JP2006169158A - Method for producing optically active amino acids - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing an optically active valine and an optically active 2-aminobutanoic acid, with no need of any special apparatus in their production, by an optical resolution technique enabling relatively easily making its scale-up to industrial scale, without the need of functional group protection. <P>SOLUTION: The method comprises the following process: A racemic valine or racemic 2-aminobutanoic acid is reacted with a specific optically active 2-phenoxypropionic acid derivative in a medium consisting of water, a lower alcohol or a mixture thereof to form a sparingly soluble diastereomer composed of an optically active valine or optically active 2-aminobutanoic acid and the optically active 2-phenoxypropionic acid derivative followed by making a solid/liquid separation and then splitting the diastereomer in a mixture of water and a sparingly water-soluble organic solvent. Thereafter, the objective optically active valine or optically active 2-aminobutanoic acid and the optically active 2-phenoxypropionic acid derivative are retrieved from the aqueous layer and the organic solvent layer, respectively. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing optically active valine or optically active 2-aminobutanoic acid using an optical separating agent, and a diastereomer obtained in the step of optical separation.

  Optically active amino acids are expected to be widely used as chiral pools for pharmaceuticals and agricultural chemicals. For example, 2-aminobutanoic acid is reported to be used as an antiepileptic drug (Patent Document 1), an antihypertensive drug (Patent Document 2), etc. Has been.

There are the following methods (a to c) for producing optically active amino acids, but no special equipment is required during production, and c is an optical resolution because it can be scaled up relatively easily to an industrial scale. The law is drawing attention.
a. Biocatalytic method b. Asymmetric synthesis c. Optical resolution method

In optical resolution of amino acids, functional group protection is generally performed on either an amino group or a carboxy group. As an example of amino acid resolution that does not require functional group protection, for example, in 2-aminobutanoic acid, optical resolution using the following compounds has been announced.
1. Optical resolution using optically active sulfonic acid (Non-patent Document 1).
2. Optical resolution using optically active mandelic acid (Patent Document 3).
However, 1 is difficult to obtain a resolving agent and difficult to recover. As for No. 2, there is no description about the isolation of an amino acid from an amino acid-mandelic acid complex, and the optical purity of the amino acid is not described.

  The present inventors previously established a production method by optical resolution of optically active pipecolic acid using optically active 2-phenoxypropionic acid (Patent Document 4).

International Publication No. 2003/014080 Pamphlet European Patent Application No. 629627 JP 58-1105 A JP 2001-178253 A Bull.Chem.Soc.Jpn., Vol67 3012-3020 (1994)

    The present invention eliminates the need for special equipment at the time of manufacture, and is effective from racemic-valine or racemic-2-aminobutanoic acid without the need for functional group protection by an optical resolution method that can be scaled up relatively easily to an industrial scale. It is another object of the present invention to provide a method for separating and producing optically active valine or optically active 2-aminobutanoic acid.

The present invention adopts the following configurations (1) to (4) as means for solving the above problems.
(1) reacting racemic-valine or racemic-2-aminobutanoic acid with an optically active 2-phenoxypropionic acid derivative represented by the general formula (1) in a medium comprising water, a lower alcohol or a mixture thereof; A hardly soluble diastereomer that is a complex composed of an optically active valine and an optically active 2-phenoxypropionic acid derivative or an optically active 2-aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative is generated and separated into solid and liquid. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid.

(2) The optically active 2-phenoxypropionic acid derivative is separated from the mother liquor after the solid-liquid separation in the method of (1) above, and then the optical opposite to the optically active 2-phenoxypropionic acid derivative used It is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative by adding and reacting active 2-phenoxypropionic acid derivative. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid, wherein a hardly soluble diastereomer is produced and separated into solid and liquid.

(3) optically active valine or optically active 2-aminobutanoic acid which is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative The diastereomer is dissolved or suspended in a mixed solution of water and a water-insoluble organic solvent, and stirred to decompose the diastereomer, and optically active valine or optically active 2-aminobutanoic acid is separated from the aqueous layer. A method for producing optically active valine or optically active 2-aminobutanoic acid, wherein an optically active 2-phenoxypropionic acid derivative is respectively recovered from an organic solvent layer.

