JPH10218863A - Production of optically active 2-piperazine carboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for medicines by a method high in the recovery of a resolving agent and in production efficiency by using an optically active acidic amino acid derivative as the resolving agent. SOLUTION: The mixture of a (+)-2-piperazinecarboxylic acid derivative with (-)-2-piperazinecarboxylic acid derivative as a raw material is brought into contact with a resolving agent such as an optically active N-acyl acidic amino derivative of the formula [R<1> is H, a 1-10C alkyl; (n) is 1, 2] in an amount of 0.4-1.1 mole per mole of the raw material to produce the diastereoisomer salt. The obtained diastereoisomer salt is usually deposited from the solution at 0-100 deg.C, and the deposited salt is disintegrated to separate the optically active (+)-2-piperazinecarboxylic acid derivative, etc., from the resolving agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an industrial method for producing an optically active 2-piperazinecarboxylic acid derivative useful as a pharmaceutical intermediate or the like.

[0002]

2. Description of the Related Art As a method for producing an optically active 2-piperazinecarboxylic acid derivative, for example, 1) a method of optically resolving using L-pyroglutamic acid as a resolving agent (WO95-2116)
2), 2) a method of optically resolving using an optically active α-oxy acid such as L-malic acid as a resolving agent (WO95-29170),
3) A method of optical resolution using N-tosyl-L-phenylalanine as a resolving agent (EP710652) is known. However, since the resolving agents used in 1) and 2) have high solubility in water, they have a disadvantage that the resolving rate of the resolving agent after splitting is low. The N-tosyl-L- used in 3)
Phenylalanine has the advantage of low solubility in acidic aqueous solutions and high recovery of the resolving agent.However, since the solubility of diastereomeric salts is low, the salt concentration cannot be increased in the resolution step, and expensive phenylalanine must be used. It has disadvantages such as low production efficiency.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a process for producing an optically active 2-piperazinecarboxylic acid derivative by a diastereomer salt resolution method, which has a high resolving agent recovery rate and a high production efficiency. It is in.

[0004]

Means for Solving the Problems The present inventors have studied optical activity 2
As a result of intensive studies on the industrial production of piperazine carboxylic acid derivatives, the purpose of this study was to use a derivative obtained by chemically modifying an optically active acidic amino acid available at a low cost as a resolving agent.
-It has been found that this can be achieved by optical resolution of a piperazinecarboxylic acid derivative.

That is, the present invention provides an optical resolution of a 2-piperazinecarboxylic acid derivative by using a resolving agent selected from an optically active N-acyl acidic amino acid derivative and an optically active N-sulfonyl acidic amino acid derivative. This is a method for producing an active 2-piperazinecarboxylic acid derivative.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active acidic amino acid derivative which is a resolving agent used in the present invention is an optically active amino acid derivative having two or more carboxyl groups and amino groups in the molecule, and is an optically active N-amino acid derivative. Examples include acyl acidic amino acid derivatives and optically active N-sulfonyl acidic amino acid derivatives. Specifically, it is selected from N-acyl derivatives and N-sulfonyl derivatives of optically active aspartic acid and optically active glutamic acid, and its D-form and L-form can be used properly according to the purpose.

The optically active N-acyl derivative is represented by the following general formula (I)

Embedded image (Wherein R ¹ is i) hydrogen, ii) unsubstituted or halogen-substituted linear or branched alkyl group having 1 to 10 carbon atoms, iii) unsubstituted or alkyl having 1 to 10 carbon atoms Group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a halogen group, or an aryl group substituted with a hydroxyl group; iv) an aromatic ring is unsubstituted or
To an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a halogen group, or an aralkyl group substituted with a hydroxyl group, v) an aromatic ring is unsubstituted, or 1 to 10 carbon atoms.
Represents an alkyl group, an alkoxyl group having 1 to 10 carbon atoms, a halogen group, or an aralkyloxy group substituted with a hydroxyl group, and n represents 1 or 2. ) Can be used, and specifically, acetyl aspartic acid, formyl glutamic acid, benzoyl aspartic acid, benzoyl glutamic acid, paratoluoyl aspartic acid, paratoluoyl glutamic acid,
Examples include paranitrobenzoyl aspartic acid, paranitrobenzoyl glutamic acid, parachlorophenylacetyl aspartic acid, benzyloxycarbonyl aspartic acid, and benzyloxycarbonyl glutamic acid.

