Preparation of Sitagliptin M2 and M5 Metabolites and Degradation Impurities through a Stereo Controlled Amidine Reduction

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. 

Surprisingly, the last strep, catalytic hydrogenation of the Amidine using Pd/C was found to be stereo selective and resulted in only one of the two possible stereoisomers (cis isomer), probably due to its transition state lower energy. This was in contrast to degradation and metabolic routes, which form both possible stereoisomers. Zinc/AcOH reduction was found to provide both isomers in a 1:2.5 ratio (cis/trans).