(4) Optically active valine and the optically active 2-phenoxypropionic acid derivative represented by the general formula (1) or optically active 2-aminobutanoic acid and the optically active 2-phenoxypropionic acid derivative represented by the general formula (1) A diastereomer of optically active valine or optically active 2-aminobutanoic acid, which is a composed complex.

  According to the present invention, an optically active 2-phenoxypropionic acid derivative as an optical resolving agent is allowed to act on racemic valine or 2-aminobutanoic acid, whereby the optically active valine or optically active 2- A diastereomer that is a complex composed of aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative is produced, separated and then decomposed to provide an optical useful as an intermediate for the synthesis of agricultural chemicals and pharmaceuticals. Active valine or optically active 2-aminobutanoic acid can be produced efficiently.

The present invention uses an optically active 2-phenoxypropionic acid derivative as an optical resolving agent, and from optically active valine or optically active 2 from racemic-valine or racemic-2-aminobutanoic acid (both are abbreviated as racemic-amino acid), respectively. -Aminobutanoic acid (a combination of the two and optical activity-abbreviated as amino acid) is produced. The specific manufacturing process is as follows.
1) A racemic amino acid and an optically active 2-phenoxypropionic acid derivative as an optical resolution agent are added to an appropriate solvent and dissolved by heating.
2) After cooling this solution, the resulting poorly soluble diastereomer (a complex composed of an optically active amino acid and an optically active 2-phenoxypropionic acid derivative) was separated and optically purified with an appropriate solvent, Separate and dry.

3) This diastereomer is dissolved or suspended in a mixture of a water-insoluble organic solvent and water, and stirred to separate into optically active amino acid and optically active 2-phenoxypropionic acid derivative. And separating into an aqueous layer and an organic solvent layer.
4) Water is removed from the aqueous layer by distillation under reduced pressure and the like, and the optically active amino acid is removed. The organic solvent is removed from the organic solvent layer by distillation under reduced pressure and the optically active 2-phenoxypropionic acid derivative is isolated.

5) The diastereomer was separated in 2) above, and if necessary, the optically active 2-phenoxypropionic acid derivative used in 1) was separated into the mother liquor opposite to that used in 1). After adding and heating the optically active 2-phenoxypropionic acid derivative which is the isomer, the same operation as 2) is performed, and the diastereomer of the amino acid enantiomer opposite to that obtained in 2) is isolated. .
6) The diastereomer obtained by the operation of 5) is subjected to the operations of 3) and 4) to obtain an optically active amino acid which is the opposite enantiomer of the amino acid obtained in 4).

In the present invention, an optically active 2-phenoxypropionic acid derivative represented by the general formula (1) is used as an optical resolution agent. In particular, optically active 2-phenoxypropionic acid, 2- (4′-methylphenoxy) propionic acid, and 2- (4′-chlorophenoxy) propionic acid are preferable.

  When an (S) -2-phenoxypropionic acid derivative is used as an optical resolving agent for racemic amino acids, diastereomers with (S) -amino acids or (R) -amino acids correspond to the respective combinations. When the (R) -2-phenoxypropionic acid derivative is used, a diastereomer with (R) -amino acid or (S) -amino acid is generated corresponding to each combination. Here, the diastereomer obtained as an intermediate product of the optical resolution of racemic amino acid is a complex composed of optically active amino acid and optically active 2-phenoxypropionic acid derivative. , All new substances.

  Although preparation of the diastereomers according to the above 1) and 2) is possible even under solvent-free conditions, it is usually preferable to use a solvent. The solvent dissolves the optically active 2-phenoxypropionic acid derivative and the racemic-amino acid, and simultaneously precipitates a diastereomer composed of the optically active 2-phenoxypropionic acid derivative and the optically active amino acid as a hardly soluble diastereomer. A solvent capable of dissolving the amino acid of the other optical isomer that does not form a mer is preferred in terms of operation. Here, a solvent having an affinity for water is preferable. Specifically, water, alcohol solvents such as methanol and ethanol, acetone, 1,4-dioxane or a mixture thereof can be used. From the viewpoint of production costs and environmental considerations, water, lower alcohols such as methanol and ethanol, or mixtures thereof are preferable.

