Synthesis Of Vildagliptin

Diabetes,a very common type of chronic non-infectious lifelong illness.Severity makes it the first non-infectious disease in addition to cancer and cardiovascular and cerebrovascular diseases.At present,in order to alleviate diabetes,the world is striving to develop new drugs.The market of dipeptidyl peptidase-Ⅳ(DPP-Ⅳ)inhibitors brings hope to patients.Its pharmacodynamic effect is to impede the biological activity of DPP-Ⅳ,strengthen the biological activity of glucagon-like peptide-I(GLP-I),stimulate the secretion of insulin,strengthen the absorption of glucose in the blood,and achieve the purpose of alleviating the diseaseThe classic drug of DPP-IV inhibitor,vildagliptin,was originally produced by Novartis AG in Switzerland to alleviate type Ⅱ diabetes.It was officially listed in EU countries in February 2008 and entered under the trade name "Jiaweile" in 2011.In the Chinese market,it has the advantages of small oral dosage,high efficiency,and small side effects,and has been widely used in clinical practiceThis paper studies the synthesis process of vildagliptin and optimizes the corresponding process conditions.According to literature analysis,the synthesis of vildagliptin is a stepwise synthesis of two key intermediates,3-amino-1-adamantanol(?)and(S)-1-(2-chloroacetyl)pyrrolidine.2-carbonitrile(?),which is condensed Based on the existing literature,this paper has improved its synthesis method and process,and obtained a complete synthesis process of vildagliptin with simple operation and mild conditionsUnder the background of industrial development,this paper refers to the relevant literature patents and carries out some process improvements:The first part was the N-chloroacetylation of L-valine(2)and chloroacetyl chloride to obtain the compound(?),and then the compound(?)was synthesized by carbonyl amination of dicyclohexylcarbodiimide.Then,the amidation reaction of trifluoroacetic anhydride was carried out to form the intermediate compound(?),and DCC and TFAA were used instead of the expensive condensing agent,the poisonous dehydrating agent,and the yield was improved by studying the crystallization solvent.This step was difficult and optimization point.The second part was the use of amantadine hydrochloride(6)to produce nitrification under mixed acid conditions,followed by strong base hydrolysis to form intermediate compound(?),and through the improvement of key conditions,the amount of mixed acid and alkali was decreased.And recycling waste liquid to reduced post-treatment pollution.Finally,5 and 8 produced the target product vildagliptin(?)under the action of potassium iodide and potassium carbonate,and the total yield reached 38.5%,which was higher than the 26.6%reported in the literatureCompound(?),Compound(?),and Compound(?)were confirmed by 1H NMR,MS and IR analysis.