Mechanism and kinetic study for the intensification of two‐step synthesis of a dolutegravir intermediate in microreactor
Xiao Xue, Rongkun Jiang, Chengmin Xie, Guozhi Qian, Minjing Shang, Weiping Zhu, Yuanhai Su
Abstract
Abstract Multi‐step reaction processes are frequently encountered in the synthesis of pharmaceuticals, separate study on each step however is easily neglected. Herein, we separately investigated two reaction steps for the synthesis of an intermediate (DTG‐6) of an anti‐HIV drug dolutegravir (DTG) in microreactors. The first step (i.e., deprotection of DTG‐4) was optimized to achieve a high DTG‐5 yield (i.e., 96.7%) in the microreactor after the parametric screening on the DTG‐4 concentration, methanesulfonic acid loading, molar ratio of reaction components, and so forth. Reaction kinetics was revealed based on substantial experimental data and mechanism cognition. Validation experiments showed the accuracy of this reaction kinetics. After thoroughly understanding this deprotection step, we combined it with the following annelation step in a cascade microreactor system for the two‐step synthesis of DTG‐6 with a much higher yield even at a remarkably shorter residence time compared with literature reports, thus indicating efficient process intensification.