The optically active N-sulfonyl derivative is represented by the following general formula (II):

Embedded image (Wherein R ² is i) an unsubstituted or halogen-substituted linear or branched alkyl group having 1 to 10 carbon atoms, ii) an unsubstituted or alkyl group having 1 to 10 carbon atoms, 1 to 10 alkoxyl groups, nitro groups,
A halogen group or an aryl group substituted with a hydroxyl group, i
ii) an aralkyl 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 halogen group, or a hydroxyl group;
n represents 1 or 2. The optically active acidic amino acid derivative represented by) can be used, and specifically, methanesulfonyl aspartic acid, methanesulfonyl glutamic acid, benzenesulfonyl aspartic acid, benzenesulfonyl glutamic acid, paratoluenesulfonyl aspartic acid, paratoluenesulfonylglutamic acid, paranitrobenzene Sulfonyl aspartic acid, paranitrobenzenesulfonylglutamic acid, parachlorobenzenesulfonylaspartic acid, parachlorobenzenesulfonylglutamic acid and the like.

These optically active amino acid derivatives can be easily synthesized from inexpensive aspartic acid or glutamic acid by a known method, and when the resolving agent is recovered, it can be used under acidic or neutral conditions at room temperature to 50 ° C. There is little degradation or racemization below.

As the 2-piperazinecarboxylic acid derivative to be optically resolved, for example, a compound represented by the following general formula (IV):

Embedded image (Wherein R ⁴ and R ⁵ may be the same or different, i) a hydrogen atom, ii) an alkyl group having 1 to 10 carbon atoms, iii) unsubstituted or alkyl having 1 to 10 carbon atoms An aryl group substituted with an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group, iv)
An aralkyl 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, v) a carbon atom having 1 carbon atom
Represents 10 to 10 alkoxycarbonyl groups, and tBu is
Indicates a tert-butyl group. 2-piperazinecarboxylic acid derivative represented by the general formula (V):

Embedded image (In the formula, tBu represents a tert-butyl group.), General formula (VI)

Embedded image (In the formula, tBu represents a tert-butyl group.) A 2-piperazinecarboxylic acid derivative represented by the following formula can be used, and N-tert-butyl-2-piperazinecarboxamide is particularly preferred.

In the present invention, 2 used as a raw material
-The piperazine carboxylic acid derivative can be produced by a known method. For example, hydrogenation of pyrazine carboxylic acid derivatives,
Alternatively, N, N-dialkylethylenediamine and 2,3
The compound can be produced by performing a condensed cyclization reaction with a dihalopropionic acid ester, followed by further chemical modification.

Here, the 2-piperazinecarboxylic acid derivative used as a raw material includes not only a racemic mixture containing an equal amount of a (+)-2-piperazinecarboxylic acid derivative and a (-)-2-piperazinecarboxylic acid derivative, A mixture containing at least one of the optical isomers in an equal amount or more can be used.

The optical resolution of the 2-piperazinecarboxylic acid derivative is preferably performed according to the following procedure and conditions.

The resolving agent selected from the group consisting of the optically active N-acyl acidic amino derivative and the optically active N-sulfonyl acidic amino acid derivative is 0.4 to 1.1 mol per mol of the 2-piperazinecarboxylic acid derivative in the solvent. , Preferably 0.
Make diastereomeric salts by contacting with 5 to 1.0 moles. At this time, mineral acids such as hydrochloric acid and sulfuric acid, and organic carboxylic acids such as formic acid and acetic acid may coexist. The amount of the mineral acid or the organic carboxylic acid used is 0.5 to 1 to 1 mol of the 2-piperazinecarboxylic acid derivative together with the resolving agent.
1 mole, more preferably 0.6 to 1.0 mole.

