JPS63218655A - Optical resolution of n-carbamoylmethionine - Google Patents

Abstract

PURPOSE:To form two kinds of diastereomeric salts and optically resolve the resultant salts, by reacting (+ or -)-N-carbamoylmethionine with optically active alpha-ethylbenzylamine or 2-amino-1-butanol as a resolving agent. CONSTITUTION:Optically active alpha-ethylbenzylamine (abbreviated to EBA) or 2-amino-1-butanol (abbreviated to 2AB) and a solvent, such as water r alcohols, are added to (+ or -)-N-carbamoylmethionine [abbreviated to (+ or -)-NCM] and dissolved at 50 deg.C - boiling temperature while heating to provide supersaturation. The resultant mixture is then cooled to room temperature and the formed diastereomeric salts are resolved. The optically active EBA or 2AB is used in a molar amount of 0.3-1.5 times based on the (+ or -)-NCM. The methionine is one of essential amino acids and useful as a medicine, such as formula feed for domestic animals, food and amino acid transfusion solution.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for optical resolution of (±)-N-carbamoylmethionine (hereinafter abbreviated as (±)-NCM) represented by the formula %[00]. It is related to.

[Conventional technology and its problems]

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

Various methods have been proposed for obtaining optically active methionine by optical resolution.

For example, 1) methionine is N-acetylated and then optically resolved as an ammonium salt by preferential crystallization (Japanese Patent Publication No. 39-24440), 2) acylated methionine is enzymatically resolved using aminoacylase. Method (Yakushu, No. 113 (1955)), 3) Methionine amide is converted into tartrate (Yakushu, No. 73.357 (1953)
)) and pyrrolidone carboxylate (Special Publication No. 3225-1973)
4) A method of dividing as a methionine-mandelic acid complex (Japanese Patent Publication No. 58-1105). However, method 1) is -
The disadvantage is that the production volume per cycle is extremely small, and industrially, large-scale equipment is required and the equipment is expensive. In addition, method 2) requires acylation to produce an acyl derivative, and is disadvantageous from an industrial perspective because it uses biological enzymes. The disadvantage of method 3) is that methionine must be made into a derivative. Method 4) has the disadvantage that the mandelic acid used as the resolving agent is difficult to recover, and is still far from satisfactory.

[Means for solving problems]

Currently, (±)-methionine is industrially produced mainly by a synthetic method 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, it is easily converted into a free α-amino acid.

Therefore, the present inventors believed that if N-carbamoylmethionine could be easily optically resolved, it could be an industrially simple and inexpensive method for producing optically active methionine, and as a result of extensive investigation, they discovered that optically active α-ethylbenzylamine (hereinafter E
(abbreviated as BA) or 2-amino-1-butanol (abbreviated as BA) or 2-amino-1-butanol (abbreviated as BA) or 2-amino-1-butanol (
The present invention was completed by discovering that (±)-NCM can be optically resolved with high optical purity and high yield by using 2AB (hereinafter abbreviated as 2AB).

That is, the present invention is a method for optically resolving (±)-NCM by allowing optically active EBA or 2AB to act as a resolving agent to generate two types of diastereomer salts.

Next, the dividing method of the present invention will be specifically described. First, (±)
Add optically active EBA or 2AB and a solvent to NCM, heat and dissolve to make supersaturated, cool to room temperature, and then
If necessary, a small amount of seed crystals of poorly soluble optically active NCM-EBA salt or NCM·2AB salt is inoculated and allowed to stand, and the precipitated same kind of sparingly soluble salt is separated.

Solvents used include water, alcohols, ketones,
Solvents commonly used for optical resolution operations such as esters or mixtures thereof may be used, but in the case of water, NCM
Since it is poorly soluble in water, NCM is made into an alkali metal salt, amine salt, ammonium salt, etc. and dissolved in water, and at the same time, EBA
Alternatively, 2AB is dissolved in water as a hydrochloride, and this is added to react.

The reaction temperature is below the boiling point of the reaction solvent and above 0°C, preferably in the range from 50°C to the boiling point.

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

The amount of optically active EBA or 2AB used here is (
±) 0.3 to 1.5 times the mole of NCM is used, but it is preferable to use 0.5 to 1.2 times the mole because efficient optical resolution can be achieved.

Alternatively, a solution of diastereomeric salts may be separated by chromatography on silica gel.

The optically active NCM-EBA salt or NCM-2AB salt obtained in this way is recrystallized if necessary, then an alkali is added to decompose the salt, and EBA or 2AB salt is dissolved in an organic solvent.
When AB is extracted and removed and neutralized with a mineral acid such as hydrochloric acid, sulfuric acid, or nitric acid, optically active NCM is precipitated. By filtering this and recrystallizing it if necessary, highly pure N
You can get commercials.

