The Synthesis Of (S)-3-aminoquinuclidine Dihydrochloride

Currently, S-3-aminoquinuclidine dihydrochloride play an important role in anticancer drugs. For instance, Palonosetron and Azasetron are new anti-cancer chemotherapy antiemetic drugs which are made from S-3-aminoquinuclidine dihydrochloride. They have a good effect to prevent the cancer vomiting which patients undergo chemotherapy. Currently Palonosetron widely used in clinical in the foreign. In China Palonosetron application has made a large of progress. But S-3-aminoquinuclidine is mainly dependent on imports. Accordingly, study on effective, low cost and scale-up preparation of S-3-aminoquinuclidine dihydrochloride has important practical value.In this thesis, synthesis and resolution of S-3-aminoquinuclidine have been studied, a route with higher optical purity, higher yield was found. It will lay the foundation for industrial production.Resolution of 3-aminoquinuclidine dihydrochloride:D-10-Camphorsulfonic acid was used as resolving agent. Factors affecting resolution, such as alkali, solvent, the molecular ratio of racemate to resolving agent, crystallization temperature and crystallization were studied. As a result, the yield of resolution is 35%, optical purity is 99%.Asymmetric synthesis of S-3-aminoquinuclidine dihydrochloride:With 3-quinuclidinone hydrochloride as starting material, S-3-aminoquinuclidine dihydrochloride is made through reduction. O-methyloxime was reduced with the chiral reducing agent prepared from KBH4, lewis acid and the chiral amino alcohol. various chiral amino alcohol and lewis acid activation were studied, we choosed chiral amino alcohol S-2-amino-3-methyl-1,1-diphenyl-l-butanol and lewis acid ZnCl2 and AlCl3 as reduction reagents, S-3-aminoquinuclidine dihydrochloride was prepared with optical purity of 56%.