posted on 2018-05-14, 11:36authored byNeil A. Strotman, Yichen Tan, Kyle W. Powers, Maxime Soumeillant, Simon W. Leung
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.