肺动脉高压孤儿药Selexipag合成工艺的优化

首先，以二苯基乙二酮和2-氨基乙酰胺为原料，通过环合反应和羟基氯代合成了5，6-二苯基吡嗪-2-醇（Ⅰ） 和5-氯-2，3-二苯基吡嗪（Ⅱ）。其次，化合物?Ⅱ?与4-异丙氨基丁醇反应得到4-［（5，6-二苯基-2-基）（异丙基）氨基］-1-丁醇（Ⅲ）。然后，化合物?Ⅲ?和溴乙酸甲酯发生Willianmson反应得到2-｛4-［N-（5，6-二苯基吡嗪-2-基）-N-异丙基氨基］丁氧基｝乙酸甲酯（Ⅳ）。最后，Ⅳ与甲基磺酰胺在叔丁醇钠作用下缩合得到目标产物Selexipag。对各步反应进行了优化，羟基氯代反应条件为: n （Ⅰ）∶n （POCl3）=1.0∶1.7，120?℃反应4 h。胺基化条件为: n （4-异丙氨基丁醇）∶n （Ⅱ）=4.0∶1.0，170?℃反应68?h。Willianmson反应条件为: n （Ⅲ）∶n （溴乙酸甲酯）∶n （四丁基溴化铵）∶n（氢氧化钠）=1.0∶1.0∶0.1∶15.0，甲苯为溶剂，80?℃反应5?h。酰胺化反应条件为: n （Ⅳ）∶n （甲基磺酰胺）∶n （叔丁醇钠）=1.05∶1.0∶1.5，室温反应2 h。优化工艺总收率达到74.5%，且反应条件温和，分离方法简单，适合工业化生产。

Review of Application Studies on Ozone

Ultraviolet radiation， electrolysis and dielectric barrier discharge are the main ways to produce ozone. Ozone has been widely used in industrial wastewater treatment， aquaculture wastewater purification and domestic water disinfection. Ozone has strong disinfect capability in wastewater treatment and has the advantages of high efficiency and high cleanliness. However， ultraviolet irradiation and electrolysis have the problems of low efficiency and high cost， and harmful by-products will be produced by dielectric barrier discharge. Ozone has certain harmfulness in practical application， and its potential value has not been utilized. To realize the sustainable development of economic society， we should continue to explore more efficient and clean preparation technology combined with the actual demand， and carry out the research on the intellectualization of ozone preparation production equipment， improving the application research on ozone and utilization of ozone in medical application.