WO2012033187A1

WO2012033187A1 - Method for producing optically active 2-aminobutyric acid

Info

Publication number: WO2012033187A1
Application number: PCT/JP2011/070575
Authority: WO
Inventors: 哲雄安藤; 井上　敦; 将紀杉田
Original assignee: 三菱瓦斯化学株式会社
Priority date: 2010-09-09
Filing date: 2011-09-09
Publication date: 2012-03-15
Also published as: JP2013241338A

Abstract

The present invention pertains to a method for producing optically active 2-aminobutyric acid containing a step for obtaining a diastereometric salt of optically active 2-aminobutyric acid and optically active tartaric acid by combining optically active tartaric acid and aldehyde with 2-aminobutyric acid in an organic solvent, and heating the same. The present invention makes it possible to produce optically active 2-aminobutyric acid easily and with a high yield, without requiring any special facilities.

Description

Method for producing optically active 2-aminobutyric acid

Reference to related applications

This application is based on Japanese Patent Application No. 2010-2018867 (filing date: September 9, 2010), which is a prior Japanese patent application, and claims the benefit of its priority. The entirety is hereby incorporated by reference.

Background of the Invention

The present invention relates to a process for producing optically active 2-aminobutyric acid.

Related Art Optically active 2-aminobutyric acid is well known as an intermediate for producing pharmaceuticals, agricultural chemicals and industrial chemicals. For example, it can be used as a raw material for the antiepileptic drug levetiracetam.

As a method for producing optically active 2-aminobutyric acid, a method using an enzyme reaction, a method using preferential crystallization or optical resolution with a resolving agent, and the like are known.

Examples of the production method using an enzymatic reaction include a method of obtaining D-2-aminobutyric acid by reacting hydantoinase with 5-ethylhydantoin, or an optically active 2-aminobutyric acid by reacting 2-aminobutyric acid amide with amidase. The method of obtaining is known. However, the method using an enzyme reaction is generally slow, and the desired optically active 2-aminobutyric acid stereo is limited by the stereoselectivity of the enzyme. Moreover, in an enzyme reaction, impurities derived from microorganisms may be mixed. For this reason, the removal operation of microorganisms is needed and a process becomes complicated.

As a method of resolution by preferential crystallization, a method of preferential crystallization using 2-aminobutyric acid as p-toluenesulfonate is known. As a method of utilizing optical resolution by a resolving agent, a diastereomeric method is known in which a fractional crystallization is performed by forming a diastereomeric salt using an optically active 2-phenoxypropionic acid derivative as a resolving agent. However, in these methods, when racemic 2-aminobutyric acid is used as a raw material, the yield of the target optically active 2-aminobutyric acid is limited to 50%. In addition, since the target steric enantiomer remains only by preferential crystallization or optical resolution with a resolving agent, it is difficult to obtain optically active 2-aminobutyric acid with high optical purity. Therefore, the optical purity must be further improved by a refining operation such as recrystallization, and the number of operation procedures is increased, which is practically disadvantageous.

The isomerization crystallization method is known as a method for obtaining an optically active amino acid at a high yield exceeding the theoretical yield of 50% in the above preferential crystallization and diastereomer methods. In the isomerization crystallization method, an amino acid of a diastereomeric salt composed of an optically active amino acid and an optically active resolving agent is epimerized in the presence of a catalyst such as an aldehyde, and the diastereomeric salt of the target optically active amino acid is obtained. Crystallize.

The isomerization crystallization method has been reported for specific amino acids such as proline (Chem. Rev. 2006, 106, 2711-2733). Further, in the optically active 2-aminobutyric acid amide of a derivative of 2-aminobutyric acid, an optically active 2-aminobutyric acid is obtained by epimerizing 2-aminobutyric acid amide of a diastereomeric salt composed of 2-aminobutyric acid amide and optically active tartaric acid. A method for obtaining an amide in a high yield is known (Japanese Patent Laid-Open No. 2009-19036). In the isomerization crystallization method, as in the diastereomer method, an appropriate resolving agent must be selected. However, since the usable optical resolution agent is specific for each substance to be resolved, it is difficult to predict the resolution agent. Therefore, the isomerization crystallization conditions used in the production of optically active 2-aminobutyric acid amide are not necessarily applicable to the production of optically active 2-aminobutyric acid. Therefore, there is no known method for epimerizing diastereomeric salts with respect to 2-aminobutyric acid.

