JPH11322684A - Isomerization of amino acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the isomerization process, in other words, racemization and epimerization for optically active amino acids, typically alanine, α- aminobutanoic acid, valine, leucine, isoleucine, phenylalanine, tryptophane and methionine, in the presence of a lower fatty acid and an aldehyde and provide an high-efficiency isomerization process for amino acids with lowered energy consumption and easy recycle of the lower fatty acid and aldehyde as the isomerization catalyst. SOLUTION: An optically active amino acid is dispersed in an inert solvent that substantially does not dissolve amino acids, preferably an aromatic hydrocarbon such as benzene, toluene, xylene or halogenated benzene. A lower fatty acid, preferably a 1-5C saturated fatty acid as acetic acid, propionic acid or butanoic acid and an aliphatic aldehyde or an aromatic aldehyde, preferably an aromatic aldehyde such as benzaldehyde or salicylaldehyde are allowed to act on the dispersion to effect the isomerization. The mixture of the optical isomers of the crystallized amino acid separating from the solvent are collected by the solid-liquid phase separation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for obtaining a racemic or epimeric mixture by isomerizing an optically active amino acid. In the following description, "isomerization"
It is meant to include racemization and epimerization, and may be represented by "racemization".

[0002]

2. Description of the Related Art As is well known, optically active amino acids are often used as intermediates for producing pharmaceuticals and agricultural chemicals. When this is obtained from a racemate by an optical resolution method, it is desirable to recover an unnecessary enantiomer remaining after separation of a desired enantiomer, to perform racemization or epimerization, return to the optical resolution step, and reuse. Especially in industrial practice, such isomerization is almost essential.

[0003] In order to achieve this object, various methods have been proposed and put into practical use since ancient times. Those,
Regarding amino acids, they can be summarized as follows (Ichiro Chibatake et al., “Chemical Review No.4 Chemistry of Asymmetric Reactions” p.23
3-262, 1974).

1) Chemical method: It is converted into N-acetyl form or N-benzoyl form, which is heated in acetic acid with acetic anhydride.

2) Method by heat: An amino acid is heated under acidic or alkaline conditions. It is known that an aqueous solution of a certain free amino acid is racemized by heating it to 150 to 250 ° C. in a closed vessel, and is often employed industrially. Depending on the amino acid,
Heating in a lower fatty acid medium facilitates racemization.

3) A method using a catalyst: A racemicization reaction is remarkably accelerated by adding a small amount of salicylaldehyde or a derivative thereof to an amino acid which is hardly racemized only by heating as a solution of water or a lower fatty acid and heating. Often.

4) Method using enzymes and microorganisms: Enzymes that racemize amino acids by various mechanisms are known and put into practical use. Several highly efficient methods for producing only the desired optically active substance in combination with other enzymatic reactions have been developed.

[0008] The specific method of the above 3) (JP-A-57-12)
3150) consists of dissolving various amino acids in glacial acetic acid, adding a salicylaldehyde in a molar ratio of 0.2 to the amino acids, and heating to 100 ° C. for 1 hour. This allows the racemization rate of about 3 to 35% without addition of aldehyde to be 90 to 100% racemized.

However, it is not always easy to recover the target amino acid from the reaction mixture after racemization by this method. In the case of an amino acid that dissolves well in acetic acid, it is necessary to concentrate the reaction solution under reduced pressure to dryness, add a solvent such as alcohol or acetone, and crystallize from the solvent. Certain amino acids such as phenylglycine, p-hydroxyphenylglycine, serine, etc.
By simply cooling the reaction solution using an acetic acid solvent, a racemized amino acid precipitates as a crystal and can be separated by filtration, but the amino acid capable of such a filtration is limited. The higher the solubility of the amino acid in acetic acid, the more it is necessary to concentrate and remove a large amount of acetic acid, and the energy consumption is unbearably increased.In addition, it is difficult to recover the aldehyde added as a catalyst. The racemization of amino acids is often not suitable for industrial practice.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems associated with the isomerization of amino acids, to isomerize amino acids with high efficiency and low energy consumption.
Another object of the present invention is to provide a method for isomerizing an amino acid, in which aldehydes used as a catalyst can be easily recovered and reused.

