Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin

Abstract

Alogliptin (1) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (10) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide (6) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.