Furthermore, when the isomerization crystallization method is carried out with an appropriate resolving agent, the optically active amino acid is obtained as a diastereomeric salt with the resolving agent. In order to obtain only the optically active amino acid, the optical resolving agent must be separated from the diastereomeric salt. In general, when an optically active compound is desired to be obtained from a diastereomer salt by a diastereomer method or the like, a method of separating the resolving agent into an acid salt or a base salt by adding an acid or a base is performed. For example, when a racemic amine is optically resolved with optically active tartaric acid, a method of separating and recovering optically active tartaric acid as a sodium salt or potassium salt by adding an inorganic base to the obtained diastereomeric salt has been reported ( JP-A-7-188097). However, amino acids have the property of being easily dissolved in water and difficult to dissolve in organic solvents, like the inorganic acid salt or inorganic base salt of the resolving agent. Therefore, in the case of diastereomeric salts of amino acids, the method of adding an inorganic base cannot be applied in many cases, and it is difficult to efficiently isolate amino acids by separation, separation or extraction.

JP-A-5-070415 (EP0499376A1) discloses a method for obtaining a preferred optically active isomer by dividing an optically active isomer mixture of α-amino acids. However, the amino acids and resolving agents here are different from those of the present invention. In addition, when the reaction was actually attempted using the amino acids and the resolving agent used in the present invention with reference to the description in the examples of the patent application, the asymmetric conversion did not proceed well.

In the known methods for producing optically active 2-aminobutyric acid using an optical resolving agent, when racemic 2-aminobutyric acid is used as a raw material, the theory of the desired optically active 2-aminobutyric acid is used. The yield was 50%. In addition, when the enantiomer of the target optically active 2-aminobutyric acid is excessively present, the yield is further reduced, and thus it is not practical from the viewpoint of productivity.

Therefore, in order to achieve an improvement in yield, it is considered effective to establish an isomerization crystallization method into a diastereomeric salt composed of a target optically active 2-aminobutyric acid and an optically active resolving agent, We proceeded with the examination. In this case, it is necessary to remove the resolving agent after obtaining the diastereomeric salt of optically active 2-aminobutyric acid. Therefore, there is a demand for a method for producing optically active 2-aminobutyric acid in a simple and high yield without requiring special equipment.

In the presence of an organic solvent, the inventors of the present invention aimed at producing L-2-aminobutyric acid represented by the following formula (1) or D-2-aminobutyric acid represented by the following formula (2), or a mixture thereof. The optically active 2-tarbutyric acid that can form a sparingly soluble diastereomeric salt is reacted with the optically active 2-tarbutyric acid to perform optical resolution by the diastereomeric method, and at the same time, by heating and stirring in the presence of an aldehyde. Aminobutyric acid was racemized to successfully produce the desired diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid.

Further, by separating the optically active 2-aminobutyric acid from the diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid obtained in the above reaction mixture or in the above reaction, the optically active 2-aminobutyric acid is separated. We succeeded in obtaining butyric acid in high yield.

The present invention is based on these findings.

Therefore, an object of the present invention is to provide a method for producing optically active 2-aminobutyric acid simply and in high yield without requiring special equipment.

That is, the present invention relates to a method for producing optically active 2-aminobutyric acid as follows.
[1] The method includes a step of obtaining a diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid by heating the optically active tartaric acid and aldehyde in the presence of 2-aminobutyric acid in an organic solvent. And a method for producing optically active 2-aminobutyric acid.
[2] The method according to [1] above, comprising a step of separating optically active 2-aminobutyric acid from the diastereomeric salt.
[3] The method of [2], wherein the optically active 2-aminobutyric acid is separated from the diastereomeric salt by adding an amine.
[4] The amine is represented by the following formula (3):

(In the formula, R1, R2, and R3 are hydrogen atoms or hydrocarbon groups, and R1, R2, and R3 have a total carbon number of 1 to 8, and these may be bonded to each other to form a ring. )
The method of [3] above, which is at least one selected from the group consisting of amines represented by the formula:
[5] The method according to any one of [1] to [4], wherein the aldehyde is salicylaldehyde.
[6] Any of the above [1] to [5], wherein the organic solvent is at least one selected from the group consisting of alcohols having a linear or branched alkyl group having 1 to 8 carbon atoms. That way.

