JP2001131145A - Method for producing optically active 3-aminopyrrolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an optically active 3-aminopyrrolidine derivative, while inhibiting the deterioration of optical purity. SOLUTION: An optically active 3-aminopyrrolidine-2,5-dione derivative is produced through an optically active asparaginic acid anhydride derived from an optically active asparaginic acid and then reduced with boron hydride or a metal borohydride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an optically active 3-aminopyrrolidine derivative which is an intermediate useful as a raw material for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art As a method for producing an optically active 3-aminopyrrolidine derivative, (1) L-aspartic acid is used as a raw material, (a) a step of forming N-protected aspartic acid, and (b) diol is obtained by reduction with hydride. (C) deriving a diol with thionyl chloride or the like, (d) reacting with an amine to form a pyrrolidine ring, and (e) removing the N-protecting group (US (Japanese Patent No. 5177217), (2) a method of synthesizing 3-aminopyrrolidone by cyclizing optically active 2,4 diaminobutyric acid and then reducing it with lithium aluminum hydride (JP-A-8-23936)
No. 1) is known. Also, (3) a method of optically resolving a racemic 3-aminopyrrolidine derivative (Japanese Patent Laid-Open No. 9-2)
No. 16866, JP-A-9-176115) and the like are also known.

[0003]

The method (1) using L-aspartic acid as a starting material is an excellent method in that the optically active site is derived from inexpensive L-aspartic acid, but the number of steps is small. Method (2) is difficult in industrial production, for example, optically active 2,4 diaminobutyric acid and lithium aluminum hydride are expensive and water-free reaction conditions are essential. There is. The method (3) of optically resolving a racemate is an excellent method in that a product having a high optical purity can be obtained, but there is a problem in mass production because the racemic material as a raw material is expensive. That is, the present invention is to solve these problems and to provide a method for producing an optically active 3-aminopyrrolidine derivative by a simple operation.

[0004]

Means for Solving the Problems The present inventors have studied optical activity 3
As a result of intensive studies on a method for producing an aminopyrrolidine derivative, the present invention has been achieved. That is, an optically active 3-aminopyrrolidine derivative can be efficiently produced by reducing an optically active 3-aminopyrrolidine-2,5-dione derivative which can be produced from inexpensive optically active aspartic acid with borohydride or a metal salt of borohydride. They have found that they can do this and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (1)

[0006]

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(Where R ¹ represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group, and R ² and R ³ represent hydrogen, an alkyl group, a phenyl group, an aralkyl group, Group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, or an aralkylsulfonyl group, which may be the same or different. * Indicates that the carbon atom with this symbol has an asymmetric center at the carbon atom. When producing an optically active 3-aminopyrrolidine derivative represented by the general formula (2):

[0008]

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(Where R ¹ , R ² , R ³ , * is the formula (1)
Are the same as those described above. Optical activity 3)
A method for producing an optically active 3-aminopyrrolidine derivative, comprising reducing an -aminopyrrolidine-2,5-dione derivative. And “General formula (2)

[0010]

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(Where R ¹ represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group, and R ² and R ³ represent hydrogen, an alkyl group, a phenyl group, an aralkyl group, Group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, or an aralkylsulfonyl group, which may be the same or different. * Indicates that the carbon atom with this symbol has an asymmetric center at the carbon atom. The optically active 3-aminopyrrolidine-2,5-dione derivative represented by the general formula (4)

[0012]

Embedded image

(Where R ² and R ³ are hydrogen, an alkyl group,
A phenyl group, an aralkyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, or an aralkylsulfonyl group, which may be the same or different, except when R ² and R ³ are both hydrogen. * Indicates that the carbon atom with this symbol is an optically active compound having an asymmetric center. ) And an optically active N-protected aspartic anhydride represented by the general formula (5): R ¹ NH ₂ (5) (where R ¹ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, and A method for producing an optically active 3-aminopyrrolidine derivative, which is obtained by reacting a primary amine represented by any of the following: ".

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active substance of the present invention means an optically active substance having an optical purity of 50% ee or more, and is an L-form (S
) Or D-form (R-form) is in excess of 50% e
e.

