Synthetic Process And Quality Control Of Azilsartan

The hypertension is a serious disease and increasing over world. Azilsartan, anovel drug of angiotensin II receptor antagonist, can reduce the blood pressuresignificantly with fewer side effects, so it has great value to develop azilsartan as ageneric drug. In this thesis, the suitable synthetic route was designed for industrialproduction of azilsartan, and the exprements on the lab and pilot scales were carriedout with the methodology for quality control.As a starting material,3-amino-2-[(2’-cyanobiphenyl-4-yl)-methyl] amino]benzoate cyclized with Tetraethyl orthocarbonate, followed by the addition reactionwith hydroxylamine to give2-ethoxy-1-[(2’-hydroxy-amidino-4-methyl)-1H-benzi-midazole-7-carboxylate, then condensation reaction was occurred with diphenylcarbonate to synthesize1-[[2’-(2,5-dihydro-5-oxo-1,2,4,-oxadiazol-3-yl)-biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate. Finally, azilsartan wasreleased by Hydrolysis reaction. The various parameters including reaction solvent,catalyst, temperature, time and recrystallization solvent were tested. Each unitoperation was optimized in the process. The chemical structure of final product andintermediates were indentied and confirmed with chromatography and spectralmethods.Guided by Part II of Chinese Pharmacopoeia (2010edition), the method ofquality control for azilsartan was established by detecting the physical and chemicalproperties, related substance and the content of azilsartan.After the pilot scales, the total yield of azilsartan reach to39.9%, the purity reachto99.83%and the content reach to99.98%. The thesis provided technical supports forindustrial production of azilsartan.