JP2002212155A - Optically active asparagine ester derivative, optically active 3-aminopyrolidine-2,5-dione derivative and optically active 3-aminopyrrolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an asparagine ester derivative, a 3-aminopyrrolidine-2,5- dione derivative and a 3-aminopyrrolidine derivative having a high optical purity from inexpensive raw materials by a small number of processes in a high optical purity in a high yield. SOLUTION: An optically active N-acylaspartic acid is reacted with an alcohol to produce the optically active asparagine ester derivative in which the derivative is esterified and the N-acyl group is deprotected simultaneously. The product is further subjected to ring formation to produce an optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative. The derivative is further reduced to give an optically active 1-substituted-aminopyrrolidine derivative. The derivative is further subjected to hydrogenolysis to give an optically active 3-aminopyrrolidine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active 3-aminopyrrolidine derivative which is important as a raw material for medicines and agricultural chemicals, and an optically active asparagine ester derivative and an optically active 3-aminopyrrolidine-2, which are important as intermediates thereof.
This is a method for producing a 5-dione derivative.

[0002]

2. Description of the Related Art As a method for producing an optically active 3-aminopyrrolidine derivative, for example, racemic 1-benzyl-
A method of optically resolving 3-aminopyrrolidine with an optically active carboxylic acid is known. However, since the racemic 1-benzyl-3-aminopyrrolidine produced by a complicated route is further optically resolved, it cannot be said to be an inexpensive production method. Therefore, there is a need for a method for producing an optically active 3-aminopyrrolidine derivative at low cost.

[0003] Optically active 3-aminopyrrolidine-2,5-
As a method for producing a dione derivative, N-benzyloxycarbonyl-L-asparagine methyl ester is used in 0.1%.
(S) -3- by reacting with 95 equivalents of sodium hydroxide
Benzyloxycarbonylaminopyrrolidine-2,5-
A dione is produced, and (S) -3-
A method for producing benzyloxycarbonylaminopyrrolidine is known (tetrahedron; asymmetry 3: 1239-1242 (1992)). Further, in the case of producing the 1-substituted product, as shown in the figure below, a method of performing N-benzylation by an interphase reaction in the presence of a quaternary ammonium salt is also disclosed in the same document.

[0004]

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This method has a high reaction selectivity and an optical activity of 3
-Is an excellent method for producing aminopyrrolidine derivatives, (1) using expensive L-asparagine as a starting material, (2) a large number of steps, complicated, (3) further,
There is a problem as an industrial production method such as the use of a water-inhibited and expensive reducing agent (LiAlH ₄ ).

As a method for producing an optically active asparagine ester derivative, for example, a method is known in which optically active asparagine is suspended in methanol or ethanol to saturate hydrogen chloride (peptide synthesis).
Published in 1975, Maruzen Co., Ltd., p. 65).

[0007]

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This method is an excellent method for esterifying optically active amino acids, and it is possible to produce optically active asparagine methyl ester in a high yield while suppressing racemization. The economy is low because there is.

[0009]

That is, the present invention provides:
An optically active 1-substituted-3-aminopyrrolidine derivative and its intermediate, an optically active asparagine ester derivative, and an optically active 3-amino, inexpensive raw materials, in a small number of steps, in a high yield, and with a high optical purity. Pyrrolidine-
An object of the present invention is to provide a method for producing a 2,5-dione derivative.

[0010]

Means for Solving the Problems The present inventors have intensively studied a method for solving the above-mentioned problems, and as a result, have reached the present invention.

That is, the present invention provides an optically active N-acyl asparagine derivative represented by the formula (1), an optically active N-acyl isoasparagine derivative represented by the formula (2), or a mixture thereof. Is reacted with an alcohol to produce an optically active asparagine ester derivative represented by the formula (4), an optically active isoasparagine ester derivative represented by the formula (5), or a mixture thereof.

Further, the produced optically active asparagine ester derivative represented by the formula (4), the optically active isoasparagine ester derivative represented by the formula (5), or a mixture thereof is subjected to a cyclization reaction to obtain a compound having the formula Optically active 3-aminopyrrolidine-2 represented by (8),
A 5-dione derivative can be produced.

The optically active 3-aminopyrrolidine derivative represented by the formula (9) is reduced by reducing the obtained optically active 3-aminopyrrolidine-2,5-dione derivative represented by the formula (8). Can be manufactured. When the substituent at the 1-position is a substituted or unsubstituted benzyl group, an optically active 3-aminopyrrolidine derivative at the 1-position can be produced by further hydrogenolysis.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, an optically active N-acyl asparagine derivative represented by the formula (1) or an optically active N-acyl isoasparagine derivative represented by the formula (2) is summarized. And referred to as an optically active N-acyl asparagine derivative. The optically active asparagine ester derivative represented by the formula (4) or the optically active isoasparagine ester derivative represented by the formula (5) is collectively referred to as an optically active asparagine ester derivative.

