Optimized Synthesis Of Vildagliptin Used For Treatment Of Diabetes

Vildagliptin is used for the treatment of type 2 diabetes.The influences of reaction conditions for each step reaetion, such as material ra tio,reaction temperature, reaction time were studied and optimal conditions were de termined.1-(Chloroacetyl)-2-pyrrolidinecarbonitrile was prepared from L-Prolinamid e via ammonolysis, dehydration. The optimum conditions are as follows:Ammonoly sis at 25℃for 3h using chloroacetylchloride with the ratio of n(Chloroacetylchlo ride):n(L-Prolinamide) beingl.05:1;Dehydration at 35℃for 2h with the ratio of n (L-Prolinamide):n(Cyanuricchloride) being 2:1;The yield based on L-Prolinamide is 52.9%.3-Amino-l-hydroxyadamantane was prepared from amantadine via esterifieation and hydrolysis. The optimum conditions are as follows:Oxidation and esterification at 25℃for 30h with the ratio of n(HNO3):n(Amantadine) being 2.5:1;Hydrolysis at 80℃with the ratio of n(KOH):n(Amantadine) being 1.2:1.The yield based on Amantadine is 74.9%.Vildagliptin was prepared from 3-Amino-l-hydroxyadamantane and 1-(Chloroac etyl)-2-pyrrolidinecarbonitrile via condensation. The optimum conditions are as follo ws:The condensation of 1-(Chloroacetyl)-2-pyrrolidinecarbonitrile and 3-Amino-l-hy droxyadamantane was at 55℃for 24h with the ratio of n[1-(Chloroacetyl)-2-pyrrolid inecarbonitrile]:n(3-Amino-l-hydroxyadamantane) being 1.2:1.The yield based on 1-(Chloroacetyl)-2-pyrrolidinecarbonitrile is 73.1%.The total yield based on L-Prolina mide is 38.7%.