Continuous processing enabled the highly energetic double conjugate addition of ethanolamine to divinylsulfone to prepare 2 kg of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide, as an intermediate in the synthesis of HIV Maturation Inhibitor BMS-955176. In situ IR was employed to monitor the steady state of the transformation for increased robustness via appearance of the thiomorpholine dioxide moiety and disappearance of the divinylsulfone. Surprisingly, a series of oligomers formed as intermediates, which converted to product with extended aging or heating, consistent with computational predictions. By running this process in flow, the highly exothermic reaction could be safely executed in an equal volume of water as the only solvent, despite an adiabatic temperature rise of 142 °C, leading to a streamlined and efficient process.

中文翻译：

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4-（2-羟乙基）硫吗啉1,1-二氧化物安全，高通量连续生产方法的开发

连续处理使乙醇胺向二乙烯基砜中高能双共轭加成，从而制备了2千克4-（2-羟乙基）硫代吗啉1,1-二氧化物，作为HIV成熟抑制剂BMS-955176的合成中间体。原位红外用于监测转化的稳态，以通过二氧化硫吗啉部分的出现和二乙烯基砜的消失来提高鲁棒性。出乎意料的是，形成了一系列作为中间体的低聚物，这些低聚物转化为经过长时间老化或加热的产物，与计算预测相符。通过将这一过程进行流动操作，尽管绝热温度上升了142°C，但仍可以在等体积的水中作为唯一的溶剂安全地进行高度放热的反应，从而简化了流程并提高了效率。