Here, an optically active acyl asparagine derivative represented by the formula (1) or (2), an optically active asparagine ester derivative represented by the formula (4) or (5), and a formula (8) The optically active 1-substituted-3-aminopyrrolidine-2,5-dione, the optically active 1-substituted-3-aminopyrrolidine represented by the formula (9) and the optically active 3-aminopyrrolidine derivative in which the 1-position is unsubstituted are , L body (S
) And D-form (R-form) include excess optically active forms. Also, these acid salts are included.

The feature of the present invention is that the general formula (1) or the general formula (2)

[0017]

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(Where R ¹ is a group selected from a lower alkyl group having 1 to 4 carbon atoms, an aryl group and an aralkyl group, and R ² is hydrogen or an alkyl group having 1 to 3 carbon atoms. * is an optically active N- acyl aspartic derivative represented by the show.) that the carbon atom marked with this symbol is an asymmetric center, the general formula ^{(3) R 3 OH (3} ) ( wherein, R ³ Represents an alkyl group having 1 to 3 carbon atoms), thereby reacting an alcohol represented by the general formula (4) or the general formula (5).

[0019]

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[0020] (wherein, R ^1, * is the same as the formula (1), R ³
Is the same as in the formula (3)) to produce an optically active asparagine ester derivative represented by the formula (3). According to this method, esterification of the carboxylic acid group and deacylation of the amino group at the 3-position can be performed in one step.

In the formula (1), R ¹ is preferably a group selected from a lower alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted benzyl group. Unsubstituted benzyl groups are preferred.

The optically active N-acyl asparagine derivative of the formula (1) can be used alone, or the optically active N-acyl isoasparagine derivative of the formula (2) can be used alone or as a mixture of both. The optical purity of the compound is preferably 95% ee or more.

In the formula (3), R ³ is an alkyl group having 1 to ³ carbon atoms. That is, methanol, ethanol, propanol, isopropanol and the like can be used as the alcohol of the formula (3). Preferably, it is methanol or ethanol, and more preferably, methanol. The amount of the alcohol to be used may be at least twice the molar amount of the optically active N-acyl asparagine derivative represented by the formula (1) or (2). Five-fold moles are preferred. When the alcohol also serves as a reaction solvent, the molar ratio is preferably 14 to 30 times, more preferably 15 to 20 times. Further, they can be used in a mixture with an organic solvent.
Examples of the organic solvent include ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, ketones such as acetone, and halides such as chloroform.

In carrying out the esterification reaction, it is preferable to add an acid. The acid acts as a catalyst to increase the esterification reaction rate and efficiently deacylate the 3-position amino group. As the acid, mineral acids such as hydrochloric acid and sulfuric acid, sulfonic acids such as toluenesulfonic acid, Lewis acids such as iron chloride and zinc chloride, and cation exchange resins can be used. In this case, it is preferable to carry out the reaction while removing water generated by the esterification reaction out of the system. The amount of the acid to be used needs to be the sum of the amount for neutralizing the amino group of the optically active asparagine ester derivative represented by the formula (4) or (5) and the amount for catalyzing the esterification. However, considering the reaction rate, economic efficiency, and load of the purification step, the molar ratio is preferably 1.02 to 1.10 times the molar amount of the optically active asparagine ester derivative.

Here, thionyl chloride can be used instead of adding an acid. In this case, water is not generated in the esterification reaction, so that the reaction operation is simplified and the reaction yield is improved, so that it is particularly preferable. Also, even without adding an acid, thionyl chloride reacts with a carboxylic acid group in the reaction system to generate hydrochloric acid, which acts as an acid catalyst. The amount of thionyl chloride to be used is preferably 0.9 to 2.5 times, more preferably 1.1 to 2.0 times, the mol of the optically active asparagine ester derivative.
Hydrochloric acid by-produced in the reaction and excess thionyl chloride can be removed from the system by a simple operation such as concentration, so that a large amount of thionyl chloride can be used to increase the reaction rate.

The reaction temperature is preferably from 0 to 80 ° C, more preferably from 10 to 40 ° C. Within this range, the reaction yield is high and racemization is suppressed. The reaction time varies depending on the conditions, but is usually 1 to 20 hours.

The resulting optically active asparagine ester derivative represented by the formula (4) or (5) or an acid salt thereof is isolated by a conventional method. If you use a lot of alcohol. After concentration under reduced pressure to remove alcohol, low boiling point acid or excess thionyl chloride, an organic solvent such as tetrahydrofuran is again added and stirred, and the precipitated crystals are filtered or concentrated under reduced pressure and dried. ,
The acid salt of the optically active asparagine ester derivative represented by the formula (4) or (5) can be isolated. Also, the concentrated solution concentrated under reduced pressure can be used as it is as a starting material for the cyclization reaction.

