Citation: Li Li Zeng, Ying Jie Ding, Gui Cheng Zhang, Hong Rui Song, Wen Hui Hu. A practical synthesis of trifluorophenyl R-amino acid:The key precursor for the new anti-diabetic drug sitagliptin[J]. Chinese Chemical Letters, ;2009, 20(12): 1397-1399. doi: 10.1016/j.cclet.2009.06.036 shu

A practical synthesis of trifluorophenyl R-amino acid:The key precursor for the new anti-diabetic drug sitagliptin

a Laboratory of Anti-diabetic Drug Discovery, Center for Synthetic and Natural Drugs, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China;
b The School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China

Received Date: 20 April 2009

Fund Project: This work was supported in part by grant from Science and Technology Program of Guangdong Province (No.2007B031503005).

Sitagliptin is the first new anti-diabetic drug in DPP-IV inhibitor class.The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment.Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert homologation, the optically pure precursor R-amino acid is difficult to prepare.We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in >99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure.This protocol requires only cheap starting materials and friendly reaction condition.The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare a-amino acid and the subsequent β-amino acid.
- Sitagliptin,
- β-Amino acid,
- DPP-IV inhibitor,
- Practical synthesis
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