JP2008127308A - Method for producing optically active 5-oxopyrrolidine-3-carboxylic acid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial method for producing an optically active 5-oxopyrrolidine-3-carboxylic acid derivative having high optical purity in high efficiency. <P>SOLUTION: The method for producing an optically active 5-oxopyrrolidine-3-carboxylic acid derivative expressed by general formula (3) (wherein R<SP>5</SP>is an alkyl group or the like; and the carbon atom labeled with * means an asymmetric center) comprises the optical resolution of a racemic 5-oxopyrrolidine-3-carboxylic acid derivative in an organic solvent by using an optically active phenylalaninamide derivative having a specific structure as an optical resolution agent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention is a process for producing optically active 5-oxopyrrolidine-3-carboxylic acid derivatives useful as pharmaceuticals or intermediates thereof.

There have been many reports on methods for synthesizing racemic 5-oxopyrrolidine-3-carboxylic acid derivatives (Patent Documents 1 and 2), and various compounds have been synthesized by converting the derivatives. However, although this 5-oxopyrrolidine-3-carboxylic acid derivative is a useful intermediate, there are very few methods for easily producing the optically active substance, for example, racemic 5-oxopyrrolidine-3-carboxylic acid derivative. Only an asymmetric hydrolysis reaction in which an enzyme is allowed to act on is known (Non-patent Document 1), and a production example in which optical resolution is performed using a commercially available or chemically synthesized optical resolution agent has been reported. Absent. In the above-mentioned known examples, a racemic 5-oxopyrrolidine-3-carboxylic acid derivative is asymmetrically hydrolyzed with an enzyme to separate an optically active substance with high optical purity, but the reaction solution is racemic 5 as a raw material. The concentration of -oxopyrrolidine-3-carboxylic acid is very dilute at 1.5% by weight, the productivity is low and it is difficult to carry out industrial production. In other words, the activity of the enzyme is usually greatly affected by the reaction conditions, and the activity decreases as the concentration is increased. Therefore, it is difficult to carry out the reaction at a concentration that can be put to practical use.
Japanese Patent Laid-Open No. 04-112868 Japanese Patent Publication No. 07-054991 Tetrahedron asymmetry. , 12, 3241, (2001)

  Therefore, an industrial production method capable of efficiently producing an optically active 5-oxopyrrolidine-3-carboxylic acid derivative with high optical purity has been desired.

  As a result of intensive studies aimed at solving the problems, the present inventors have completed the present invention.

That is, the present invention provides “general formula (1)

(Where R ¹ represents i) a hydrogen atom, ii) a halogen atom, iii) a nitro group, iv) a cyano group, v) an alkyl group having 1 to 4 carbon atoms, or vi) an alkoxy group having 1 to 4 carbon atoms. R ² and R ³ may be the same or different, i) a hydrogen atom, ii) an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, iii) no aromatic ring An aralkyl group substituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a halogen atom, a nitro group, or a cyano group is shown. In addition, an optically active phenylalaninamide derivative represented by the formula (2) is used as an optical resolution agent.

Wherein R ⁴ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group. The racemic 5-oxopyrrolidine-3-carboxylic acid derivative represented by the formula is optically resolved in an organic solvent. General formula (3)

(Wherein R ⁵ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group. The carbon atom marked with * means an asymmetric center.) “Method for producing oxopyrrolidine-3-carboxylic acid derivative”.

  According to the present invention, an optically active 5-oxopyrrolidine-3-carboxylic acid derivative with high optical purity can be obtained efficiently.

  The racemic 5-oxopyrrolidine-3-carboxylic acid derivative used as a starting material in the present invention is a compound represented by the general formula (4) or (5)

Is a mixture of compounds represented by Here, R ⁴ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group, preferably hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms, Preferred examples include aralkyl groups having 7 to 12 carbon atoms. Further, the optically active 5-oxopyrrolidine-3-carboxylic acid derivative means an optically active substance in which either one is in excess of 80% or more, that is, a mixture having an optical purity of 80% ee or more. Specific examples of 5-oxopyrrolidine-3-carboxylic acid derivatives include 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, 5-oxopyrrolidine-3-carboxylic acid, 1-methyl-5-oxopyrrolidine-3- Carboxylic acid, 1-phenyl-5-oxopyrrolidine-3-carboxylic acid, 1-p-chlorophenyl-5-oxopyrrolidine-3-carboxylic acid and the like can be preferably used. Acid is particularly preferred. Here, the starting 5-oxopyrrolidine-3-carboxylic acid derivative can be produced by any method, but can be produced, for example, according to the following reaction formula (see JP-A-4-112868).

