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.
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