In the present invention, an optically active 3-aminopyrrolidine derivative is produced by reducing the optically active 3-aminopyrrolidine-2,5-dione derivative represented by the general formula (2). The optically active 3-aminopyrrolidine-2,5-dione derivative has the general formula (4)

[0016]

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(Where R ² and R ³ are hydrogen, an alkyl group, a phenyl group, an aralkyl group, an alkoxylcarbonyl group,
It represents any one of an alkylsulfonyl group, an allylsulfonyl group, and an aralkylsulfonyl group, which may be the same or different, but excludes the case where they are simultaneously hydrogen. *
It indicates that the carbon atom with this symbol is an optically active compound having an asymmetric center. )) Can be obtained by reacting an optically active N-protected aspartic anhydride with a primary amine.

The optically active N-protected aspartic anhydride represented by the general formula (4) can be obtained from N-protected aspartic acid.

The N-protected aspartic acid as a starting material of the present invention can be synthesized from optically active aspartic acid. Here, the N-protecting group of the optically active aspartic acid includes an aralkyloxycarbonyl group such as benzyloxycarbonyl, an alkyloxycarbonyl group such as t-butoxycarbonyl, ethoxycarbonyl and methoxycarbonyl, an alkylsulfonyl group such as methanesulfonyl, and benzene. Allylsulfonyl groups such as sulfonyl; aralkylsulfonyl groups such as benzylsulfonyl;

The N-protected aspartic acid obtained as described above is anhydrated by a conventional method, and then the N-protected aspartic anhydride is reacted with a primary amine to give optically active 3-aminopyrrolidine-2. , 5-Dione derivatives are preferred.

The primary amine is represented by the general formula (5) R ¹ NH ₂ (5) (where R ¹ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms,
A phenyl group or an aralkyl group). Specifically, alkylamines having 1 to 4 carbon atoms such as methylamine, ethylamine and butylamine, aralkylamines such as benzylamine, phenethylamine and paramethylbenzylamine, or arylamines such as aniline and 4-methoxyaniline Are preferred, and can be used with or without a substituent on the aromatic ring.

The amount of the primary amine used is preferably 0.8 to 1.2 times mol of the N-protected aspartic anhydride.
Within this range, there is no problem in reaction yield and selectivity. The reaction is preferably carried out in an organic solvent. As the solvent, a solvent having a solubility in water of 5 g or less at room temperature and azeotropic with water is preferable. For example, aromatic hydrocarbons such as benzene, toluene and cumene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and octane, and halogen compounds such as chloroform, and particularly preferred are aromatic compounds Hydrocarbons.

As a reaction method, there is a method in which N-protected aspartic acid and a primary amine are heated at 100 to 160 ° C., but the cyclization yield is high, but it is not preferable because racemization may occur at the same time. In order to react under mild conditions, there is a method of deriving an N-protected aspartic anhydride. But N
The method of deriving the protected aspartic acid diester also requires temperatures above 100 ° C. to react with the amines,
It is difficult to suppress racemization. For cyclization without lowering the optical purity, a method of converting N-protected aspartic acid to an acid anhydride and then reacting with an amine is excellent. N-protected aspartic anhydride can be easily prepared by reacting N-protected aspartic acid with acetic anhydride in the solvent. Even in the method of reacting N-protected aspartic anhydride with amines, a two-step reaction system is preferable because racemization may occur at a high reaction temperature. A low-temperature reaction in which N-protected aspartic anhydride is mixed with the above solvent and the amine is added at 0.8 to 1.2 times the mole of N-protected aspartic anhydride while stirring at 0 to 50 ° C. This is a two-step reaction consisting of a step and a high-temperature cyclization step in which heating is subsequently performed at 40 to 110 ° C.

The reaction time of the low-temperature reaction step varies depending on the type of the substituent and the reaction temperature, but is usually 1 to 5 hours.
The reaction temperature is preferably as mild as possible.
C is particularly preferred. In addition, the high-temperature cyclization reaction step is 60 to 1
10 ° C. is more preferable, and usually 3 to 10 hours. Racemization can be suppressed by performing the reaction under these reaction conditions.

