Synthesis Of Related Substances Of Pantoprazole And Rabeprazole

Drug related substances usually refer to some potential impurities other than pure drug products.The related substances of pantoprazole and rabeprazole described in this article are related impurities of pantoprazole and rabeprazole.Prazole drugs refer to various proton pump inhibitor drugs,which are used to treat gastric acid-related diseases.At present,the representative drugs for clinical treatment of gastroesophageal reflux disease and peptic ulcer are mainly H2 receptor resistance agents and proton pump inhibitors.Proton pump inhibitors have become one of the most commonly used drugs on the market due to their remarkable curative effect and strong gastric acid suppression effect.However,side reactions,degradation and deterioration will occur during production,storage and transportation,improper production processes and storage methods,and other uncontrollable factors will produce impurities,which will reduce the purity of the drug.The presence of impurities will greatly affect the drug’s performance efficacy.Particularly,some genotoxic impurities will have a great impact on the human body,and even cause cancer.Therefore,the study of impurities in prazole drugs is very important.In this paper,based on the literature methods we have further optimized the synthesize routes toward three drug impurities,namely pantoprazole impurity RC E,pantoprazole disubstituted sulfide impurity RC V and rabeprazole impurity RC E.The synthetic route of pantoprazole impurity RC E starts with 1-difluoromethoxy-3-nitrobenzene,and undergoes zinc powder reduction/rearrangement,acylation,nitration,hydrolytic deacylation,reduction nitro group into amino group,cyclization of benzimidazole derivative,thioether formation followed by m-CPBA oxidation,Pantoprazole sulfide di-substituted impurity RC V is obtained by the reaction of 5-difluoromethoxy-2-mercaptobenzimidazole and 4-chloro-2,3-dimethoxypyridine hydrochloride in two sequential steps or by a two-step method or one one-pot manner.Rabeprazole impurity RC E uses 4-chloro-2,3-dimethyl-pyridine nitrogen oxide as the starting raw material,which undergoes methoxylation with sodium methoxide and further react with acetic anhydride to obtain intermediate ester intermediate.After saponification reaction of ester intermediate,sequential reaction with thionyl chloride and 2-mercaptobenzimidazole resulted in the formation of thioether,which is subjected to oxidation to form product RC E.This current work provides practical synthetic methods of prazole impurities:pantoprazole impurity RC E,RC V and rabeprazole impurity RC E.The reaction process is monitored by thin layer chromatography TLC,and the formation of the target products and purity are confirmed by NMR,MS and HPLC characterizations,which meets the requirements for impurity reference.