Method for producing optically active mandelic acid derivatives

Details Method for producing optically active mandelic acid derivatives Method for producing optically active mandelic acid derivatives

2002-10-23

2004-08-17

Redding, David A. (Department: 1744)

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

C435S128000, C435S130000, C435S829000, C435S830000, C435S840000, C435S843000, C435S853000, C435S859000, C435S930000, C435S940000

Reexamination Certificate

active

06777224

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method for producing optically active mandelic acid derivatives that are widely used as raw materials or synthetic intermediates of various pharmaceuticals.
BACKGROUND OF THE INVENTION
As methods for producing optically active mandelic acids that have substituent(s) on the benzene ring, following methods are known:
an optical resolution method by fractional crystallization of racemates (Unexamined Published Japanese Patent Application No. (JP-A) 2001-72644);
an optical resolution method by chromatography (Journal of Chromatography. (1983), 282, 83-8);
a method using nitrilase (JP-A Hei 4-99496 and JP-A Hei 6-237789);
a method for obtaining an optically active substance by oxidizing one of the racemates (JP-A Hei 6-165695); and
a method using hydroxylnitrile lyase (JP-A 2001-354616).
The optical isomers of interest are recovered through optical resolutions by fractional crystallization of racemates and by chromatography. On the other hand, the undesired enantiomers cannot be utilized, which leads to a loss of a part of raw material. That is, a raw material cannot be used efficiently according to these methods, which causes an increase in the cost of production. Similarly, when an optically active substance is obtained through the oxidation of one of the racemates, the optically active substance of interest is recovered while the undesired enantiomers cannot be utilized, which again causes an increase in the cost. Although a method wherein the undesired enantiomers are recovered and racemized to be recycled as the raw material has been reported, it requires complicated operation.
The production method that uses nitrilase requires a mandelonitrile derivative as the raw material. Hydrocyanic acid is necessary for the synthesis of a mandelonitrile derivative. In the method using hydroxynitrile lyase, benzaldehyde and sodium cyanide are used as raw materials. Due to its toxicity, hydrocyanic acid must be handled with care.
Enzymes not only have high catalytic functions, but also display stereospecificities, as well as substrate specificities and reaction specificities. Most stereo-specificities of enzymes are absolute, although with some exceptions.
As recent researches have become more exact, the importance of using optically active substances has been increased in the fields of pharmaceuticals, agricultural chemicals, feedstuffs, and aroma chemicals. This is because optical isomers sometimes have completely different biological activities. For example, while D(R)-thalidomide does not have teratogenicity, L(S)-form thalidomide has strong teratogenicity, and the practical use of the racemate of thalidomide caused drug induced suffering. Often time one of the enantiomers displays effective biological activity and the other not only lacks the activity but also competitively inhibits the effective enantiomer. This results in a drastic decrease in the biological activity of the racemate to less than ½ of the activity of the effective enantiomer. Therefore, obtaining (synthesizing or resolving) an optically pure enantiomer is an important industrial task. Aiming at this purpose, a technique wherein a racemate is synthesized and then effectively optically resolved has been widely used; and enzymatic optical resolutions that do not generate by-products or large quantity of waste fluid have been attracting attention.
Methods for obtaining optically active mandelic acids, wherein phenylglyoxylic acids that have no substituent on the benzene ring are asymmetrically reduced by microorganisms, are known in the art (See JP-A Sho 57-198096, JP-A Sho 57-198097, JP-A Sho 63-32492, JP-A Hei 6-7179, etc.).
A method that allowed for the production by enzymatic reaction of optically active mandelic acids that have substituent(s) on the benzene ring would be of great utility. However, until now, no enzymatic methods that can be performed on an industrial scale are known.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an enzymatic method for producing optically active mandelic acids that have substituent(s) on the benzene ring.
The present inventors have vigorously investigated methods that satisfy such a high level requirement, and discovered that optically active mandelic acid derivatives that have substituent(s) on the benzene ring (hereinafter, referred to as mandelic acid derivatives) can be advantageously derived from phenylglyoxylic acid derivatives that have substituent(s) on the benzene ring (hereinafter, referred to as phenylglyoxylic acid derivatives) by the asymmetric reduction utilizing the reducing power of microorganisms.
As described above, methods for obtaining optically active mandelic acids by asymmetrical reduction of phenylglyoxylic acids that have no substituent on the benzene ring using microorganisms are known in the art. However, it is generally difficult to expect the same microorganisms to catalyze similar reactions with a different substrate, namely a phenylglyoxylic acid having a substituent on the benzene ring. The analogous reaction is not expected to occur due to the differences in steric hindrance by the substituent, toxicity of the substrate compound or the products to the microorganisms, as well as the difference in electronic effect of the substrate due to the substituent(s). For example, as is apparent from the Example described below,
Candida famata
IFO 0856 (JP-A Hei 6-7179) that act on phenylglyoxylic acid derivatives with no substituent cannot act on orthochlorophenylglyoxylic acid of the formula (I). This compound has the structure of a phenylglyoxylic acid derivative with a chlorine (Cl) substitution at ortho position of the benzene ring.
Therefore, the findings obtained by the present inventors were quite unexpected. More surprisingly, the optical purity of the optically active mandelic acids produced by the microorganisms was very high, at a level which implies no problem for practical use. Based on these findings, the inventors have accomplished the present invention.
Specifically, the present invention relates to a method for producing optically active mandelic acids as described below:
[1] a method for producing an optically active mandelic acid derivative, which comprises the steps of:
(a) reacting a culture or cell bodies of a microorganism, or processed products thereof that can steroselectively reduce a phenylglyoxylic acid derivative of the formula (I) with said phenylglyoxylic acid derivative of the formula (I):
wherein: X is hydrogen, alkali metal, or alkaline earth metal; R indicates one or more substituents at ortho, meta, or para position, wherein the substituent is halogen, hydroxyl group, alkyl group having 1 to 3 carbon atoms, alkoxy group, thioalkyl group, amino group, nitro group, mercapto group, phenyl group, or phenoxy group,
(b) stereo-specifically reducing said phenylglyoxylic acid derivative with the microorganism culture, cell bodies, or processed products to yield an optically active mandelic acid derivative of the formula (II):
wherein: X and R is defined for formula (I), and
(c) recovering said optically active mandelic acid derivative;
[2] the method for producing an optically active mandelic acid derivative according to [1], wherein the resulting optically active mandelic acid is in the (R)-form, and the microorganism belongs to any of the genus selected from the group consisting of:
Candida;
Cryptococcus;
Hansenula;
Ogataea;
Pichia;
Rhodosporidium;
Rhodotorula;
Saccharomyces;
Trichosporon;
Yamadazyma;
Rhodococcus;
Amycolatopsis;
Alcaligenes;
Arthrobacter;
Brevibacterium;
Comamonas;
Corynebacterium;
Enterobacter,
Enterococcus;
Lactobacillus;
Leuconostoc;
Microbacterium;
Micrococcus;
Proteus; and
Pseudomonas;
[3] the method for producing an optically active mandelic acid derivative according to [2], wherein the microorganism is selected from the group consisting of:
Candida ernobii;
Candida gropengiesseri;
Candida magnoliae;
Candida sake;
Candida shehatae;
Candida silvatica;
Cryptoc

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