Synthetic Research Of Trelagliptin

Trelagliptin was developed by Takeda Pharmaceutical Company Limited and launched in Japan in March 2015.It is a dipeptidyl peptidase IV(DPP-4)inhibitor for the treatment of type 2 diabetes marketed.It is a small molecule hypoglycemic agent that takes once a week.It can effectively control blood glucose through continuous and selective inhibition of DPP-4.And the side effects are small.Two synthetic routes of Trelagliptin were designed:(1)Route one starts with D-glutamic acid.The(R)3-aminopiperidine was synthesized in six steps by amino protection,carboxymethyl esterification,hydrogenation reduction,hydroxyl protection,loop reaction and deprotection.(R)3-aminopiperidine is further docked with the intermediate 2-(6-chloro-3-methyluracil)-4-fluoro-benzonitrile to give the final product,Trelagliptin,with a total yield of 49%;(2)Route one starts with L-glutamic acid.The(R)3-azidopiperidine was synthesized in six steps by diazotization,amidation,intramolecular ester amine exchange,hydrogenation reduction,hydroxyl azide and deprotection.(R)3-azidopiperidine is then docked with the intermediate 2-(6-chloro-3-methylur-acil)-4-fluorobenzonitrile,and the azide is hydrogenated to give the final product,Trelagliptin,with a total yield of 39%.The product purity of both synthetic routes can reach more than 99.9%.Comparing the two routes,it can be seen that the raw material price of Route one is slightly more expensive,but the reaction operation is simple,both the intermediate yield and total yield are higher.In contrast,the raw material of Route 2 is relatively inexpensive,and the key intermediate is more stable in the form of azide.It can avoid the formation of by-products when interlinking with the intermediate 2-(6-chloro-3-methyluracil)-4-fluoroben-zonitrile and improve es the yield at docking.Based on the technological point of view,Route two is more suitable for industrial production.