or a mixed solvent of 2-methyltetrahydrofuran and N,N-dimethylformamide, and more preferred is ethyl acetate.

[0044] The reaction temperature in step B is usually preferably in the range of -20°C to the boiling point of the solvent used, more preferably in the range of 0°C to the boiling point of the solvent, and even more preferably 0 to 10°C.

[0045] The reaction in step A is a step in which a compound represented by formula (2) and a compound represented by formula (3) are treated with at least one base selected from alkali metal amides, alkali metal hydrides, and alkali metal alkoxides to obtain a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by formula (1).

[0046] "Alkali metal amide" refers to a compound in which the hydrogen atoms of amines are replaced with metal atoms. Examples of alkali metal amides include lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium tetramethylpiperidide, lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide (NaHMDS), and potassium hexamethyldisilazide (KHMDS). Among these, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide is preferred as the alkali metal amide, and potassium hexamethyldisilazide is more preferred.

[0047] "Alkali metal alkoxide" is a compound in which the hydroxyl group of an alcohol is substituted with an alkali metal. Examples of alkali metal alkoxides include sodium methoxide (NaOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), lithium tert-butoxide (tBuOLi), sodium tert-pentoxide (C2H5C(CH3)2ONa), and potassium tert-pentoxide (C2H5C(CH3)2OK).

[0048] Among these, potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide is preferred as the alkali metal alkoxide, and potassium tert-butoxide is more preferred.

[0049] Examples of the "alkali metal hydride" include lithium hydride, sodium hydride, and potassium hydride.

[0050] The amount of base used is not particularly limited, but is usually preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents, relative to the compound represented by formula (2).

[0051] The reaction temperature in step A is usually preferably in the range of -20 to 100°C, more preferably 30 to 65°C, and even more preferably 40 to 50°C.

[0052] It is usually preferable to use a solvent for the reaction in step A. Examples of the solvent include alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, ethylene glycol, and diethylene glycol, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene, and xylene, hydrocarbons such as hexane, heptane, and cyclohexane, cyclic ethers such as 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran, ethers such as tert-butyl methyl ether, dimethoxyethane, and diglyme, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and N-methylpyrrolidone, and mixtures thereof.

[0053] Among these, the solvent preferably used in step A is N,N-dimethylformamide, tetrahydrofuran or toluene, more preferably tetrahydrofuran.

[0054] As described above, according to this embodiment, a pyrrolidine derivative can be obtained in fewer steps. Furthermore, the method of the present embodiment has a higher yield, does not require the use of expensive reagents, and produces fewer by-products in the reaction, compared to the method described in Patent Document 1. Therefore, the method of the present embodiment is more suitable for industrial production of the pyrrolidine derivative represented by formula (1).

[0055] The 4-oxopyrrolidine-3-carboxylic acid amide derivative obtained by the method of the present embodiment can be converted into an optically active form of (3R,4S)-3-alkylaminomethyl-4-fluoropyrrolidine or its enantiomer, which is useful as an intermediate for the production of pharmaceuticals, by known methods (Japanese Patent No. 5844739 and International Publication No. 2007 / 102567).

[0056] Therefore, this embodiment provides a method that is more suitable for industrial production of an optically active (3R,4S)-3-alkylaminomethyl-4-fluoropyrrolidine or its enantiomer. [Example]

[0057] The present invention will be described in more detail below by way of examples, but the scope of the present invention is not limited to these examples.

[0058] In the Examples, Reference Examples, and Comparative Examples, the term "double volume" refers to the volume of solvent (mL) relative to the mass (g) of the substrate.

[0059] Example 1 [Process C] Preparation of N-Carbobenzoxyglycine Methyl Ester Glycine ethyl ester hydrochloride (50.0 g, 358 mmol) was dissolved in water (200 mL), and sodium bicarbonate (66.2 g, 376 mmol) was slowly added at room temperature, followed by ethyl acetate (200 mL). Benzyl chloroformate (53.0 mL, 376 mmol) was added dropwise at room temperature, and the mixture was heated and stirred at an internal temperature of 45 to 50°C for 2 hours.

[0060] The reaction mixture was cooled to room temperature, and the organic layer was separated. A 10% sodium chloride solution (200 mL) was added to the organic layer, and the organic layer was separated and concentrated under reduced pressure. Ethyl acetate (150 mL) was added to the concentrated residue, and the solution was dissolved. The mixture was then concentrated under reduced pressure to give 91.5 g of the title compound as a colorless oil.

[0061] [Process B] Production of N-cyclopropylacrylamide Cyclopropylamine (39.9 mL, 473 mmol) and triethylamine (71.9 mL, 516 mmol) were added to ethyl acetate (300 mL). After cooling, a solution of acryloyl chloride (34.7 mL, 430 mmol) in ethyl acetate (75.0 mL) was added dropwise at an internal temperature of 10°C or below, and the mixture was stirred at an internal temperature of 10°C or below for 1 hour.

[0062] The insoluble matter was filtered off and washed with ethyl acetate (200 mL), and then the filtrate and washings were concentrated under reduced pressure to give 52.6 g of the title compound as a yellow oil.