In the reaction with a primary amine, the coexistence of an organic acid is preferred because it has the effect of further suppressing racemization. As the organic acid to coexist, formic acid, acetic acid, propionic acid and the like are preferable. The amount added is such that the reaction system does not become basic and becomes acidic, and is preferably 0.1 to 1.4 times, more preferably 0.1 to 0.5 times, the mole of the primary amine. Is a mole. Amination and cyclization can be carried out subsequent to the N-protected aspartic anhydride production step.

In the present invention, the optically active 3-aminopyrrolidine-2,5-dione derivative is reduced. By reducing the optically active 3-aminopyrrolidine-2,5-dione derivative under mild conditions, the optically active 3-aminopyrrolidine derivative can be efficiently obtained without racemization.
Optically active 3-aminopyrrolidine-2,5 used here
The dione derivative is represented by the general formula (2)

[0027]

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(Where R ¹ represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group, and R ² and R ³ represent hydrogen, an alkyl group, a phenyl group, an aralkyl group, Group, an allylsulfonyl group, or an aralkylsulfonyl group, which may be the same or different. * Indicates that the carbon atom with this symbol is an optically active substance having an asymmetric center.) Wherein the 3-position amino group is an unsubstituted amino group, an alkylamino group having 1 to 4 carbon atoms such as methylamino, dimethylamino, ethylamino, and butylamino; an aralkylamino group such as benzylamino; A group or the like can be used with or without a substituent on the aromatic ring. Further, it is an amino group substituted with an ethoxycarbonyl group, a butoxycarbonyl group, a benzylcarbonyl group or the like, or a substituted amino group such as methanesulfonyl, benzenesulfonyl, or benzylsulfonyl. The N-substituent of the pyrrolidine ring is unsubstituted or an alkyl group such as methyl, ethyl and butyl, an aralkyl group such as a benzyl group, and an aryl group such as a phenyl group, and has a substituent on the aromatic ring. Can be used with or without.

Here, when the 3-position amino group is an alkoxycarbonyl group such as an ethoxycarbonyl group, a butoxycarbonyl group, a benzylcarbonyl group, etc., when the reduction reaction of the present invention is carried out, the 3-position substituent is simultaneously reduced. A 3-methylaminopyrrolidine derivative is obtained. When producing a 3-aminopyrrolidine derivative in which the 3-position is substituted with an alkoxycarbonyl group, 3-aminopyrrolidine-2,
A method in which the 5-dione derivative is reduced and converted into a 3-aminopyrrolidine derivative, and then the 3-position is derived again into an alkoxycarbonyl group can be employed.

The reaction is carried out by dissolving or suspending the optically active 3-aminopyrrolidine-2,5-dione derivative in an organic solvent and then stirring the mixture with a reducing agent such as borohydride or a metal salt of borohydride. It is preferred to react. As the reaction solvent used here, ethers such as diethyl ether and tetrahydrofuran, cellosolves such as dimethoxyethane, and aromatic hydrocarbons such as toluene can be used alone or as a mixture.

The borohydride can be used in a free state or in a stabilized complex such as a methylsulfide complex and a tetrahydrofuran complex. Further, as the metal borohydride, any of an alkali metal salt and an alkaline earth metal salt can be used, but preferably, the general formula (3) MBH ₄ (3) (where M is Na, K, Li Sodium borohydride, lithium borohydride, and potassium borohydride represented by any of the following formulas: Optical activity 3
Although it depends on the basicity of the nitrogen atom of the -aminopyrrolidine-2,5-dione derivative, it is usually 2 to 10 moles, preferably 3 to 5 moles. Within this range, the reaction yield is high and the reaction can be carried out without any problem.

