The Synthesis Of Vildagliptin And Its Derivatives

The advent of dipeptidyl peptidase-Ⅳ inhibitor is a majorbreakthrough in the field of diabetes drugs. By inhibiting dipeptidylpeptidase-Ⅳ, this inhibitor prolong the action of glucagon-like peptide-1which stimulates the secretion of insulin, inhibits the secretion of glucagonand gadtric emptying, protects β-cells and increases insulin sensitivity, toindirectly control blood sugar concentration in type Ⅱ diabetes. Therefore,dipeptidyl peptidase-Ⅳ inhibitor has become new anti-diabetic drugs.Vildagliptin, developed by Novartis for the treatment of type Ⅱdiabetes, is dipeptidyl peptidase-Ⅳ inhibitor with a cyano-pyrrolidine,which is launched officially in European Union in2008. As a competitive,reversible and selective dipeptidyl peptidase-Ⅳ inhibitor for the treatmentof type Ⅱ diabetes, the study of synthesis of vildagliptin is of greatsignificance. On the basis of relevant synthetic route, L-proline was used asthe starting material via three steps of chloroacetylation, carboxylamination and carboxamide dehydration to afford the key intermediate1-(2-chloroacetyl) pyrrolidine-2-carbonitrile. To prepare the targetcompound vildagliptin, the intermediate was treated with3-amino -1-adamantanol through condensation. The content of vildagliptin wasdetermined and its chemical structures was confirmed by melting point,TLC, NMR and IR.In the second part, the chemical structure of vildagliptin is modified.A patent reports that vildagliptin was treated with lipoic acid to affordlipoic vildagliptin. Subsequently, the action of the control blood sugarconcentration of lipoic vildagliptin is very effective by the validation ofpharmacology experiments. Using the experience of lipoic vildagliptin,vildagliptin is modified to obtain new chemical structures of which theaction of the control blood sugar concentration is effective and the sideeffects is mild. As a result, the structure of vildagliptin was derived withparatoluenesulfonyl chloride and o-ethoxy benzoic acid to gain two newchemical structures that paratoluenesulfonyl vildagliptin and o-ethoxybenzoic vildagliptin.In summary, the study of the synthesis of vildagliptin and itsderivatives achieves the preliminary purpose of the design in the article.