安立生坦合成工艺研究

发布时间：2018-10-30 20:30

【摘要】：肺动脉高压(Pulmonary Arterial Hypertension, PAH)是在病理学上以血管阻塞为主要特征的一类疾病,最终导致血管阻力增加和右心衰竭。目前治疗途径主要有以下3个：内皮素(endothelin, ET)、胆碱酯酶（PDE-5）和前列环素(PGI2)系统。安立生坦是治疗肺动脉高压的第一个口服的内皮素受体拮抗剂，该药的作用机制为:降低肺动脉中膜肥厚,使血管孔径扩大；阻断平滑肌内皮质受体的激动作用,使肺血管紧张性降低。安立生坦化学名为(+)-(2s)-2-[(4,6-二甲基嘧啶-2-基)氧基]-3-甲氧基-3,3-二苯丙酸，本论文以二苯甲酮作为初始原料，经Darzens反应，醇解，水解反应得到2-羟基-3-甲氧基-3,3-二苯基丙酸，，然后经非对映体拆分得到(S)-2-羟基-3-甲氧基-3,3-二苯基丙酸，最后与4,6-二甲基-2-甲磺酰基嘧啶亲核取代得到安立生坦，五步反应总收率30%。
[Abstract]:Pulmonary hypertension (Pulmonary Arterial Hypertension, PAH) is a kind of disease characterized by vascular obstruction in pathology, which ultimately leads to increased vascular resistance and right heart failure. At present, there are three main therapeutic approaches: endothelin (endothelin, ET), cholinesterase (PDE-5) and prostacyclin (PGI2) system. Anlitam is the first oral endothelin receptor antagonist in the treatment of pulmonary hypertension. Blocking the activation of cortical receptors in smooth muscle reduces pulmonary vascular tension. The chemical name of Anlisentan is ()-(2s) -2- [(4- (4-dimethylpyrimidine-2-yl) oxyyl)] -3-methoxy-3- diphenylalanine. In this paper, benzophenone was used as the initial raw material, which was alcoholized by Darzens reaction. 2-hydroxy-3-methoxy-3-diphenylpropionic acid was obtained by hydrolysis, and then separated by enantiomers to obtain (S) -2-hydroxy-3-methoxy-3-diphenyl propionic acid. Finally, the nucleophilic substitution of 4-dimethyl-2-methanesulfonyl pyrimidine was carried out with the total yield of 30%.
【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

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