RESOLUTION OF THREO-METHYLPHENIDATE

Abstract: A process for preparing substantially single enantiomer d-threo-methylphenidate, proceeds by means of a classical salt resolution using (-)-menthoxyacetic acid.

Description: RESOLUTION OF m O-METHYLPHENIDATE Field of the Invention This invention relates to the resolution of threo methyiphenidate via crystallisation of diastereomeric salts. Background of the Invention Methyiphenidate was first prepared as a mixture of the erythro and threo racemates. US-A-2957880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereomer. The resolution of threo methyiphenidate can be achieved using the expensive resolving agent 1, r-binaphthyl-2,2'-diylhydrogen phosphate, a process first reported by Patrick et al (The Journal of Pharmacology and Experimental Therapeutics, 241 : 152- 158 (1987)), and subsequently used by other workers in the field (e.g. Aoyama et al, Journal of Chromatography, 494:420 (1989)). This is perceived to be a more efficient procedure than the method disclosed in US-A-2957880, wherein the corresponding amide of erythro methyiphenidate (i.e. R-CONR 2 rather than R-CON 2 Me) is resolved with tartaric acid prior to amide hydrolysis and equilibration at the benzylic centre, followed by esterification of the resultant threo-acid. An improved resolution process is described in PCT/GB97/00185. Such a resolution can be combined with the racemisation described in PCT/GB97/00281. Summary of the Invention This invention is based upon the discovery that racemic threo methyiphenidate can be resolved using inexpensive (-)-menthoxyacetic acid. Description of the Invention The process of this invention may be carried out under conditions that are generally known to those skilled in the art of classical salt resolution procedures. For example, a mixture of threo methyiphenidate free base and 1 molar equivalent of (-)- menthoxyacetic acid in an inert organic solvent is heated and then allowed to cool; the resultant precipitate is filtered, washed with an appropriate solvent and dried to afford directly a salt enriched in 98% ee d-threo methyiphenidate. This is a great improvement on the literature method using 1, -binaphthyI-2,2'-diylhydrogen phosphate, described by Patrick et al, supra, in which the first crystallisation gave a salt corresponding to 85-90% ee material, and further recrystallisation of this material was necessary to raise the ee to 95-97%. The latter level of optical purity is achieved in the present invention in one crystallisation, with an overall higher yield. The method of this invention is therefore more efficient and more economical than the one described by Patrick et al. The following Example illustrates the resolution of threo methyiphenidate using (-)-menthoxyacetic acid. Example dJ-threo methyiphenidate (1.0 g, 3.7 mmol) was suspended in water (20 mi) and treated with caustic solution. The liberated free base was extracted with MTBE (3 x 25 ml), dried over MgSO and evaporated to a light oil. This was dissolved in IP A ( 15 ml) and heated to 60°C. (-)-Menthoxyacetic acid (0.79 g, 3.79 mmol) in EPA (5 ml) was added. Heating was continued for a further 30 min and the mixture was gradually cooled to 10 °C. The resulting white crystalline product was filtered off, washed with cold IP A and dried (0.85 g, 47% by weight, corresponding to 98% ee d-threo methyiphenidate, as determined by chiral HPLC after salt cracking).

Claims: CLAIM A process for preparing substantially single enantiomer <i-/Λreo-methylphenidate, which proceeds by means of a classical salt resolution using (-)-menthoxyacetic acid.

Inventors: ZAVAREH HOOSHANG SHAHRIARI, ZAVAREH, HOOSHANG, SHAHRIARI
Applicants: MEDEVA EUROP LTD, ZAVAREH HOOSHANG SHAHRIARI, MEDEVA EUROPE LIMITED, ZAVAREH, HOOSHANG, SHAHRIARI
Application year: 1997
Main classification: C07D211
IPC codes: C07D211