If the above method is used, the optical purity is 90%.
ee The optically active asparagine ester derivative represented by the formula (4) or (5) or an acid salt thereof can be produced. Here, if the optical purity of the optically active N-acyl asparagine derivative represented by the formula (1) or (2) used is 98% ee or more, the formula (4) or the formula having an optical purity of 95% ee or more is used. An optically active asparagine ester derivative represented by (5) can be obtained. In addition, the obtained acid salt of the optically active asparagine ester derivative represented by the formula (4) or (5) can be neutralized into a free optically active asparagine ester derivative, but it is chemically unsatisfactory. Because it is stable, it is preferable to store it as an acid salt.

The acid salt of the optically active asparagine ester derivative represented by the formula (4) or (5) thus produced is subjected to a cyclization reaction to give a compound of the general formula (8)

[0030]

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(Wherein R ¹ and * are the same as in formula (1)) represented by the optically active 1-substituted-3-aminopyrrolidine-
2,5-dione derivatives can be produced. The optically active asparagine ester derivative represented by the formula (4) or (5) used here can be used alone or as a mixture at any ratio. The optical purity of the compound is preferably 90% ee or more.

The cyclization reaction can be carried out in an organic solvent or in water. In particular, it is preferably performed in a water-containing solvent obtained by mixing an organic solvent and water. The pH of the reaction solution is preferably 3 to 8, more preferably 5 to 7.5, and still more preferably 6 to 7.5.
~ 7. Here, the pH may be adjusted after forming an aqueous solution of the acid salt of the optically active asparagine ester derivative, or the optically active asparagine ester derivative may be dissolved in the aqueous solution whose pH has been adjusted in advance. Here, as the organic solvent, lower alcohols such as methanol and ethanol, tetrahydrofuran and the like are preferable, and methanol is particularly preferable. It is preferable to use an alkali metal salt for pH adjustment. Examples of the alkali metal salt include alkali metal organic acid salts such as sodium formate and potassium formate, sodium acetate and potassium acetate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate. Salts and the like, or a mixture thereof can be used. Preferred are sodium acetate, sodium carbonate or sodium bicarbonate, particularly preferred is sodium bicarbonate.

[0033] The reaction temperature is preferably from 0 to 80 ° C, more preferably from 20 to 60 ° C. The reaction time varies depending on the reaction reagents and conditions, but is 1 to 72 hours. The racemization ratio in the cyclization reaction varies somewhat depending on the pH of the reaction solution, the reaction temperature, the amount of the cyclization accelerator added, and the like. Optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative can be produced. Here, if the optical purity of the optically active asparagine ester derivative represented by the formula (4) or (5) used is 95% ee or more, it is represented by the formula (8) having an optical purity of 90% ee or more. An optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative can be obtained.

A conventional method can be used to isolate the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative from the reaction solution. For example, the reaction solution may be adjusted to be basic and then extracted with an organic solvent. Any organic solvent can be used as long as it is a compound that is stable to the reaction. For example, toluene, chloroform and the like can be preferably used. Here, when the substituent at position 1 of the optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (8) is an aryl group or an aralkyl group, for example, In the case of -amino-1-benzylpyrrolidine-2,5-dione, it is easily extracted into an organic solvent, so that isolation and purification are easy.
The concentrate obtained by concentrating the extract under reduced pressure may be used as it is in the next step.

The optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (8) thus produced is reduced to give a compound of the formula (9)

[0036]

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(Here, R ¹ and * are the same as those of the formula (1).) An optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (1) can be produced.

The optically active 1-substituted-3-aminopyrrolidine-2,5-dione derivative represented by the formula (8) used herein may be an isolated and purified one or a concentrate of an extract directly used. Can be used, but the optical purity is 81% ee
The above is preferred.

As the solvent used here, ethers such as butanol, tetrahydrofuran, glyme and diglyme can be used. Preferred is tetrahydrofuran, glyme or diglyme, and particularly preferred is glyme.

As the reducing agent, a borohydride compound that is chemically stable and easy to handle is preferable. As borohydride compounds, diborane, borane diethyl ether,
Borane dimethyl sulfide or sodium borohydride in the reaction system is preferred. When using sodium borohydride, borane generated by adding an activator such as sulfuric acid or boron trifluoride can also be used. Reaction temperature is -20 to 80 ° C
And more preferably -10 to 30 ° C. The reaction time varies depending on the conditions, but is usually 3 to 20 hours.

