JPH09124595A - Reagent for optical resolution and production of optically active 3-aminopyrrolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a reagent for optical resolution capable of producing an optically active 3-aminopyrrolidine derivative useful as a synthetic raw material for medicines and agrochemicals in high optical purity and yield by chemically modifying an optically active amino acid or optically active tartaric acid. SOLUTION: This compound is selected from an optically active N-acrylamino acid derivative of formula I (R<1> is a 1-10C alkyl or unsubstituted aromatic ring or a substituted aryl, etc.; R<2> is H, a 1-10C alkyl, etc.), an optically active N-sulfonylamino acid derivative of formula II [R<3> is a (substituted)1-10C alkyl or an unsubstituted aromatic ring or a substituted aryl, etc.; R<4> is a 1-10C alkyl, an aromatic group such as an unsubstituted aromatic or a substituted aryl, etc.] and an optically active tartaric anilide of formula III (R<5> is H, a 1-10C alkyl, an alkoxy, nitro or a halogen), specifically, optically active N- acetylphenylalanine, optically active N-p-toluoylphenylglycine, optically active N-p-nitrobenzoylalanine, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for industrially producing an optically active 3-aminopyrrolidine derivative useful as a synthetic raw material for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, as a method for producing an optically active 3-aminopyrrolidine derivative, (1) a method of stereoselectively converting an optically active 3-hydroxypyrrolidine compound (JP-A-1-316349 and JP-A-2). No. 290870), and (2) a method of optically resolving racemic 1-benzyl-3-aminopyrrolidine using optically active tartaric acid (JP-A-2-218664).

[0003]

In the method (1), an optically active 3-hydroxypyrrolidine compound is used as a starting material. The optically active 3-hydroxypyrrolidine compound is synthesized by various methods, but a relatively expensive drug is often used. Moreover, it is optically active through multi-step reaction 3
-Conversion to the aminopyrrolidine derivative so that partial racemization occurs. Therefore, in order to obtain a product with high optical purity, further optical resolution must be performed, and the yield is not high. Further, the method (2) of optically resolving with optically active tartaric acid requires recrystallization many times, and the yield is not sufficient. Moreover, since tartaric acid dissolves well in water, it is difficult to recover it, which cannot be said to be an industrial production method.

[0004]

Therefore, as a result of diligent studies of the method for industrially producing an optically active 3-aminopyrrolidine derivative, the present inventors have found that the purpose is to obtain an optically active amino acid or an optically active tartaric acid which can be obtained at low cost. By optically resolving the chemically modified derivative as a resolving agent,
I found that I could achieve it.

That is, the present invention provides an optical resolving agent for a 3-aminopyrrolidine derivative selected from an optically active N-acyl amino acid derivative, an optically active N-sulfonyl amino acid derivative and an optically active anilide tartaric acid, and optical resolution using these. Is a method for producing an optically active 3-aminopyrrolidine derivative.

[0006]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described below in detail.

The resolving agent used in the present invention is an optically active N
-Acyl amino acid derivative, optically active N-sulfonyl amino acid derivative and optically active anilide tartaric acid, and the D-form or L-form thereof can be used properly according to the purpose.

As the optically active N-acyl amino acid derivative, for example, the following general formula (I) is used.

Embedded image (Wherein R ¹ is i) an alkyl group having 1 to 10 carbon atoms, i
i) an aromatic ring which is unsubstituted, or an aryl group which is substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group, iii) an aromatic ring which is unsubstituted,
Alternatively, it represents an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, or an aralkyl group substituted with a hydroxyl group, R ² is i) a hydrogen atom, ii) an alkyl group having 1 to 10 carbon atoms, iii) The aromatic ring is unsubstituted, or an alkyl group having 1 to 10 carbon atoms, an aryl group substituted with an alkoxy group having 1 to 10 carbon atoms, a nitro group or a halogen group, iv) the aromatic ring is unsubstituted or has 1 carbon atoms To an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, or an aralkyl group substituted with a halogen group. The amide compound represented by these can be used.

