Nickel‐Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin. Issue 1 (6th December 2021)

• Record Type: Journal Article
• Authors: Sudhakaran, Shana; Shinde, Prasad G.; Aratikatla, Eswar K.; Kaulage, Sandeep H.; Rana, Priksha; Parit, Ratan S.; Kavale, Dattatry S.; Senthilkumar, Beeran; Punji, Benudhar
• Is Part Of: Chemistry, an Asian journal. Volume 17:Issue 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-06
• Subjects: antidiabetic drug -- asymmetric hydrogenation -- chiral resolution -- nickel -- sitagliptin; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/asia.202101208
• Languages: English
• ISSNs: 1861-4728

Abstract

Abstract: 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. Abstract : 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.