Preparation of Sitagliptin M2 and M5 metabolites and degradation impurities through a stereocontrolled amidine reduction

Abstract

We report the preparation of two metabolites and degradation products of the drug Sitagliptin, M2 and M5. The overall synthetic route of both compounds involved 7 steps. The key methylimidothioate intermediate was prepared in 5 steps starting from a triazolo-pyrazine. Then, in-situ cyclization with a commercial amino ester yielded the imino precursor of M2 and M5. Surprisingly, catalytic hydrogenation of the amidine using Pd/C was found to be stereoselective and resulted in only one of the two possible stereoisomers (cis isomer). This was in contrast to degradation and metabolic routes, which form both possible stereoisomers. Additionally, Zinc/AcOH reduction was found to provide both isomers in a 1:2.5 ratio (cis/trans).