【作者】 刘志超；

【导师】 张帆；

【作者基本信息】 锦州医科大学 ， 药物化学， 2016， 硕士

【摘要】 目的西地那非是由美国辉瑞公司开发的选择性磷酸二酯酶5型抑制剂,用于治疗男性勃起功能障碍。2014年9月西地那非在中国的专利保护到期,探索反应条件温和、操作简便、成本低廉的西地那非合成方法具有重要的社会意义和经济意义。方法在查阅文献和实验摸索的基础上,确定了西地那非中间体邻乙氧基苯甲酸、2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐和西地那非的合成方法,并对它们的合成工艺进行了优化。邻乙氧基苯甲酸的合成方法:以水杨酸甲酯为起始原料,经乙基化、水解反应制得目标化合物。2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐的合成方法:(1)以水杨酸甲酯为起始原料,经氯磺化、磺酰胺化、乙基化、水解反应制得目标化合物;(2)以水杨酸为起始原料,经乙基化、氯磺化、磺酰胺化、水解反应制得目标化合物。西地那非的合成方法:以2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐为原料,经酰氯化,再与1-甲基-3-丙基-4-氨基吡唑-5-甲酰胺缩合、环合制得目标化合物。结果以水杨酸甲酯为原料合成邻乙氧基苯甲酸,反应总收率为94.3%(以水杨酸甲酯计),目标化合物的纯度为99.4%,优化工艺条件:水杨酸甲酯与硫酸二乙酯的摩尔比为1∶1.1,氢氧化钾与水杨酸甲酯的作用时间为40 min,水杨酸甲酯与氢氧化钠的摩尔比为1∶1.8。以水杨酸甲酯为原料合成2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐,反应总收率为57.7%(以水杨酸甲酯计),目标化合物的纯度为99.4%,优化工艺条件:水杨酸甲酯与氯磺酸和氯化亚砜的摩尔比为1∶2.6∶1,化合物3与N-甲基哌嗪和碳酸钾的摩尔比为1∶1.05∶1.05,化合物4与硫酸二乙酯和氢氧化钾的摩尔比为1∶1.2∶1.2,化合物5与氢氧化钠的摩尔比为1∶1.8。以水杨酸为原料合成2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐,反应总收率为52.3%(以水杨酸计),目标化合物的纯度为99.1%,优化工艺条件:水杨酸与硫酸二乙酯和碳酸钾的摩尔比为1∶2.5∶2.5,化合物6与氯磺酸的摩尔比为1∶4,化合物7与N-甲基哌嗪和碳酸钾的摩尔比为1∶1.05∶1.05,化合物8与氢氧化钠的摩尔比为1∶1.8。以2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐和1-甲基-3-丙基-4-氨基吡唑-5-甲酰胺为原料合成西地那非,反应总收率为83.7%(以1-甲基-3-丙基-4-氨基吡唑-5-甲酰胺计),目标化合物的纯度为99.4%。邻乙氧基苯甲酸、2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐、西地那非和中间体的化学结构经核磁共振氢谱和质谱确证。结论本文采用未见文献报道的方法合成了西地那非中间体邻乙氧基苯甲酸和2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐,并对各步反应条件进行了工艺优化。以2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)苯甲酸盐酸盐为原料按照文献方法制得了纯度较高的西地那非。改进后的合成方法成本较低、收率较高,适合工业化生产。更多还原

【Abstract】 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.更多还原