As the optically active N-sulfonylamino acid derivative, the following general formula (II)

[Chemical 6] (In the formula, R ³ is i) unsubstituted or substituted with a carboxyl group, an alkyl group having 1 to 10 carbon atoms, ii) an aromatic ring is unsubstituted, or an alkyl group having 1 to 10 carbon atoms,
An aryl group substituted with an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group, iii) an aralkyl having an aromatic ring which is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group Represents a group, R ⁴ is i) an alkyl group having 1 to 10 carbon atoms, i
i) an aryl group in which an aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group, ii.
i) An aralkyl group in which the aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group. The compound represented by these can be used.

Further, the optically active tartaric acid anilide has the following general formula (III):

Embedded image (In the formula, R ⁵ is hydrogen, an alkyl group having 1 to 10 carbon atoms,
An alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group is shown. The compound represented by these can be used.

The optically active N-acyl amino acid derivative, the optically active N-sulfonyl amino acid derivative and the optically active tartaric acid anilide are represented by R in the general formula (I).
¹ is an alkyl group having 1 to 5 carbon atoms, a phenyl group, a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or an alkoxyl group, and a benzyl group, and R
² is hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group,
A compound which is a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or a nitro group, or a benzyl group is preferable, and in the general formula (II), R ³ is an alkyl group having 1 to 5 carbon atoms or a carboxyl group. An alkyl group having 1 to 5 carbon atoms substituted with, a phenyl group, a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or an alkoxyl group, or a benzyl group, and R ⁴
Compounds in which is an alkyl group having 1 to 5 carbon atoms, a phenyl group, a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms, or a benzyl group are preferable. In the general formula (III), R ⁵ is hydrogen, or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms,
Those having a nitro group or a halogen group can be preferably used. Specifically, optically active N-acetylphenylalanine, optically active N-p-toluoylphenylglycine,
Optically active N-p-nitrobenzoylalanine, optically active N-p-toluenesulfonylphenylglycine, optically active N-p-toluenesulfonylaspartic acid, optically active N-benzenesulfonylaspartic acid, optically active N
-Benzenesulfonylglutamic acid, optically active m-chlorotartaric acid anilide and the like are preferably used.

These optically active amino acid derivatives can be easily synthesized from inexpensive amino acids, and even when recovering the resolving agent, they are decomposed or racemized at room temperature to 50 ° C. under acidic or neutral conditions. Almost never. Similarly, optically active tartaric acid anilide can be easily synthesized from inexpensive tartaric acid, is chemically stable, and has a very high recovery rate. The resolving agent of the present invention can be used for producing an optically active 3-aminopyrrolidine derivative. In particular, it is useful when producing optically active 1-benzyl-3-aminopyrrolidine.

The 3-aminopyrrolidine derivative is represented by the following general formula (IV)

Embedded image (In the formula, R ⁶ represents an unsubstituted benzyl group or a benzhydryl group substituted with an alkyl group or an alkoxyl group having 1 to 4 carbon atoms, and R ⁷ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a benzyl group. , A benzhydryl group, a benzyl group or a benzhydryl group substituted with an alkyl group or an alkoxyl group having 1 to 4 carbon atoms, R ⁸
Represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. ) And the like can be used.

3 used as a raw material in the present invention
The aminopyrrolidine derivative can be produced, for example, by subjecting an aspartic acid derivative to cyclization reduction.

Here, the 3-aminopyrrolidine derivative used as a raw material is not limited to a racemic mixture containing an equal amount of (R) -3-aminopyrrolidine derivative and (S) -3-aminopyrrolidine derivative, but either one of them. A mixture containing an equal amount or more of the optical isomer of can be used.

