Research On The Synthesis Process Of Sitagliptin Phosphate Intermediate

Sitagliptin Phosphate, as a novel DDP-IV inhibitor, has good effects on the treatment of type â…¡ diabetes mellitus.According to reported literature,3-oxo-4-(2,4,5-trifluorophenyl)ethyl butyrate as the critical intermediate of sitagliptin phosphate was normally synthesized from2-(2,4,5-trifluorophenyl) acetic acid and2,2-dimethyl-1,3-dioxane-4,6-dione. This synthesis route was expensive and difficult to get. Thus, a brand new route to synthesize3-oxo-4-(2,4,5-trifluorophenyl) ethyl butyrate from1,2,4-trifluorobenzene and diethyl malonate as raw materials was develop. The designed route with five steps, which include benzyl chloride reaction, preparation of grignard reagent, hydrolysis of ester, preparation of acyl chlorination and RMgX reaction, can be performed under mild and green condition.The raw materials were cheap and easy to obtain, which offered this method with greater industrial value. The final purity of the target product was97.5%and the yield of benzyl chloride reaction reached to85.1%, higher than literature75%.Methyltetrahydrofuran was used as solvent in the preparation of RMgX, thereby the yield was raised and the amounts of solvents were reduced.Furthemore, The optimization work had been investigated on the reported synthesis route of3-oxo-4-(2,4,5-trifluorophenyl)ethyl butyrate with the raw material from2-(2,4,5-trifluorophenyl)acetic acid and2,2-dimethyl-1,3-dioxane-4,6-dione.