After the reaction, the resulting optically active 1-substituted-3-
Aminopyrrolidine can be isolated by a usual method. For example, after adding methanol to the reaction solution and concentrating to decompose and remove excess borane, the concentrate is dissolved in water, made basic, and extracted with chloroform. A 3-aminopyrrolidine derivative can be extracted. By concentrating the obtained chloroform layer, an optically active 3-aminopyrrolidine derivative can be obtained. According to the above method, the optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9) can be obtained with an optical purity of 80% ee or more. Here, the optically active 1-substituted-3 represented by the formula (8) was used.
-Aminopyrrolidine-2,5-dione derivative is 92% e
If it is e or more, an optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9) having an optical purity of 90% ee or more can be obtained.

In the thus obtained optically active 1-substituted-3-aminopyrrolidine derivative represented by the formula (9),
When the substituent at the 1-position is a substituted or unsubstituted benzyl group, hydrogenolysis is carried out in the presence of a noble metal catalyst,
An optically active 3-aminopyrrolidine derivative in which the 1-position is unsubstituted can be produced.

The noble metal catalyst is preferably palladium supported on activated carbon. The hydrogen pressure is preferably from 0.1 to 5 MPa, more preferably from 0.5 to 1 MPa.

The hydrogenolysis is preferably performed in a solvent. As the solvent, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as toluene can be preferably used. More preferably, it is methanol or ethanol.

The reaction temperature is preferably from 20 to 100 ° C, more preferably from 40 to 70 ° C. The reaction time varies depending on the conditions, but is usually 3 to 20 hours.

After the reaction, the produced optically active 3-aminopyrrolidine derivative can be isolated by a usual method. For example, an optically active 3-aminopyrrolidine derivative can be obtained by filtering the reaction solution, filtering out the noble metal catalyst, and then concentrating and distilling. According to the method described above, the optically active 3-aminopyrrolidine derivative has an optical purity of 80% e.
e or more are obtained.

According to the above method, the optically active acyl asparagine derivative represented by the formula (1) or (2) can be obtained in a small number of steps, in a high yield and with a high optical purity.
An optically active 3-aminopyrrolidine derivative and an optically active asparagine ester derivative as an intermediate thereof, and 3
-Aminopyrrolidine-2,5-dione derivatives can be produced. In the reduction reaction, a borohydride compound that is chemically stable and easy to handle can be used as a reducing agent.

The optically active acyl asparagine derivative represented by the formula (1) or (2) is also advantageous in that it can be produced from inexpensive optically active aspartic acid as a starting material. In the present invention, as the optically active acyl asparagine derivative represented by the formula (1) or (2), one produced from a raw material other than the optically active aspartic acid can be used. It is particularly preferable to use optically active aspartic acid as a starting material.

The method for producing an optically active acyl asparagine derivative represented by the formula (1) or (2) from optically active aspartic acid is not particularly limited, but one embodiment is shown below.

[0050]

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An optically active aspartic acid is reacted with an organic acid anhydride to obtain a compound of the general formula (7)

[0052]

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(Where R ² and * are the same as in formula (1)) to produce an optically active N-acyl aspartic anhydride. Here, the optically active aspartic acid can be used in any of the L-form and the D-form according to the purpose.
The optical purity is preferably 99% ee or more. Further, as the organic acid anhydride, acid anhydrides such as formic anhydride, acetic anhydride and propionic anhydride, or heteroacid anhydrides such as formic acetic anhydride can be used. Preferred are acetic anhydride and formic acetic anhydride, and more preferred is formic acetic anhydride.

The optically active N-acyl aspartic anhydride represented by the formula (7) includes N-formyl aspartic anhydride, N-acetyl aspartic anhydride, N-acetyl aspartic anhydride and N-acetyl aspartic anhydride.
Propionyl aspartic anhydride and the like are preferred. More preferably, it is N-formyl aspartic anhydride or N-acetyl aspartic anhydride, and even more preferably, it is N-formyl aspartic anhydride.

As the reaction method, a conventional method can be used. For example, while stirring acetic anhydride and formic acid, L-aspartic acid is mixed with formic acetic anhydride, which has been prepared in advance, and then stirred for 5 minutes.
After reacting at 0 to 70 ° C. for 2 to 5 hours, the mixture is cooled to room temperature, and toluene is added to crystallize N-formyl-L-aspartic anhydride, which is separated by filtration. In this step, the reaction proceeds smoothly without adding an acid catalyst,
Under normal conditions, racemization rarely occurs.

Next, an optically active N-acyl aspartic anhydride represented by the formula (7) and a general formula (6) R ¹ NH ₂ (6) (where R ¹ is the same as in the formula (1)) ) To produce an optically active N-acyl asparagine derivative represented by the formula (1) or (2). As the optically active N-acyl aspartic anhydride represented by the formula (7), any of an L-form and a D-form can be used depending on the purpose, but the optical purity is preferably 98% ee or more.

