Nickel‐Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin

• Published in: Chemistry, an Asian journal Vol. 17; no. 1; pp. e202101208 - n/a
• Main Authors: Sudhakaran, Shana, Shinde, Prasad G., Aratikatla, Eswar K., Kaulage, Sandeep H., Rana, Priksha, Parit, Ratan S., Kavale, Dattatry S., Senthilkumar, Beeran, Punji, Benudhar
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 03.01.2022
• Subjects: antidiabetic drug; Antidiabetics; asymmetric hydrogenation; Asymmetry; Chemical synthesis; Chemistry; chiral resolution; Enantiomers; Esters; Hydrogenation; Nickel; Phenylethylamine; sitagliptin; antidiabetic drug; nickel; sitagliptin; asymmetric hydrogenation; chiral resolution
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.202101208

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. Sitagliptin intermediate, 3‐R‐Boc‐amino‐4‐(2,4,5‐trifluorophenyl)butyric ester, an antidiabetic drug candidate, has been synthesized using inexpensive, naturally abundant, sustainable nickel catalysis.