Here, as a solvent to be used, both the 2-piperazinecarboxylic acid derivative and the resolving agent can be charged at a salt concentration of 25 wt% or more without chemically deteriorating in the solution. Any material can be used as long as it selectively precipitates one optically active diastereomer salt. For example, water, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and tert-butanol, or a mixed solvent thereof can be used.

Here, the salt concentration means the concentration of the salt formed by the 2-piperazinecarboxylic acid derivative to be split and the resolving agent. When splitting by adding a mineral acid or an organic carboxylic acid, It means the concentration of the entire salt formed by the 2-piperazinecarboxylic acid derivative and the resolving agent, and the mineral acids and organic carboxylic acids to be added. Specifically, it is expressed by (2-piperazinecarboxylic acid derivative + resolving agent + added mineral acid or organic carboxylic acid) / total weight × 100.

As a method of bringing the resolving agent into contact with the 2-piperazinecarboxylic acid derivative, the 2-piperazinecarboxylic acid derivative and the resolving agent may be added to the solvent at once, or they may be added sequentially. Further, a salt previously prepared from a 2-piperazinecarboxylic acid derivative and a resolving agent,
It may be dissolved in the solvent. Similarly, when mineral acids, organic carboxylic acids and the like coexist, they may be added at once, or they may be added sequentially. The order in which they are added is not particularly limited.

When the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, a sparingly soluble diastereomer salt precipitates out of the solution.

The temperature at which the sparingly soluble diastereomer salt is precipitated 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 according to the purpose. A range is preferred.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation. By subjecting the crystals of the sparingly soluble diastereomer salt to a recrystallization operation, the intended high-purity diastereomer salt can be obtained.

The diastereomer salt thus obtained is desolvated by an appropriate method to separate and collect the (+)-2-piperazinecarboxylic acid derivative or the (-)-2-piperazinecarboxylic acid derivative and the resolving agent. can do.

As a method for desolving a diastereomer salt, a generally known method, that is, a method of treating with an acid or an alkali in an aqueous solvent, a method of using an ion exchange resin, and the like can be applied. For example, when a diastereomer salt is salted by adding an aqueous alkali solution such as sodium hydroxide in water and then extracted with an organic solvent such as dichloromethane, the 2-piperazinecarboxylic acid derivative is extracted into an organic layer. Is concentrated and crystallized to obtain the desired optically active 2-piperazinecarboxylic acid derivative. Then
After adding a mineral acid such as hydrochloric acid or sulfuric acid to the raffinate aqueous layer to adjust the pH to 1 to 2, the precipitated resolving agent is separated by filtration.
Alternatively, the resolving agent can be recovered by extraction with an organic solvent such as dichloromethane.

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

The optically active 2-piperazinecarboxylic acid derivative obtained according to the present invention is useful as an intermediate for pharmaceuticals.

[0025]

