JPH0784433B2 - Optical resolution of N-carbamoylmethionine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] And a method for optical resolution of (±) -N-carbamoylmethionine (hereinafter abbreviated as (±) -NCM).

[Conventional technology and its problems]

Methionine is one of the essential amino acids, and is a compound that is in great demand as a mixed feed for livestock, pharmaceutical products such as foods and amino acid infusions. Since an optically active substance is required when used as a drug, a method for obtaining a large amount of optically active methionine is desired.

Various methods have been proposed as methods for obtaining optically active methionine by optical resolution. For example, 1) a method in which methionine is N-acetylated, and then optically resolved as an ammonium salt by a preferential crystallization method (Japanese Patent Publication No. 39-2444).
No. 0), 2) enzymatically splitting acylated methionine using aminosylase (Pharmaceutical Journal, 75 , 113 (1955)),
3) Methioninamide was converted to tartrate (Pharmaceutical Journal, 73 , 357 (195
3)) or a pyrrolidonecarboxylic acid salt (Japanese Patent Publication No. 45-32250), and a chemical method of 4) Methionine-mandelic acid complex (Japanese Patent Publication No. 58-1105). However, the method 1) has the drawbacks that the production amount per one time is extremely small, industrially requires a large-scale device, and the facility is expensive. In addition, the method 2) is disadvantageous because an acyl derivative or the like must be once obtained by acylation, and industrially, an enzyme such as a living organism is used. The method 3) has the drawback that methionine must be a derivative. The method 4) has a drawback in that mandelic acid used as a resolving agent is difficult to recover, and is not yet satisfactory.

[Means for solving problems]

Currently, (±) -methionine is industrially produced by a synthetic method mainly via hydantoin. When this hydantoin is hydrolyzed with an alkali under normal pressure, an N-carbamoyl compound is easily obtained, and when this N-carbamoyl compound is hydrolyzed, a free α-amino acid is easily obtained.

Therefore, the inventors of the present invention thought that if N-carbamoylmethionine could be easily optically resolved, it could be an industrially simple and inexpensive method for producing an optically active methionine. (Hereinafter EB
The present invention was completed by finding that (±) -NCM can be optically resolved with high optical purity and high yield by using A) or 2-amino-1-butanol (hereinafter abbreviated as 2AB).

That is, the present invention provides (±) -NCM with optically active EBA or 2AB
Is used as a resolving agent to generate two types of diastereomeric salts, and optical resolution is performed.

Next, the dividing method of the present invention will be specifically described. First, (±)
− Add optically active EBA or 2AB and a solvent to NCM, dissolve by heating to achieve supersaturation, cool to room temperature, and then, if necessary, a seed crystal of an insoluble optically active NCM ・ EBA salt or NCM ・ 2AB salt. Inoculate a small amount and leave it to separate the same kind of sparingly soluble salt that precipitates.

As the solvent used, water, alcohols, ketones,
A solvent such as an ester or a mixture thereof which is generally used for an optical resolution operation may be used, but in the case of water, NCM is poorly soluble in water, so NCM is changed to an alkali metal salt, amine salt, ammonium salt, etc. Dissolve in water and simultaneously EBA or 2
AB is dissolved as a hydrochloride in water, and this is added and reacted.

The reaction temperature is not higher than the boiling point of the reaction solvent and is not lower than 0 ° C, preferably 50 ° C to the boiling point.

The crystallization temperature is not particularly limited as long as it is not higher than the boiling point of the solvent used, but is preferably in the range of 0 ° C to 50 ° C.

The amount of optically active EBA or 2AB used here is (±)-
It is used in an amount of 0.3 to 1.5 times the molar amount of NCM, but 0.5 to 1.2 times the molar amount thereof is preferably used because the optical resolution can be efficiently performed.

Alternatively, the diastereomeric salt solution may be subjected to silica gel chromatography for partitioning.

The optically active NCM / EBA salt or NCM thus obtained
-If necessary, recrystallize the 2AB salt, add an alkali to decompose the salt, extract and remove EBA or 2AB with an organic solvent, and neutralize with a mineral acid such as hydrochloric acid, sulfuric acid, or nitric acid to obtain optically active NCM precipitates. NCM with high purity can be obtained by filtering this and recrystallizing if necessary.

In addition, optically active EBA or 2AB extracted with an organic solvent
Is easily recovered by removing the solvent under reduced pressure and can be reused.

〔Example〕

 Next, the present invention will be described in more detail with reference to examples.