The method for producing optically active 2-aminobutyric acid of the present invention increases the abundance of the target optically active substance by performing both racemization of 2-aminobutyric acid and optical resolution of 2-aminobutyric acid with optically active tartaric acid. The yield can be improved. Therefore, the theoretical yield is 50% in the conventional optical resolution method, whereas the theoretical yield can be improved to 100% according to the method of the present invention. Therefore, according to the present invention, the productivity of the target optically active 2-aminobutyric acid can be made extremely high.

The optically active 2-aminobutyric acid obtained by the method of the present invention is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and industrial chemicals.

Detailed description of the invention

More specifically, the method for producing optically active 2-aminobutyric acid according to the present invention heats 2-aminobutyric acid in an organic solvent in the presence of optically active tartaric acid and an aldehyde, and passes through the aldehyde and a Schiff base. Both the racemization of 2-aminobutyric acid and the optical resolution of 2-aminobutyric acid with optically active tartaric acid proceed to enrich the desired diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid. Process.

Furthermore, the present invention relates to an optically active 2-aminobutyric acid obtained by heating in the presence of 2-aminobutyric acid, optically active tartaric acid, and aldehyde, and then purifying the reaction mixture or the reaction mixture. Separation and acquisition of D-form or L-form 2-aminobutyric acid from a diastereomeric salt of and an optically active tartaric acid. Preferably, the separation is performed by adding an amine.

2-Aminobutyric acid The 2-aminobutyric acid used as a raw material in the present invention is an L-form represented by the following formula (1), a D-form represented by the following formula (2), a mixture thereof, or a D-form And a racemate in which an equal amount of L form exists. When an inorganic salt, a strong acid or a strong base is contained, 2-aminobutyric acid is preferably freed by neutralization or solvent washing.

Optically active tartaric acid In the method of the present invention, optically active tartaric acid is used as a resolving agent.

The optically active tartaric acid used is D-form, L-form, or a mixture thereof. When a mixture of D-form and L-form is used, desirably, the optical purity of tartaric acid is 95% e.e. e. (Enantiomeric excess) or more, preferably 98% e.e. e. That's it.

The optically active tartaric acid is used in a molar amount relative to 2-aminobutyric acid, which is a raw material, because tartaric acid is a dibasic acid and excessive use of tartaric acid may inhibit Schiff base formation. The ratio is preferably in the range of 0.5 to 5.0, more preferably in the range of 0.5 to 1.0.

As the optically active tartaric acid to be used, D-tartaric acid is used when producing L-2-aminobutyric acid, and L-tartaric acid is used when producing D-2-aminobutyric acid.

Aldehyde In the process of the present invention, an aldehyde is used as a catalyst.

The type of aldehyde to be used can be appropriately determined in consideration of the difficulty of side reactions and the ease of purification in the subsequent steps. Aromatic aldehydes such as salicylaldehyde and benzaldehyde are preferred specific examples, among which salicylaldehyde is particularly preferred.

If the amount of aldehyde used is large, the reaction can be completed in a short time, but if the amount used is excessive, it may be economically disadvantageous. For this reason, the amount of aldehyde used is preferably in the range of 0.05 to 0.75, more preferably in the range of 0.1 to 0.5 in terms of molar ratio to 2-aminobutyric acid as a raw material. It is.

In addition to the other components , formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, etc., for the raw material 2-aminobutyric acid, in order to rapidly advance the racemization and crystallization of the desired diastereomeric salt A lower fatty acid, an inorganic acid such as hydrochloric acid, or an inorganic salt such as ammonium chloride may be added as a catalytic amount as appropriate. If the amount used is large, the optical purity of the target optically active 2-aminobutyric acid may be lowered. Further, the amine in the separation step of the optically active 2-aminobutyric acid performed after the diastereomeric salt crystallization is performed. The amount added may be economically disadvantageous.

