Synthesis of (R)‐3‐(tert‐Butoxycarbonylamino)‐4‐(2,4,5‐trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5‐trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β‐amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc‐amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol. A novel synthesis of (R)‐3‐(tert‐butoxycarbonylamino)‐4‐(2,4,5‐trifluoro phenyl) butanoic acid, which is a key starting material in the synthesis of sitagliptin has been developed by using commercially available starting materials featuring a stereoselective catalytic asymmetric reduction and stereoselective Hoffmann rearrangement for the installation of chiral β‐amino center present in sitagliptin.