Examples of the amine represented by the formula (6) include lower alkylamines having 1 to 4 carbon atoms such as methylamine and propylamine, arylamines such as aniline and anisidine, and aralkylamines such as benzylamine. Can be used. The reaction can be carried out without any problem using any of the amines. When the obtained optically active acylasparagine derivative represented by the formula (1) or (2) is subsequently used as a raw material for a cyclization reaction or a reduction reaction, an amine corresponding to the target compound may be used. . Considering the efficiency of extraction from the reaction system with an organic solvent and the deprotection in a subsequent step, benzylamine can be preferably used. The amount of the amine used is 0.8 to 5 with respect to the optically active N-acyl aspartic anhydride represented by the formula (7).
The equivalent is preferred, and more preferably 0.99 to 1.5 equivalent. When the amount of the amine used is within this range, the reaction yield is high and the economic efficiency is high. Use of a large amount of the amine is not preferred because it not only lowers the economic efficiency but also tends to cause racemization of the optically active N-acyl aspartic acid derivative represented by the formula (1) or (2).

The reaction is preferably carried out after dilution with an organic solvent. As the solvent, any compound that does not react with the reaction substrate can be used.Examples include alcohols such as ethanol, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, alkyl halides such as chloroform, ketones such as acetone, and acetic acid. And esters such as carboxylic acid and butyl acetate. Preferred solvents are tetrahydrofuran or acetic acid. These solvents can be used alone or as a mixture. The amount of the solvent to be used may be any amount as long as the concentration allows the stirring operation. However, from the viewpoint of economy, it is usually preferable that the concentration of the substrate be about 5 to 30 wt%. The reaction temperature is preferably from 0 to 60 ° C, more preferably from 10 to 40 ° C. When the reaction temperature is increased, racemization tends to occur at the same time. Therefore, the reaction is preferably performed in this range. The reaction time varies depending on the conditions, but is usually 1 to 20 hours.

After the reaction, the produced optically active N-acylasparagine derivative represented by the formula (1) or (2) is concentrated or cooled, and the precipitate is isolated by filtration. Further, the concentrated solution can be used as it is in the next step of the esterification reaction. By performing the method described above, an optically active N-acyl asparagine derivative represented by the formula (1) or the formula (2) having an optical purity of 95% ee or more can be obtained.

By using the thus obtained optically active acylasparagine derivative represented by the formula (1) or (2) as a raw material for the above-mentioned reaction of the present invention, an inexpensive optically active aspartic acid can be used as a raw material. The optically active 3-aminopyrrolidine derivative and its intermediate, the optically active asparagine ester derivative, and the optically active 3 in a small number of steps, with high yield and high optical purity.
-Aminopyrrolidine-2,5-dione derivatives can be produced.

[0061]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to this range. The chemical purity of the optically active asparagine ester derivative represented by the formula (4) or (5) was determined by HPLC. According to the following formula, the optical purity is converted into a tartaric acid derivative after hydrolysis,
Determined by LC.

[0062]

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The calculation of the optical purity was obtained by the method of Equation 1.

[0064]

(Equation 1)

Here, X: L-derivative (or D-derivative) Y: D-derivative (or L-derivative) Further, 1-substituted-3-aminopyrrolidine-2,5-derivative represented by the formula (8) The optical purity of the dione derivative was determined by HPLC after chemical induction according to the following formula.

[0066]

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The optical purity of the 1-substituted-3-aminopyrrolidine derivative was determined in the same manner. The reagent used in the examples was a commercially available first-grade reagent.

Example 1 5 equipped with a stirrer, dropping funnel, Dimroth and thermometer
112.5 g of acetic anhydride was placed in a 00 ml four-necked flask.
(1.10 mol), and 30 g (0.65 mol) of formic acid was added dropwise while stirring at room temperature. After stirring at room temperature for 2 hours, L-aspartic acid 6 having an optical purity of 99.5% ee
6.5 g (0.5 mol) was added, and the mixture was heated to 60 to 70 ° C and stirred for 10 hours. The temperature was lowered to room temperature while stirring, and 80 g of toluene was further added and stirred. The precipitated crystals were filtered under reduced pressure and rinsed with 10 g of toluene. The crystals were dried under vacuum to obtain 60.1 g of N-formyl-L-aspartic anhydride. The chemical purity was 99% and the optical purity was 99% ee or more.

In a 200 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 7.2 g (0.05 mol) of the N-formyl-L-aspartic anhydride and 60 g of toluene were charged. Stirred at 30 ° C. While maintaining the liquid temperature, 5.4 g of benzylamine (0.0 g
5 mol), and the mixture was further stirred for 4 hours. The precipitated crystals were filtered under reduced pressure and rinsed with 10 g of toluene. The crystals were dried under vacuum to obtain 14.2 g of a mixture of N-formyl-L-asparagine benzylamide (referred to as FAB) and N-formyl-L-isoasparagine benzylamide (referred to as IFAB).

