SYNTHESIS AND RESOLUTION OF THE OPTICAL ISOMERS OF THIENCYNONATE HYDROCHLORIDE

Thiencynonate hydrochloride (N-methyl-9α-(3-azabicyclo(3,3,1)nonanyl)-2ʹ-cyclopentyl-2ʹ- hydroxyl-2ʹ-thienylacetate, I·HCl), an new muscarinic receptor antagonist, was synthesized and its enantiomers were obtained form the optical pure of demethylation product II. A convenient resolution method of demethylation product II has been developed with N-p- toluenesulfonylglutamic acid as the resolution reagent. The structures of I and II were elucidated by X-ray analysis. 1 In 1996, the FDA announced it would consider further incentives for developing single isomer drugs for their better pharmacokinetics prosperity, safety, and tolerability. 2 Our recent drug candidate: N-MethylL-9α-(3-azabicyclo(3,3,1)nonanyl)-2ʹ-cyclopentyl- 2ʹ-hydroxyl-2ʹ-thienylacetate hydrochloride (Thiencynonate hydrochloride, I·HCl, Chart 1), is a potent selective M 1 antagonist. It is composed of a tertiary hydroxyl acid as a key component as like many of the muscarinic receptor antagonists. It exhibits classical antimuscarine side effects, such as dry mouth. The preliminary biology results suggest that the (S)-(-)-configuration of the tile compound display an improved therapeutic profile compared to its racemic counterpart. The optical resolution of racemates via diastereoisomeric salt formation is a common way for the preparation of optical isomers. 3,4 We didn't found a suitable acid for the resolution of I due to the weak alkalescence of the tertiary N structure. In our efforts to have a production of the enantiopure, we synthesized the demethylation compound II to enhance the alkalescence. We found that inclusion crystallisation with N-p-toluenesulfonylglutamic acid(TSGA) as a chiral host is an effective method for the resolution of II with high enantiomeric excess.