Here, when a metal borohydride is used, it is preferable to coexist with an activating agent. As the activator, any one of iodine, sulfuric acid, hydrochloric acid and boron trifluoride is preferable, and the amount used is an amount sufficient to neutralize the metal borohydride. The reaction temperature is preferably from 0 ° C. to the boiling point of the solvent used. The reaction time varies depending on the type of the raw material, the reaction temperature, the type of the solvent, the amount of the hydrogenated borane or the metal salt of the hydrogenated borane, and the type of the activator.
20 hours is preferred.

The reaction is carried out by dissolving or suspending the optically active 3-aminopyrrolidine-2,5-dione derivative in a solvent, adding borohydride while stirring at a predetermined temperature, and adding the borohydride until the reaction is completed. Heating for several hours is preferred.

When a metal borohydride is used, the reaction is preferably carried out by the following method. That is, an optically active 3-aminopyrrolidine-2,5-dione derivative and a metal borohydride are dissolved or suspended in a solvent and stirred at a predetermined temperature. Next, the activator may be added as it is or after being diluted with a solvent and reacted for a predetermined time, and then heated for several hours to complete the reaction.

After the completion of the reaction, the reaction mixture is concentrated to remove the organic solvent, and then made acidic by adding an aqueous solution of sulfuric acid or hydrochloric acid, followed by stirring at 30 to 80 ° C. for 1 to 6 hours. Then
After basification with sodium hydroxide or the like, the product is extracted and distilled with an organic solvent such as toluene to obtain an optically active 3-aminopyrrolidine derivative. When the optically active 3-aminopyrrolidine derivative is optically active 1-benzyl-3-aminopyrrolidine, the optically active 3-aminopyrrolidine can be produced by hydrogenolysis in the presence of a Pd / C catalyst.

[0036]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Details will be described below with reference to embodiments. In addition, chemical purity and optical purity were determined by GC or HPLC.

[0037]

(Equation 1)

Here, X: L-derivative Y: D-derivative In addition, as the reagent used in the examples, a commercially available first-grade reagent was used. Example 1 106.9 g of N-benzyloxy-L-aspartic acid
(0.40 mol), 41.4 g (0.41 mol) of acetic anhydride, and 100 g of toluene were mixed, and stirred.
The reaction was performed at 0 to 60 ° C for 5 hours. After cooling to room temperature, the precipitated crystals were filtered to obtain N-benzyloxy-L-aspartic anhydride. No rinsing was performed. As a result of the purity analysis, N-benzyloxy-L-aspartic anhydride was 85.8 g (0.35 mol). A filtered crystal and 180 g of toluene were placed in a 1 L flask equipped with a Dean-Stark dehydrator, and stirred while stirring.
At 5 to 20 ° C, 200 g of a toluene solution containing 37.5 g (0.35 mol) of benzylamine was added over 1 hour.
After further stirring for 1 hour, the mixture was heated and heated under reflux for 6 hours to effect dehydration cyclization, then cooled to room temperature and the precipitated crystals were filtered. The crystals were rinsed with toluene and dried to give 1-benzyl-3-.
Benzyloxyaminopyrrolidine-2,5-dione 10
8.3 g (0.32 mol) were obtained. The yield from N-benzyloxy-L-aspartic acid was 80.0%.

Example 2 1-benzyl-3-benzyloxyaminopyrrolidine-
33.8 g (0.10 mol) of 2,5-dione, 100 ml of methanol, and 1.7 g of 5% Pd / C were mixed, and 5
At 0 ° C., hydrogen gas was blown into the liquid for 1 hour. Then, after cooling to room temperature, Pd / C was filtered, and the filtrate was concentrated and diluted with 100 g of tetrahydrofuran.
Here, 15.9 g of sodium borohydride (0.42 g)
Mol), the mixture is stirred at 15 to 20 ° C.,
g of a tetrahydrofuran solution containing 100 g was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. Next, after the temperature was raised to 60 to 65 ° C. and the reaction was performed for 2 hours, the solvent was removed under reduced pressure. Add 100 g of a 10% aqueous hydrochloric acid solution to the concentrate, and add
After cooling to room temperature, the pH was adjusted to 11 to 12 with a 48% aqueous sodium hydroxide solution, and the mixture was extracted twice with 100 g of toluene. The toluene layer was concentrated to obtain 18.5 g of a concentrate. As a result of purity analysis, 1-benzyl-3-aminopyrrolidine was 15.6 g.
1-benzyl-3-benzyloxyaminopyrrolidine-
The yield from 2,5-dione was 88.5%.