For example, when acetic acid, which is a lower fatty acid, is added, the amount used is preferably within a range of 0.01 to 0.5, more preferably 0.05 to 0 in terms of a molar ratio with respect to the amino acid that is a raw material. Within the range of .25.

Organic Solvent As an organic solvent used in the present invention, a solvent in which a salt of 2-aminobutyric acid and tartaric acid causes a difference in solubility due to the difference in stericity of 2-aminobutyric acid is appropriately selected. Furthermore, a solvent having low reactivity with 2-aminobutyric acid, tartaric acid, and aldehyde is preferable, and alcohols, aromatic hydrocarbons, and nitriles are preferable. For example, the alcohol is preferably an alcohol having a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Examples include 2-butanol, isobutanol, cyclohexanol, and benzyl alcohol. Preferred examples of aromatic hydrocarbons include benzene, toluene and xylene, and preferred examples of nitriles include acetonitrile.

These organic solvents are used alone or in admixture of two or more.

As the organic solvent to be used, alcohols are preferable from the viewpoint of higher optical purity and chemical purity, more preferably alcohol having a linear or branched alkyl group having 1 to 8 carbon atoms, Specific examples of suitable solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or isobutanol.

The water content of the organic solvent used in the present invention may be appropriately determined in consideration of the difficulty of side reactions and the solubility of diastereomeric salts in the solvent. When the water content is high, the yield may decrease due to an increase in the solubility of the diastereomeric salt in the solvent.

Therefore, the water content of the organic solvent is preferably in the range of 0.001 to 5.0% by mass, more preferably in the range of 0.1 to 2.0% by mass.

The amount of the organic solvent used may be appropriately adjusted according to the amount of 2-aminobutyric acid used as a raw material, and is not particularly limited. If the amount of the solvent is small, both chemical purity and optical purity become insufficient, and the slurry concentration becomes high and stirring may become difficult. Further, if the amount of the solvent is large, it may lead to industrial disadvantage because it leads to a decrease in volumetric efficiency and a decrease in yield.

Therefore, the amount of the organic solvent used is preferably within a range of 1.5 to 10.0, more preferably within a range of 2.0 to 6.0, by mass ratio with respect to 2-aminobutyric acid as a raw material. Amount.

Amine The amine used in the present invention is appropriately selected from those capable of dissociating the salt of 2-aminobutyric acid and tartaric acid and forming a good salt with tartaric acid. As a preferable amine, a salt of tartaric acid and an amine has high solubility in an organic solvent, and more preferable examples include the following formula (3):

(In the formula, R1, R2, and R3 are hydrogen atoms or hydrocarbon groups, and R1, R2, and R3 have a total carbon number of 1 to 8, and these may be bonded to each other to form a ring. )
And amines represented by

In the above formula, the hydrocarbon group that can be selected as R1 to R3 is preferably a linear or branched alkyl group having 1 to 8 carbon atoms (more preferably 1 to 4 carbon atoms), carbon number A cycloalkyl group having 3 to 8 carbon atoms, or an aromatic hydrocarbon group having 6 to 8 carbon atoms. Specific examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, and isobutyl. Specific examples of the cycloalkyl group include cyclopentyl and cyclohexyl. Can be mentioned. The aromatic group includes phenyl, and the aromatic hydrocarbon group having 6 to 8 carbon atoms includes benzyl in addition to phenyl.

In addition, when R1 to R3 are bonded to each other to form a ring, R1 and R3, R2 and R3, or R1 and R3 may form a heterocycle together with the nitrogen atom in the formula. In this case, the remainder not related to ring formation is preferably a hydrogen atom or a hydrocarbon group (preferably a hydrogen atom).

More specifically, examples of the amine include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, n-propylamine, isopropylamine, diisopropylamine, n-butylamine, tert-butylamine, sec-butylamine, diisobutylamine, Examples include cyclohexylamine, benzylamine, and aniline. These amines are used alone or in admixture of two or more. Specific examples of preferred amines include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, n-propylamine, isopropylamine, diisopropylamine, n-butylamine, tert-butylamine, sec-butylamine, diisobutylamine. More preferred specific examples include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and triethylamine.

