Study On The Synthetic Process Of Iguratimod

Iguratimod is a specific drug developed by Japan's Toyama Chemical Company in the face of rheumatoid arthritis and osteoarthritis.The drug was approved and listed in August2012.In China,Iguratimod was developed by Simcere and Tianjin Institute of Medicine in2003.In 2004,it received CDE clinical approval.In 2008,Simcere completed clinical research and submitted NDA to the state.In 2011,it was approved by the State Food and Drug Administration and listed on the market.This paper is a detailed overview of the three synthetic routes of Iguratimod that have been published so far,and systematically integrates the advantages and disadvantages of these three routes.Through the screening of reaction conditions and the elimination of side reactions,we finally designed and studied a new synthetic process of Iguratimod with low production cost,high yield,high purity,simple operation,good safety and suitability for industrial production.In the reaction,4-chloro-3-nitroanisole is taken as an initial raw material,sodium hydride is taken as a base and phenol is reacted to generate a product which is nucleophilic substituted with 4-chloro-3-nitroanisole to generate 4-phenoxy-3-nitroanisole;And then is reduced into 4-phenoxy-3-aminoanisole in a reaction system of hydrazine hydrate catalyzed by raney nickel;Then reacts with methanesulfonyl chloride to generate 4-phenoxy-3-methanesulfonyl anisole;Under the catalysis of anhydrous aluminum trichloride,the product in the previous step reacts with aminoacetonitrile hydrochloride to generate N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride;Formylation with mixed anhydride in weakly basic system to generate N-[4-(2-formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide;Selective demethylation in anhydrous aluminum trichloride,sodium iodide and acetonitrile system to generate N-[4-(2-formylaminoacetyl)-5-phenolic hydroxyl-2-phenoxyphenyl] methanesulfonamide;At last,it reacts with DMFDMA to produce the final product Iguratimod.The whole process includes 7 steps of nucleophilic substitution reaction,nitro reduction,methanesulfonylation,Houben-Hoesch reaction,formylation,demethylation of methoxy group and cyclization.Under these conditions,the total yield and purity of the reaction reached 42.5% and 99.8%,respectively.