Process for the preparation of a pharmacologically active...

Details Process for the preparation of a pharmacologically active... Process for the preparation of a pharmacologically active...

1999-11-12

2001-01-30

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S077000

Reexamination Certificate

active

06180793

ABSTRACT:

This invention relates to the novel process of preparation of compounds of general formula (VI)—wherein X stands for halogen atom.
It is known that methyl (2-halogenophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetates and their salts can favourably 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 third section of reaction scheme 1. The optically active compounds of general formula (VI) are prepared either from the optically active compounds of general formula (VII), or starting from the optically active intermediates obtained by resolving the intermediates of general formula (VIII), or by resolving the racemic compounds of general formula (VI).
According to our invention a racemic or optically active compound of general formula (VII)—wherein the meaning of X is halogen atom—is transformed into the racemic or optically active compound of general formula (VIII)—wherein the meaning of X is halogen atom—, and if desired, the resulting racemic compound of general formula (VIII) is resolved into its optically active isomers, and then by ring closure, by a method known per se, the compounds of general formula (VIII) are transformed into the racemic or optically active compound of general formula (VI), and if desired, the racemic compounds of general formula (VI) are resolved into their optical isomers and/or they are transformed into their salts, and/or the racemic or optically active compound are liberated from their salts.
Preferably, the compounds of general formula (VII) are reacted with methanol in the presence of methyl hydrogen sulfate. The reaction can also be performed under pressure, preferably under 5-20 bar. The most advantageous temperature range is between 50° C. and 150° C. Methyl hydrogen sulfate is prepared in the reaction pot, by refluxing methanol and sulfuric acid.
Ring closure of the resulting compounds of general formula (VIII) is carried out by a method known per se. Resolution of the known racemic intermediates of general formula (VIII) or that of the racemic compounds of general formula (VI) is performed by a resolution method known per se, leading to optically active compounds of general formula (VI).
Preparation of the starting compounds applied in our invention is demonstrated in the examples. The starting materials shown in scheme 1 may be purchased, synthesis of the compound of formula (II) is described e.g. in the French patent application publication No. 2608607.
Further details of the invention are illustrated by the following examples, without limiting the scope of the invention to the examples.


REFERENCES:
patent: 4847265 (1989-07-01), Badorc
patent: 0099802 (1984-02-01), None
patent: 0274324 (1988-07-01), None
patent: 0420706 (1991-04-01), None
patent: 0466569 (1992-01-01), None

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