Studies On The Synthesis Of Tenatoprazole H～+, K～+-ATPase Inhibitor

Peptic ulcer is one of the most familiar diseases, in which the gastric ulcer and duodenal ulcer are the regular symptoms. H⁺,K⁺-ATPase inhibitor can inhibit gastric acid secretion caused by sorts of reasons via a irreversible reaction with the H⁺,K⁺-ATPase in the gastric mucosa. Tenatoprazole (TU-199) is a kind of new H⁺,K⁺-ATPase inhibitor, which has a stronger ability of inhibiting the H⁺,K⁺- ATPase's activity than omeprazole and so on. Tenatoprazole suggests the potent in many ulcer tests and the high stability.In this paper, the synthetic route of tenatoprazole, including direct amination, Raney Ni reduction, cyclization, contraction, and oxidation, was selected via retro-synthetic analysis of the structure corresponding to a total yield of 45%. The 6-methoxy-3-nitropyridine was chosen as the starting compound. Catalyzed by CuCl₂, the crucial intermediate 6-methoxy-2-amino-3-nitropyridine was synthesized with the method of direct amination corresponding to a yield of 90%. The demethylation reaction was found when ZnCl₂ instead of ZnSO₄ was used in the course of direct amination. The sodium and magnesium of tenatoprazole were prepared in this article in order to improve the stability of these compounds. In additional, The single enantiomer of tenatoprazole was obtained via the method of inclusion resolution, which were not reported before.