(Here, R ⁴ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group.)
That is, a racemic 5-oxopyrrolidine-3-carboxylic acid derivative can be obtained by heating and refluxing a carboxylic acid such as itaconic acid and an amine such as benzylamine in a solvent.
The optical resolution agent used in the present invention is represented by the general formula (5).

(Where R ¹ represents i) a hydrogen atom, ii) a halogen atom, iii) a nitro group, iv) a cyano group, v) an alkyl group having 1 to 4 carbon atoms, or vi) an alkoxy group having 1 to 4 carbon atoms. R ² and R ³ may be the same or different, i) a hydrogen atom, ii) an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, iii) no aromatic ring An aralkyl group substituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a halogen atom, a nitro group, or a cyano group is shown. In addition, the carbon atom with * means an asymmetric center) is a D or L optically active phenylalaninamide derivative represented by: one of which is an optically active substance in excess of 95% or more, The optical purity is preferably 95% ee. Or more, more preferably 98% ee. Further, whether to use the L form or the D form may be selected according to the conformation of the target optically active 5-oxo-3-pyrrolidinecarboxylic acid derivative. For example, optically active phenylalanine amide, optically active phenylalanine methylamide, optically active phenylalanine dimethylamide, optically active phenylalanine ethylamide, optically active phenylalanine diethylamide, optically active phenylalanine propylamide, optically active phenylalanine dipropylamide, etc. Active phenylalanine anilide, optically active phenylalanine-p-chloroanilide, optically active phenylalanine benzylamide and the like can be mentioned, and optically active phenylalanine benzylamide is preferable.

  The amount of the optically active phenylalaninamide derivative used for the optical resolution is preferably 0.4 to 1.2 moles, more preferably 0.5 to 1.0, with respect to the 5-oxopyrrolidine-3-carboxylic acid derivative. Molar times.

  The solvent used for the optical resolution must be an organic solvent that does not react with the substrate. For example, alcohols having 1 to 8 carbon atoms, nitriles such as acetonitrile, and ethers such as tetrahydrofuran can be used. Preferably it is a C1-C4 alcohol. Although there is no restriction | limiting in particular in the usage-amount of the organic solvent to add, It is preferable to prepare so that the density | concentration of a racemic 5-oxopyrrolidine-3-carboxylic acid derivative may be 5-30 weight%, More preferably, it is 10-25 weight %.

  Moreover, it is preferable that water is present in the system when performing optical resolution. The amount of water in the system is not particularly limited, but considering the quality and operability of the diastereomeric salt crystals obtained, the amount of water in the system is 0. 0 relative to the racemic 5-oxopyrrolidine-3-carboxylic acid derivative. 1-6 mole times is preferable, More preferably, it is 0.5-6 mole times.

  The temperature at which the optical resolution is performed varies depending on the racemic 5-oxopyrrolidine-3-carboxylic acid derivative, the optical resolution agent, and the organic solvent, but is usually a temperature not higher than the boiling point of the organic solvent used from 0 ° C.

  As a method for optical resolution, a method in which a racemic 5-oxopyrrolidine-3-carboxylic acid derivative, an optical resolution agent and an organic solvent are charged, and a deposited salt is filtered can be employed. In this case, the batch preparation method, the raw racemic 5-oxopyrrolidine-3-carboxylic acid derivative and the solvent are added, and the optical resolution agent is added while stirring. On the contrary, the solvent and the optical resolution agent are added and the mixture is stirred. However, there is a method of charging the raw material 5-oxopyrrolidine-3-carboxylic acid derivative, but it is not particularly limited. After these are charged, the temperature is raised and dissolved, or the mixture is sufficiently equilibrated in a slurry state and then gradually cooled, and the precipitated crystals are isolated by filtration. When the influence of the mother liquor is large or when producing products with high optical purity, it is possible to easily increase the optical purity by adding a solvent again to dissolve or wash the slurry, and filter the precipitated crystals. can do.

  Isolating the optically active 5-oxopyrrolidine-3-carboxylic acid derivative from the obtained crystals can be carried out according to a conventional method. For example, the optically active 5-oxopyrrolidine-3-carboxylic acid derivative can be obtained by adding the crystals to a mixed solvent of water and hydrochloric acid and filtering the precipitated crystals, while the crystals are mixed with water and caustic soda. An organic solvent is used to extract an optical resolving agent on the organic layer side and an optically active 5-oxopyrrolidine-3-carboxylic acid derivative on the aqueous layer side, and the aqueous layer is separated, and then an organic solvent such as sulfuric acid and toluene is used. It can be isolated by extracting the optically active 5-oxopyrrolidine-3-carboxylic acid derivative on the organic layer side and concentrating it.

  According to the production method of the present invention, not only an optically active 5-oxopyrrolidine-3-carboxylic acid derivative can be efficiently produced with high optical purity, but also the resolving agent can be recovered and recycled, so that the resource-saving production method It can be said. Further, if the recovered optically active 5-oxopyrrolidine-3-carboxylic acid derivative, which is an unnecessary optical isomer, is racemized and reused, it becomes a more resource-saving production method.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.