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

The optical purity of the 2-piperazinecarboxamides contained in the diastereomer salts obtained in the examples was determined, for example, by the following method. The crystals of the diastereomer salt were salted with 10% ammonia water at a molar ratio of 5 times the amount of N-tert-butyl-2-piperazinecarboxamide, and then dichloromethane was added, followed by stirring for 10 minutes. Next, the dichloromethane layer obtained by liquid separation was dried over anhydrous magnesium sulfate, and then dichloromethane was distilled off to obtain crude optically active N-tert-butyl-2-piperazinecarboxamide. Its optical activity N-te
rt-butyl-2-piperazinecarboxamide 10
To 0.1 ml of a solution of 15 mg of acetonitrile in 10 ml of acetonitrile was added 1 ml of a solution of 400 mg of O, O'-di-p-toluoyl-L-tartaric anhydride in 100 ml of acetonitrile, and the mixture was allowed to stand for about 10 minutes. Nt
tert-Butyl-2-piperazinecarboxamide was reacted with O, O'-di-p-toluoyl-L-tartaric anhydride. 0.2 g of 85% phosphoric acid in 100 m of water
Then, 1 ml of the solution dissolved in 1 l was added, and the mixture was allowed to stand for about 10 minutes to hydrolyze excess O, O'-di-p-toluoyl-L-tartaric anhydride. The column used for the analysis was CAPCELLPAK
C18 SG120 (SHISEIDO), mobile phase 0.
04% phosphoric acid aqueous solution / acetonitrile = 30/70 (v /
v) was used. Column temperature 25 ° C, flow rate 0.7ml / m
In, detection was performed at UV (210 nm). (+)-
The diastereomer formed by reacting N-tert-butyl-2-piperazinecarboxamide with O, O'-di-p-toluoyl-L-tartaric anhydride is 7.3 minutes,
The diastereomer formed by the reaction of (-)-N-tert-butyl-2-piperazinecarboxamide with O, O'-di-p-toluoyl-L-tartaric anhydride is 8.8.
Detected in minutes. The optical purity of 2-piperazinecarboxamides in which the hydrogen atoms at the 1- and 4-positions were substituted with a benzyl group or the like was determined by high performance liquid chromatography using a CHIRALCEL OD column (manufactured by Daicel Chemical Industries, Ltd.). And asked.

Example 1 (±) -N-tert-butyl-2-piperazinecarboxamide (hereinafter referred to as (±) -N-tert-butyl-2
-Piperazinecarboxamide with "(±) -BPCA"
Abbreviated. 27.8 g (0.15 mol), 45.2 g (0.15 mol) of N-tosyl-D-glutamic acid and 90 g of water were equipped with a thermometer, a condenser and a stirrer.
The mixture was charged into a one-liter 1 L flask and heated to 50 ° C. 50 ℃
And cooled to 30 ° C. over 4 hours.
After stirring at 30 ° C. for 2 hours, the precipitate was filtered to obtain 37.3 g of a diastereomer salt as white crystals. The optical purity of (+)-BPCA in the crystal was 95.0% ee,
The yield based on (+)-BPCA was 70.2%.
In addition, the charged salt concentration was 44.7% by weight. Example 2 (±) -BPCA 27.8 g (0.15 mol) and N-benzenesulfonyl-L-glutamic acid 43.1 g (0.
15 mol) and 75 g of water were charged into a four-necked 1 L flask equipped with a thermometer, a condenser, and a stirrer, and heated to 62 ° C. After stirring at 62 ° C. for 1 hour, 30
Cooled to ° C. After stirring at 30 ° C. for 2 hours, the precipitate was filtered to obtain 32.7 g of a diastereomer salt as white crystals. The optical purity of (−)-BPCA in the crystal is 72.1%
ee, and the yield based on the charged (−)-BPCA is 7
1.7%. The salt concentration was 48.6 wt%.
Met.

Example 3 (±) -BPCA 18.5 g (0.10 mol), N-benzenesulfonyl-L-aspartic acid 13.7 g
(0.05 mol), 1.8 g (0.05 mol) of hydrochloric acid, and 60 g of 80 wt% methanol were charged into a four-neck 1 L flask equipped with a thermometer, a condenser, and a stirrer.
Heated to ° C. After stirring at 71 ° C for 1 hour, the mixture was cooled to 30 ° C over 3 hours. After stirring at 30 ° C. for 2 hours, the precipitate was filtered, and 20.0 g of a diastereomer salt of white crystals was obtained.
I got The optical purity of (−)-BPCA in the crystal was 96.
It was 3% ee, and the yield based on the charged (-)-BPCA was 82.1%. The salt concentration was 36.3 wt.
%Met.

[0029]

The optically active 2- (2-piperazinecarboxylic acid) derivative is optically resolved using the resolving agent of the present invention.
Since the piperazine carboxylic acid derivative is produced in high yield, the recovery rate of the resolving agent is high, and high concentration charging is possible, so that an optically active 2-piperazine carboxylic acid derivative with high production efficiency can be produced.

