西他列汀关键中间体的合成研究

Research on the Synthesis of Key Intermediate of Sitagliptin

水合肼(2)经三氟乙酸乙酯和氯乙酰氯取代反应,Vilsmeier试剂关环,得中间体3,再经乙二胺取代,盐酸乙醇关环制得西他列汀关键中间体3-三氟甲基-5,6,7,8-四氢-1,2,4-三唑-[4,3-a]并吡嗪盐酸盐(1),其结构经H NMR和MS确证,总收率达55%。此反应条件温和,同时避免含磷废水产生,更适合工业化生产。

Using hydrazine hydrate(2)as the raw material,compound 3 was obtained through the reaction with ethyl trifluoroacetate,then chloracetylation,cyclization using Vilsmeier reagent.Compound 3 was subjected to ethylendiamine,dehydration and recyclization under hydrochloric acid to obtain the key intermediate of sitagliptin(1)in an overall yield of 55%.The structures of the intermediate and product were characterized by~1H NMR and MS spectra.The advantages of this present process include mild reaction condition and avoiding phosphorus wastewater.Therefore it is promising for industrial application.