【摘要】：男性勃起功能障礙(ED)是男性疾病的一大問題，全球有很多男性正經受著不同程度上的性功能障礙疾病的困擾。而PDE家族中的PDE5廣泛存在于陰莖海綿體平滑肌內，其抑制劑可通過調節(jié)cGMP和cAMP來調控陰莖海綿體的松弛或是收縮。Avanafil是PDE5抑制劑，用于男性勃起性功能障礙治療。 本論文主要內容是研究Avanafil的合成，以及利于工業(yè)放大生產的工藝路線。主要可分為以下幾個方面： (1)以對甲氧基芐胺為原料，與磺酰氯進行親電取代反應制得中間體3-氯-4-甲氧基芐的合成及工藝優(yōu)化。 (2)以S-甲基異硫脲硫酸鹽和乙氧基甲叉丙二酸二乙酯為原料，在堿性條件下環(huán)合得到4-羥基-5-乙氧基羰基-2-甲硫基嘧啶，然后再經氯代后得到中間體4-氯-5-乙氧羰基-2-甲硫基嘧啶。 (3)以2-氰基嘧啶為原料，通過嘗試不同的還原體系，經還原而得到中間體2-氨甲基嘧啶。 (4)以L-脯氨酸為原料通過還原反應，制得中間體L-脯氨醇。 (5)以中間體3-氯-4-甲氧基芐胺和4-氯-5-乙氧羰基-2-甲硫基嘧啶為原料，二者通過親核取代反應得到4-(3-氯-4-甲氧基芐基氨基)-5-乙氧基羰基-2-甲硫基嘧啶，再前后經過甲硫基的氧化反應，與L-脯氨醇的親核取代反應，酯水解，與2-氨甲基嘧啶的縮合反應，最后得到目標化合物Avanafil (6)同樣以中間體3-氯-4-甲氧基芐胺和4-氯-5-乙氧羰基-2-甲硫基嘧啶為原料，二者通過親核反應得到4-(3-氯-4-甲氧基芐基氨基)-5-乙氧基羰基-2-甲硫基嘧啶，隨后先后經過酯水解，與2-氨甲基嘧啶的縮合反應，對甲硫基的氧化反應，與L-脯氨醇的縮合反應，最后的得到目標化合物avanafil。 本論文的主要目的是，在已有文獻和相關報道的基礎上，對avanafil進行合成路線的設計，，并通過實驗對其進行研究，篩選出對于中間體的合成路線以及對于合成總路線的最優(yōu)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.
【學位授予單位】：天津大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5

【參考文獻】

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1 張博;尤啟冬;高署;;磷酸二酯酶3抑制劑的功能和臨床應用[J];安徽醫(yī)藥;2010年10期

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