Claims (9)

[Claims] 1. A method for producing an optically active 2-piperazinecarboxylic acid derivative, comprising: performing optical resolution of a 2-piperazinecarboxylic acid derivative using an optically active acidic amino acid derivative as a resolving agent at a salt concentration of 25% by weight or more. . 2. An optically active acidic amino acid derivative represented by the following general formula (I): (Wherein R ¹ is i) hydrogen, ii) unsubstituted or halogen-substituted linear or branched alkyl group having 1 to 10 carbon atoms, iii) unsubstituted or alkyl having 1 to 10 carbon atoms Group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a halogen group, or an aryl group substituted with a hydroxyl group; iv) an aromatic ring is unsubstituted or
To an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a halogen group, or an aralkyl group substituted with a hydroxyl group, v) an aromatic ring is unsubstituted, or 1 to 10 carbon atoms.
Represents an alkyl group, an alkoxyl group having 1 to 10 carbon atoms, a halogen group, or an aralkyloxy group substituted with a hydroxyl group, and n represents 1 or 2. 2. An optically active acidic amino acid derivative represented by the formula:
3. The method for producing an optically active 2-piperazinecarboxylic acid derivative according to item 1. 3. An optically active acidic amino acid derivative represented by the following general formula (II): (Wherein R ² is i) an unsubstituted or halogen-substituted linear or branched alkyl group having 1 to 10 carbon atoms, ii) an unsubstituted or alkyl group having 1 to 10 carbon atoms, 1 to 10 alkoxyl groups, nitro groups,
A halogen group or an aryl group substituted with a hydroxyl group, i
ii) an aralkyl 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 halogen group, or a hydroxyl group;
n represents 1 or 2. 2. The method for producing an optically active 2-piperazinecarboxylic acid derivative according to claim 1, which is an optically active acidic amino acid derivative represented by the formula: 4. An optically active acidic amino acid derivative represented by the following general formula (III): Wherein R ³ is i) hydrogen, ii) a straight or branched alkyl group having 1 to 4 carbon atoms, iii) a nitro group, i
v) represents a halogen group, and n represents 1 or 2. 4. The method for producing an optically active 2-piperazinecarboxylic acid derivative according to claim 3, which is an optically active acidic amino acid derivative represented by the formula: 5. A 2-piperazinecarboxylic acid derivative represented by the following general formula (IV): (Wherein R ⁴ and R ⁵ may be the same or different, i) a hydrogen atom, ii) an alkyl group having 1 to 10 carbon atoms, iii) unsubstituted or alkyl having 1 to 10 carbon atoms An aryl group substituted with an alkoxyl group having 1 to 10 carbon atoms, a nitro group or a halogen group, iv)
An aralkyl 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, v) a carbon atom having 1 carbon atom
Represents 10 to 10 alkoxycarbonyl groups, and tBu is
Indicates a tert-butyl group. The optical activity 2 according to any one of claims 1 to 4, wherein
A method for producing a piperazine carboxylic acid derivative. 6. A 2-piperazinecarboxylic acid derivative represented by the formula (V): The method for producing an optically active 2-piperazinecarboxylic acid derivative according to claim 5, wherein the compound is a compound represented by the formula: wherein tBu represents a tert-butyl group. 7. The 2-piperazinecarboxylic acid derivative has the formula (VI): The method for producing an optically active 2-piperazinecarboxylic acid derivative according to claim 5, wherein the compound is a compound represented by the formula: wherein tBu represents a tert-butyl group. 8. The method according to claim 1, wherein
A method for producing an optically active 2-piperazinecarboxylic acid derivative, wherein the resolving solvent is water, an alcohol, or a mixed solvent of water and an alcohol. 9. The method according to claim 1, wherein:
A method for producing an optically active 2-piperazinecarboxylic acid derivative, wherein the molar ratio of the resolving agent to the 2-piperazinecarboxylic acid derivative is 0.4 to 1.1.