JPS60178850A - Production of optically active phenylalanine - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a raw material of pharmaceuticals, economically in an industrial scale, by removing mandelic acid from the optically resolved complex of DL-phenylalanine and optically active mandelic acid in an aqueous solvent containing HCl, a 3-4C fatty acid, etc. CONSTITUTION:The DL-phenylalanine-optically active mandelic acid complex is subjected to the optical resolution in an aqueous solvent containing HCl, a 3- 4C fatty acid (e.g. propionic acid, butyric acid, acrylic acid, crotonic acid, etc.), a lower aliphatic hydroxy acid (e.g. lactic acid) or a lower aliphatic dicarboxylic acid (e.g. oxalic acid, malonic acid). The mandelic acid is removed from the resultant complex of the optically active phenylalanine and optically active mandelic acid to obtain the objective optically active phenylalanine. The amount of the liquid used in the optical resolution can be reduced to about 1/2-1/5 of the conventional method, and the process is extremely advantageous in view of industrial purpose.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active phenylalanine,
More specifically, it is obtained by optically resolving I) L-phenylalanine/optically active mandelic acid complex in an aqueous solvent containing hydrochloric acid, a 03-C5 fatty acid, a lower aliphatic oxyacid, or a lower aliphatic dicarboxylic acid. The present invention relates to a method for selecting optically active phenylalanine, which comprises removing mandelic acid from an optically active phenylalanine/optically active mandelic acid complex.

When DL-phenylalanine is optically resolved by the method of the present invention, the amount of mother liquor to be resolved can be reduced to about 1/2 to 115 times that of the conventional method, so it is an extremely advantageous method industrially.

A method for optically resolving D L-phenylalanine with optically active mandelic acid is already known [Nikka-shi 92 (11
,) 999-1002 (1971)].

However, the present inventors conducted additional tests on the known method and found that the solubility of the phenylalanine/mandelic acid complex in water was extremely low at 2.6% when converted to phenylalanine. It has been found that the ratio is extremely low, which is extremely disadvantageous industrially.

Therefore, the present inventors investigated to improve the above drawbacks and found that hydrochloric acid, C3 to C5 fatty acids, lower aliphatic oxyacids,
or in an aqueous solvent containing a lower aliphatic dicarboxylic acid,
The D J, -phenylalanine/optically active mandelic acid complex is optically resolved without decomposition, and the split liquid cap is reduced to 1/2 to 1/2 compared to when these acidic compounds are not used.
It was found that the number can be reduced to 15.

The present invention has been completed based on the above findings.

For example, the method of the present invention may be carried out as follows. That is, 1) L-phenylalanine and optically active mandelic acid are dissolved in an aqueous solvent containing hydrochloric acid, a C3-C4 fatty acid, a lower aliphatic oxyacid, or a lower aliphatic dicarboxylic acid. ff1l by generating an active mandelic acid complex and then cooling the solution or concentrating it as necessary.
Selective crystallization of the ffl soluble complex is performed, followed by solid-liquid separation, and the resulting optically active phenylalanine/optically active mandelic acid complex is decomposed by a method such as fire/exchange resin treatment or neutralization to remove mandelic acid. By doing so, optically active phenylalanine is obtained.

C3. used in the present invention. C4 fatty acids include saturated fatty acids such as propionic acid and butyric acid, acrylic acid,
Unsaturated fatty acids such as crotonic acid and vinyl acetic acid, lower aliphatic oxyacids such as lactic acid, lower aliphatic dicarboxylic acids such as oxalic acid, malonic acid, saturated aliphatic dicarboxylic acids, and maleic acid. Examples include unsaturated aliphatic dicarboxylic acids. These acids are sodium,
It can also be used as a salt with potassium, etc.

There is no particular restriction on the amount of these acids used as long as they are soluble in the solvent used; for example, if the concentration of these acids is 20 to 90
% of the solvent may be used.

When hydrochloric acid is used, the amount used is, for example, less than 2 times the mole of D L-phenylalanine, preferably 0.
It is about 2 to 16 times the mole, more preferably about 06 to 1.2 times the mole.

The solvent used in the present invention is not particularly limited as long as each of the above-mentioned dolic acids and phenylalanine/mandelic acid can be dissolved therein, and phenylalanine and mandelic acid can form a complex in the solvent, but industrial implementation is not possible. Considering this, water is most preferable.

1] 1. - The ratio of phenylalanine and mandelic acid to be used when producing a phenylalanine/optically active mandelic acid complex is at least 0.1 times equivalent of mandelic acid to phenylalanine, preferably 0.5 to 6 times equivalent, more preferably 1 to 3 times equivalent. The boost power is about -111, but it is determined as appropriate depending on the amount of the acidic compound added.

The temperature at which the complex is formed is not particularly limited as long as it is 0.8G or higher, but it is preferably in the range of 50C to the boiling point of the solvent.

Especially if the crystallization temperature is below the boiling point of the solvent used, <Il
Although there is no limit, a range of 0°C to 50°C is preferred.

When crystallizing the optically active composite, it is not particularly necessary to add seed crystals, but there is no problem in adding a 4Φ product with a diameter of 11 to speed up the crystallization.

If the optically active complex obtained is not yet optically pure, a pure complex can be easily obtained by recrystallization or the like, if necessary.