The amount of amine used can be appropriately adjusted according to the amount of tartaric acid used as a resolving agent and the type of amine. If the amount of amine used is small, the dissociation of the salt of 2-aminobutyric acid and tartaric acid becomes insufficient, and the purity of the optically active 2-aminobutyric acid may be reduced. In addition, when the amount of amine used is large, the yield of optically active 2-aminobutyric acid may decrease because 2-aminobutyric acid and amine form a salt.

For this reason, the amount of amine used is preferably in the range of 1.0 to 4.0, more preferably in the range of 1.5 to 2.5 as a molar ratio to tartaric acid.

Hereinafter, details of the production method according to the present invention will be described.

First, 2-aminobutyric acid, optically active tartaric acid and aldehyde are mixed in an organic solvent, and racemization of 2-aminobutyric acid and optical resolution of 2-aminobutyric acid with optically active tartaric acid are allowed to proceed in solution. A diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid is produced.

The reaction temperature for producing a diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid depends on the type and amount of the organic solvent used, and the desired optically active 2-aminobutyric acid and optical activity depend on the reaction temperature. The effect of the enrichment crystallization rate of the diastereomeric salt with tartaric acid and the solubility of the diastereomeric salt in the solvent are different and are not particularly limited. However, when the reaction temperature is low, the completion of the reaction may be delayed.

Therefore, the reaction temperature is typically 30 ° C. or higher and below the boiling point of the organic solvent used, preferably 50 ° C. or higher and below the boiling point of the organic solvent used, more preferably 65 ° C. or higher and below the boiling point of the organic solvent used. Is desirable. The reaction time is not particularly limited, and may be appropriately determined while monitoring the deviation of the optical purity of 2-aminobutyric acid by tracking the reaction using an analytical instrument such as high performance liquid chromatography.

In order to achieve the desired reaction temperature, heat generated by mixing the raw materials may be used, but since the temperature can be adjusted appropriately and quickly, heat treatment is usually performed.

If the reaction does not proceed sufficiently, or the reaction rate is slow and the reaction time is long, the reaction can be promoted by appropriately performing a concentration operation, catalyst addition, or poor solvent addition.

As a method for separating optically active 2-aminobutyric acid from a diastereomeric salt, tartaric acid can be removed using, for example, an electrodialyzer. Alternatively, tartaric acid can be removed as an amine salt by adding an amine in a solvent. Alternatively, optically active 2-aminobutyric acid can be crystallized by adding a poor solvent in an aqueous solution after the inorganic base treatment. Alternatively, tartaric acid can be removed using an ion exchange resin after the inorganic or organic base treatment. *

Of these, the method of removing tartaric acid as an amine salt by adding an amine in a solvent is preferred because of the ease of operation.

The amine may be added as it is to the crystallization solution of the diastereomeric salt (one-pot treatment), or the amine may be added after the diastereomeric salt is isolated.

Examples of methods for isolating diastereomeric salts include filtration by suction filtration, filtration by pressure filtration, and centrifugation. The recovered diastereomeric salt is then dissolved in an organic solvent and an amine is added. As a result, the tartaric acid moiety in the diastereomeric salt can be converted to an amine salt, which can be separated from the optically active 2-aminobutyric acid. Here, the organic solvent for dissolving the diastereomeric salt can be selected from the same range as the organic solvent containing the above-mentioned raw materials, and this may be the same organic solvent used in the above step. May be different.

Although it is the reaction temperature at the time of adding amine, it may be suitably adjusted according to the kind of amine and the organic solvent to be used, and is not particularly limited. When the reaction temperature is low, tartaric acid / amine salt may be precipitated. In this case, the resulting optically active 2-aminobutyric acid is lowered in purity. Therefore, the reaction temperature at the time of amine addition is usually 0 ° C. to 100 ° C. or below the boiling point of the organic solvent used, preferably 20 ° C. to 100 ° C. or below the boiling point of the organic solvent used.

Finally, the optically active 2-aminobutyric acid remaining undissolved is separated and recovered. Separation is performed using a method such as filtration or centrifugation. The obtained optically active 2-aminobutyric acid is washed with a solvent as required (for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or isobutanol as a solvent washing solvent) These solvents can be used alone or in admixture of two or more types), and purification such as recrystallization may be performed.

