Study On Synthesis Of Rotigotine Hydrochloride

Rotigotine hydrochloride which belongs to5-hydroxy-2-aminotetralin derivatives is an even more potent D-2receptor agonist. It can be used for caring inactive Parkinson’s disease and restless leg syndrome.In this study, starting from1,6-dimethoxynaphthalene,5-methoxy-2-te-tralone was obtained through Na/EtOH reduction and hydrolysis. Then racemic5-methoxy-2-(N-propylamino)tetralin was prepared from this ketone by a reductive amination reaction using n-propylamine. To obtain the chiral compound (-)-5-methoxy-2-(N-propylamino)tetralin, this racemic compound was resolved. Subsequently the chiral compound was converted in (-)-5-hy-droxy-2-(N-propylamino)tetralin via a demethylation. Then the optical purity Rotigotine hydrochloride was synthesized by N-alkylation. The overall yield of the reactions was7.4%. Structure of intermediate compounds and the product was characterized by elemental analysis, IR,’H-NMR and13C-NMR. In addition, structure of Rotigotine was characterized by MS and single-crystal X-ray structure determination.The whole synthetic process of experiments has been improved and optimized. Using one-step reaction of reductive amination, not only the synthesis step was shortened, but also the yield was improved from72.5%to88.7%. Through the research of repetitive enlarged experiments in laboratory, the whole synthetic process presented no special difficulty in enlarged experiments.In this study, the synthesis of (-)-5-methoxy-2-(N-propylamino)tetralin hydrochloride was another researching content. Through the study on this reductive amination of5-methoxy-2-tetralone with D-1-phenyl ethylamine, the diastreoisomers were prepared. After alkylation of the diastreoisomers with1-iodo-propane and acidification, the diastreoisomers of5-methoxy-2-(N-1-methylbenzyl-N-n-propylamino)tetralin hydrochloride were obtained. Using ethyl acetate to wash the salt one configurational product was separated, and the product was converted in (-)-5-methoxy-2-(N-n-propylamino)tetralin hydrochloride via debenzylation. This synthesis scheme hasn’t been reported heretofore.