  The amount of the solvent used is such that the 2-phenoxypropionic acid derivative and the racemic amino acid are dissolved, the diastereomer is precipitated, and the amino acid of the other optical isomer not forming the diastereomer is dissolved. Desirably, it is usually in the range of 1 to 50 times the weight of the racemic amino acid.

The reaction temperature of the 2-phenoxypropionic acid derivative and the racemic amino acid ranges from the melting point to the boiling point of the solvent. For example, when water is used, the mixture is heated and dissolved at 60 to 90 ° C., cooled to 10 to 30 ° C., and the precipitated crystals are solid-liquid separated to obtain a diastereomer. When the optical purity of the target optically active amino acid in the separated diastereomer is low, it can be purified by recrystallizing the diastereomer once to several times.
The mixing ratio of racemic amino acid and optically active 2-phenoxypropionic acid is 10: 1 to 1:10, preferably 2: 0.8 to 1.2.

  In the steps 3) and 4), the organic solvent used for isolating the optically active amino acid from the diastereomer is hardly soluble in water and is inert to the amino acid and 2-phenoxypropionic acid derivative. Solvents can also be used. That is, alcohol solvents such as 1-butanol, acetate solvents such as ethyl acetate and butyl acetate, ketones such as 4-methyl-2-pentanone, alkyl halides such as chloroform, dichloromethane and 1,2-dichloroethane , Hydrocarbons such as toluene and hexane, and ether solvents such as t-butyl methyl ether can be used. In view of economy and safety, ethyl acetate, t-butyl methyl ether, and 4-methyl-2-pentanone are preferable. The amount of organic solvent used is practically 2 to 10 times the amount of diastereomer. Moreover, the usage-amount of the water used for melt | dissolution of a diastereomeric crystal | crystallization is 2-10 times amount with respect to a diastereomer practically.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
[Example 1]
Racemic-valine 100 g (0.85 mol), (S) -2-phenoxypropionic acid 71.0 g (0.427 mol), and deionized water 855 g were mixed and stirred at 85 to 95 ° C. for 1 hour. The temperature of the solution was cooled to 20-30 ° C. overnight, and the resulting crystals were separated and dried to obtain 98 g of a crude diastereomer. The optical purity of (R) -valine in the obtained diastereomeric crystals was 40% ee from the optical rotation.
Recrystallization was carried out by dissolving 97.5 g of this crude diastereomeric crystal in 487 g of deionized water in an amount five times that of the diastereomeric crystal to obtain 68.3 g of purified diastereomeric crystal. This diastereomer is a complex (R-Val / S-APP) composed of (R) -valine and (S) -2-phenoxypropionic acid.

To 10 g of the purified diastereomeric crystals obtained, 100 ml of t-butyl methyl ether and 100 ml of water were added and stirred at 20-30 ° C. for 30 minutes. Thereafter, liquid separation was performed, and water was distilled off from the aqueous layer under reduced pressure to quantitatively obtain (R) -valine. The optical rotation of the obtained (R) -valine was −23.4 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v).
On the other hand, the t-butyl methyl ether layer was concentrated and (S) -2-phenoxypropionic acid could be recovered quantitatively.

[Example 2]
The operation of adding 100 ml of t-butyl methyl ether to the crude diastereomer separation mother liquor obtained in Example 1 and separating the solution after stirring was repeated three times. 71.0 g (0.427 mol) of (R) -2-phenoxypropionic acid was added to the aqueous layer obtained by this operation, and the mixture was stirred at 85 to 95 ° C. for 1 hour. Thereafter, the temperature of the solution was cooled to 20 to 30 ° C. overnight, and the resulting crystals were separated and dried to isolate 95 g of a crude diastereomer (an amino acid was isolated from a part of this diastereomer and the optical rotation was measured. As a result, the optical purity was 50% ee).
94.5 g of this crude diastereomeric crystal was dissolved in 472 g of deionized water 5 times the amount of the diastereomeric crystal, and then recrystallized to obtain 66.0 g of purified diastereomeric crystal. This diastereomer is a complex (S-Val / R-APP) composed of (S) -valine and (R) -2-phenoxypropionic acid.

