The asymmetric synthesis of (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid with a novel method that building block of sitagliptin

Sitagliptin is dipeptidylpeptidase-4 (DPP-IV) inhibitor and consists of a chiral β-amino acid and triazolopyrazine unit. In this work, a new method for the asymmetric synthesis of the (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid which constitutes the main structure of the Sitagliptin compound was developed. In the synthesis, the chiral starting compound was used thereby placed the chiral center within the molecule during the starting phase. Starting from (S)-serine, -amino acid building block of sitagliptin was synthesized in ten steps and with an overall yield of 30%. The crucial step of the total synthesis was the ring-opening of (R)-aziridine-2-ylmethanol with 2,4,5-trifluorophenyl magnesium bromide to give (R)-2-amino-3-(2,4,5-trifluorophenyl)propan-1-ol. For this reason, the optimum conditions for this stage have been determined. From the ring opening reaction, the amino alcohol was obtained in high yield (93%). Subsequently, the synthesis of the targeted β-amino acid compound was carried out by chemical transformations applied to the amino alcohol compound.