Study On Synthesis Of Sildenafil And Its Intermediates

ObjectiveSildenafil developed by Pfizer is an inhibitor of selective phosphodiesterase type 5,which was used for treatment of male erectile dysfunction.Chinese patent of sildenafil has been expired in september 2014.Searching of better synthetic method of sildenafil has important social and economic significance.MethodsOn the base of literatures and experimental attempts,the synthetic method of o-ethoxy benzoic acid,2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoic acid hydrochloride and sidenafil was determined,and their synthetic processes were optimized.o-Ethoxy benzoic acid was synthesized via ethylation and hydrolysis reaction with methylsalicylate as starting material.2-Ethoxy-5-(4-methylpiperaz in-1-sulfonyl)benzoic acid hydrochloride was obtained via chlorosulfonation,sul fonamidation,ethylation and hydrolysis reaction starting from methyl salicylate.Meanwhile,2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoic acid hydrochloride was synthesized via ethylation,chlorosulfonation,sulfonamidation and hydroly sis reaction with salicylic acid as starting material.Sildenafil was prepared via acyl chloride,condensation with 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and cyclization reaction using 2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-b enzoic acid hydrochloride as starting material.Resultso-Ethoxy benzoic acid was synthesized from methyl salicylate,overall yield was 94.3%,which was calculated by methyl salicylate,purity of the target compound was 99.4%.Optimized conditions: The molar ratio of methyl salicylate and diethyl sulfate was 1?1.1.The reaction time of methyl salicylate and potassium hydroxide was 40 min.The molar ratio of methyl salicylate and sodium hydroxide was 1?1.8.2-Ethoxy-5-(4-methylpiperaz in-1-sulfonyl)benzoic acid hydrochloride was synthesized from methyl salicylate,overall yield was 57.7%,purity of the target compound was 99.4%.Optimized conditions: The molar ratio of methyl salicylate,chlorosulfonic acid and thionyl chloride was 1?2.6?1.The molar ratio of compound 3,N-methylpiperazine and potassium carbonate was 1?1.05?1.05.The molar ratio of compound 4,diethyl sulfate and sodium hydroxide was 1?1.2?1.2.The molar ratio of compound 5 and sodium hydroxide was 1?1.8.2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoic acid hydrochloride was synthesized from salicylate,overall yield was 52.3%,purity of the target compound was 99.1%.Optimized conditions: the molar ratio of salicylic acid,diethyl sulfate and potassium carbonate was 1?2.5?2.5.The molar ratio of compound 6 and chlorosulfonic acid was 1?4.The molar ratio of compound 7,N-methylpiperazine and potassium carbonate was 1?1.05?1.05.The molar ratio of compound 8 and sodium hydroxide was 1?1.8.Sildenafil was synthesized from 2-ethoxy-5-(4-methylpiperazin-1-sulfon-yl)benzoic acid hydroc hloride and 1-methyl-3-propyl-4-aminopyrazole-5-carbo-xamide,overall yield was 83.7%,purity of the target compound was 99.4%.The chemical structures of o-ethoxy benzoic acid,2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoic acid hydrochloride,sildenafil and the intermediates were confimed by 1HNMR and MS.ConclusionsIn this paper,o-ethoxy benzoic acid and 2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoic acid hydrochloride were synthesized by unreported method in the literature.Meanwhile,reaction conditions were optimized.High-purity sildenafil was prepared using 2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)benzoicacid hydrochloide as starting material according to the literature.The starting materials are cheap and the procedures are relatively simple.The improved synthetic method has an economic advantage in view of the application to large-scale synthesis.