Synthesis Research Of Paratoluenesulfonyl Vildagliptin And Synthesis And Structure Characterization Of Vildagliptin Derivative

Inflammation is an immune response of biological organisms to different injury factors stimuli that damage part of the body or the whole body.Many common diseases belong to the category of inflammation,such as autoimmune diseases,cancer,wound repair,and atherosclerosis.In recent years,anti-inflammatory drugs have been used more and more widely.Therefore,it is of great significance to find new anti-inflammatory drugs with strong anti-inflammatory activity,safe and effective,and small side effects.Paratoluenesulfonyl Vildagliptin(CQMUH-011)was synthesized by Professor Hu Xiangnan laboratory from School of Pharmacy of Chongqing Medical University.The pharmacological experiments on CQMUH-011 by Professor Liu Yingju research group from Chongqing Medical University showed that CQMUH-011 has obvious anti-inflammatory and hepatoprotective properties.The pharmacological activity of CQMUH-011 has been studied.However,the synthetic route of CQMUH-011 has some shortcomings such as long reaction steps,complicated operation and low yield.Therefore,this paper uses a simple method to optimize the route.Firstly,3-aminoadamantanol was synthesized from 1-aminoadamantane hydrochloride.Secondly,(S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile was synthesized from L-proline through chloroacetylation,amidation,and dehydration cyanidation.Finally,the target product CQMUH-011 was prepared with 3-aminoadamantanol,(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile and 4-toluene sulfonyl chloride in a one-pot process.The preparation process was optimized by the central composite design-response surface methodology.This method reduces the reaction cost and experimental steps,simple operation and improves the yield.At the same time,the whole reaction process does not involve expensive reagent,and conforms to the current advocated synthesis concept of resource saving and environmental friendly.As is known to all,the development of "Me-too" drugs to discover new drugs can greatly accelerate the research speed of new drugs.More and more pharmaceutical companies are also applying the "Me-too" method to modify and improve the molecular structure of many existing drugs.There are many successful cases.Vildagliptin,designed by Novartis,is a orally active dipeptidyl peptidase IV(DPP-IV)inhibitor for the treatment of type 2 diabetes.As the star drug of DPP-IV inhibitor,its "Me-too" research is also a hot research topic for many pharmaceutical companies.According to reports in the literature,the derivative of vildagliptin,lipoyl vildagliptin was prepared by Professor Xu Wenfang of Shandong University.The pharmacological data results showed that it has better effective than vildagliptin in hypoglycemic activity.And the biological half life is longer.According to reports in the literature,the derivative of vildagliptin,5-chlorovaleryl vildagliptin was prepared by Professor Hu Xiangnan from School of Pharmacy of Chongqing Medical University.The pharmacological data results showed that its hypoglycemic effect is similar to that of vildagliptin.But its toxic and effects are reduced.Besides,it can penetrate the blood-brain barrier and reduce the content of triglycerides and low-density lipoprotein,and avoid the damage of neurons.In addition,CQMUH-011 has obvious anti-inflammatory effects.Learn from the case of structural modification above,and twelve new vildagliptin derivatives were synthesized in this paper.At the same time,their structures were characterized and screened for enzyme inhibiting activity.It is expected to obtain new drugs that have higher biological activity and less side effects,which provides certain reference for the future research of vildagliptin "Me-too" new drugs.