  Here, a method for synthesizing optically active 1-benzyl-5-oxopyrrolidine-3-carboxylic acid from racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid using L-phenylalanine benzylamide as an optical resolution agent explain.

<Analysis method>
(Optical purity analysis method)
The optical purity of optically active 1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the examples was measured by high performance liquid chromatography (HPLC) according to the following analytical conditions. The sample for analysis was prepared by neutralizing diastereomeric salt crystals obtained by optical resolution with 10% HCl aqueous solution, extracting with tetrahydrofuran and sodium chloride, separating the organic layer, and concentrating. 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was diluted with the mobile phase.
Column: CHIRALPAK AD-RH 0.46 cmφ × 15 cm (Daicel Chemical Co., Ltd.)
Moving bed: pH 2 phosphoric acid aqueous solution / acetonitrile = 84/16 (v / v)
Flow rate: 0.5 ml / min Temperature: 40 ° C
Detector: UV (220 nm)
Retention time: R-form: 15.2 minutes, S-form: 16.8 minutes.

(Chemical purity analysis method)
The chemical purity of racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and optically active 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was analyzed by HPLC according to the following analytical conditions.
Column: CAPCELL PAK C-18, 4.6 mm x 150 mm (Shiseido)
Moving bed: 5 mM sodium dodecyl sulfate aqueous solution (adjusted to pH 2.5 with phosphoric acid) / acetonitrile = 70/30 (0 min to 30 min) → 36/64 (30 min to 40 min) → 70/30 (40 min to 45 min) → 70 / 30 (45min to 55min)
Flow rate: 1.0 ml / min Temperature: 40 ° C
Detector: UV (210 nm)
Retention time: 3.0 minutes.

The absolute configuration of the obtained optically active 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was determined according to a known document (Tetrahedron Asymmetry, 12, 3241, (2001)). For example, when the optical rotation of optically active 1-benzyl-5-oxopyrrolidine-3-carboxylic acid is [α] _D = + 15.5 (C = 0.5, ethanol), the absolute configuration is (S) . The optical rotation was measured using a polarimeter.

Reference Example Synthesis of racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid In a 2 L 4-necked flask equipped with a thermometer, a dropping funnel and Dean Stark, 140.53 g (1.08 mol) of itaconic acid and 1001.68 g of toluene, Then, 116.2 g (1.08 mol) of benzylamine was added, the temperature was raised to 108 ° C. while stirring, and the mixture was stirred for 4 hours while maintaining the temperature. It stirred for 12 hours, cooling to 30 degreeC after completion | finish of reaction. The obtained crystals were separated into solid and liquid and rinsed with toluene. As a result of drying under reduced pressure, 220.03 g of powdery white crystals (chemical purity 98%, yield 93%) was isolated.

  The following experiment was conducted using crystals of racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid as a raw material.

Example 1
In a 100 ml four-necked flask equipped with a stirrer, a thermometer and a condenser, 10.0 g (45.7 mmol) of racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 11.5 g of L-phenylalanine benzylamide (45 0.7 mmol), and 18.8 g of 2-propanol and 3.0 g (2.6 mol times) of water were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. 1-Benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained wet cake was 4.02 g, and the optical purity was 94.2% ee. 10.3 g of the obtained wet cake was put into a 100 ml four-necked flask, 9.14 g of 2-propanol and 1.48 g of water (2.6 mol times) were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred. When the solution became uniform, it was cooled to 65 ° C. to 50 ° C., a part of the wet cake (optical purity 94.2% ee.) Obtained earlier was inoculated as a seed, stirred for 2 hours, and the resulting slurry Was separated into solid and liquid using a Kiriyama funnel, and the wet cake was 11.6 g. The 1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained cake was 3.49 g, and the optical purity was 98.8. % Ee.

  After 28 g of toluene, 12.1 g of 48% sodium hydroxide aqueous solution and 22 g of water were added to the obtained wet cake and stirred, the pH was confirmed to be 12, and a liquid separation operation was performed. 42.5 g of the obtained aqueous layer was separated, and then 7.5 g of 95% sulfuric acid and 16.5 g of tetrahydrofuran were added to the aqueous layer and stirred. The upper layer separated into two layers was separated and concentrated to dryness. A 10 g portion of toluene was added to the concentrated solid, followed by azeotropic dehydration. To the obtained crystals, 10 g of toluene was added and dissolved at 60 ° C. and stirred for 1 hour. After cooling to 28 ° C., the mixture was stirred for 5 hours at 28 ° C., and the precipitated crystals were filtered to obtain 3.02 g of (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid. Its optical purity was 98.5% ee. The yield was 30.1% (referred to the yield relative to the raw material racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid).

