Study On Synthesis Of S-(+)-Rivastigmine Hydrogentartrate

Rivastigmine hydrogentartrate which belongs to physostigmine derivati-ves is a sort of acetylcholinesterase inhibitor. It can be used in symptomatic treatment of mild to moderate Alzheimer’s Disease.In this study, racemic [1-(3-methoxyphenyl)ethyl]dimethylamine was prepared by using3-methoxyacetophenone as the starting material via reductive amination with dimethylamine.[1-(3-methoxyphenyl)ethyl]dimeth-ylamine was converted to racemic3-(1-dimethylam-inoethyl)phenol via demethylation with hydrobromic acid.3-(1-dimethylam-inoethyl)phenol was successfully resolved to give the chiral compound S-(-)-3-(1-dimethylamino-ethyl)phenol. S-(-)-3-(1-dimethylaminoethyl)phenol reacted with N-ethyl-N-methylcarbamoyl chloride to give S-(-)-rivastigmine. S-(-)-rivastigmine reacted with L-(+)-tartaric acid to get S-(+)-rivastigmine hydrogentartrate. The total yield of the reaction is6.7%. Structures of intermediate compounds and the final product were characterized by elemental analysis, IR,’H-NMR,13C-NMR and MS.The procedure of synthesis of rivastigmine hydrogentartrate has been studied in our works. By the study of the added amount of some materials, reacted time, and the sequence of different material added in reaction, the optimum conditions were obtained. In additional, the resolution of [1-(3-methoxypheny-1)ethyl]dimethylamine and3-(1-dimethylaminoethyl)ph-enol has been studied. As a result,1-(3-methoxyphenyl)ethyl]dimethylamine can’t be resolved by R-phosphric acid, S-(+)-camphor-10-sulfonic acid, and L-(+)-tartaric acid. And3-(1-dimethylaminoethyl)phenol only can be resolved by S-(+)-camphor-10-sulfonic acid rather than R-phosphric acid and L-(+)-tartaric acid.In this study, the synthesis of [1-(3-methoxyphenyl)ethyl]dimethylamine was another researching content. In the research,[1-(3-methoxyphenyl)ethyl]-dimethylamine was prepared by using3-methoxyacetophenone as the starting material via catalystic hydrogenation reductive amination with dimethylamine. This procedure belongs to green chemistry and has good atom economy. By the study, the yield of the reaction has been improved. Through the study on the time of the reaction, the amount of catalyst, the temperature of the reaction, and different catalyst, the optimum conditions were obtained. This procedure hasn’t been reported heretofore.