In a 100 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 5 g (0.02 mol) of the mixture of FAB and IFAB, toluene 6
g, and 0.06 mol (3 equivalents) of methanol were charged and stirred at 40 ° C. While maintaining the liquid temperature at 40 ° C., 2.7 g (0.023 mol) of thionyl chloride was added dropwise and reacted for 4 hours. The mixture was concentrated under reduced pressure at 40 ° C to give a mixture of L-asparagine benzylamide methyl ester hydrochloride (referred to as ABN hydrochloride) and L-isoasparagine benzylamide methyl ester hydrochloride (referred to as IABN hydrochloride) in a yield of 9%.
Obtained at 7.4%.

Example 2 A reaction was carried out in the same manner as in Example 1 except that the amount of methanol was changed to 0.08 mol (4 equivalents). A mixture of ABN hydrochloride and IABN hydrochloride was obtained in 98.0% yield.

Example 3 A reaction was carried out in the same manner as in Example 1 except that the amount of methanol added was 0.10 mol (5 equivalents). A mixture of ABN hydrochloride and IABN hydrochloride was obtained in a yield of 99.5%.

Example 4 A reaction was carried out in the same manner as in Example 1 except that the solvent was changed from toluene to acetone. A mixture of ABN hydrochloride and IABN hydrochloride was obtained in a yield of 87.5%.

Example 5 A reaction was carried out in the same manner as in Example 3 except that the solvent was changed from toluene to acetone. A mixture of ABN hydrochloride and IABN hydrochloride was obtained in a yield of 92.2%.

Comparative Example 1 N-benzoyl asparagine benzylamide (formula (1)
R ¹ = benzyl, R ² = phenyl) 3.3 g (10.0
Mmol) and 1.8 g of paratoluenesulfonic acid (10.
(5 mmol) was dissolved in 30 g of ethanol and reacted at 60 ° C. for 10 hours. The yield of asparagine benzylamide ethyl ester was 5% or less.

Comparative Example 2 N-formylasparagine benzylamide (formula (1)
2.5 g (0.01 mol) of R ¹ = benzyl and R ² = hydrogen) were dissolved in 30 g of isopropanol and heated under reflux for 15 hours, but the yield of asparagine benzyl amide isopropyl ester was 5% or less.

Example 6 N-formyl-L-asparagine benzylamide (Formula (1) R ¹ = benzyl, R ² = hydrogen Optical purity 99
% Ee) 2.5 g (10.0 mmol), thionyl chloride 1.4 g (11.8 mmol), methanol 1.6 g
(50.0 mmol) and 10 g of toluene were mixed and stirred at 40 ° C. for 3 hours. After cooling to room temperature, the mixture was concentrated and dried to obtain 2.7 g of asparagine benzylamide methyl ester hydrochloride. The chemical purity was 99%, and the optical purity was 98% ee or more.

Example 7 N-formyl-L-asparagine benzylamide (Formula (1) R ¹ = benzyl, R ² = hydrogen Optical purity 99
% Ee), 2.5 g (10.0 mmol) of thionyl chloride, 1.78 g (10.5 mmol) of thionyl chloride, 5 g of ethanol and 20 g of toluene were mixed, heated to reflux for 15 hours, concentrated and dried to dryness, and asparagine was added. 2.9 g of benzylamide ethyl ester hydrochloride was obtained. The chemical purity was 98%, but the optical purity was slightly lower at 89% ee.

Example 8 5 equipped with a stirrer, dropping funnel, Dimroth and thermometer
112.5 g of acetic anhydride was placed in a 00 ml four-necked flask.
(1.10 mol), and 30 g (0.65 mol) of formic acid was added dropwise while stirring at room temperature. After stirring at room temperature for 2 hours, L-aspartic acid 6 having an optical purity of 99.5% ee
6.5 g (0.5 mol) was added, and the mixture was heated to 60 to 70 ° C and stirred for 10 hours. The temperature was lowered to room temperature while stirring, and 80 g of toluene was further added and stirred. The precipitated crystals were filtered under reduced pressure and rinsed with 10 g of toluene. The crystals were dried under vacuum to obtain 60.1 g of N-formyl-L-aspartic anhydride. The chemical purity was 99% and the optical purity was 99% ee or more.

In a 200 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel, and a thermometer, 7.2 g (0.05 mol) of the N-formyl-L-aspartic anhydride and 60 g of toluene were charged. Stirred at 30 ° C. While maintaining the liquid temperature, 5.4 g of benzylamine (0.0 g
5 mol), and the mixture was further stirred for 4 hours. The precipitated crystals were filtered under reduced pressure and rinsed with 10 g of toluene. The crystals were dried under vacuum to obtain 14.2 g of a mixture of N-formyl-L-asparagine benzylamide (referred to as FAB) and N-formyl-L-isoasparagine benzylamide (referred to as IFAB).

