Trelagliptin succinate, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, was approved for the Japanese market on March 26, 2015

Trelagliptin exhibited a better potency against human DPP-4 than alogliptin and sitagliptin, along with its excellent selectivity and slow-binding properties that may partially contribute to its sustained efficacy. In phase III clinical studies, once-weekly oral trelagliptin provided long-term safety and efficacy in both monotherapy and combination with other antidiabetic medicines and was proved to be noninferior to its analogue alogliptin used once daily.

2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile Monosuccinate (1)

Synthesis of Trelagliptin Succinate

Shenghui Xu , Qun Hao, Hongyan Li, Zhenren Liu, and Weicheng Zhou^*

State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 201203, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00013

An improved process for the synthesis of antidiabetic drug trelagliptin succinate through unprotected (R)-3-aminopiperidine was described. The impurity profile with different conditions of the key substitution was illustrated, and then the best reaction condition was identified. The optimizations also included the bromination of 4-fluoro-2-methylbenzonitrile so that the process became efficient and concise.

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