[0063] [Process A] Preparation of benzyl 3-(cyclopropylcarbamoyl)-4-oxopyrrolidine-1-carboxylate N-Carbobenzoxyglycine methyl ester (91.5 g) synthesized in step C and N-cyclopropylacrylamide (52.6 g) synthesized in step B were added to tetrahydrofuran (200 mL). The mixture was heated, and a tetrahydrofuran solution of potassium tert-butoxide (1.0 mol / L, 394 mL, 394 mmol) was added dropwise at an internal temperature of 45°C to 50°C, followed by stirring at an internal temperature of 45°C to 50°C for 2.5 hours.

[0064] After cooling the reaction mixture, water (350 mL) and toluene (350 mL) were added dropwise at an internal temperature of 0°C to 10°C, followed by stirring for 30 minutes at an internal temperature of 0°C to 10°C. The aqueous layer was separated at an internal temperature of 0°C to 10°C, and 2-propanol (250 mL) was added dropwise to the aqueous layer at an internal temperature of 0°C to 10°C. 1 mol / L hydrochloric acid (350 mL) was added dropwise at an internal temperature of 0°C to 10°C, and the addition was discontinued when the solution became cloudy. After confirming crystallization, the mixture was stirred for 30 minutes at an internal temperature of 0°C to 10°C, and the remaining 1 mol / L hydrochloric acid and water (250 mL) were added dropwise at an internal temperature of 0°C to 10°C. The mixture was heated and stirred for 30 minutes at an internal temperature of 30°C to 35°C, then cooled and stirred for 30 minutes at an internal temperature of 0°C to 10°C. The precipitated crystals were collected by filtration and washed with water (500 mL) to give 165 g of wet crystals of the title compound.

[0065] The wet crude crystals of the title compound were added to a mixture of methanol (300 mL) and water (1.10 L), then heated and stirred at an internal temperature of 45 to 50°C for 1 hour. After cooling and stirring at an internal temperature of 0 to 10°C for 30 minutes, the crystals were collected by filtration and washed with water (500 mL). After drying under reduced pressure at 50°C, 81.0 g (74.8% yield) of the title compound was obtained as a white powder. EI-MS m / z: 413(M + ). 1 H-NMR(400MHz,CDCl3)δ:0.50-0.59(2H,m),0.75-0.86(2H,m),2.70-2.77(1H,m),3.41(1H,brs),3.89(1H,d,J =19.9Hz),4.04(1H,d,J=19.5Hz),4.17-4.27(2H,m),5.15-5.18(2H,m),6.62-6.69(1H,m),7.31-7.38(5H,m).

[0066] Example 2 Preparation of benzyl 3-(cyclopropylcarbamoyl)-4-oxopyrrolidine-1-carboxylate N-Carbobenzoxyglycine methyl ester (93.9 g) synthesized in Step C of Example 1 and N-cyclopropylacrylamide (52.5 g) synthesized in Step B of Example 1 were added to tetrahydrofuran (300 mL). The mixture was heated, and a tetrahydrofuran solution of potassium tert-butoxide (21%, 211 g) was added dropwise at an internal temperature of 45°C to 50°C, followed by stirring at an internal temperature of 45°C to 50°C for 2.5 hours.

[0067] After cooling the reaction mixture, water (350 mL) and toluene (350 mL) were added dropwise at an internal temperature of 0°C to 10°C, followed by stirring for 30 minutes at an internal temperature of 0°C to 10°C. The aqueous layer was separated at an internal temperature of 0°C to 10°C, and 2-propanol (250 mL) was added dropwise to the aqueous layer at an internal temperature of 0°C to 10°C. 1 mol / L hydrochloric acid (350 mL) was added dropwise at an internal temperature of 0°C to 10°C, and the addition was discontinued when the solution became cloudy. After confirming crystallization, the mixture was stirred for 30 minutes at an internal temperature of 0°C to 10°C, and the remaining 1 mol / L hydrochloric acid and water (250 mL) were added dropwise at an internal temperature of 0°C to 10°C. The mixture was heated and stirred for 30 minutes at an internal temperature of 30°C to 35°C, then cooled and stirred for 30 minutes at an internal temperature of 0°C to 10°C. The precipitated crystals were collected by filtration and washed with water (500 mL) to give 154 g of wet crystals of the title compound.

[0068] The wet crude crystals of the title compound were added to methanol (300 mL) and dissolved by heating. Water (1.10 L) was added dropwise at an internal temperature of 45-50°C. When the solution became cloudy, the addition was discontinued. After confirming crystallization, the mixture was stirred at an internal temperature of 45-50°C for 30 minutes. The remaining water was added dropwise at an internal temperature of 45-50°C, and the mixture was stirred at an internal temperature of 45-50°C for 30 minutes. The mixture was cooled and stirred at an internal temperature of 0-10°C for 30 minutes. The crystals were then filtered and washed with water (500 mL). The mixture was dried under reduced pressure at 50°C to obtain 81.0 g (71.5% yield) of the title compound as a white powder. [Industrial Applicability]

[0069] According to this embodiment, it is possible to provide a pyrrolidine derivative in a short number of steps and in a high yield, and this is industrially useful.

Claims

[Request 1] Formula (1) 【Chemical 1】 [In formula (1), PG １ represents a protecting group for an amino group, and R １ represents a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group, Project A: Formula (2) 【Chemistry 2】 [In formula (2), PG １ represents the same as above, and R ２ represents a C1 to C6 alkyl group.] and a compound represented by formula (3) 【Chemistry 3】 [In formula (3), R １ represents the same as above.] in a solvent with at least one base selected from alkali metal alkoxides, alkali metal hydrides and alkali metal amides to obtain a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by formula (1).

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