波生坦的合成

On synthesis of bosentan

波生坦作为非选择性内皮激素受体拮抗剂,具有可以口服,耐受性较好的特点,能明显改肺动脉高压善患者的运动能力,提高患者的存活率.以5-(2-甲氧基-苯氧基)-丙二酸二乙酯为起始原料,经氯化、磺酰化、醚化得到波生坦.目标产物和中间体结构经IR、1 H-NMR、MS确认.采用单因素分析法确定了各步反应的最佳工艺条件,优化后反应的总收率可达71.5%.该工艺的氯化反应去除了缚酸剂,同时三氯氧磷的用量大幅度削减;磺酰化反应引入相转移催化剂,缩短了反应时间,提高了反应收率;醚化反应一步引入羟乙氧基,缩短了反应步骤,具有路线简捷、环保经济的特点.

Bosentan is an orally active dual endothelin （ET） receptor antagonist, can improve exercise capacity and survival in patients with pulmonary arterial hypertension. With 5-（2-methoxy-phenyl）-2- （pyrimidin-2-yl）-tetrahydropyr-imidin-4,6-dione as starting material, bosentan （1） was prepared by chlorination, sulfonylation and etherification,. The structures of target molecule and intermediates were confirmed by IR.1H-NMR and MS . Using single factor analysis and the uniform design, the optimal reaction conditions of each reaction were obtained. The total yield was up to 71. 5%. The chlorination reaction of this process gets rid of deacid reagent and uses less phosphorus oxychloride; phase transfer catalyst in sulfonylation reaction shortens reaction time and increases reaction yield; etherification reaction introduces hydroxyethoxy group only in one step, decreasing reaction steps. Therefore the process is concise, environmental friendly and economically.