Intermediates and process for the preparation thereof

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

2000-05-03

2001-04-10

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

06215005

ABSTRACT:

This invention relates to the new intermediates of general formula (I)—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 advantageously be used in the treatment, first of all owing to their platelet-aggregation-inhibitory and antithrombotic effects.
An especially favourable representative of these compounds, falling under general formula (VI)—wherein X means chloro atom—, is the dextrorotatory methyl(+)-[(S)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate hydrogen 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 earlier feasible only through the strongly lacrimatory and mucous membrane irritant &agr;-halogenophenylacetic acid derivatives, which are difficult to handle during the technology and which are unfavourable from the view of health and environment (European patent applications, Publication 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.
Since 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, the possibility is open, to use—from the first step on—optically active compounds as intermediates. The economical 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, 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 first section of reaction scheme 1. The optically active compounds of general formula (I) are prepared by resolution of the appropriate racemate.
According to our invention
a) the compound of formula (II) in the form of an acid addition salt of it is reacted with a cyanide of general formula (III)—wherein M stands for alkali metal—and with an o-halogenobenzaldehyde of general formula (V)—wherein X means halogen—; or
b) the o-halogenobenzaldehyde of general formula (V)—wherein X stands for halogen—is reacted with the hydrogen sulfite of general formula (IV)—wherein M means alkali metal—, subsequently with the compound of formula (II), and finally with a cyanide of general formula (III)—wherein M stands for alkali metal—, and if desired, the resulting compound of general formula (I)—wherein X means halogen atom—is resolved into its optical isomers, and if desired, liberated from its salts or transformed into its salt.
The process according to the invention is preferably carried out in the presence of solvents, preferred solvents are water, or mixtures of water and a water-miscible solvent, e.g. an alcohol, most preferably a mixture of water and ethanol is applied. Suitable temperature range for the process is 10° C.-100° C., preferably 20° C.-60° C. The reagents are preferably applied in equimolar ratios.
Synthesis of the thienylamine of formula (II) is, among others, described in the French patent application publication No. 2608607. Compounds of general formulae (III), (IV) and (V) may be purchased.


REFERENCES:
patent: 5204469 (1993-04-01), Descamps et al.
patent: 6127550 (2000-10-01), Grondard et al.
patent: 0068983A1 (1983-01-01), None
patent: 0099802A1 (1984-02-01), None
patent: 0274324A1 (1988-07-01), None
patent: 0281459A1 (1988-09-01), None
patent: 2614619 (1988-11-01), None
patent: 0420706A2 (1991-04-01), None
patent: 0466569A1 (1992-01-01), None

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