Example 1 (±) -NCM 9.60 g (50 mmol), sodium hydroxide 2.00
A solution of g (50 mmol) in 25 ml of water was added and heated to 50 ° C. with stirring. (+)-EBA 4.05g (30mmo
A solution prepared by adding 1 ml of hydrochloric acid (30 ml) to (l) was added. The reaction was completed by heating to 70 ° C with further stirring. This was cooled and allowed to stand at 30 ° C. for 2 hours, the precipitated crystals were filtered off, and the crude (+)-NCM. (+)-EBA salt 8.49 g (26.0 mmol)
Got By suspending and purifying this salt with 30 ml of water, 5.85 g (17.9 mmol) of pure (+)-NCM. (+)-EBA salt was obtained. The physical properties of this product were as follows.

[Α] _D ¹⁹ ; + 3.3 ° (C1, methanol) mp; 179-184 ° C. Yield based on the (+)-form contained in (±) -NCM used;
71.6% Sodium hydroxide 0.82g (21.0mmol) in water 12m
The solution dissolved in 1 was added, and the released (+)-EBA was extracted and removed with benzene. Concentrated hydrochloric acid (1.5 ml) was added to the aqueous layer, and the precipitated crystals were filtered and dried to give crude (-)-NCM 2.43 g (12.6 mmo
l) got. This was recrystallized with 20 ml of water to obtain 1.99 g (10.4 mmol) of pure (+)-NCM. The physical properties of this product were as follows.

[Α] _D ¹⁹ ; + 17.4 ° (C1, ethanol) mp; 165-168 ° C Optical purity; 100% Yield with respect to the (+) form contained in (±) -NCM used;
41.6% The benzene layer during benzene extraction should have a 1 molar concentration of hydrochloric acid 25
3.10 g of (+)-EBA hydrochloride by back extraction with ml
(18.1 mmol) was recovered.

Example 2 (±) -NCM 1.92 g (10 mmol) and (+)-EBA 1.49 g (11 mm
was dissolved in 14 ml of a mixed solvent of methanol: water (6: 1) under heating. The crystals precipitated after standing at room temperature for 2 hours are filtered off,
1.29 g (3.9 mmol) of (+)-NCM * (+)-EBA salt was obtained.
The physical properties of this product were as follows.

[Α] _D ³⁰ ; + 1.8 ° (C1, methanol) mp; 191-195 ° C Yield based on the (+) form contained in (±) -NCM;
78.0% To this salt, 0.24 g (5.9 mmol) of sodium hydroxide is added to 2.5 m of water.
The solution dissolved in 1 was added, the released (+)-EBA was extracted and removed with ether, 1 ml of 6N hydrochloric acid was added to the aqueous layer, and the precipitated crystals were separated by filtration and dried (0.36 g (+)-NCM ( 1.9 mmol)
Got The physical properties of this product were as follows.

[Α] _D ²⁶ ; + 16.2 ° (C1, ethanol) mp; 151-155 ° C Optical purity; 93.1% Yield based on the (+) isomer contained in (±) -NCM used;
38.0% Example 3 (±) -NCM 1.92 g (10 mmol) and (+)-2AB 0.98 g (11 mm
ol) in methanol: 2-propanol (1: 1) mixed solvent 10m
It melted by heating. The crude (+)-NCM. (+)-2AB salt 1. was obtained by filtering the precipitated crystals after leaving them at room temperature for 2 hours.
54 g (5.5 mmol) was obtained. 5.5 ml of the above mixed solvent
Recrystallize with 1.00 g (3.6) of pure (+)-NCM • (+)-2AB salt.
mmol) was obtained. The physical properties of this product were as follows.

[Α] _D ²⁵ ; -9.1 ° (C0.5, MeOH) mp; 111-118 ° C Yield based on the (+)-form contained in (±) -NCM;
72% To this salt, 0.6 ml of 6M hydrochloric acid was added, and the precipitated crystals were filtered to obtain 0.56 g (2.9 mmol) of (+)-NCM. The physical properties of this product were as follows.

[Α] _D ²⁷ ; -13.8 ° (C1, ethanol) mp; 145-152 ° C Optical purity; 79% Yield based on (+) form contained in (±) -NCM used;
58%

Claims (1)

[Claims] 1. An optically active α-ethylbenzylamine or 2-amino-into (±) -N-carbamoylmethionine.
An optical resolution method of (±) -N-carbamoylmethionine, which comprises reacting 1-butanol in a solvent and resolving the resulting diastereomeric salt.