Example 3 In Example 2, when 1-benzyl-3-benzyloxyaminopyrrolidine-2,5-dione having an optical purity of 99% ee was used, the obtained 1-benzyl-3-aminopyrrolidine was used. The optical purity was 98% ee, and the decrease in the optical purity was slight.

Example 4 22 g (0.10 mol) of 1-benzyl-3-acetylaminopyrrolidine-2,5-dione having an optical purity of 98.0% ee was dissolved in 100 g of tetrahydrofuran.
While stirring at 0 ° C., 1M borane-tetrahydrofuran 5
A 00 ml solution was added dropwise over 1 hour, and the mixture was further stirred for 1 hour.
Next, 18.5 g of a concentrate was obtained in the same manner as in Example 2.
As a result of a purity analysis, 1-benzyl-3-ethylaminopyrrolidine was 17.4 g, and the optical purity was 97% ee. The yield from 1-benzyl-3-acetylaminopyrrolidine-2,5-dione was 85.2%.

Example 5 60.3 g of N-formyl-L-aspartic anhydride
(0.40 mol) (95% chemical purity, 98% optical purity)
e), 20 g of acetic acid, and 300 g of toluene were charged into a 1 L flask equipped with a Dean-Stark dehydrator, and 42.9 g of benzylamine at 15 to 20 ° C. with stirring.
(0.40 mol) of a toluene solution containing 200 g was added over 2 hours. After stirring for additional 2 hours, the mixture was heated and refluxed for 6 hours to effect dehydration cyclization, cooled to room temperature, and the precipitated crystals were filtered, dried and dried with 1-benzyl-3-formylaminopyrrolidine-2,5-. 76.6 g of dione (0.33 mol)
I got The yield from N-formyl-L-aspartic anhydride was 82.5%, and the optical purity was 97% ee.

Example 6 1-benzyl- (3S) -formylaminopyrrolidine-
23.2 g of 2,5-dione (0.10 mol, optical purity 9
7% ee), 25 g of 25% hydrochloric acid aqueous solution, methanol 10
0 ml were mixed and reacted at 60 to 70 ° C. for 6 hours.
After the reaction, the mixture was concentrated and diluted with 200 g of tetrahydrofuran, and 46.0 g (0.42 mol) of sodium borohydride was carefully added while stirring at 15 to 20 ° C. Then, sulfuric acid was added at 25 to 20 ° C. while stirring at 25 ° C.
g of a tetrahydrofuran solution containing 100 g was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. Next, after raising the temperature to 60 to 65 ° C. and reacting for 2 hours, the solvent was removed under reduced pressure. Thereafter, the same treatment as in Example 2 was performed to obtain 19.2 g of a concentrate.
This was distilled under reduced pressure to obtain 1-benzyl-3-aminopyrrolidine as a fraction at 116 to 118 ° C / 0.5 kPa.
1 g was obtained. Chemical purity 99.3%, optical purity 97% e
e.

Example 7 17.6 g (0.1 mol, optical purity 99% ee) of 1-benzyl-3-aminopyrrolidine obtained in Example 6 was dissolved in 100 ml of methanol, and 1.0 g of 5% Pd / C was obtained. Was added and reacted at 70 to 75 ° C. under a hydrogen pressure of 10 kg / cm ^{2 for} 6 hours. Then, after cooling to room temperature, Pd / C was filtered and the filtrate was distilled under reduced pressure to obtain 7.8 g of 3-aminopyrrolidine as a fraction at 44 to 45 ° C / 1.3 kPa. Yield 9
0.1%. 99.5% chemical purity, 99% ee optical purity
Met.