[0011]

The process for isomerizing optically active amino acids according to the present invention which achieves the above object is basically accomplished by converting an optically active amino acid into an inert solvent which does not substantially dissolve the amino acid. And a mixture of optical isomers of amino acids crystallized from a solvent is obtained by solid-liquid separation by the action of a lower fatty acid and an aliphatic or aromatic aldehyde to cause isomerization.

[0012]

DETAILED DESCRIPTION OF THE INVENTION The aromatic hydrocarbon used as the main reaction medium in the present invention hardly dissolves amino acids. Therefore, apparently, the reaction proceeds in a state where the optically active amino acid is suspended in the medium. The racemic or epimeric mixture formed by the isomerization reaction does not dissolve in the reaction medium and precipitates out, so that it can be easily separated from the medium by finally filtering. As can be seen from the examples described later, considering that the optically active amino acid as the raw material is fine powder, which shows better results in both the racemization rate and the recovery rate of the amino acid, a small amount of It is presumed that the lower fatty acid assists the sequential partial dissolution of the optically active amino acid, and the isomerization reaction itself proceeds in a homogeneous system.

However, in any case, the fact that the isomerization reaction of the optically active amino acid proceeds promptly in the suspension state and the reaction product is obtained with high purity is contrary to the general common sense that the reaction in the solution state is preferable. The present invention has this surprising discovery as its basis.

The optically active amino acids that can be isomerized by the method of the present invention include a wide range of natural and synthetic α-amino acids. Especially neutral amino acids,
Specifically, alanine, α-aminobutanoic acid, valine,
Leucine, isoleucine, serine, threonine, cystine, cysteine, methionine, tryptophan, phenylalanine, tyrosine, DOPA, phenylglycine,
In the case of p-hydroxyphenylglucin, etc., the isomerization is completed in a practical reaction time, and after the reaction, crystals of the isomerized amino acid are precipitated only by cooling, and the target is obtained in high yield only by filtration. Can be obtained. The present invention is most effective in the reaction of isomerizing optically active isoleucine to obtain an epimeric mixture of L-isoleucine and D-alloisoleucine.

The starting optically active amino acids are not limited to pure ones containing almost no optical isomers, but may be those having low optical purity, that is, a mixture of a racemic form and one of the optically active forms. Needless to say. Of course, the method of the invention can also be applied to mixtures of two or more amino acids.

Various inert solvents which do not substantially dissolve amino acids can be used. They are aliphatic hydrocarbons such as hexane, heptane, octane,
Aromatic hydrocarbons such as cyclohexane and methylcyclohexane such as benzene, toluene, xylene, halogenated benzene, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate, butyl acetate and ethers such as diethyl ether; Tetrahydrofuran,
1,4-dioxane, methyl-t-butyl ether, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, and alcohols such as isopropanol, n-butanol and isobutanol.

Of these, aromatic hydrocarbons are preferred, and especially when toluene or xylene is used,
The isomerization reaction proceeds quickly, which is advantageous. These solvents are inexpensive, easily available, and easy to recover.

The lower fatty acids added to the reaction medium include C
Saturated fatty acids ₁ -C _5, specifically, formic acid, acetic acid, propionic acid, butanoic acid and pentanoic acid are preferred. Acetic acid and propionic acid are particularly advantageous because they are easily available and have a high rate of isomerization. An appropriate amount of the lower fatty acid is 3 to 10 times the molar amount of the amino acid. If the amount is too small, the rate of isomerization is low, and if the amount is large, the reaction is quicker, but the amino acid dissolves in this, resulting in a lower product recovery. In any case, since the main medium of the reaction is an inert solvent, the amount of the lower fatty acid to be used is much smaller than when the lower fatty acid itself is used as the reaction medium.