Optically active phenylalanine can be isolated from the obtained Jt optically active complex by a known method. For example, an aqueous solution of an optically active phenylalanine/optically active mandelic acid complex is neutralized with caustic alkali to precipitate the desired optically active phenylalanine, and then P is removed. This can be easily carried out by washing with water, eluting with aqueous ammonia, concentrating the eluate, and counting the precipitated crystals.

Among the optically active phenylalanines obtained in the present invention,
It is useful as a component of acid infusions, as a raw material for synthetic flavoring agents, and as a raw material for pharmaceuticals.

Next, the present invention will be specifically explained with reference to Examples.

Example 1゜J) L-phenylalanine 29.0 g-1 L-mandelic acid 32.0! v-80% propionic acid 113.3
After melting by heating at 70''C, the mixture was cooled to 25°C over a period of 2.5 hours.

L-phenylalanine/L-mandelic acid complex 0.035' was inoculated at 50°C, left at 25°C for 2 hours, precipitated crystals were collected by filtration, washed with water, and dried to form L- Phenylalanine/L-mandelic acid complex 20.2
I got P. This crystal 1001 was neutralized to pl-16.0 by adding water G (1, (dissolved by heating to 1me, 20% hydroxide) IJum 601. The precipitated crystals were filtered and washed with water. and dried to obtain IJ-phenylalanine 4.oy ([α]”-33,1° (C = 2.11
z O)) An optical purity of 950% was obtained.

Example 2 1) I, -phenylalanine 387J, 1) -mandelic acid 712.77 to 50% malonic acid 113.3. 70 to P
After heating and dissolving at .degree. C., the mixture was cooled to 25.degree. C. for 2.5 hours.

5 (1°C K TeI)-phenylalanine 1]-mandelic acid complex 0. (135) was inoculated, left at 25°C for 2 hours, the precipitated crystals were collected by filtration, washed with water, and dried to obtain D-phenylalanine/D-mandelic acid complex 25.09-. . Thereafter, treatment was carried out in the same manner as in Example 1, resulting in 1)-phenylalanine 10. (17・([
α Redundancy 0+3L6° (C=2.I20) Optical purity 9
1.3%).

Example 3 DL-phenylalanine 29.0P and L-mandelic acid 32, Of were dissolved in 80% lactic acid 113.28g at 70°C by heating, and then cooled to 25°C over 2.5 hours.

1. Inoculated 0.03P of -CI, -phenylalanine-L-mandelic acid complex at 50°C, left at 25°C for 2 hours, filtered the precipitated crystals, washed the crystals with water, and dried. -Phenylfuranine-L-mandelic acid complex 19
I got 2J. Thereafter, treatment was carried out in the same manner as in Example 1, and L-
Phenylalanine 7.71 ([α] 20-30.6° (
C=2. I(20) optical purity 88.7%) was obtained.

Example 4 38.7 g of DL-phenylalanine - 42.7 g of 1L-mandelic acid was added to 113.3 P of 30% maleic acid (7 (1
After heating and dissolving at 25°C, it was cooled to 25°C over a period of 25 hours. At 42°C, 003 g of L-phenylalanine/Shima/delic acid complex was inoculated and left at 25°C for 2 hours.
The precipitated crystals were collected by filtration, washed with water, and dried to obtain L-phenylalanine/IJ-mandelic acid complex 1.
Obtained 8.8P. Thereafter, treatment was carried out in the same manner as in Example 1, resulting in I)-phenylalanine 7,5 P (Cα) tongue 0-3
1.7° (C22.lI20) optical purity 91.6%)
I got it.

Example 5゜1) 1 No Phenylalanine 33.1,7. D-mandelic acid: 36.6 Ft in 1.4% hydrochloric acid aqueous solution 312.2
g- and heated to dissolve at 75°C, then cooled to 27°C.

J)-phenylalanine/D-mandelic acid complex 0.08 at 60°C? Inoculate with K and leave at 27°C for 2 hours, filter out the precipitated crystals, wash the crystals with water, and dry.
l: t) 195 g of I)-phenylalanine/1]-mandelic acid complex was obtained.

The obtained complex was treated in the same manner as in Example 1 to obtain L-phenylalania 7.89-.

Specific optical rotation [α element'--31.7° (C=2.1-1□
O) Optical purity 91.6% Reference example 1゜Water 100mJKDL-Phenylalaniy33. IP, L
-Mandelic acid 73.2, V- was added and the temperature was raised to 80-90°C, but since it did not dissolve uniformly, water was gradually added.

Dissolution occurred when 775 ml of water was added. This was gradually cooled in the same manner as in Example 1, seed crystals of 0.271 L-phenylalanine/L-mandelic acid complex were added during the course of the reaction, and the mixture was further cooled to 30'G after about 3 hours. This was washed with ρ water and dried to obtain a 52.9'4P L-phenylalanine/L-mandelic acid complex (molar ratio phenylalanine:mandelic acid=1:1).

This material was treated in exactly the same manner as in Example 1, and the L of 21.27
- Phenylalanine was obtained.

Specific optical rotation [α几' = -28,9° (C = 2. II
□0) Optical purity 84. ], O% Patent applicant Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) Optical resolution of I) L-phenylalanine/optically active mandelic acid complex in an aqueous solvent containing hydrochloric acid, a C1 to C4 fatty acid, a lower aliphatic oxyacid, or a lower aliphatic dicarboxylic acid. Active phenylalanine
1. A method for producing optically active phenylalanine, which comprises removing mandelic acid from an optically active mandelic acid complex.