Comparative Example 1 N-benzyloxycarbonyl-L-aspartic acid 2
6.7 g (0.10 mol) (98% ee of optical purity), benzylamine 10.7 g (0.1 mol), cumene 300
g was charged into a 1-L flask equipped with a Dean-Stark dehydrator and reacted for 6 hours while continuously dehydrating under heating and reflux. Then, the reaction was carried out in the same manner as in Example 2, and 1-
Benzyl-3-aminopyrrolidine was obtained. Optical purity is 2
It was 2% ee.

Comparative Example 2 N-benzyloxycarbonyl-L-aspartic acid diethyl ester 32.3 g (0.10 mol) (optical purity 98% ee), benzylamine 10.7 g (0.1 mol), toluene 300 g The mixture was charged into a 1 L flask equipped with a Dean-Stark dehydrator and reacted for 6 hours while continuously dehydrating under reflux with heating. Then, the reaction was carried out in the same manner as in Example 2 to obtain 1-benzyl-3-aminopyrrolidine. The optical purity was reduced to 35% ee.

[0047]

According to the present invention, an optically active 3-aminopyrrolidine derivative useful as a pharmaceutical intermediate can be efficiently produced from optically active aspartic acid which can be obtained at low cost.

Claims (8)

[Claims] 1. A compound of the general formula (1) (Where R ¹ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms,
And R ² or R ³ represents any one of hydrogen, an alkyl group, a phenyl group, an aralkyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, and an aralkylsulfonyl group. And may be the same or different. *
Indicates that the carbon atom with this symbol is an optically active compound having an asymmetric center. When producing the optically active 3-aminopyrrolidine derivative represented by the general formula (2): (Here, R ¹ , R ² , R ³ , * are the same as those described in the formula (1).) Reduction of an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the following formula: A method for producing an optically active 3-aminopyrrolidine derivative, characterized by the following. 2. The method according to claim 1, wherein the reduction is carried out with borohydride and / or a metal salt of borohydride.
The method for producing the optically active 3-aminopyrrolidine derivative described above. 3. The metal borohydride salt is a compound represented by the general formula (3) MBH ₄ (3) (where M represents any one of Na, K and Li). A method for producing the optically active 3-aminopyrrolidine derivative according to claim 2. 4. The process for producing an optically active 3-aminopyrrolidine derivative according to claim 2, wherein an activator is added. 5. The method for producing an optically active 3-aminopyrrolidine derivative according to claim 4, wherein the activator is one of iodine, sulfuric acid, hydrochloric acid, and boron trifluoride. 6. A compound of the general formula (2) (Where R ¹ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms,
And R ² or R ³ represents any one of hydrogen, an alkyl group, a phenyl group, an aralkyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, and an aralkylsulfonyl group. And may be the same or different. *
Indicates that the carbon atom with this symbol is an optically active compound having an asymmetric center. The optically active 3-aminopyrrolidine-2,5-dione derivative represented by the general formula (4) is represented by the following formula: (Where R ² and R ³ are hydrogen, an alkyl group, a phenyl group,
It represents any of an aralkyl group, an alkoxylcarbonyl group, an alkylsulfonyl group, an allylsulfonyl group, and an aralkylsulfonyl group, which may be the same or different, except when R ² and R ³ are both hydrogen. *
Indicates that the carbon atom with this symbol is an optically active compound having an asymmetric center. ) And an optically active N-protected aspartic anhydride represented by the general formula (5): R ¹ NH ₂ (5) (where R ¹ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, and 2. The method for producing an optically active 3-aminopyrrolidine derivative according to claim 1, which is obtained by reacting a primary amine represented by any of the following: 7. The method for producing an optically active 3-aminopyrrolidine derivative according to claim 6, wherein an organic acid is present in the step of obtaining the 3-aminopyrrolidine-2,5-dione derivative. 8. The step of obtaining a 3-aminopyrrolidine-2,5-dione derivative includes: (1) reacting an optically active N-protected aspartic anhydride with a primary amine at 0 to 50 ° C .; (2) Next, a step of heating at 40 to 110 ° C., 2
The method for producing an optically active 3-aminopyrrolidine derivative according to claim 6 or 7, which is a step reaction.