As the aldehyde acting as a catalyst, any of aliphatic and aromatic aldehydes, which are known to have an effect on isomerization of amino acids, can be used.
Examples of the aliphatic aldehyde include formaldehyde, acetaldehyde, propionaldehyde, and butyraldehyde, and examples of the aromatic aldehyde include benzaldehyde and salicylaldehyde. Aside from these, a heterocyclic aldehyde such as furfural can also be used, and the term aromatic aldehyde in the present invention includes a heterocyclic aldehyde. Benzaldehyde and salicylaldehyde may be substituted with a halogen atom. Particularly successful are salicylaldehyde. The amount of the aldehyde to be used is suitably from 0.01 to 0.3 mol, especially from 0.05 to 0.2 mol, per amino acid.

In the isomerization method of the present invention, a system of a solvent, an optically active amino acid, a lower fatty acid and an aldehyde mixed in an arbitrary order is treated at a temperature of 60 to 120 ° C., preferably 80 to 1 ° C.
Proceed by heating to 10 ° C. and stirring.
The temperature is conveniently the reflux temperature of the solvent. The reaction speed varies depending on the solvent, raw materials, reaction conditions and the like, but is generally almost completed in 1 to 10 hours. As described above, this method is performed without completely dissolving the amino acid, and in order to realize a high reaction rate and conversion, it is effective to make the particles of the starting amino acid as fine powder as possible. It is important to perform proper stirring.

After completion of the isomerization reaction, the reaction solution is cooled to around room temperature, and the precipitated amino acid crystals are separated by filtration and washed with an appropriate solvent to obtain a highly pure amino acid isomer. Most of the lower fatty acid and aldehyde remain in the solvent in the mother liquor of the filtration, and can be used as it is in the next isomerization step only by supplementing a small loss.

[0022]

According to the method for isomerizing amino acids of the present invention, isomerization is performed by using an aldehyde as a catalyst while dispersing the amino acids in a medium in which a lower fatty acid is added to an inert solvent which does not substantially dissolve the amino acids. The reaction is performed by a technique that has not been attempted before. This greatly simplifies the process since the isomerized amino acid can be obtained only by filtration and washing. In addition, since the step of evaporating the acetic acid solution, which is required in the known method, is not required, energy consumption is significantly reduced. The mother liquor after filtration can be used as it is for the next reaction, especially since the loss of relatively expensive aldehyde is negligible.
It is also advantageous in terms of cost. Thus, the present invention
It is preferable from the viewpoint of advanced use of resources and environmental conservation,
It is valuable for industrial production of various optically active amino acids.

The present inventors have invented an optical resolution method for obtaining D-alloisoleucine with high purity from an epimeric mixture of L-isoleucine and D-alloisoleucine, and have already proposed it (Japanese Patent Application No. 10-39365). By performing the optical resolution method in combination with the isomerization method of the present invention, D-alloisoleucine, which has been difficult to mass-produce, is easily produced from L-isoleucine which has been mass-produced. This is possible. Needless to say, this facilitates industrial production of various medicines and pesticides.

[0024]

EXAMPLES In the following examples, the racemization ratio and epimerization ratio of amino acids were calculated from the values of optical purity measured by HPLC. Amino acid analysis was performed under the conditions listed in Table 1, respectively.

Table 1 Amino acid Column mobile phase flow rate Column temperature 2 mM CuSO ₄ (%) IPA (%) MeOH (%) ml / min (° C.) Alanine A 1000 00 0.530 Valine A 100 00 1.2 40 Leucine A 95550 1.030 Isoleucine A 95550.030 Phenylalanine A 90 100 1.030 Tryptophan B 8500150.840 Methionine A 95550.030 Serine A1000 0 0.240 Column A: SUMICHIRAL OA-5000 5 μm 4.6 mmφ × 15 cm Column b: DAICEL CHIRALPAK MA (+) 4.6 mmφ × 5 cm Detector: JASCO “UV-975” wavelength 254 nm.

The isomerization ratio (racemization ratio and epimerization ratio) in Examples is determined by the optical purity of the amino acid before isomerization.
0, when the it P1 after isomerization, wherein isomerization rate (%) = is defined by _{{(P 0 -P 1) /} P 0} × 100.

