新型磷酸二酯酶5抑制剂Avanafil的合成研究
发布时间：2018-11-11 10:40
【摘要】：男性勃起功能障碍(ED)是男性疾病的一大问题，全球有很多男性正经受着不同程度上的性功能障碍疾病的困扰。而PDE家族中的PDE5广泛存在于阴茎海绵体平滑肌内，其抑制剂可通过调节cGMP和cAMP来调控阴茎海绵体的松弛或是收缩。Avanafil是PDE5抑制剂，用于男性勃起性功能障碍治疗。 本论文主要内容是研究Avanafil的合成，以及利于工业放大生产的工艺路线。主要可分为以下几个方面： (1)以对甲氧基苄胺为原料，与磺酰氯进行亲电取代反应制得中间体3-氯-4-甲氧基苄的合成及工艺优化。 (2)以S-甲基异硫脲硫酸盐和乙氧基甲叉丙二酸二乙酯为原料，在碱性条件下环合得到4-羟基-5-乙氧基羰基-2-甲硫基嘧啶，然后再经氯代后得到中间体4-氯-5-乙氧羰基-2-甲硫基嘧啶。 (3)以2-氰基嘧啶为原料，通过尝试不同的还原体系，经还原而得到中间体2-氨甲基嘧啶。 (4)以L-脯氨酸为原料通过还原反应，制得中间体L-脯氨醇。 (5)以中间体3-氯-4-甲氧基苄胺和4-氯-5-乙氧羰基-2-甲硫基嘧啶为原料，二者通过亲核取代反应得到4-(3-氯-4-甲氧基苄基氨基)-5-乙氧基羰基-2-甲硫基嘧啶，再前后经过甲硫基的氧化反应，与L-脯氨醇的亲核取代反应，酯水解，与2-氨甲基嘧啶的缩合反应，最后得到目标化合物Avanafil (6)同样以中间体3-氯-4-甲氧基苄胺和4-氯-5-乙氧羰基-2-甲硫基嘧啶为原料，二者通过亲核反应得到4-(3-氯-4-甲氧基苄基氨基)-5-乙氧基羰基-2-甲硫基嘧啶，随后先后经过酯水解，与2-氨甲基嘧啶的缩合反应，对甲硫基的氧化反应，与L-脯氨醇的缩合反应，最后的得到目标化合物avanafil。 本论文的主要目的是，在已有文献和相关报道的基础上，对avanafil进行合成路线的设计，，并通过实验对其进行研究，筛选出对于中间体的合成路线以及对于合成总路线的最优方案。
[Abstract]:Male erectile dysfunction (ED) is a major problem in male diseases. PDE5 in the PDE family is widely found in the smooth muscle of the cavernous body of the penis, and its inhibitors can regulate the relaxation or contraction of the cavernous body by regulating cGMP and cAMP. Avanafil is a PDE5 inhibitor for the treatment of erectile dysfunction in men. The main content of this thesis is to study the synthesis of Avanafil and the process route of industrial magnification. It can be divided into the following aspects: (1) the intermediate 3-chloro-4-methoxybenzyl was synthesized by electrophilic substitution reaction with sulfonyl chloride using p-methoxybenzylamine as raw material. (2) 4-hydroxy-5-ethoxycarbonyl-2-methionopyrimidine was synthesized by cyclization of S-methylisothiourea sulfate and ethyl ethoxymethoxymalonate under alkaline conditions. The intermediate 4-chloro-5-ethoxycarbonyl-2-methionopyrimidine was obtained after chlorination. (3) the intermediate 2-aminomethyl pyrimidine was obtained by using 2-cyanopyrimidine as raw material and different reduction systems were tried. (4) the intermediate L-proline was synthesized from L-proline by reduction reaction. (5) starting from intermediates 3-chloro-4-methoxybenzylamine and 4-chloro-5-ethoxycarbonyl-2-methionopyrimidine, By nucleophilic substitution reaction, 4- (3-chloro-4-methoxybenzyl amino) -5-ethoxycarbonyl-2-methionopyrimidine was obtained by nucleophilic substitution reaction. In the end, the target compound Avanafil (6) was obtained from the intermediates of 3-chloro-4-methoxybenzylamine and 4-chloro-5-ethoxycarbonyl-2-methylthiouracil. By nucleophilic reaction, 4- (3-chloro-4-methoxybenzyl amino) -5-ethoxycarbonyl-2-methionopyrimidine was obtained by nucleophilic reaction, which was subsequently hydrolyzed by ester and condensed with 2-aminomethyl pyrimidine. The target compound avanafil. was obtained by oxidation of p-methylthio and condensation of L-proline. The main purpose of this thesis is to design the synthetic route of avanafil on the basis of the previous literatures and related reports, and to select the optimal route for the synthesis of intermediate and the total route of synthesis through experiments.
【学位授予单位】：天津大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5
本文编号：2324592
[Abstract]:Male erectile dysfunction (ED) is a major problem in male diseases. PDE5 in the PDE family is widely found in the smooth muscle of the cavernous body of the penis, and its inhibitors can regulate the relaxation or contraction of the cavernous body by regulating cGMP and cAMP. Avanafil is a PDE5 inhibitor for the treatment of erectile dysfunction in men. The main content of this thesis is to study the synthesis of Avanafil and the process route of industrial magnification. It can be divided into the following aspects: (1) the intermediate 3-chloro-4-methoxybenzyl was synthesized by electrophilic substitution reaction with sulfonyl chloride using p-methoxybenzylamine as raw material. (2) 4-hydroxy-5-ethoxycarbonyl-2-methionopyrimidine was synthesized by cyclization of S-methylisothiourea sulfate and ethyl ethoxymethoxymalonate under alkaline conditions. The intermediate 4-chloro-5-ethoxycarbonyl-2-methionopyrimidine was obtained after chlorination. (3) the intermediate 2-aminomethyl pyrimidine was obtained by using 2-cyanopyrimidine as raw material and different reduction systems were tried. (4) the intermediate L-proline was synthesized from L-proline by reduction reaction. (5) starting from intermediates 3-chloro-4-methoxybenzylamine and 4-chloro-5-ethoxycarbonyl-2-methionopyrimidine, By nucleophilic substitution reaction, 4- (3-chloro-4-methoxybenzyl amino) -5-ethoxycarbonyl-2-methionopyrimidine was obtained by nucleophilic substitution reaction. In the end, the target compound Avanafil (6) was obtained from the intermediates of 3-chloro-4-methoxybenzylamine and 4-chloro-5-ethoxycarbonyl-2-methylthiouracil. By nucleophilic reaction, 4- (3-chloro-4-methoxybenzyl amino) -5-ethoxycarbonyl-2-methionopyrimidine was obtained by nucleophilic reaction, which was subsequently hydrolyzed by ester and condensed with 2-aminomethyl pyrimidine. The target compound avanafil. was obtained by oxidation of p-methylthio and condensation of L-proline. The main purpose of this thesis is to design the synthetic route of avanafil on the basis of the previous literatures and related reports, and to select the optimal route for the synthesis of intermediate and the total route of synthesis through experiments.
【学位授予单位】：天津大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5
【参考文献】
相关期刊论文 前1条
1 张博;尤启冬;高署;;磷酸二酯酶3抑制剂的功能和临床应用[J];安徽医药;2010年10期
本文编号：2324592
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