Laboratory Systhesis And Industrialization Design Of The Anti-Hypertension Drug Azilsartan

The prevalence of hypertension is rising continuously,the anti-hypertension drug azilsartan has a good antihypertensive effect and is widely used in the clinical application.There is no mature process of azilsartan reported in China,therefore,a new laboratory systhetic route about the azilsartan and its industrialization design will have important application value.The synthetic route of azilsartan was summarized and compared,there are lots of synthetic routes of Azilsartan,and the starting raw material also much more,for example: 2-Carboxy3-nitrobenzoate,2-cyano-4'-methylbiphenyl,2-aldehyde-4'-bromomethylbiphenyl,2,2-diamino-benzoic acid.After comparison with these lots of synthetic routes,raw materials and intermediates,a similar intermediate 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl] aminobenzoate has been found which was in the commercial market,this means the starting raw material can be supplied adequately,therefore,3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl] aminobenzoate(compound AZ2)has been determined as the starting raw material.During laboratory stage,after optimization with the solvents and reaction conditions of each step continuously,the optimal solvent and optimal reaction conditions have been obtained finally.Firstly,in the tetraethyl orthocarbonate,compound AZ2 cyclized with tetraethyl orthocarbonate at 75-85? to gain the intermediate compound AZ3.Compound AZ3 was reacted with hydroxylamine hydrochloride in DMSO at 75-85? as an addition reaction,and compound AZ4 was gained.Compound AZ4 was condensed with ethyl chloroformate in dichloromethane at 20-30? to gain the intermediate AZ5 which is an oil product;this compound AZ5 directly cyclized in the ethanol under refluxing condition to gain the compound AZ6 using “one pot” process.Compound AZ6 was hydrolyzed with alkali solution in methanol under reflux condition to gain the azilsartan crude product;finally,purified in ethanol and decoloring with active carbon and filtering to gain the high quality azilsartan.The reaction conditions of this route is mild,less waste,the raw materials are green and environmentally friendly,the yield is stable and the yield is a bit high.The total yield was about 40%,and the purity of azilsartan was more than 99%.Based on the above synthetic process,the industrialization process of 25 tons per year of azilsartan was designed.The materials and heat balances for each step were calculated manually,such as cyclization 1,addition,condensation,cyclization 2 and hydrolysis,and obtained reactants and products related data and heating data.Based on this data and charging factor of each equipment,the capacity of the proper reactors and post-treatment equipment were calculated.The material of equipment was selected according to the nature of materials which contacted.Finally,relevant parameters such as capacity and material can be determined.The environment and safety protection also described.All of them provided the foundation of industrialization process of azilsartan.