Example I Various L-amino acids were racemized. For example, in the case of isoleucine, L-isoleucine 5.0 g (38.12 mmol)
Was suspended in 25 mL of toluene, and 8.7 mL of acetic acid was added thereto.
(152.5 mmol) and 0.93 g of salicylaldehyde
(7.62 mmol) was added, and the mixture was stirred under reflux for 2 hours. Thereafter, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed three times with 5 mL of toluene each time, and dried. 4.45 g of isoleucine having an epimerization rate of 89% and a recovery rate of 8
Obtained at 9%. Table 2 shows the results of the racemization, including other amino acids.

[0028] The racemization of Table 2 L- amino acid No. Amino acid racemization rate (%) Recovery (%) I-1 alanine 94 93 I-2 valine 48 90 I-3 leucine 98 88 I-4 isoleucine * 89 89 I-5 phenylalanine 85 90 I-6 tryptophan 82 87 I -7 Methionine 86 86 I-8 Serine 81 92 I-9 Aminobutanoic acid 96 85 * Epimer mixture of L-isoleucine and D-alloisoleucine.

Example II Various amino acids were racemized, and it was examined how the racemization rate changes depending on the reaction time. Racemization is performed with L-amino acid 5.0.
g was suspended in 25 mL of toluene, acetic acid having a molar ratio of 4 and salicylaldehyde having a molar ratio of 0.2 were added to the L-amino acid, and the mixture was stirred for 0.5, 1, 2 or 3 hours while heating under reflux. I did it. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed with 5 mL of toluene three times, and dried. Table 3 shows the racemization rate and the recovery rate.

Table 3 No. Amino acid Reaction time (hour) Racemization rate (%) Recovery (%) II-1 Alanine 0.5 21 94 II-2 Alanine 151 95 II-3 Alanine 294 93 II-4 Alanine 397 92 II-5 Leucine 0.5 80 91 II-6 Leucine 196 90 II-7 Leucine 298 88 II-8 Leucine 398 84 II-9 Isoleucine * 155 90 II-10 Isoleucine * 289 89 II-11 Isoleucine * 3 100 86 II-12 Phenylalanine 0.5 48 92 II-13 Phenylalanine 172 91 II-14 Phenylalanine 285 90 II-15 Phenylalanine 3 8782 II-16 Serine 1 52 94 II-17 Serine 281 92 II-18 Serine 3 79 88 * as epimeric mixture of L-isoleucine and D-alloisoleucine.

Example III The effect of the type of solvent on the isomerization of amino acids was examined by taking L-isoleucine epimerization as an example. 10.0 g of L-isoleucine was suspended in 50 mL of various solvents listed in Table 4, acetic acid at a molar ratio of 4 and salicylaldehyde at a molar ratio of 0.2 were added, and the mixture was stirred for 6 hours while heating under reflux.
After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed with 10 mL of the same solvent as used in the reaction, and dried.
Table 4 shows the epimerization ratio and the recovery ratio together with the reaction temperature, that is, the reflux temperature of the solvent.

Table 4 No. Solvent Epimerization ratio (%) Recovery (%) Reflux temperature (° C) III-1 Methylcyclohexane 100 96 92 III-2 Benzene 49 95 80 III-3 Methyl ethyl ketone 98 94 89 III-4 Isopropyl acetate 100 84 98 III- 5 1,4-dioxane 82 77 106 III-6 1,2-dichloroethane 99 85 87 III-7 isopropanol 40 90 80 [Example IV] The effect of the type of the solvent on the isomerization of amino acids was investigated. In particular, the racemization of L-amino acids of aromatic hydrocarbons (benzene, toluene, xylene) was examined. 4. Various L-amino acids listed in Table 5.
Then, 0 g was suspended in 25 mL of each of the three solvents, acetic acid at a molar ratio of 4 and salicylaldehyde at a molar ratio of 0.2 were added to the L-amino acid, and the mixture was stirred for 2 hours while heating under reflux. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed with 5 mL of the same solvent as used in the reaction, and dried. Table 5 shows the racemization rate and the recovery rate.

