The Study Of Rivaroxaban Impurity And The Synthesis Of Chicoric Acid

This thesis work consists of two chapters:1.The profile and control of impurity in rivaroxaban was investigated in chapter one.Rivaroxaban was a novel oxazolidinone oral drug directly inhibiting Xa factor and having anti-thrombotic properties,used in the adult patients for elective hip or knee replacement surgery to prevent venous thrombus embolism(VTE).Usually,normal impurities in drugs may lead to the reducing of drug active ingredient content,and then affect the therapeutic effect of drugs.Moreover,Toxicity impurities in drugs will even threaten life.So,it becomes important and significative of the research for Rivaroxaban impurities.In this thesis the reported synthetic routes of rivaroxaban were reviewed and the possible impurity sources in the reported routes were reasonably proposed.Four observed impurities in the synthetic process of rivaroxaban developed by our lab were separated or synthesized.The structures of the impurities were confirmed by NMR and MS and the origins of formation were also mapped out.In addition,the method to lower the concentrations of these impurities to levels accepted by ICH is proposed.2.In second chapter the synthesis of chicoric acid was studied.Chicoric acid is a very important kind of natural products.It has been reported to be used for regulating immunity,anti-inflammatory,anti-fungal,anti-viral,anti-free radicals,anti-oxidant effect,and promoting insulin secretion.The natural product L-chicoric acid,a bis-catechol derivative of(-)-tartaric,which can regulate immunity and promote insulin secretion.In recent reported literatures,L-chicoric acid was one of the most powerful HIV-1 integrase inhibitors.Chicoric acid could be extracted from plants and its price was high due to low extraction rate.Several synthetic routes have been reported on the synthesis of L-chicoric acid,however,there are several drawbacks such as use of tedious chromatography for purification,use of potential explosive reagent during the reaction and low yield of the intermediate and final product.To solve the above mentioned problems,we designed a route that using tartaric acid and caffeic acid as starting materials,with an acetyl group to protect phenolic hydroxyl group of caffeic acid.After acylating with tartaric acid in a nonpolar solvent then removal the acetyl protecting group we can get raw L-chicoric acid.After salt formation or recrystallization from water the final product was obtained with HPLC purity of 99.7%.In this chapter D-chicoric acid and Meso-chicory acid were synthesized from D-tartaric acid and DL-tartaric acid respectively according the synthetic method of L-chicoric acid.The structures of all the synthesized compounds were confirmed by NMR,MS,HPLC and polarimetric method.This environmentally friendly process(no need for the protection of carboxyl group in tartaric acid)featured with inexpensive and easily available starting materials make it suitable for scale-up production.