The Study On Synthesis Process Of Antihypertensive Drug Irbesartan

In recent years,cardiovascular and cerebrovascular diseases have seriously endangered human life and health,and hypertension,as the main risk factor for the development of cardiovascular and cerebrovascular diseases,has attracted extensive attention.Therefore,the research of antihypertensive drugs has potential application value and significance.Angiotensin Ⅱ receptor type 1antagonists（sartans）have been widely used in clinic as a new type of antihypertensive drugs.Irbesartan stood out among sartans because of its good antihypertensive effect,high bioavailability,less adverse reactions and protective effect on target organs.A novel synthetic route of Irbesartan was designed in this subject.We chose the cheap and commercial available starting material glycine methyl ester hydrochloride,which greatly reduced the process cost and avoided the use of highly toxic cyanide.The key intermediate imidazolinone ring compound was constructed through nucleophilic substitution reaction,ammonolysis of ester and intramolecular cyclization.The key intermediate of azaspiro ring was constructed by alkylation of highly active methylene in imidazolinone ring with disubstituted halohydrocarbons.Finally,we successfully opened up the process route,obtained the end product of Irbesartan through five steps,and detected and characterized each intermediate and end product by ¹H-NMR,¹³C-NMR,high-resolution mass spectrometry and high-performance liquid chromatography.In this paper,we optimized the synthesis conditions of various intermediates,such as reaction temperature,kind and consumption of solvents and catalysts,etc.The process impurities were researched,and the by-product 4-aminomethyl-2-cyano-biphenyl was recycled.After the optimization of the process,the total yield of the synthetic route was 47.1%,and the relative purity of HPLC was 99.7%.After the preliminary amplification for 30 g in the laboratory,the yield can also remain stable.The major advantages of this process are cheap and low toxicity starting materials,green process,effective cost,simple and short process and high yield,which not only lays a good foundation for industrial amplification,but also promotes the research of Irbesartan generic drugs to a great extent.