Optical resolution of the 3-aminopyrrolidine derivative is preferably carried out according to the following procedure and conditions. The resolving agent selected from an optically active N-acyl amino acid derivative, an optically active N-sulfonyl amino acid derivative, and an optically active anilide tartaric acid is 0.4 to 1.6 mol per 1 mol of a 3-aminopyrrolidine derivative in a solvent, The diastereomeric salt is prepared by contacting with preferably 0.5 to 1.3 mol, more preferably 0.5 to 1.0 mol. At this time, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as formic acid, acetic acid and propionic acid may coexist. The amount of the mineral acid or organic acid used, including the resolving agent, is 0.6 to 2.0 mol, preferably 0.8 to 1 mol equivalent of the 3-aminopyrrolidine derivative.
˜1.5 mol, more preferably 0.8 to 1.2 mol.

The solvent used here does not chemically alter the 3-aminopyrrolidine derivative and the resolving agent in the solution and selectively precipitates one diastereomeric salt. If For example, water, methanol, ethanol, 1-propanol,
2-propanol, 1-butanol, 2-butanol,
Use alcohols such as, tetrahydrofuran, ethers such as 1,4-dioxane, 1,3-dioxolane and isopropyl ether, organic solvents such as acetonitrile, ethyl acetate, chloroform, chlorobenzene, cyclohexane and toluene, or a mixed solvent thereof. You can

As a method for bringing the resolving agent into contact with the 3-aminopyrrolidine derivative, the 3-aminopyrrolidine derivative and the resolving agent may be added to the solvent at once, or they may be sequentially added. Furthermore, a salt prepared in advance from a 3-aminopyrrolidine derivative and a resolving agent may be dissolved in the solvent. Similarly, when a mineral acid, an organic acid or the like is allowed to coexist, it may be added all at once or may be added sequentially. The order of adding them is not particularly limited.

When the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, the hardly soluble diastereomer salt is precipitated from the solution.

The temperature for precipitating the hardly soluble diastereomeric salt from the solution may be in the range from the freezing point to the boiling point of the solvent used and can be appropriately selected depending on the purpose, but it is usually from 0 ° C to 100 ° C. Ranges are preferred.

Crystals of the sparingly soluble diastereomeric salt can be easily separated by a usual solid-liquid separation method such as filtration or centrifugation. The crystal of the poorly soluble diastereomer salt can be recrystallized to obtain the desired high-purity diastereomer salt.

By separating the diastereomeric salt thus obtained by a suitable method, the (R) -3-aminopyrrolidine derivative or (S) -3-aminopyrrolidine derivative and the resolving agent are separated and collected. You can

As a method for desolving the diastereomeric salt, a generally known method, that is, a method of treating with an acid or an alkali in an aqueous solvent can be applied. For example, when a diastereomer salt is made acidic by adding a mineral acid such as hydrochloric acid or sulfuric acid in water, a resolving agent is precipitated. After this is subjected to solid-liquid separation, an alkaline aqueous solution such as sodium hydroxide is added to the filtrate to make it alkaline, and then extracted with an organic solvent such as toluene or chloroform to extract an optically active 3-aminopyrrolidine derivative. Therefore, the optically active 3-aminopyrrolidine derivative can be easily obtained by concentrating and distilling the extract.

The optically active 3-aminopyrrolidine derivative thus obtained can be led to an optically active 1H-3-aminopyrrolidine compound in good yield by catalytic hydrogenation.

The resolving agent used in the present invention can be recovered in a high yield by any of the usual salt-removing methods, and is hardly racemized during the recovery process. That is, since these resolving agents retain their optical activity, they can be reused for optical resolution.

