Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1995-02-21
1997-06-03
Naff, David M.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
546321, 514356, 435122, 435136, C12P 4100, C07D213803, A01N 4340
Patent
active
056353952
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to intermediate compounds for optically active 1,4-dihydropyridine derivatives which are useful for the prevention and treatment of ischemic heart diseases or hypertension, and to a process for producing the intermediate compounds.
BACKGROUND ART
A 1,4-dihydropyridine compound which contains two different carboxylic acid esters each other at the 3- and 5-positions of the dihydropyridine ring possesses an asymmetric carbon atom at the 4-position thereof and thus has two optical isomers. It is reported that recent studies on biological properties of these optically active compounds reveal differences of the isomers in pharmacological activity, kinetics in vivo and safety (K. Tamazawa et al., J. Med. Chem., 29, 2504 (1986)). Where these compounds with an asymmetric carbon atom are employed as pharmaceuticals, it has been a general tendency to administer only one of the isomers that is preferable as a pharmaceutical, under such a consensus that any undesirable load should not be borne to the living body. From such a viewpoint, studies have been focused on a process for preparing optically active 1,4-dihydropyridine derivatives. As a conventional process for synthesis of optically active 1,4-dihydropyridine derivatives, there is known a process for introducing a desired ester residue into a (4R)-1,4-dihydropyridinecarboxylic acid mono-ester as an intermediate (A. Ashimori et al., Chem. Pharm. Bull., 39, 108 (1991)). For preparing this optically active intermediate, (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid mono-ester, there are known the chemical process by Shibanuma et al. (Chem. Pharm. Bull., 28, 2809 (1980)) and the enzymatic methods by Achiwa et al. (Tetrahedron Letters, 32, 5805 (1991)) and by Charles J. Sih et al. (Tetrahedron Letters, 32, 3465 (1991)). However, any method for asymmetric direct hydrolysis of diesters by microbiological technique is not disclosed in these publications.
The chemical synthesis of optically active (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid mono-ester described above encounters disadvantages that not only the process requires a protective group for the amino group on the dihydropyridine ring but the formed mono-carboxylic acid racemate requires optical resolution since the reaction is not asymmetric hydrolysis.
On the other hand, the process by Achiwa et al. comprises using as a substrate a dihydropyridine ester derivative having pivaloyloxymethyl at the 3- and 5-positions of the dihydropyridine ring, enzymatically hydrolyzing one of the esters asymmetrically to form an optically active dihydropyridine monocarboxylic acid derivative as an intermediate for synthesis of pharmaceuticals. However, this process involves a defect that the overall yield is not very good, because the process requires a number of steps such as synthesis of the substrate, conversion of pivaloyloxymethyl into other substituents to form compounds useful as pharmaceuticals.
According to the process of Sih et al. acetoxymethyl ester is used instead of pivaloyloxymethyl ester in the process of Achiwa et al. Both processes are basically the same.
It has thus been desired to develop a process for efficiently preparing optically active (4R)-1,4-dihydropyridine 3,5-dicarboxylic acid mono-esters.
DISCLOSURE OF INVENTION
As a result of extensive investigations to solve the problems described above, the present inventors have found a process for efficiently preparing (4R)-1,4-dihydropyridine-3,5-dicarboxylic acid mono-ester derivatives, utilizing a microorganism. The present invention has thus been accomplished.
That is, the present invention provides a process for preparing an optically active (4R)-1,4-dihydro-2,6-dimethyl-4-(nitrophenyl)pyridine-3,5-dicarboxylic acid mono-ester derivative which comprises reacting a compound represented by formula (I) below: ##STR1## wherein R represents a lower alkanoyl group, a heterocyclic carbonyl group, a halo-substituted acetyl group, an alkoxyacetyl group, an aryloxyacetyl group, a substituted or unsubstituted ph
REFERENCES:
patent: 5100892 (1992-03-01), Wheeler
patent: 5234821 (1993-08-01), Achiwa
patent: 5395941 (1995-03-01), Isshiki et al.
Patent Abstracts of Japan, vol. 17, No. 409, 30 Jul. 93 JP 5-84089.
Adachi T et al., Tetrahedron: Asymmetry 4(9):2061-68 (1993).
Adachi Takashi
Isshiki Kunio
Nakashima Takashi
Ota Tomomi
Tsunekawa Hiroshi
Mercian Corporation
Naff David M.
Saucier S.
Taisho Pharmaceutical Co. Ltd.
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