To 10 g of the purified diastereomeric crystals obtained, 100 ml of t-butyl methyl ether and 100 ml of water were added and stirred at 20-30 ° C. for 30 minutes. Thereafter, liquid separation was performed, and water was distilled off from the aqueous layer under reduced pressure to quantitatively obtain (S) -valine. The optical rotation of the obtained (S) -valine was + 23.7 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v).
Further, the t-butyl methyl ether layer was concentrated, and (R) -2-phenoxypropionic acid could be recovered quantitatively.

Example 3
100 g (0.854 mol) of racemic-valine, 71.0 g (0.427 mol) of (R) -2-phenoxypropionic acid, and 855 g of deionized water were mixed, and the mixture was stirred at 85 to 95 ° C. for 1 hour. The temperature of the solution was cooled to 20-30 ° C. overnight, and the resulting crystals were separated and dried to obtain 94 g of crude diastereomers (optical purity of amino acids in the obtained diastereomeric crystals: 40% ee).
94 g of the crude diastereomeric crystals were recrystallized with deionized water to obtain 66.0 g of purified diastereomeric crystals. This diastereomer is a complex (S-Val / R-APP) composed of (S) -valine and (R) -2-phenoxypropionic acid.

  10 g of the obtained purified diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -valine. The optical rotation of the obtained (S) -valine was + 23.8 ° (temperature: 25 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). Further, (R) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer as in Example 1.

Example 4
100 g (0.970 mol) of racemic-2-aminobutanoic acid, 80.6 g (0.485 mol) of (S) -2-phenoxypropionic acid, and 903 g of deionized water were mixed, and the same operation as in Example 1 was performed. 115 g of crude diastereomeric crystals were obtained. The optical purity of the contained amino acid analyzed by HPLC (high performance liquid chromatography) was 95% ee.
114.5 g of this crude diastereomeric crystal was recrystallized in the same manner as in Example 1 to obtain 70.0 g of purified diastereomeric crystal. This diastereomer is a complex (R-2-ABA / S-APP) composed of (R) -2-aminobutanoic acid and (S) -2-phenoxypropionic acid.

10 g of the obtained purified diastereomer crystal was operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water, to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid is −20.6 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). The optical purity analyzed by HPLC was 99% ee or higher.
Further, (S) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

Example 5
Racemic-2-aminobutanoic acid 100 g (0.970 mol), (R) -2-phenoxypropionic acid 71.0 g (0.427 mol), and deionized water 903 g were mixed and the same operation as in Example 1 was performed. 106 g of crude diastereomeric crystals (optical amino acid purity analyzed by HPLC is 95% ee) was obtained.
105 g of this crude diastereomeric crystal was recrystallized in the same manner as in Example 1 to obtain 69.0 g of purified diastereomeric crystal. This diastereomer is a complex (S-2-ABA / R-APP) composed of (S) -2-aminobutanoic acid and (R) -2-phenoxypropionic acid.

10 g of the obtained purified diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water, to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid is + 20.1 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v), The optical purity analyzed by HPLC was 99% ee or higher.
In addition, (R) -2-phenoxypropionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

Example 6
The same as in Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 87.4 g (0.485 mol) of (S) -2- (4′-methylphenoxy) propionic acid, and 937 g of deionized water were mixed. Then, 85 g of crude diastereomeric crystals (containing amino acid optical purity analyzed by HPLC is 70% ee) was obtained. This diastereomer is a complex (S-2-ABA / S-4-Me-APP) composed of S-2-aminobutanoic acid and (S) -2- (4′-methylphenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid was + 14.4 ° (temperature: 25 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). .
In addition, (S) -2- (4′-methylphenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

Example 7
The same as in Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 87.4 g (0.485 mol) of (R) -2- (4′-methylphenoxy) propionic acid, and 937 g of deionized water were mixed. Thus, 88 g of crude diastereomer crystals (containing amino acid optical purity analyzed by HPLC: 65% ee) was obtained. This diastereomer is a complex (R-2-ABA / R-4-Me-APP) composed of R-2-aminobutanoic acid and (R) -2- (4′-methylphenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid was −13.7 ° (temperature: 27 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). It was.
In addition, (R) -2- (4′-methylphenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

