Process for producing optically active alpha-methylcysteine derivative

Abstract

The present invention provides a simple industrial process for producing an L- or D-optically active α-methylcysteine derivative or its salt, which is a useful pharmaceutical intermediate, from readily available, inexpensive raw materials. In a process for producing an L- or D-optically active α-methylcysteine derivative or its salt, a racemic N-carbamoyl-α-methylcysteine derivative or its salt is D-selectively cyclized with hydantoinase to produce a D-5-methyl-5-thiomethylhydantoin derivative or its salt and an N-carbamoyl-α-methyl-L-cysteine derivative or its salt, which are then subjected to deprotection of the amino group and the sulfur atom, and hydrolysis.

Description

TECHNICAL FIELD[0001]The present invention relates to a process for producing an optically active L- or D-α-methylcysteine derivative or its salt which is useful as an intermediate for pharmaceutical products.BACKGROUND ART[0002]Known processes for producing an optically active L- or D-α-methylcysteine derivative or its salt include the following:[0003]1) A process asymmetric methylation of an optically active thiazolidine compound produced from optically active cysteine and pivalaldehyde (WO01 / 72702).[0004]2) A process of asymmetric thiomethylation of an optically active oxazolone compound produced from optically active alanine and benzaldehyde (J. Org. Chem., 1996, 61, 3350-3357).[0005]3) A process of methylation of a thiazoline compound produced from cysteine and cyanobenzene, and isolating and purifying the resulting racemic thiazoline compound by chiral HPLC (Synlett., 1994, 9, 702-704).[0006]4) A process of asymmetric bromomethylation of an optically active diketopiperazine co...

AI Technical Summary

Benefits of technology

The present invention provides a process for easily producing optically active L- or D-α-methylcysteine derivatives or their salts, which are useful as pharmaceutical intermediates. The process involves selectively cyclizing the D-isomer of a N-carbamoyl-α-methylcysteine derivative or its salt using a hydantoinase, and then decarbamoylating and deprotecting the sulfur atom. The invention also provides a simple method for effectively producing a racemic N-carbamoyl-α-methylcysteine derivative. The process is industrially practical and cost-effective.

Problems solved by technology

Process 5) is complicated by a large number of steps, and requires various kinds of expensive reagents.

The key step of process 6) is the desymmetrization of the diester by PLE as esterase etc., but PLE cannot be easily stably secured on an industrial scale because of difficulty in mass production of PLE, thereby making the process unpractical.

Therefore, any one of the processes has problems to be solved as an industrial process for producing an optically active methylcysteine derivative or its salt.

However, there has been no known example of isolation of optically active α-methylcysteine or its salt by crystallization.

However, as a result of isolation of the compound according to this method, the inventors have found that a solid is precipitated with concentration of the aqueous solution, and at the same time, the solid becomes a large lump containing water to make stirring difficult.

Therefore, the operation of concentrating the aqueous solution to precipitate a solid is disadvantageous as an industrial operation, and the solid tends to be aggregated with concentration.

This causes difficulty in stirring a crystallization solution and isolating the solid.

Therefore, the isolation methods disclosed in the above WO01 / 72702 etc. are unsuitable for industrial production.

Furthermore, if the insoluble inorganic salts generate and are mixed in the optically active α-methylcysteine or its salt obtained by deprotection of optically active methylcysteine derivative during the reaction or a post-treatment step like neutrization etc., the inorganic salt cannot be removed by the above-described conventional method.

Furthermore, α-methylcysteine or its salt is unstable against oxidation and is easily converted to a disulfide by dimerization.

Also, dimerization of α-methylcysteine proceeds to produce a disulfide, and the disulfide cannot be easily removed and is unavoidably mixed in a product.

However, a process for producing the racemic N-carbamoyl-α-methylcysteine derivative in a small number of steps and high yield has not yet been established.

However, in this method, the ureylene group (—NHCONH—) of the racemic 5,5-disubstituted hydantoin cannot be effectively used as the ureido group (carbamoylamino group: —NHCONH2) of the racemic N-carbamoyl-α-disubstituted amino acid derivative.

Also, the method requires the three steps and is thus inefficient.

However, as a result of production of a racemic N-carbamoyl-α-methylcysteine derivative according to this method, the inventors found that the target compound can be obtained in only 25% yield.

Namely, a process for producing a racemic N-carbamoyl-α-disubstituted amino acid derivative, particularly a racemic N-carbamoyl-α-methylcysteine derivative, in a small number of steps and high yield has not yet been established.

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