[0026]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

In the examples, the optical purity of 1-benzyl-3-aminopyrrolidine (hereinafter 1-benzyl-3-aminopyrrolidine is abbreviated as "BAP") was determined by the following method. 0.1 ml of 0.18% BAP in acetonitrile (for direct analysis of diastereomeric salt, 0.4 ml of 0.4% water / acetonitrile solution of diastereomer salt was added to 0.4 ml of tetramethylhexahexadiene in advance). 0.4% GITC (GITC: 2, 3, 4, 6 is added to 0.1 ml of acetonitrile solution of methylenediamine).
-Tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate) (0.2 ml) was added and reacted at room temperature for 10 minutes, and then 0.2 ml of 0.2% ethanolamine in acetonitrile was added. Add 3
Let stand for 5 minutes, then 2.0 ml of 0.05% phosphoric acid aqueous solution
To obtain a sample solution. 5 μl was injected into HPLC, and the optical purity was measured by the area ratio. The column used for the analysis was CAPCELL PAK C18 SG120 (S
ISEIDOU) 4.6 mmφ × 150 mm, and the mobile phase was pH 4 aqueous solution (aqueous solution adjusted to pH 4 by adding 5% acetic acid aqueous solution to 0.03% ammonia aqueous solution) / methanol = 62/38. Flow rate is 0.8 ml / min
The column temperature was 30 ° C., and the detection was performed with UV254 nm. The GITC derivative of R-BAP is 21.4 mi
n, S-BAP GITC derivative is 23.7 min
Detected.

Example 1 RS-BAP 60.0 g (0.34 mol), N-benzenesulfonyl-L-aspartic acid 93.0 g (0.3
4 mol), toluene 700 ml and ethanol 200
2 ml of 4 ml equipped with thermometer, condenser and stirrer
The mixture was placed in a one-necked flask and dissolved by heating. It was cooled to room temperature in 2 hours and stirred at 10 ° C. for 15 hours. The precipitate was filtered to obtain 69.2 g of white diastereomeric salt. The salt was recrystallized from 1.2 L of 5% water / ethanol to 49.8.
g was obtained. The optical purity of S-BAP in the crystal is 98% ee.
The above is the yield with respect to the charged S-BAP, 65.2.
%Met.

49.0 g (0.109 mol) of the above S-BAP.N-benzenesulfonyl-L-aspartate
Was suspended in a mixed solution of 80 g of water and 25.0 g of 35% hydrochloric acid and stirred at room temperature to precipitate white crystals. After stirring for 2 hours, the precipitate was filtered, washed with water, and dried under reduced pressure at 50 ° C. to give 27.
8 g of N-benzenesulfonyl-L-aspartic acid was obtained. The recovery rate was 93%. Toluene 10 in the filtrate
0 g was added, and a 48% sodium hydroxide aqueous solution 21.4 was added.
g was added dropwise at 35 ° C or lower, and the mixture was stirred for 30 minutes and then separated. 50 g of toluene was added to the aqueous layer, and the mixture was extracted twice more. The collected toluene layers are combined, washed with water, concentrated by an evaporator, and distilled to obtain S-BAP102 ° C./270 Pa.
A fraction of 16.3 g was obtained. The optical purity was 98% or higher and the chemical purity was 99%.

Example 2 30.0 g (0.17 mol) of RS-BAP and 46.5 g (0.1%) of N-benzenesulfonyl-L-aspartic acid.
7 mol) and 75.0 g of water, thermometer, condenser,
A 200 ml four-necked flask equipped with a stirrer was charged and dissolved by heating. It was cooled to room temperature in 5 hours and stirred at 10 ° C. overnight. The precipitate was filtered to obtain 32.5 g of white diastereomeric salt. The optical purity of S-BAP in the crystal is 8
6% ee, the yield based on the charged S-BAP is 85.
%Met.

Example 3 RS-BAP 30.0 g (0.17 mol), N-benzenesulfonyl-L-glutamic acid 48.8 g (0.17)
Mol), toluene 600 ml and ethanol 80 ml
Was charged into a 1 L four-necked flask equipped with a thermometer, a condenser and a stirrer, and dissolved by heating. The mixture was cooled to room temperature in 3 hours and further stirred at 10 ° C. overnight. The precipitate is filtered,
34.7 g of a white diastereomeric salt was obtained. The salt was recrystallized from 300 ml of toluene and 80 ml of ethanol to obtain 27.7 g. The optical purity of S-BAP in the crystal was 95% ee, and the yield based on the charged S-BAP was 70.3%.

