Study On The Preparation Of Vildagliptin For Inhibition Of DDP-Ⅳ

Recently, the patients suffering from type2diabeties have increased dramatically innumber,and become a death factor of cardiovascular disease and tumor. DPP-4inhibitors haveattracted an extensive attention as a new kind of abtidiabetic drugs.Vildagliptin, developed byNovartis, is a new DPP-4inhibitor, and has a huge market potential and scientificsignificance.On the basis of the synthetic routes reported in literature, a new synthetic route forpreparing vildagliptinwas proposed. The reaction conditions of our method are mild, and thestarting materials are common and inexpensive.L-prolineasth starting materialwas N-acylatedwith chloroacetyl chlorideunder nocatalyst condition to afford (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid. And then (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile, anintermediate for Vildagliptin, was prepared by “one pot” method, in which urea was used asthe N-source and sulfamic acid as the dehydrating agent.3-Amino-1–adamantanol,anotherintermediate, was prepared by a nitration reaction, in which1-adamantylamine was used as theraw material, the mixture of sulfuric acid and sodium nitrate as the nitrating agent, and boricacid as the catalyst, and by a nucleophilic substitution reaction, in which potassium hydroxidewas used asthe nucleophilic agent. The target compound, vildagliptin, was obtained by thereaction of (S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile with3-amino-1–adamantanolin THF solvent, with potassium iodide as the catalyst and potassium carbonate as theacid-binding agent. The overall yield was about47.7%. Besides, some impurities invildagliptin were also synthesized. The chemical structures of these compounds wereconfirmed by IR,1H NMR, MS, and elemental analysis.