Synthesis And Characterization Of Sitagliptin And Piperazine Derivatives

In recent years, the incidence of diabetes (Diabetes Mellitus) appears a rapid growth tendency. Diabetes, coronary heart disease and cancer are referred to as three major killers of mankind health. As the dipeptidyl peptidase-Ⅳ(DPP-Ⅳ) inhibitor used to treat type 2 diabetes, Sitagliptin win good graces of type 2 diabetes patients of all ages due to its good efficacy, high safety, good tolerance and few side effects.This paper summarized the basic knowledge, treatment methods and therapeutic drug of diabetes, and mainly introduced the dipeptidyl peptidase-Ⅳinhibitors and its representative drug Sitagliptin. Many different synthetic route of sitagliptin reported in the literature were also described in detail.Based on the analysis of the reported synthetic routes in the literature, a simple and feasible synthetic route was studied out. With malonic acid,2-chloropyrazine, 2,4,5-Trifluorophenylacetic acid and S-benzene glycine as starting materials, four key intermediates and one chiral inducer were achieved. They are 2,2-dimethyl-1,3-dioxane-4,6-dione,3-trifluoromethyl-[1,2,4]triazole[4,3-α]piperazine hydrochloride, 5-[1-hydroxy-2-(2,4,5-trifluoro-phenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-Ⅱketone,4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazine-7(8 H)-yl]-1-(2,4,5-trifluoro-phenyl)butane-2-one, and S-phenylglycine amide. Ater 12 simple reactions, final product-Sitagliptin were synthesised with total yield 8.39%. The synthetic technology of 5-[1-hydroxy-2-(2,4,5-trifiuoro-phenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-Ⅱketone and 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1, 2,4] triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluoro-phenyl)butane-2-one were optimized, which decrease costs and increase yield. In the synthetic route, there is no high pressure and temperature reactions, operation of the reactions is also simple and practicable.In addition, two new derivatives of the trizolopiperazine were designed and synthesized. They are 3-amino-3-(4-methoxyphenyl)-1-(3-(trifluoromethyl)-5,6-dihy-dro-[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl)propan-1-one and 1-isobutyl-3-(2-methyl-5-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine-7-carbonyl) phenyl)urea The structure of the two compounds and their intermediates were confirmed by IR,1H NMR,13C NMR and MS.