Study On The Synthesis Of Antihypertensives Candesartan Cilexetil

This thesis researched on the industrial synthetic process of dyazide Candesartan Cilexetil,which is a prodrug of Candesartan acting on Renin-Aldosterone system.This thesis briefly describes the current global incidence of hypertension and its harm to humans,the development of antihypertensive drugs profiles,the mechanism of action of the antihypertensive drug Candesartan Cilexetil and its advantages with other varieties of drugs,and focus on the research of synthesis of Candesartan Cilexetil.In this thesis,we referred to the patent literature routes,designed and got through a synthetic route of Candesartan Cilexetil.The synthetic route was thoroughly optimized to shorten the reaction time,facilitate operation and reduce emissions of"three wastes"with increasing yield and reducing costs,which improved the market competitiveness of the product.3-Nitrophthalic acid?CST-0?was used as the starting material,then the methyl2-??tert-butoxycarbonyl?amino?-3-nitrobenzoate?CST-2?was synthesized via three steps of single esterification,azide and amidation.After nucleophilic substitution reaction and deprotective reaction of tert-butyl oxycarbonyl group,methyl2-??2'-cyano-[1,1'-biphenyl]-4-yl?amino?-3-nitrobenzoate?CST-4?was obtained,whichwasthenreducedbystannouschloridetoyieldmethyl3-amino-2-??2'-cyano-[1,1'-biphenyl]-4-yl?amino?benzoate?CST-5?.Subsequent cyclizationofCST-5withtetraethylorthocarbonateyieldmethyl1-??2'-cyano-[1,1'-biphenyl]-4-yl?methyl?-2-ethoxy-1H-benzo[d]-imidazole-7-carboxy late?CST-6?.Compound CST-6 went through five steps of tetrazolization,hydrolysis,N-protection,esterification and deprotection to obtain the final product candesartan cilexetil with the kg-scale total yield 31.7%.The structures of Candesartan Cilexetil and its intermediates were confirmed by¹HNMR,¹³C-NMR and MS.