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.
Herein, we show the detailed behavior of palladium leaching
from
palladium on charcoal by aqueous HCl, directly observed by X-ray absorption
spectroscopy measurement employing a simplified reaction setup. While
Pd0 is not affected by the addition of HCl, palladium oxide
in nanoparticles readily reacts with HCl to form the ionic species
[PdIICl4]2–, even though these
ions mostly remain adsorbed on the surface of activated charcoal and
can only be detected at a low level in the solution phase. This finding
provides a new aspect for control of the leaching behavior and robust
usage of palladium on charcoal in organic reactions.
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