Study On The Synthesis Of Azilsartan And Azilsartan Kamedoxomil In Antihypertensive Drugs

In this paper,we studied the synthesis of azilsartan API and azilsartan kamedoxomil API(the prodrug of azilsartan)in antihypertensive drugs.Part 1: Studied on the synthesis of azilsartanFirstly,a suitable synthetic route is selected based on the existing synthetic route,the route is based on 3-nitrophthalic acid,included esterification,acylation,azide,Curtius rearrangement,condensation,deprotection,reduction,imidazole ring,ammoximation,cyclization,hydrolysis.Then we optimized the reaction conditions and post-treatment of each step of the synthetic route.In the Curtius reaction,the drying step of the acyl azide compound was removed,the wet product of the acyl azide compound was dissolved with toluene,and the water was seperated by washing with saturated brine,avoiding the security risk of drying the acyl azide compound,effectively controlling the formation of the impurity methyl 2-amino-3-nitrobenzoate,canceling the column purification,the yield was increased from 57% to 90%.The column purification was canceled in the condensation,the yield was increased from 85% to 98%.Methanol was used instead of a mixed solvent of ethanol and ethyl acetate as the deprotection reaction solvent.Ethanol was used instead of a mixed solvent of methanol and THF as the reduction reaction solvent.Fe(OH)3 was used instead of FeCl3,reduced the safety risk of the reduction reaction.The methanol is used instead of isopropyl ether as the refined solvent,canceling the column purification.The yield of this step was increased from 64% to 80%.In the post-treatment of the imidazole ring reaction,the crude was stirred with dilute sodium hydroxide solution of methanol instead of the mixed solvent of ethyl acetate and chloroform.The purity of the product was more than 99.8%.The temperature of ammoximation reaction was optimized from 85-90? to 75±1?.The purity of the product is increased from 87% to more than 98%.The toluene was used instead of THF in the cyclization reaction.The ethanol is used instead of cyclohexane and dichloromethane as the refined solvent.The yield of this step was increased from 68% to 82%,the purity of the product was increased from 96% to 99.61%.In the post-treatment of the hydrolysis reaction,the acidification pH was optimized from 2-3 to 3-3.5,the acidification temperature is optimized from 10-15? to 0-5?,the hydrolysis impurity was well controlled,and the acetone was used instead of isopropyl alcohol as the refined solvent.The yield was increased from 75% to 95%.The total yield of the process was increased from 8.5% to 25.6%.The purity of azilsartan was more than 99.9% and the maximum single impurity was less than 0.05%.Part 2: Studied on the synthesis of azilsartan kamedoxomilFirstly,we selected a better synthetic route from the existing synthetic routes,the route is based on azilsartan,included esterification,salification.Then we optimized the reaction conditions and post-treatment of the two-step reaction.To facilitate the recovery of solvent and avoid the difficult task of wastewater containing DMA,dichloromethane was used instead of DMA as a reaction solvent in the esterification.The reaction can be completed,using triethylamine instead of potassium carbonate.The drying temperature is optimized from 40? to 25-30 ?,effectively controlling the degradation impurity azilsartan(<0.05%).The amount of base is optimized from 0.96 eq to 0.90 eq and the dissolution temperature is optimized from 50 ? to 25-30? in the salification,effectively controlling the formation of the impurity azilsartan(<0.10%).The total yield of the process was increased from 60% to 81.6%.The purity of the azilsartan kamedoxomil is more than 99.8% and the individual impurity is not more than 0.10%.