A 100 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer was charged with 14.2 g (0.048 mol) of the mixture of FAB and IFAB and 17.3 g (5.4 mol) of methanol. , 30-35
Stirred at ° C. While maintaining the liquid temperature at 30 to 35 ° C., 7.4 g (0.062 mol) of thionyl chloride was added dropwise.
The temperature was raised to 0 to 45 ° C., and the mixture was further stirred for 3 hours. The solution was concentrated under reduced pressure at 40 ° C., and L-asparagine benzylamide methyl ester hydrochloride (referred to as ABN hydrochloride) and L-isoasparagine benzylamide methyl ester hydrochloride (IAB)
N hydrochloride) was obtained in an amount of 20.9 g.

In a 200 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 20.9 g of a mixture of the above L-asparagine benzylamide methyl ester hydrochloride and L-isoasparagine benzylamide methyl ester hydrochloride and water were placed. 50 g was charged, and 4.0 g of sodium hydrogen carbonate was added while stirring at room temperature. The pH of the reaction solution was 5.8. After heating to 40 ° C. and stirring for 6 hours, the mixture was cooled to room temperature, adjusted to pH 10 to 11, and extracted three times with 100 ml of chloroform. All the chloroform layers were concentrated under reduced pressure to obtain 9.5 g of (S) -1-benzyl-3-aminopyrrolidine-2,5-dione. The optical purity was 91% ee. The overall yield from L-aspartic acid was 91%.

In a 200 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth and a thermometer, the (S)-
9.5 g of 1-benzyl-3-aminopyrrolidine-2,5-dione, 50 ml of tetrahydrofuran and 8.8 g (0.23 mol) of sodium borohydride were charged, and 98% sulfuric acid was added under stirring under ice-cooling. A solution obtained by diluting 7 g (0.06 mol) in 20 ml of tetrahydrofuran was added dropwise over about 30 minutes, and the mixture was further stirred for 2 hours. Reaction solution 6
The temperature was raised to 5 ° C., and the mixture was further stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. After adding and dissolving 70 g of water, concentrated hydrochloric acid 2 was added.
5 g was added, and the mixture was stirred at 65 ° C. for 4 hours. The reaction solution was cooled to room temperature, and stirred, 32 g of 46% sodium hydroxide.
And neutralized. Extract three times with 100 ml of toluene,
All the toluene layers were combined and concentrated under reduced pressure. The concentrate was distilled under vacuum to obtain 7.3 g of (S) -3-benzylpyrrolidine as a fraction at 130 to 133 ° C./1.3 kPa. As a result of analyzing the distillate, the chemical purity was 99% and the optical purity was 91%.
ee.

The above (S) was placed in a 100 ml autoclave.
-3-benzylpyrrolidine 7.0 g, methanol 25 m
1 and 0.7 g of 5% Pd / C, and hydrogen was adjusted to a gauge pressure of 1 MPa. The temperature was raised to 70 ° C., and the mixture was stirred for 8 hours. After completion of the reaction, the pressure was released after cooling to room temperature, and the content was filtered. Concentrate and distill the filtered mother liquor, 80-83
3.2 g of (S) -3-aminopyrrolidine was obtained as a fraction at 40 ° C / ° C. As a result of analyzing the distillate, the chemical purity was 99% and the optical purity was 91% ee.

Example 9 3 equipped with a stirrer, dropping funnel, Dimroth and thermometer
102 g (1.0 mol) of acetic anhydride was charged into a 00 ml four-necked flask, and 96% formic acid was stirred at room temperature.
1 g (1.4 mol) was added dropwise, and the mixture was further stirred for 2 hours to produce formic acid acetic anhydride.

In a 1,000 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 133.1 g (1.0 mol) of D-aspartic acid and acetic anhydride 14 were added.
2.8 g (1.4 mol) was charged, and the formic acid acetic anhydride was added dropwise with stirring at 50 ° C. After stirring was further continued for 5 hours, 500 ml of toluene was added, and the mixture was cooled with ice while stirring to precipitate crystals. The precipitated crystals were filtered and dried to obtain 140.0 g (0.98 mol) of N-formyl-L-aspartic anhydride. Chemical purity 99
% And optical purity of 99% ee.

In a 2,000 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 140.0 g of the above-mentioned N-formyl-L-aspartic anhydride (0.
98 mol) and 1 kg of tetrahydrofuran.
Stirred at ２５25 ° C. 105.0 g of benzylamine
(0.98 mol) was added dropwise over 1 hour and continued for another 3 hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were filtered and rinsed with 100 g of tetrahydrofuran to obtain 280.3 g of wet crystals. As a result of analysis, N-formyl-D-asparagine benzylamide and N-formyl-D
233. Isoasparagine benzylamide mixture.
5 g, and the combined yield was 95.2%.