In this way, optically active 2-aminobutyric acid useful as an intermediate for producing pharmaceuticals, agricultural chemicals and industrial chemicals can be obtained simply and in high yield.

Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the following examples.

The reaction tracking and optical purity measurement of the present invention were performed under the following conditions.
HPLC Analysis conditions <br/> eluent 1 mM CuSO ₄ solution flow rate 0.5 mL / min
Column SUMICHIRAL OA-5000
(Made by Sumika Chemical Analysis Co., Ltd.)
Column thermostat 30 ° C
Detector UV254nm

Example 1
10.0 g of L-2-aminobutyric acid and 8.1 g of L-tartaric acid were suspended in 50 g of 2-butanol / methanol mixed solvent (weight composition ratio 1: 1), and 2.3 g of salicylaldehyde was added. After stirring with heating at 75 ° C. for 45 hours, suction filtration was performed to obtain a diastereomeric salt of D-2-aminobutyric acid / L-tartrate (molar composition ratio 2: 1). The weight of the obtained diastereomeric salt was 14.2 g (yield 79%), and the optical purity was 86.3% e.e. e. Met.

The obtained D-2-aminobutyric acid / L-tartrate (molar composition ratio 2: 1) was suspended in 50 g of a 2-propanol / methanol mixed solvent (weight composition ratio 1: 2), and the reaction temperature was 30 ° C. 14 g of 30% trimethylamine aqueous solution was added. After stirring at the same temperature for 4 hours, suction filtration was performed, and the resulting cake was washed with 35 g of methanol. Thereafter, the obtained cake was dried to obtain 6.19 g of D-2-aminobutyric acid (total yield: 62%) as a white powder. As a result of analyzing the obtained D-2-aminobutyric acid by high performance liquid chromatography (HPLC), the chemical purity was 99.9%, and the optical purity was 99.8% e.e. e. Met.

Example 2
2.01 g of D-2-aminobutyric acid and 1.65 g of D-tartaric acid were suspended in 10 g of a 2-propanol / methanol mixed solvent (weight composition ratio 1: 1), and 0.47 g of salicylaldehyde was added. After heating and stirring at 75 ° C for 43 hours and gradually cooling to 40 ° C, 1.4 g of 70% ethylamine aqueous solution and 5 g of methanol were added. After stirring at the same temperature for 4 hours, suction filtration was performed, and the resulting cake was washed with 15 g of methanol. Thereafter, the obtained cake was dried to obtain 1.46 g of L-2-aminobutyric acid (yield 73%) as a white powder. As a result of analyzing the obtained L-2-aminobutyric acid by high performance liquid chromatography (HPLC), the chemical purity was 99.7% and the optical purity was 99.9% e.e. e. Met.

Example 3
20.0 g of D-2-aminobutyric acid and 16.1 g of D-tartaric acid were suspended in 80 g of a 2-propanol / methanol mixed solvent (weight composition ratio 1: 1), and 4.7 g of salicylaldehyde was added. After stirring with heating at 70 ° C. for 18 hours and gradually cooling to 30 ° C., 18.9 g of a 51% dimethylamine aqueous solution and 100 g of methanol were added. After stirring at the same temperature for 3 hours, suction filtration was performed, and the resulting cake was washed with 120 g of methanol. Thereafter, the obtained cake was dried to obtain 13.9 g of L-2-aminobutyric acid (yield 70%) as a white powder. As a result of analyzing the obtained L-2-aminobutyric acid by high performance liquid chromatography (HPLC), the chemical purity was 99.7% and the optical purity was 99.7% e.e. e. Met.

Example 4
L-2-aminobutyric acid 2.0 g and L-tartaric acid 1.65 g were suspended in 10 g of 2-propanol / methanol mixed solvent (weight composition ratio 1: 1), and 0.24 g of salicylaldehyde was added. After heating and stirring at 75 ° C. for 72 hours and gradually cooling to 30 ° C., 2.21 g of triethylamine and 5 g of methanol were added. After stirring at the same temperature for 24 hours, suction filtration was performed, and the resulting cake was washed with 15 g of methanol. Thereafter, the obtained cake was dried to obtain 1.43 g of D-2-aminobutyric acid (yield 72%) as a white powder. As a result of analyzing the obtained D-2-aminobutyric acid by high performance liquid chromatography (HPLC), the chemical purity was 99.9% and the optical purity was 93.6% e.e. e. Met.