Example 4 15.0 g (0.085 mol) of RS-BAP and Np-
Toluoyl-D-phenylglycine 23.1 g (0.0
(85 mol) and 300 ml of tetrahydrofuran were placed in a 0.5 L four-necked flask equipped with a thermometer, a condenser and a stirrer and dissolved by heating. It was cooled to room temperature in 3 hours and further stirred at 15 ° C. overnight. The precipitate was filtered to obtain 14.2 g of white diastereomeric salt. R in the crystal
-The optical purity of BAP is 92% ee, and the charged RB
The yield based on AP was 75%.

Example 5 RS-BAP 15.0 g (0.085 mol) and Np-
Toluoyl-D-phenylglycine 23.1 g (0.0
(85 mol) and 150 ml of ethanol were placed in a 0.3 L four-necked flask equipped with a thermometer, a condenser and a stirrer and dissolved by heating. Cool to room temperature in 3 hours, 20
Stir overnight at ° C. The precipitate was filtered to obtain 15.1 g of white diastereomeric salt. The optical purity of R-BAP in the crystals was 88% ee, and the yield based on the charged R-BAP was 79.8%. 130m of this salt
The optical purity of the product recrystallized with l was 97% ee.

Example 6 19.8 g (0.112 mol) of RS-BAP and Np-
Toluenesulfonyl-D-phenylglycine 34.1 g
(0.111 mol) and 65 ml of ethanol were placed in a 0.2 L four-necked flask equipped with a thermometer, a condenser and a stirrer, and dissolved by heating. It was cooled to room temperature in 3 hours and stirred at 10 ° C. overnight. The precipitate was filtered to give a white diastereomeric salt. 60 ml of this salt in ethanol
The crystals were recrystallized from 16.2 g to give 16.2 g. The optical purity of S-BAP in the crystals was 98% ee or higher, and the yield based on the charged S-BAP was 60%. Obtained S-BAP · N
When the -p-toluenesulfonyl-D-phenylglycine salt was desalted in the same manner as in Example 1, Np-toluenesulfonyl-D-phenylglycine was obtained with a recovery rate of 98%.

Example 7 RS-BAP 15.0 g (0.085 mol) and D-tartaric acid-m-chloroanilide 22.1 g (0.085 mol)
And 175 ml of ethanol with a thermometer, condenser,
It was charged in a 0.3 L four-necked flask equipped with a stirrer and dissolved by heating. It was cooled to room temperature in 3 hours and stirred at 20 ° C. overnight. The precipitate is filtered and the white diastereomeric salt 1
5.7 g was obtained. The optical purity of S-BAP in the crystal is 89.
% Ee, and the yield based on the charged S-BAP is 85%.
Met. This salt was recrystallized with 95 ml of ethanol to give 1
3.4 g were obtained. The optical purity of S-BAP in the crystal is 98.
% Ee or more.

[0036]

By using the resolving agent of the present invention, an optically active 3-aminopyrrolidine derivative can be obtained with high optical purity and high yield. Further, the optically active resolving agent can be recovered in a high yield, and the resolving agent can be reused, which is industrially feasible.

Claims (11)

