Synthesis Research Of Intermediate Of Vildagliptin, Synthesis And Characterization Of Vildagliptin Derivative

Diabetes(DM)is a comprehensive disease characterized by persistent hyperglycemia.It is generally caused by environmental and genetic factors,resulting in insulin resistance or insufficient insulin secretion.In recent years,the number of people with diabetes has grown rapidly.According to the 9th edition of the Diabetes Map released by the International Diabetes Federation,there are more than 463 million adults with diabetes worldwide.Type 2 diabetes mellitus accounts for 90% to 95% of all cases of diabetes.Vildagliptin is a new type of anti-diabetes drug researched by Novartis.It is also a highly selective,orally-available DPP-Ⅳ inhibitor.Because of its unique clinical effect,good tolerability,and good efficacy when used alone or in combination,it provides new options for the treatment of type 2diabetes mellitus.With the expiry of the patent of vildagliptin,its research has set off a wave,and(S)-1-(2-Chloroacetyl)pyrrolidine-2-carbonitrile is the key intermediate for its preparation.The authors of this article found that the existing synthetic methods of this intermediate have some shortcomings by consulting the relevant synthetic routes.In this paper,L-proline was used as a starting material,and the intermediate ofvildagliptin was synthesized by two simple methods.Method 1: L-proline via chloroacetyl chlorid,performed with acetonitrile in the presence of sulfuric acid via one-pot reactions;Method 2: L-proline via chloroacetyl chlorid,and then the important intermediate of vildagliptin was prepared with ethyl carbamate and thionyl chloride in a one-pot process.Both methods reduce the reaction steps,and the operation is simple,which provides new ideas and options for the synthesis of vildagliptin."Me-too" drugs are modified on the basis of the original drug,and in the premise of ensuring safety,in order to find drugs with better efficacy and higher activity."Me-too" drugs has the advantages of good curative effect,low research difficulty,relatively small capital investment,etc.,and it is also widely used in clinical applications.Professor Xu Wenfang of Shandong University and others prepared a derivative of lipoyl vildagliptin,and the pharmacological results showed that it has better hypoglycemic activity on a rat model of diabetes induced by streptavidin.Our team synthesized 5-chlorovaleryl vildagliptin via 5-chlorovaleryl chloride acylation of vildagliptin,and p-Toluenesulfonyl vildagliptin via p-Toluenesulfonyl chloride acylation of vildagliptin.According to pharmacological data,5-chlorovaleryl vildagliptin can significantly reduce the level of HbA1 c,and its hypoglycemic activity is similar to that of vildagliptin,and its half-life becomes longer.p-Toluenesulfonyl vildagliptin has a certain inhibitory on the production of inflammatoryfactors,can also regulate immune function,and has low toxic and side effects.Therefore,in order to obtain a new drug structure with better efficacy,fewer adverse reactions and longer half-life,the structure of vildagliptin was modified in this paper,and five new vildagliptin derivatives were synthesized.It is hoped that a new drug structure with more significant DPP-Ⅳ inhibitory activity,longer half-life,or other pharmacological activity will be obtained.