Study On The Synthesis Of The Dipeptidyl Peptidase-IV Inhibitor Vildagliptin

Diabetes mellitus is a group of chronic metabolic diseases, which can cause atherosclerosis and coronary heart disease to make patients died. According to the International Diabetes Federation latest statistics,there are 285 million diabetic patients worldwide at present,including over 43.2 million patients in China, and the global number of patients with diabetes will increase to 435 million by 2030. The existing diabetic drugs are lack of targeting effect on pancreatic isletβ-cell function decay which is the fundamental causes of diabetes and their hypoglycemic effect is independent of glucose. Glucagon-like peptide-1(GLP-1) can solve these problems effectively, but it can be degraded by dipeptidyl peptidaseâ…£(DPP-â…£) rapidly in the body. Therefore, the development of DPP-â…£inhibitor for the treatment of type 2 diabetes has significance.Vildagliptin is cyano-pyrrolidine derivative with specific inhibition of DPP-â…£, which is developed by Novartis. It is launched officially for the treatment of type 2 diabetes in the European Union in February 2008. Vildagliptin can significantly reduce the level of glycosylated hemoglobin (HbAlc) and be well tolerated either single administration or combination with other anti-diabetic drugs. Furthermore, it has no significant adverse reactions. Vildagliptin is a good prospect of diabetes drugs, but it has not been launched in our country.On the basis of relevant literature, the key intermediate (S)-1-(2-chloroacetyl) pyrrolidine -2- carbonitrile (2-2) was synthesized with L-proline as the starting material via the processes of N-chloroacetion, carbbonyl amination and carboxamide dehydration. This intermediate reacted with 3-hydroxy-1-amantadine (2-3) by condensation to product the target compound vildagliptin. The overall yield was 40.4%, which is higher than that reported in the literature (22.3%). The chemical structures of vildagliptin was confirmed by ¹H- NMR,MS,IR and elemental analysis and [α]_D²⁵ -1.013(c 1.00g·100mL^-1, CH₃OH). In the synthetic process of (S)-1-(2-chloroacetyl) pyrrolidine-2-formic acid and compound 2-3, the yield was higher than the literature value and the reaction time was shorted significantly by the method of microwave assisted synthesis; In the synthetic process of compound 2-2, the cost of reagent was saved and the yield was improved by replacing expensive reagent―trifluoroacetic anhydride with phosphorus oxychloride; In the synthetic process of (S)-1-(2-chloroacetyl) pyrrolidine -2- carboxamide, the yield was improved significantly from 52.5% (literature value) to 62.7% by extending the dropping time of N, N-Dicyclohexyl carbodiimide (DCC).The interaction between vildagliptin and three cytochrome P450 isoforms (3A4, 1A2, 2C9) was studied at molecular level by molecular docking software-AutoDock 4.2. The results showed that the binding affinity of vildagliptin with these three isoforms was weak, which was consistent with the fact that vildagliptin does not inhibit or induce CYP450 reported in the literatures. In addition, the interaction mode was also studied between the target enzyme DPP-â…£and DPP-â…£inhibitors including sitagliptin,vildagliptin,saxagliptin,,denagliptin and alogliptin which are currently listed or in clinical stageâ…¢. The results showed that the interaction mode was consistent with X-ray diffraction crystal structures which were reported in the literature.