[Claims] 1. An optical resolving agent for a 3-aminopyrrolidine derivative selected from an optically active N-acyl amino acid derivative, an optically active N-sulfonyl amino acid derivative, and an optically active anilide tartaric acid. 2. An optically active N-acyl amino acid derivative is represented by the following general formula (I): (Wherein R ¹ is i) an alkyl group having 1 to 10 carbon atoms, i
i) an aromatic ring which is unsubstituted, or an aryl group which is substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group, iii) an aromatic ring which is unsubstituted,
Alternatively, it represents an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, or an aralkyl group substituted with a hydroxyl group, R ² is i) a hydrogen atom, ii) an alkyl group having 1 to 10 carbon atoms, iii) The aromatic ring is unsubstituted, or an alkyl group having 1 to 10 carbon atoms, an aryl group substituted with an alkoxy group having 1 to 10 carbon atoms, a nitro group or a halogen group, iv) the aromatic ring is unsubstituted or has 1 carbon atoms To an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, or an aralkyl group substituted with a halogen group. ) The optical resolving agent for a 3-aminopyrrolidine derivative according to claim 1, wherein 3. An optically active N-sulfonylamino acid derivative having the following general formula (II): (In the formula, R ³ is i) unsubstituted or substituted with a carboxyl group, an alkyl group having 1 to 10 carbon atoms, ii) an aromatic ring is unsubstituted, or an alkyl group having 1 to 10 carbon atoms,
An aryl group substituted with an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group, iii) an aralkyl having an aromatic ring which is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms or a hydroxyl group Represents a group, R ⁴ is i) an alkyl group having 1 to 10 carbon atoms, i
i) an aryl group in which an aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group, ii.
i) An aralkyl group in which the aromatic ring is unsubstituted or substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group. ) Is represented by 3).
Optical resolution agent for aminopyrrolidine derivative. 4. An optically active tartaric acid anilide is represented by the following general formula (III): (In the formula, R ⁵ is hydrogen, an alkyl group having 1 to 10 carbon atoms,
An alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group is shown. ) The optical resolving agent for a 3-aminopyrrolidine derivative according to claim 1, wherein 5. In the general formula (I), R ¹ is an alkyl group having 1 to 5 carbon atoms, a phenyl group, a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or an alkoxyl group, and a benzyl group. And R ² is hydrogen,
The 3-amino group according to claim 2, which is an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or a nitro group, and a benzyl group. Optical resolution agent for pyrrolidine derivative. 6. In the general formula (II), R ³ is an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms substituted with a carboxyl group, a phenyl group, a benzyl group, and a carbon number of 1 to 4 A phenyl group substituted with an alkyl group or an alkoxyl group, or a benzyl group,
And R ⁴ is an alkyl group having 1 to 5 carbon atoms, a phenyl group,
The optical resolution agent for a 3-aminopyrrolidine derivative according to claim 3, which is a benzyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms, or a benzyl group. 7. The formula (III), wherein R ⁵ is hydrogen, or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a nitro group or a halogen group. 4. The optical resolution agent for 3-aminopyrrolidine derivative according to 4. 8. A compound selected from an optically active N-acyl amino acid derivative, an optically active N-sulfonyl amino acid derivative and an optically active anilide tartaric acid is an optically active N-acetylphenylalanine, an optically active Np-toluoylphenylglycine, an optically active compound. N-p-nitrobenzoylalanine, optically active N-p-toluenesulfonylphenylglycine, optically active N-p-toluenesulfonylaspartic acid, optically active N-benzenesulfonylaspartic acid, optically active N-benzenesulfonylglutamic acid, or optical The optical resolving agent for a 3-aminopyrrolidine derivative according to claim 1, which is an active m-chlorotartaric acid anilide. 9. A 3-aminopyrrolidine derivative represented by the following general formula (IV): (In the formula, R ⁶ represents a benzyl group or a benzhydryl group substituted with an alkyl group or an alkoxyl group having 1 to 4 carbon atoms, and R ⁷ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a benzyl group or a benzhydryl group. , A benzyl group or a benzhydryl group substituted with an alkyl group or an alkoxyl group having 1 to 4 carbon atoms, and R ⁸ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.). The optical resolving agent for a 3-aminopyrrolidine derivative according to claim 1. 10. The optical resolving agent for a 3-aminopyrrolidine derivative according to claim 9, wherein the 3-aminopyrrolidine derivative is 1-benzyl-3-aminopyrrolidine. 11. A method for producing an optically active 3-aminopyrrolidine derivative, which comprises optically resolving using the optical resolving agent according to any one of claims 1 to 10.