Reference example 1
10.0 g of L-2-aminobutyric acid and 8.1 g of L-tartaric acid were suspended in 10 g of a 2-butanol / methanol mixed solvent (weight composition ratio 1: 1), and 2.3 g of salicylaldehyde was added. After stirring with heating at 75 ° C. for 45 hours, suction filtration was performed to obtain a diastereomeric salt of D-2-aminobutyric acid / L-tartrate (molar composition ratio 2: 1). The weight of the obtained diastereomeric salt was 14.2 g (yield 79%), and the optical purity was 86.3% e.e. e. Met.

The obtained D-2-aminobutyric acid / L-tartrate (molar composition ratio 2: 1) was suspended in 35 g of a 2-propanol / methanol mixed solvent (weight composition ratio 1: 2), and the reaction temperature was 30 ° C. 12 g of 30% trimethylamine aqueous solution was added. After stirring at the same temperature for 4 hours, suction filtration was performed, and the resulting cake was washed with 35 g of methanol. Thereafter, the obtained cake was dried to obtain 4.41 g of D-2-aminobutyric acid (total yield: 44%) as a white powder. As a result of analyzing the obtained D-2-aminobutyric acid by high performance liquid chromatography (HPLC), the chemical purity was 99.9%, and the optical purity was 99.8% e.e. e. Met.

Comparative Example 1
2.02 g of D-2-aminobutyric acid and 1.63 g of D-tartaric acid were dissolved in 8.0 g of water, and 0.486 g of salicylaldehyde was added. The mixture was heated and stirred at 80 ° C. for 40 hours and gradually cooled to 30 ° C. However, the diastereomeric salt of 2-aminobutyric acid and D-tartaric acid did not precipitate in water and could not be recovered.

Comparative Example 2
2.01 g of L-2-aminobutyric acid and 2.50 g of (−)-camphorsulfonic acid were dissolved in 8.0 g of methanol, and 0.480 g of salicylaldehyde was added. The mixture was heated and stirred at 65 ° C. for 40 hours and gradually cooled to 30 ° C. However, the diastereomeric salt of 2-aminobutyric acid and (−)-camphorsulfonic acid did not precipitate in methanol and could not be recovered.

Comparative Example 3
2.01 g of L-2-aminobutyric acid and 1.64 g of (+)-mandelic acid were suspended in 8.0 g of methanol, and 0.475 g of salicylaldehyde was added. The mixture was heated and stirred at 65 ° C. for 40 hours, gradually cooled to 30 ° C., filtered with suction, and the obtained cake was washed with 12 g of methanol. Thereafter, the obtained cake was dried to obtain 1.36 g of a diastereomeric salt of 2-aminobutyric acid and (+)-mandelic acid as a white powder. The obtained diastereomeric salt of 2-aminobutyric acid and (+)-mandelic acid was analyzed by high-performance liquid chromatography (HPLC). As a result, the optical purity of 2-aminobutyric acid was 0.0% e.e. e. The racemic form of

Claims

An optical activity comprising a step of obtaining a diastereomeric salt of optically active 2-aminobutyric acid and optically active tartaric acid by heating the optically active tartaric acid and aldehyde in the presence of 2-aminobutyric acid in an organic solvent. A method for producing 2-aminobutyric acid.
The method according to claim 1, further comprising a step of separating optically active 2-aminobutyric acid from the diastereomeric salt.
The method according to claim 2, wherein the optically active 2-aminobutyric acid is separated from the diastereomeric salt by adding an amine.
The amine is represented by the following formula (3):

(In the formula, R1, R2, and R3 are hydrogen atoms or hydrocarbon groups, and R1, R2, and R3 have a total carbon number of 1 to 8, and these may be bonded to each other to form a ring. )
The method of Claim 3 which is 1 or more types chosen from the group which consists of amines shown by these.
The method according to any one of claims 1 to 4, wherein the aldehyde is salicylaldehyde.
The organic solvent according to any one of claims 1 to 5, wherein the organic solvent is at least one selected from the group consisting of alcohols having a linear or branched alkyl group having 1 to 8 carbon atoms. Method.