Preparation Of S-(-)-Amlodipine Benzene Sulfonate And Synthesis Of Related Substances

Hypertension is a common cardiovascular and cerebrovascular disease.In recent years,with the improvement of people's living standards and the increasing pressure of life,the incidence of hypertension has increased year by year and the trend of aging has increased,at present,the number of hypertension patients in China has exceeded 200million.Amlodipine is a new type of 1,4-dihydropyridine calcium inhibitor developed by Pfizer in the UK in 1990.It is mainly used in the treatment of hypertension and angina pectoris.In 1999,Shihuida Company resolved amlodipine to obtain a S-(-)-Amlodipine that exerted its pharmacological effect,and developed S-(-)-Amlodipine Benzene Sulfonate with less side effects.This paper compares the resolution methods of amlodipine that have been reported at home and abroad.A process for the resolution of amlodipine using N,N-dimethylformamide(DMF)as the solvent and L-(+)-tartaric acid as the resolving agent was determined.The L-body in racemic amlodipine is firstly salted with L-(+)-tartaric acid,dissociated by sodium hydroxide,and then formed into a salt with benzenesulfonic acid to obtain the product S-(-)-Amlodipine Benzene Sulfonate.During the process of optimizing the process,factors such as the feed ratio,temperature,and time in each step of the reaction were investigated,and the optimal process conditions were determined through single-factor experiments.The improved process route has low cost and is suitable for large-scale production.The product has high optical purity,which can reach99.52%,the yield can reach 62.34%(Based on S-(-)-Amlodipine Benzene Sulfonate),and the purity is 99.56%.Target product confirmed by ~1H-NMR.In order to conduct better quality studies on the obtained S-(-)-Amlodipine Benzene Sulfonate.This article also conducts synthetic research on the relevant substances of S-(-)-Amlodipine Benzene Sulfonate included in the European Pharmacopoeia.Through literature search and several experiments,the synthesis of related substances A,B,D,E,F,G,H was completed,and the synthesized related substances and some intermediates were confirmed by ~1H-NMR.