Example 2
In a 100 ml four-necked flask equipped with a stirrer, thermometer and condenser, 5.01 g (22.85 mmol) racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 5.80 g L-phenylalanine benzylamide (22) .81 mmol) and 32.48 g of 2-propanol and 0.25 g of water (0.6 mol times) were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. The (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained cake was 2.66 g, and the yield was 53.1% (the raw material racemic 1-benzyl-5-oxopyrrolidine- The optical purity was 69.3% ee.

Example 3
In a 100 ml four-necked flask equipped with a stirrer, thermometer and condenser, 5.05 g (23.03 mmol) racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 5.79 g L-phenylalanine benzylamide (22 .77 mmol) and 34.42 g of 2-propanol and 0.44 g of water (1.0 mol times) were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. The (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained cake was 2.35 g, and the yield was 46.5% (the raw material racemic 1-benzyl-5-oxopyrrolidine- The optical purity was 80.2% ee.

Example 4
In a 100 ml four-necked flask equipped with a stirrer, thermometer and condenser, 5.08 g (23.17 mmol) racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 5.80 g L-phenylalanine benzylamide (22 .81 mmol) and 32.42 g of 2-propanol and 0.59 g (1.4 mol times) of water were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. In the obtained cake, (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid was 2.33 g, yield 45.9% (the raw material racemic 1-benzyl-5-oxopyrrolidine-3- The optical purity was 84.1% ee.

Example 5
In a 100 ml four-necked flask equipped with a stirrer, thermometer and condenser, 5.08 g (23.17 mmol) racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 5.80 g L-phenylalanine benzylamide (22 .81 mmol) and 32.43 g of 2-propanol and 0.73 g of water (1.8 mol times) were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. The (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained cake was 2.06 g in a yield of 40.6% (the raw material racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid). The optical purity was 94.7% ee.

Example 6
In a 100 ml four-necked flask equipped with a stirrer, thermometer and condenser, 5.02 g (22.90 mmol) racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 5.80 g L-phenylalanine benzylamide (22 .81 mmol) and 32.65 g of 2-propanol and 1.52 g of water (3.7 mole times) were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. In the obtained cake, (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid was 2.01 g, yield 40.0% (raw material racemic 1-benzyl-5-oxopyrrolidine-3- The optical purity was 97.7% ee.

Example 7
In a 100 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 15.7 g (71.8 mmol) of racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and 17.84 g of L-phenylalanine benzylamide (70 .37 mmol) and 96.97 g of 2-propanol were added, and the mixture was heated to an internal temperature of 65 ° C. and stirred for 1 hour. When the solution became homogeneous, the salt of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid and L-phenylalanine benzylamide prepared beforehand by cooling from 65 ° C. to 50 ° C. (optical purity 66. A small amount of 9% ee.) Was inoculated and stirred while cooling to 28 ° C. The mixture was stirred for 12 hours, and the resulting slurry was subjected to solid-liquid separation using a Kiriyama funnel. The (S) -1-benzyl-5-oxopyrrolidine-3-carboxylic acid in the obtained cake was 7.56 g in yield of 48.1% (racemic 1-benzyl-5-oxopyrrolidine-3-carboxylic acid as the raw material). The optical purity was 29.0% ee.

Claims (3)

General formula (1)

(Where R ¹ represents i) a hydrogen atom, ii) a halogen atom, iii) a nitro group, iv) a cyano group, v) an alkyl group having 1 to 4 carbon atoms, or vi) an alkoxy group having 1 to 4 carbon atoms. R ² and R ³ may be the same or different, i) a hydrogen atom, ii) an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and iii) no aromatic ring. An aralkyl group substituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a halogen atom, a nitro group, or a cyano group is shown. In addition, an optically active phenylalaninamide derivative represented by the formula (2) is used as an optical resolution agent.

Wherein R ⁴ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group. The racemic 5-oxopyrrolidine-3-carboxylic acid derivative represented by the formula is optically resolved in an organic solvent. General formula (3)

(Wherein R ⁵ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group. The carbon atom marked with * means an asymmetric center.) A method for producing an oxopyrrolidine-3-carboxylic acid derivative. 2. The optically active 5-oxopyrrolidine-3 according to claim 1, wherein the amount of water in the system for optical resolution is 0.5 to 6 mole times that of racemic 5-oxopyrrolidine-3-carboxylic acid. -Manufacturing method of a carboxylic acid derivative. The method for producing an optically active 5-oxopyrrolidine-3-carboxylic acid derivative according to claim 1 or 2, wherein the organic solvent is an alcohol having 1 to 4 carbon atoms.