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

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 A solution of 2.00 g (50 mmol) of sodium hydroxide dissolved in 25 ml of water was added to 9.60 g (50 mmol) of (±) -N CM, and the mixture was heated at 50°C with stirring.
heated to. To this (+) -E B A4.05g (
A solution of 30 mmol) and 30 ml of 1 molar hydrochloric acid was added. The reaction was completed by heating to 70° C. while stirring. This was cooled and left to stand at 30°C for 2 hours, and the precipitated crystals were filtered off to form crude (+)-NCM・(+).
-EBA salt 8.49 g (26, Ommo 1 ) was obtained. By suspending and purifying this salt in water, the purified (
+)-NCM・(+)-EBA salt 5.85g (17,9
mmol) was obtained. The physical properties of this product were as follows.

[α)n”; +3.3° (C1, methanol) mp
; 179-184°C Yield based on the (+) form contained in ±)-NCM used; 71.6% To this salt, add 0.82 g of sodium hydroxide (21.0 m
A solution prepared by dissolving mol) in 12 ml of water was added, and the liberated (+)-EBA was extracted and removed with benzene. To the aqueous layer was added 1,5rr+1 of concentrated hydrochloric acid, and the precipitated crystals were filtered and dried to obtain 2.43g (12.6mm) of crude (+)-N CM.
ol) was obtained.

This is 20mj of water! By recrystallizing with
99 g (10.4 mmol) of NCMl was obtained. The physical properties of this product were as follows.

[α)n”; +17.4° (C1, ethanol) mp
; 165-168°C Optical purity: 100% Yield based on the (+) form contained in the (±)-NCM used; 41.6% The benzene layer during benzene extraction was diluted with 1 molar hydrochloric acid 2
Hydrochloride of (+)-EBA by back extraction with 5-
．． Log (18.1 mmol) was collected.

Example 2 (Shin-N CMl, 92 g (10 mmol) and (+
) -E B A1, 49g (llmmol) in methanol:water (6:1) mixed solvent 14ml! ! The mixture was heated and dissolved. The precipitated crystals were separated by filtration after being left at room temperature for 2 hours, and (+)
-NCM・(+)-EBA salt 1.29g (3.9mm
ol) was obtained. The physical properties of this motsu were as follows.

[α)D”; +t, 8° (C1, methanol) m
p; 191-195°C Yield based on the (+) form contained in the (±)-NCM used; 78.0% To this salt, 0.24 g of sodium hydroxide (5.9 mm
A solution of ol) dissolved in 2.5 liters of water was added to liberate (
+)-EBA was extracted and removed with ether, and 1rnI of 6N hydrochloric acid was added to the aqueous layer. was added, and the precipitated crystals were filtered and dried (
+ ) -N CMo, 36g (1.9mmol)
I got it. The physical properties of this product were as follows.

[α]. 26; +16.2″' (C1, ethanol) mp; 151-155°C Optical purity; 93.1% Yield based on the (+) form contained in the (±)-NCM used; 3B, 0% Example 3 (±) -N CMl, 92 g (10m+nol
) and (+)-2A 80.98 g (llmmol) in methanol:2-propanol (1:1) mixed solvent 10
mj! The mixture was heated and dissolved.

By leaving it at room temperature for 2 hours and filtering the precipitated crystals, 1.54 g of crude (+)-NCM/(+)-2AB salt was obtained.
(5.5 mmol) was obtained. This salt is mixed with the above mixed solvent 5.
．． Recrystallize with 5 rnl to obtain pure (+)-NCM-(+)-2
AB salt 1. OOg (3,6 mmo I) was obtained. The physical properties were as follows.

[α),”; −9,1°(C0,5,MeOH)f
U; 111-118°C Yield based on the (+) body contained in the (Sat)-NCM used; 72% By adding 6M hydrochloric acid 0.6- to this salt and filtering the precipitated crystals, the (+) -N CMo, 56g (2
, 9 mmol) was obtained. The physical properties of this product were as follows.

[α),”; −13,8° (C1, ethanol) m
p: 145-152°C Optical purity: 79% Yield based on the (+) form contained in the (±)-NCM used: 58%

Claims (1)

[Claims] (±)-N-Carbamoylmethionine optically active α-
An optical resolution method for (±)-N-carbamoylmethionine, which comprises reacting ethylbenzylamine or 2-amino-1-butanol in a solvent and separating the diastereomeric salts produced.