Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of Key Sitagliptin Intermediate.

Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3- R -Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug ( R )-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75-92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with ( R )- and ( S )-1-phenylethylamines, the partially enantioenriched ( R )- and ( S )-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided > 99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee , and has been reproduced in multiple batches.