The Rabeprazole Intermediates Study

Rabeprazole is second-generation product of proton pump inhibitors (PPIs) after the producing of Omeprazole and Lanprazole. which is comprehensively applicated in therapeusis of alimentary system. This article study on the synthesis of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl] methylthio]-l H-benzimidazole that is precursor of Rabeprazole by using our prepared 4-(3-methoxypropoxy)-2. 3-dimehtylpyridine-N-oxide products. This article emphasizes on the synthesis of four intermediate products and optimize of key factors:First is the synthesis of 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpy-ridine by using our prepared 4-(3-methoxypropoxy)-2,3-dimehtylpyridine-N-oxide products(content is 85-90%), through anhydride acetic acid's acetylization. We discover better reaction condition through single factor observe and study. Reaction yield is up to 90%, and purity of the product is up to 89%. We innovatly bring forward the method of appending certainly proportional solvent A in the anhydride acetic acid to improve reaction selective.Second is the synthesis of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylp-yridine and its salt, which is obtained by the hydrolysis of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine. We successfully change the purification of the solution of pyridine's derivates to purification of the pyridine's derivates salt because of the difference of pyridine's derivates and its salt. There are not literatures about it. We discover better reaction condition through single factor observe and study. Purity of the salt's raw product is up to 94%, yield is up to 75%. Purity is up to 98.5% by recrystallization. It can be directly selled as intermediate product. The products all are detected by NMR and IR.Third is the synthesis of 2-chloromethyl-4-(3-methoxypropoxy)-3-rnethylpy-ridine and its salt, whose hydrolysis products are obtained by SOCK chlorination. We discover better reaction condition through quadarture experiments. The salt yield of chlorination is up to 90%, content of raw product is above 95%, and Purity is up to98.5% by recrystallization. The products all are detected by NMR and IR.Fourth is the synthesis of 2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylthio]-lH-benzimidazole,which is obtained by condesation of chlorination products and 2-thiolbenzimidazole The reactio is processing in more mild condition through experiment, meanwhile we change the way of charging-up to make the technology rationality. The reaction yield is up to 93%. the purity of raw product is 96%. and it is up to 98.5% by recrystallization. The products all are detected by NMR andlR.In this article, we bring forward the new technology of refinging of Rabeprazole"s intermediate products using pyridine's derivates salt property, especially preparing high purity 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine and its salt. 2-chloromethyl-4-(3-methoxypropoxy)-3-rnethylpyridine and its salt.There has innovation in technology, supplying a gap in the field in china.