Table 5 No. Amino acid solvent Racemization rate (%) Recovery (%) IV-1 alanine benzene 3194 IV-2 alanine toluene 94 93 IV-3 alanine xylene 98 89 IV-4 valine benzene 496 IV-5 valine toluene 48 90 IV -6 Valine xylene 84 82 IV-7 leucine benzene 97 81 IV-8 leucine toluene 98 88 IV-9 leucine xylene 89 74 IV-10 isoleucine * benzene 14 77 IV-11 isoleucine * toluene 89 89 IV-12 isoleucine * xylene 98 76 IV-13 phenylalanine benzene 68 85 IV-14 phenylalanine toluene 85 90 IV-15 phenylalanine xylene 85 78 IV-16 serine benzene 55 96 IV-17 serine toluene 81 92 IV-18 serine xylene 89 93 reflux benzene As 3 ° C. epimeric mixture of toluene 104 ° C. Xylene 118 ° C. * L-isoleucine and D- allo-isoleucine.

Example V The effect of the amount of lower fatty acids on the isomerization of amino acids was determined by examining acetic acid and three L
-Checked for racemization of amino acids. 5.0 g of each amino acid shown in Table 6 was suspended in 25 mL of toluene.
Acetic acid was added to the amino acid at a molar ratio of 4, 6, 8 or 10, and salicylaldehyde was added at a molar ratio of 0.2, and the mixture was stirred for 2 hours while heating under reflux. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed three times with 5 mL each of toluene, and dried. Table 6 shows the racemization rate and the recovery rate.

Table 6 No. Amino acid Acetic acid amount (molar ratio) Racemization ratio (%) Recovery (%) V-1 valine 4 48 90 V-2 valine 6 61 87 V-3 valine 8 91 88 V-4 valine 10 99 83 V-5 phenylalanine 4 8590 V-6 Phenylalanine 68887 V-7 Phenylalanine 888984 V-8 Phenylalanine 10 91 81 V-9 Serine 4 8192 V-10 Serine 6 8891 V-11 Serine 8 96 86 V-12 Serine 10 96 79 [Example VI] The effect of the type of lower fatty acid on amino acid isomerization was examined for a combination of three lower fatty acids and racemization of three L-amino acids. 5.0 g of each L-amino acid shown in Table 7 was
of L-amino acid at a molar ratio of 4
Acetic acid, propionic acid or butanoic acid in a proportion of, and salicylaldehyde in a molar ratio of 0.2,
The mixture was stirred for 2 hours while heating under reflux. After the reaction, the reaction solution was cooled to room temperature, and the precipitated crystals were separated by filtration.
And dried three times. Table 7 shows the racemization rate and the recovery rate.

Table 7 No. Amino acid Lower fatty acid Racemization rate (%) Recovery (%) VI-1 Valine acetic acid 48 90 VI-2 Valine propionic acid 684 VI-3 Valine butanoic acid 10 84 VI-4 Isoleucine * Acetic acid 89 90 VI-5 Isoleucine * propionic acid 81 86 VI-6 Phenylalanine acetic acid 63 75 VI-7 Phenylalanine propionic acid 73 81 * As epimer mixture of L-isoleucine and D-alloisoleucine.

Example VII The effect of the type of aldehyde on amino acid isomerization was examined for a combination of six aldehydes and racemization of three L-amino acids. 5.0 g of each L-amino acid shown in Table 8 was suspended in 25 mL of toluene, and acetic acid at a molar ratio of 4 and various aldehydes at a molar ratio of 0.2 were added to the L-amino acid. All were stirred for 2 hours. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration, washed three times with 5 mL each of toluene, and dried. Table 8 shows the types of the aldehyde, the racemization rate and the recovery rate.

