New Synthetic Method Of Tenatoprazole

Peptic ulcer is one of the most familiar diseases, in which the gastric ulcer and duodenal ulcer are the regular symptoms. Tenatoprazole(TU-199), named 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfmyl]imidazole[4,5-b]pyridine, belongs to the group of drugs considered as proton pump inhibitors(PPIs), which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers.Synthetic technology of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine, a crucial intermediate of tenatoprazole, was studied. 2,6-dichloropyridine as raw material was nitrated by nitric acid / sulfuric acid, after amination, reacted with sodium methoxide, and the intermediate was reduced by H₂ with Raney Nickel, Finally cyclization was finished with carbon bisulfide to give 2-mercapto-5-methoxyimidazo[4,5-b]pyridine. The yield (five steps) was 49.6%.2,3,5-trimethyl-4-nitropyridine-N-oxide as raw material via rearrangement with acetic anhydride chlorination with SOCl₂, to obtain 2-chloromethyl-3,5-dimethyl-4-nitropyridinehydrochloride, which was condensed with 2-mercapto- 5-methoxy imidazole[4,5-b]pyridine to give 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl) methylthio]imidazole[4,5-b]pyridine, and at last Tenatoprazole was synthesized with the following two schemes, scheme 1 : 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl)methylthio]imidazole[4,5-b]pyridine was firstly methoxylated with CH₃ONa and then oxidized with MCPBA to give Tenatoprazole; Scheme 2: 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl)methylthio]imidazole[4,5-b]pyridine was oxidized with MCPBA and then methoxylated with CH₃ONa to give Tenatoprazole. The overall yield of scheme 1 and scheme 2 was 33.7% and 34.3%. Two new substance, 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl)methylthio]imidazole[4,5-b]pyridine and 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl)methylsulfinyl]imidazole[4,5-b]pyridine were synthesized, and the structure was confirmed by ¹HNMR, ESI-MS, IR.