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Lansoprazole is the generic name of 2-[[[3-Methyl-4(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1 H-benzimidazole, 1 (see Scheme 1). It is a proton pump inhibitor that reduces gastric acid secretion and has successfully been used to heal and relieve symptoms of gastric or duodenal ulcers and gastro-esophagal reflux. 1 Lansoprazole has been synthesized by an oxidation of sulfide 9 produced from a substitution reaction between 2mercaptobenzimidazole and pyridine derivatives such as 2chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine, 8. 2,3 The transformation of sulfide 9 into lansoprazole has been generally carried out with peroxyacid such as mCPBA or hydrogen peroxide in the presence of homogeneous catalyst. 3 Recently, we found that trirutile type solid oxides catalyze the hydrogen peroxide oxidation of sulfides to sulfoxides very efficiently. 4 The reaction was very selective producing sulfoxide with negligible amount of sulfone. Since the reaction is performed under heterogeneous conditions, the solid catalyst can be easily recovered by a simple filtration of the final reaction mixture. Because of these advantages in purification of the product, we decided to apply the heterogeneous sulfoxidation method to the synthesis of lansoprazole. In our approach to the synthesis of lansoprazole, we tried to devise a new process that could use 3-picoline as a starting material because it is more readily available than 2,3-lutidine, the most widely used starting material. 2,3 This strategy has become possible by adopting Matsumura’s method in the synthesis of 2-cyano-3-methyl-4-nitropyridine (3). 5 Thus, here we report a new synthetic process for lansoprazole as shown in scheme 1. 2-Cyano-3-methyl-4-nitropyridine (3), the key compound of the present approach for lansoprazole was prepared from 2 according to the literature method, with a yield of 81%. 5 The normal coupling constant (5 Hz) between H-5 and H-6 in 1 H-NMR of 3 indicates that the cyano group was selectively introduced into C2-position instead of C6. To understand the selectivity, the heat of formation of intermediates A and B (Table 1) expected in the course of substitution reaction on C2 and C6, respectively, according to the Reissert-Kaufmann type reaction mechanism (Scheme 2) 6 was calculated using semiempirical method (AM1 and PM3). 7 |