Table 8 No. Amino acid aldehyde racemization rate (%) Recovery rate (%) VII-1 valine a4890 VII-2 valine b2294 VII-3 valine c888 VII-4 isoleucine * a 8990 VII-5 isoleucine * b4687 VII-6 isoleucine * c 1780 VII-7 isoleucine * d 93 78 VII-8 isoleucine * e 4559 VII-9 isoleucine * f 73 91 VII-10 phenylalanine a 63 75 VII-11 phenylalanine b 88 88 82 VII-11 phenylalanine c 6786 a: salicylaldehyde b: 5-chlorosalicylaldehyde c: 3,5-dichlorosalicylaldehyde d: benzaldehyde e: furfural f: butyraldehyde * As epimer mixture of L-isoleucine and D-alloisoleucine.

Example VIII In order to determine the most advantageous conditions for industrially carrying out the epimerization of L-isoleucine, toluene was used as the solvent, acetic acid was used as the lower fatty acid, and salicylaldehyde was used as the aldehyde. Epimerization was performed by changing the ratio and scale of the raw materials and the solvent, the molar ratio of acetic acid and salicylaldehyde to the amino acid, and the reaction time (the temperature was the boiling point of toluene, that is, 104 ° C.). Table 9 shows the epimerization rate and the recovery rate.

Table 9 No. L-Isolotoluene acetic acid salicylure At the time of reaction Epimeric recovery Isine (g) (mL) (mol) aldehyde (mol) (hours) Conversion (%) Rate (%) VIII-15 255 4 0.2 289 89 89 VIII-2 525 504 0.23 100 86 VIII-3 550 10 0.2 395 9 79 VIII-4 10 403 0.16 100 83 VIII-5 10 40 4 0.15 97 81 VIII- 6 10 40 3 0.24 100 82 VIII-7 750 2005 0.2 295 91 VIII-8 120 600 4 0.23 100 90 [Example IX] Used for epimerization of L-isoleucine,
The mother liquor (typically a toluene solution) after filtering off the epimer contains a carboxylic acid and an aldehyde (typically acetic acid and salicylaldehyde). For industrial epimerization, it is necessary to collect this solution and use it repeatedly. Repeated use was attempted to confirm that collection and reuse were possible. The amount of acetic acid and aldehyde contained in the mother liquor after the first epimerization is analyzed, and the shortage is compensated for to perform the second epimerization.
Was repeated six times. The reaction conditions are 10.0 g of L-isoleucine, 50 mL of toluene, a molar ratio of acetic acid of 4, a molar ratio of salicylaldehyde of 0.2, and heating and refluxing for 6 hours. Table 10 shows the results of the analysis of the mother liquor and the amount of replenishment, together with the L-isoleucine recovery rate.

Table 10 L-Ile recovery mother liquor supplementation amount Ile acetate SA Tol + Ile acetate SA Tol Recovery (g) (g) (g) (g) (g) (g) (g) (g) (%) 1 10.0 − − − 18.38 2.02 43.51 84 2 10.0 14.87 1.37 38.41 3.43 0.50 5.23 90 3 10.1 18.76 1.54 35.33 0 1.57 8.27 86 4 10.1 18.39 2.35 34.32 0 0 9.18 86 5 10.0 22.38 1.46 26.76 0 0.37 16.73 82 6 10.0 10.56 1.26 46.66 7.78 0.63 5.00 82 7 10.0 15.84 1.45 47.99 2.51 0.36 0 85 Ile: Isoleucine SA: Salicylaldehyde Tol: Toluene As a result of analyzing the product of each of the seven epimerizations shown in Table 10, all of the epimerizations were completed. Was.

Example X The inventors have experienced that in the racemization of L-amino acids carried out in a heterogeneous system, the racemization ratio may vary depending on the particle size of the starting amino acid. Generally, the smaller the particle size, the better the performance. The following example is a comparison between relatively coarse and fine L-phenylalanine. For the reaction, 5 g of each of the two samples described in Table 11 was taken, suspended in 25 mL of toluene, 6.9 mL (121.1 mmol) of acetic acid and 0.74 g (6.05 mmol) of salicylaldehyde were added, and the mixture was heated. And stirred under reflux for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and the precipitated crystals were separated by filtration, washed three times with 5 mL each of toluene, and dried. The racemization rate and recovery rate were calculated, and the results shown in Table 11 were obtained.

