Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-18
2003-12-30
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S077000
Reexamination Certificate
active
06670486
ABSTRACT:
This invention relates to the novel process for the preparation of the racemic intermediates of formula (VII) wherein x is halogen.
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 therapy, first of all owing to their platelet-aggregation-inhibitory and antithrombotic effects. A particularly favourable representative of these compounds, falling under the 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], designated with the international non-propriety name (INN) clopidogrel (European patent application Publication Nr. 099802).
PCT application Nos. PCT/HU98/00046, PCT/HU98/00047 and PCT/HU98/00048 (WO 98/51682, WO 98/51681 and WO 98/51689 respectively), which are incorporated herein by reference, describe the novel synthesis of the compounds of formula (VI) as shown in the following scheme.
In the course of that synthesis, when the dextrorotatory isomers of the compounds of formula (VII) are further transformed, the levorotatory isomers of the compounds of formula (VII) form waste and cause considerable loss.
Our aim was to solve the racemization of the optically active compounds of general formula (VII) which are not used further in the synthesis and which are of different optical purity, ensuring thus the recycling of the not used isomer into the synthesis process.
We have found that the individual optically active compounds of general formula (VII) or their acid addition salts can be transformed into the racemic compounds of general formula (VII) on the effect of treating them with basic inorganic or organic compounds. Racemisation of mixtures consisting of various ratio of the levorotatory and dextrorotatory isomers of compounds of general formula (VII) can also be solved in this way. In the course of the process, as for inorganic base an alkali metal hydroxide, as for organic base an alkali metal alcoholate can favourably be used. Such are for instance, sodium hydroxide, potassium hydroxide, and sodium ethylate or methylate, potassium ethylate or methylate. The process can be performed in water-miscible or water-non-miscible organic solvents, as well as in the mixture of an organic solvent and water. Favourable solvents are methanol, ethanol, isopropanol, benzene and toluene.
The reaction is usually performed at a temperature between +20° C. and +100° C., favourably between +40° C. and +60° C.
As for starting material, optional acid addition salts of the levorotatory or dextrorotatory compounds of general formula (VII) can be used, favourable salts are tartarate and hydrochloride salts.
The amount of the base is favourably 5-500 mol %, counted for the amount of the optically active compound to be racemized, taking into consideration that when starting from an acid addition salt, a part of the base will be used for the liberation of the compound of general formula (VII).
REFERENCES:
patent: 3632646 (1972-01-01), Hageman et al.
patent: 4364958 (1982-12-01), Seres et al.
patent: 4769486 (1988-09-01), Harada et al.
patent: 5204469 (1993-04-01), Descamps et al.
patent: 466 569 (1992-01-01), None
patent: 98/51681 (1998-11-01), None
patent: 98/51682 (1998-11-01), None
patent: 98/51689 (1998-11-01), None
Alabaster R.J., et al., Tetrahedron: Asymmetry, (1997), vol. 8, No. 3, pp. 447-450.
Derwent Abstract, XP-002134523.
Bai Tiborné
Bakonyl Mária
Dombrády Zsolt
Gáspár Katalin
Supic Attila
Alexander Michael D.
Dupont Paul E.
McKane Joseph K.
Saeed Kamal
Sanofi-Synthelabo
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