Study On The Preparation Of The Intermediate Of Sitagliptin

285 million people are currently suffering from diabetes in the world, and the number of type 2 diabetes patients is upto 93.7%. The drugs for diabetes is considerable with the rising number of diabetes patients every year. A series of new diabetes drugs is on the market in recent years and among them DPP-IV inhibitors is new way to treat type 2 diabetes. Sitagliptin, the first DPP-IV inhibitor, is a new drug approved by the FDA in October 2006 for the treatment of type 2 diabetes. The purpose of this paper is on the research how to preparation of the chiral intermediate of Sitagliptin (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid.In this paper, the key intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate was prepared from 2,4,5-trifluorophenylacetic acid which is obtained from 1,2,4-trifluorobenzene. The target molecule was synthesized through using chiral reagent, reduction of double bond, hydrogenolysis and hydrolysis of ester group. There are three synthetic routes for intermediate 2,4,5-trifluorophenylacetic acid and the best method is with 1,2,4-trifluorobenzene as the starting material, through acylation, hydrolysis and rearrangement in base environment, chlorination, hydrogenolysis to afford the target product. The reaction condition is optimized and the reaction was scaled up. In the workup, chloromethane was choosed to replace methyl tert-butyl ether as the extractant and the reaction time is shortened. In the synthesis of 2,4,5-trifluorophenylacetic acid, the amount of 10% Pd/C is decreased by 57.7%. The total yield of four steps is 35.8%. There are three synthetic routes for intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate in the paper. The conclusion is that the best synthetic route is with 2,4,5-trifluorophenylacetic acid as the starting material, through activation of carboxylgroup, acylation and decarboxylation to afford methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate. The total yield of three steps is 80.1% and the reaction condition is optimized and the reaction was scaled up. In the synthesis of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate, the product was obtained through recrystallization. The structures were confirmed through IR and NMR.