Practical and Economical Approach to Synthesize Sitagliptin

Abstract

Economic syntheses of sitagliptin phosphate monohydrate, acknowledged as the first dipeptidyl peptidase 4 (DPP-4) inhibitor, have been achieved in an overall yield of 42.4% in four steps from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione. The key stereoselective reduction of this process was carried out by NaBH₄/HCOOH instead of expensive and toxic catalysts or ligands.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

GRAPHICAL ABSTRACT

Keywords:

• Chiral synthesis
• DPP-4 inhibitor
• sitagliptin

ACKNOWLEDGMENT

This work was supported by the 973 Program of the Ministry of Science and Technology of China (2010CB735601 and 2012CB724501).

Notes

^a Reducing agent was prepared in THF.

^b The ratios were determined by HPLC analysis.

^c At the end of reaction, the enaminoamide 4a was detected as the biggest spot by TLC.

^a Reducing agent was prepared in THF.

^b The ratios were determined by HPLC analysis.