Example 8
Same as Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 97.3 g (0.485 mol) of (R) -2- (4′-chlorophenoxy) propionic acid and 1000 g of deionized water were mixed. Thus, 100 g of crude diastereomeric crystals (containing optical purity of 63% ee analyzed by HPLC) was obtained. This diastereomer is a complex (R-2-ABA / R-4-Cl-APP) composed of R-2-aminobutanoic acid and (R) -2- (4′-chlorophenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (R) -2-aminobutanoic acid. The optical rotation of the obtained (R) -2-aminobutanoic acid was −12.9 ° (temperature: 26 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). It was.
In addition, (R) -2- (4′-chlorophenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

Example 9
Same as Example 1 except that 100 g (0.970 mol) of racemic-2-aminobutanoic acid, 97.3 g (0.485 mol) of (S) -2- (4′-chlorophenoxy) propionic acid and 1000 g of deionized water were mixed. Thus, 103 g of crude diastereomeric crystals were obtained. This diastereomer is a complex (S-2-ABA / S-4-Cl-APP) composed of S-2-aminobutanoic acid and (S) -2- (4′-chlorophenoxy) propionic acid.
10 g of the obtained crude diastereomeric crystals were operated in the same manner as in Example 1 using a mixed solvent of t-butyl methyl ether and water to quantitatively obtain (S) -2-aminobutanoic acid. The optical rotation of the obtained (S) -2-aminobutanoic acid was + 12.3 ° (temperature: 28 ° C., solvent: 1.0 M HCl, light source: Na Lamp, concentration: 1.0% w / v). .
In addition, (S) -2- (4′-chlorophenoxy) propionic acid could be quantitatively recovered from the t-butyl methyl ether layer.

The NMR analysis results measured for the purified diastereomers obtained in Examples 1 to 5 and the crude diastereomers obtained in Examples 6 to 9 are shown in Table 1. Table 2 shows the results of measuring the optical rotation and melting point of these samples (excluding those of Example 3). In addition, the measurement conditions of the optical rotation in Table 2 are as follows.
Temperature: 28 ° C
Solvent: acetic acid (Examples 1-5), methanol (Examples 6-9)
Light source: Na Lamp
Concentration: 1.0% w / v

  Optically active valine and 2-aminobutanoic acid obtained by the production method of the present invention are expected to be widely used as chiral pools in the field of chemicals such as pharmaceuticals and agricultural chemicals. In addition, diastereomers, which are complexes composed of optically active valine or optically active 2-aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative, have high utility as intermediate products of optical resolution of racemic amino acids. It is.

Claims (4)

Racemic-valine or racemic-2-aminobutanoic acid is reacted with an optically active 2-phenoxypropionic acid derivative represented by the general formula (1) in a medium comprising water, a lower alcohol or a mixture thereof, and optically active valine. And a liquid-soluble diastereomer which is a complex composed of an optically active 2-phenoxypropionic acid derivative or an optically active 2-aminobutanoic acid and an optically active 2-phenoxypropionic acid derivative. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid.

  An optically active 2-phenoxy which is an enantiomer opposite to the optically active 2-phenoxypropionic acid derivative used after separating the optically active 2-phenoxypropionic acid derivative from the mother liquor after solid-liquid separation in the method of claim 1 Propionic acid derivatives are added and reacted to form a hardly soluble dia which is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative. A method for producing a diastereomer of optically active valine or optically active 2-aminobutanoic acid, comprising producing a stereomer and performing solid-liquid separation.   Optically active valine or diastereomer of optically active 2-aminobutanoic acid which is a complex composed of optically active valine and optically active 2-phenoxypropionic acid derivative or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative Is dissolved or suspended in a mixed solution of water and a water-insoluble organic solvent and stirred to decompose the diastereomer, and the optically active valine or optically active 2-aminobutanoic acid is converted from the aqueous layer to the organic solvent layer. A method for producing optically active valine or optically active 2-aminobutanoic acid, wherein an optically active 2-phenoxypropionic acid derivative is respectively recovered from the product. Consists of optically active valine and optically active 2-phenoxypropionic acid derivative represented by general formula (1) or optically active 2-aminobutanoic acid and optically active 2-phenoxypropionic acid derivative represented by general formula (1) A diastereomer of optically active valine or optically active 2-aminobutanoic acid as a complex.