In a 2,000 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer, 280.3 g of the wet crystal and 149.3 g of methanol (4.
7 mol) and 365 g of toluene.
Stirred at 0 ° C. While maintaining the liquid temperature at 35 to 40 ° C, 126.2 g (1.06 mol) of thionyl chloride was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. The reaction solution was concentrated under reduced pressure and then dried under vacuum to obtain 273.0 g of a solid. As a result of analysis, a mixture of D-asparagine benzyl amide methyl ester hydrochloride and D-isoasparagine benzyl amide methyl ester hydrochloride was 271.4 g, and the total yield of both was 99.5%.

Water 305 was placed in a 2,000 ml four-necked flask equipped with a stirrer, a dropping funnel, a Dimroth funnel and a thermometer.
g, methanol 305 g, and the solid 273.0.
g, and a 20% aqueous sodium hydrogen carbonate solution was added dropwise while stirring at room temperature to adjust the pH to 6.7 to 7.0. The reaction solution was heated to 50 to 55 ° C and stirred for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, added with 1,000 ml of chloroform, adjusted to pH 8 to 9 by adding a 46% aqueous sodium hydroxide solution with stirring, and stirred for 30 minutes. The stirring was stopped and the mixture was allowed to stand, and the chloroform layer was separated. 1,000 ml of chloroform was added to the aqueous layer, and the extraction operation was repeated again. The two chloroform layers were combined and concentrated under reduced pressure to obtain 198 g of a concentrate. As a result of the analysis, (R)
-17-aminopyrrolidine-2,5-dione is 171.3.
g. 90.5% yield, 93% ee optical purity
Met.

[0090]

According to the present invention, an optically active 3-aminopyrrolidine derivative useful as a pharmaceutical intermediate and an optically active asparagine ester derivative and an optically active 3-aminopyrrolidine-2,5-dione derivative which are important intermediates thereof Can be produced in a small number of steps with high optical purity and high yield using inexpensive optically active aspartic acid as a starting material.

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Claims (10)

[Claims] 1. A compound represented by the general formula (1) or the general formula (2): (Here, R ¹ represents a group selected from a lower alkyl group having 1 to 4 carbon atoms, an aryl group, and an aralkyl group, and R ² represents hydrogen or an alkyl group having 1 to 3 carbon atoms. And the optically active N-acyl asparagine derivative represented by the following general formula (3): R ³ OH (3) (where R ³ is the number of carbon atoms) Wherein the alcohol is represented by the following general formula (4) or (5): (Where R ¹ and * are the same as in formula (1), and R ³ is the same as in formula (3)). 2. The process for producing an optically active asparagine ester derivative according to claim 1, wherein the reaction is carried out in the presence of an acid. 3. The method for producing an optically active asparagine ester derivative according to claim 1, wherein the reaction is carried out at 0 to 60 ° C. 4. The optically active asparagine according to claim 1, wherein in the formulas (1) and (2), R ² is hydrogen or a methyl group, and in the formula (3), R ³ is a methyl group or an ethyl group. A method for producing an ester derivative. 5. The compound of the formula (1) or (2) is an amine represented by the general formula (6) R ¹ NH ₂ (6) (where R ¹ is the same as the formula (1)). , General formula (7) The optically active asparagine ester derivative according to claim 1, which is obtained by reacting an optically active N-acyl aspartic anhydride represented by the formula (1) wherein R ² and * are the same as those of the formula (1). Production method. (A) reacting L-aspartic acid or D-aspartic acid with an organic acid anhydride to produce an optically active N-acylaspartic anhydride represented by the formula (7);
(b) Then, the compound is reacted with an amine represented by the formula (6) to produce an optically active N-acyl asparagine derivative of the formula (1) or (2), and (c) further represented by the formula (3) The method for producing an optically active asparagine ester derivative according to claim 1, wherein the optically active asparagine ester derivative represented by the formula (4) or (5) is produced by reacting with an alcohol. 7. The method for producing an optically active asparagine ester derivative according to claim 6, wherein the organic acid anhydride is acetic anhydride or formic acetic anhydride. 8. A cyclization reaction of an optically active asparagine ester derivative represented by the formula (4) or (5) produced by the method according to claim 1 or an acid salt thereof. Formula (8) (Here, R ¹ and * are the same as those in the formula (1).) A method for producing an optically active 3-aminopyrrolidine-2,5-dione derivative represented by the following formula: 9. An optically active 3-aminopyrrolidine-2 represented by the formula (8) produced by the method according to claim 8.
General formula (9) characterized by reducing a 5-dione derivative or an acid salt thereof. (Where R ¹ and * are the same as in formula (1)). 10. An optically active 3-aminopyrrolidine derivative represented by the formula (9) produced by the method according to claim 9, wherein R ¹ represents a substituted or unsubstituted benzyl group. A method for producing an optically active 3-aminopyrrolidine derivative which undergoes chemical decomposition.