Study On The Synthesis Of Related Substances Of Rivaroxaban And Telmisartan

With the in-depth development of the consistency evaluation of generic drugs,the national review standards for drugs have become more stringent.The patent protection period of the two original research drugs of rivaroxaban and telmisartan expires around 2020,and the scientific evaluation of effectiveness,safety and consistency is required when the generic drugs are launched on the market.During the research process,drug-related substances are required for drug safety research.In this paper,two new drugs,rivaroxaban and telmisartan,are used to study the synthesis of related substances.As a new type of anticoagulant drug,Rivaroxaban has great advantages compared with other drugs on the market.In the research process,a qualified impurity reference substance is required to support drug safety research.This article uses an independent design route to synthesize two new types of impurities:(1)Synthesis of rivaroxaban oxazole ring impurity RI-1: Riva Shaban is a raw material,after self-opening under alkaline conditions,it reacts with thionyl chloride to synthesize oxazole ring by itself to obtain rivaroxaban oxazole ring impurity((S)-2-(2-()5-chloro-N-(4-(5-((5-chlorothiophen-2-carboxamido)methyl)-2-oxooxazolidine-3-yl)p henyl)thiophen-2-formyl(Amino)ethoxy)acetic acid);(2)The synthesis of rivaroxaban isopropylidene thiophene impurity RI-2: the precursor RVB-3synthesized by rivaroxaban is used as a raw material,and under an alkaline catalyst,A one-step addition reaction of propylidene is used to prepare the intermediate RIY of rivaroxaban isopropylidene,and then triethylamine is used as an acid binding agent to react with acid chloride to obtain rivaroxaban isopropylidene thiophene impurity((S)-5-Chloro-N-(2-methyl-4-oxopent-2-yl)-N-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxaz olidine-5-yl)methyl)thiophene-2-carboxamide).The above two impurities are based on rivaroxaban itself or process intermediates,seeking effective reaction conditions,and the synthesis steps are simple and efficient.As a new type of blood pressure lowering drug,Telmisartan is mainly suitable for essential hypertension.The chlorinated telmisartan impurity is a potential impurity of the drug and lacks an efficient synthesis process.In this paper,the route is designed independently.The synthesis process takes 3-nitro-4-chloroaniline as the raw material,undergoes methylation,hydrogenation,cyclization,substitution and saponification,a total of five reactions to prepare chlorinated impurities(4-{[2-N-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-yl]methyl}biphen yl-2-carboxylic acid,found in the synthesis process This process can also be used for the synthesis of telmisartan chlorinated impurity isomers,achieving two goals with one stone.This article provides a total of four high-efficiency synthesis processes for drug-related substances.The obtained products are characterized by hydrogen nuclear magnetic spectroscopy,carbon spectroscopy,mass spectrometry,and high-performance liquid phase,all of which meet the requirements of enterprise-related reference materials.