Table 11 Sample Particle Size Racemization Rate (%) Recovery (%) 1 250% to 500μm is 84% 63 75 2 180μm or less is 100% 85 90 [Examples XI to XV] Various L-amino acids are racemic It has become. 5.0 g of each of the amino acids listed in Table 12 was dissolved in toluene 2
After dissolving in 5 mL, acetic acid and salicylaldehyde in the amounts shown in Table 12 were added, and the mixture was stirred under reflux with heating for 3 hours for XI and 2 hours for XII to XV. After the reaction, the mixture was cooled to room temperature, and the precipitated crystals were separated by filtration and washed three times with 5 mL each of toluene. After drying, the racemization and recovery were calculated. Table 12 shows the results.

Table 12 Example L-amino acid Toluene acetic acid SA * Racemization rate Recovered amount g (mmol) mL mL (mmol) g (mmol) (%) g (rate%) XI Alanine 5.0 25 12.8 1 .37 93 4.61 (56.12) (224.5) (11.2) (92) XII Valine 5.0 25 19.5 1.04 91 4.38 (42.68) (341.4) (8.54) (88) XIII Leucine 0 25 8.7 0.93 98 4.40 (38.12) (152.5) (7.62) (88) XIV phenyl 5.0 25 10.4 0.74 88 4.33 Alanine (30.27) (181.6) (6.05) (87) XV serine 5.0 25 21.8 1.16 96 4.29 (47.57) (380.6) (9.51) (86) * Salicylaldehyde.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 227/42 C07C 227/42 229/36 229/36 319/14 319/14 319/28 319/28 323/58 323/58 C07D 209/20 C07D 209/20 // C07B 61/00 300 C07B 61/00 300 C07M 7:00 (72) Inventor Kenichi Sakai 3-1-1 Nihonbashi Muromachi, Chuo-ku, Tokyo Inside Yamakawa Pharmaceutical Co., Ltd. 72) Inventor Naoichi Murakami Yamakawa Pharmaceutical Co., Ltd. 3-1-1, Nihonbashi Muromachi, Chuo-ku, Tokyo

Claims (11)

[Claims] 1. An optically active amino acid is dispersed in an inert solvent which does not substantially dissolve the amino acid, and isomerized by the action of a lower fatty acid and an aliphatic or aromatic aldehyde to form an amino acid crystallized from the solvent. A method for isomerizing optically active amino acids, comprising obtaining a mixture of optical isomers by solid-liquid separation. 2. The method according to claim 1, wherein the optically active amino acid is alanine or α-amino acid.
The isomerization method according to claim 1, which is an optically active amino acid selected from aminobutanoic acid, valine, leucine, isoleucine, phenylalanine, tryptophan or methionine. 3. The method according to claim 1, wherein an aromatic hydrocarbon is used as the inert solvent that does not substantially dissolve amino acids. 4. The aromatic hydrocarbon is benzene, toluene, xylene or halogenated benzene.
Isomerization method. 5. The isomerization method according to claim 1, wherein a C ₁ -C ₅ saturated fatty acid is used as the lower fatty acid. 6. The method according to claim 5, wherein the lower fatty acid is acetic acid, propionic acid or butanoic acid. 7. The method for isomerization according to claim 1, wherein benzaldehyde which may be substituted with a hydroxyl group or with a hydroxyl group and a halogen atom is used as the aromatic aldehyde. 8. The isomerization method according to claim 7, wherein the aromatic aldehyde is benzaldehyde or salicylaldehyde. 9. The method according to claim 1, wherein the lower fatty acid is used in an amount of 3 to 10 mol per 1 mol of the optically active amino acid. 10. The process according to claim 1, wherein the aromatic aldehyde is used in an amount of 0.01 to 0.3 mol per 1 mol of the optically active amino acid. 11. An optically active isoleucine isomerized to L
The method according to any one of claims 1 to 10, wherein an epimeric mixture of -isoleucine and D-alloisoleucine is obtained.