Intermediates and process for the preparation thereof

Details Intermediates and process for the preparation thereof Intermediates and process for the preparation thereof

1999-11-12

2001-07-10

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06258961

ABSTRACT:

This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/HU98/00047 which has an International filing date of May 11, 1998, which designated the United States of America.
This invention relates to the new intermediates of general formula (VII), wherein X stands for halogen atom, and to the process of their preparation.
It is known that methyl (2-halogenophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetates and their salts can favorably be used in the treatment, first of all owing to their platelet-aggregation-inhibitory and antithrombotic effect.
An especially favorable representative of these compounds, falling under general formula (VI)—wherein X means chloro atom, is the dextrotatory methyl (+)-[(S)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate hdyrogen sulfate], with the international non-proprietary name (INN) clopidogrel (European patent application, Publication Nr. 099802).
Large-scale preparation of compounds of general formula (VI), wherein X means halogen atom, was previously feasible only through the strongly lacrimatory and mucous membrane irritant &agr;-halogenophenylacetic acid derivatives, which are difficult to handle and are unfavourable from a health and environmental perspective. (European patent applications, Publications Nos. 099802, 0420706, 0466569). Furthermore, yields of the known methods are rather poor.
Our aim was to eliminate the use of the above unpleasant intermediates (such as for instance &agr;-bromo-(2-chlorophenyl)acetic acid and its methyl ester) and to enhance substantially the yield of compounds of general formula (VI) in the synthesis.
In the synthesis according to our present invention, each intermediate is chiral in the preparation of an optically active end-product, as for instance clopidogrel, thus, the possibility is open to use, from the first step on, optically active compounds as intermediates. The economic benefit of the method is, among others, the avoidance of preparation of an unwanted isomer.
We have found that preparing the compounds of general formula (VI) by the route shown on scheme 1, that the use of the unpleasant intermediates can be avoided, and in addition, the yield of the synthesis is much higher. The subject of the present invention is the second section of reaction scheme 1.
The optically active compounds of general formula (VII) are prepared either from the optically active compounds of general formula (I) by the process according to our invention, or by resolving the racemic compound of general formula (VII) to its optical isomers.
According to our invention a racemic or optically active compound of general formula (I), wherein the meaning of X is as defined above, or its salts are transformed, and if desired, the resulting racemic compound of general formula (VII) is resolved to its optically active isomers, and if desired, the racemic compound or the optically active isomers are transformed into their salts, or the racemic compound or the optically active isomers are liberated from their salts.
The reaction of the compounds of general formula (I) with methanol and hydrochloric acid is performed in dry organic solvent. Alkyl acetates such as for instance methyl acetate or ethyl acetate may favorably be applied as the organic solvent. The reaction is carried out at a temperature between 0° C. and +60° C., preferably between 10° C. and 50° C. The optically active compounds of general formula (VII) are prepared either from the optically active compounds of general formula (I) by the route according to our invention, or by resolution of the racemic compound of general formula (VII). As for resolving agent numerous chiral acids may be applied, very advantageous is the application of L-(+)-tartaric acid in the presence of formic acid and isopropanol.
Preparation of the compounds of general formula (I) is demonstrated in the examples and in scheme 1. Starting materials (III), (IV) and (V) of the synthesis may be purchased, synthesis of the compound of formula (II) is described, e.g. in the French patent application publication No. 2608607.


REFERENCES:
patent: 4847265 (1989-07-01), Badorc et al.
patent: 5204469 (1993-04-01), Descamps et al.
patent: 0099802A1 (1984-02-01), None
patent: 0274324A1 (1988-07-01), None
patent: 0420706A2 (1991-04-01), None
patent: 0466569A1 (1992-01-01), None

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