Mechanism and kinetic study for the intensification of two‐step synthesis of a dolutegravir intermediate in microreactor

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 twostep 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.

Alternate Preparation of Norbornene and Dimethanooctahydronaphthalene via Diels–Alder Reaction: Process Simulation and Experimental Verification

“…At a reaction temperature of 60 °C with toluene as the solvent, the final product yield can reach 62%. Considering that the reaction between CPD and ethylene is strongly exothermic, an increase in temperature can increase the reaction rate kinetically but reduce the corresponding conversion rate thermodynamically. , It has been proven that different reaction conditions have a significant impact on the reaction products . Therefore, for the application of the D–A reaction in controllable synthesis, how to design the process flow and optimize the reaction conditions has always been a crucial step.…”

Chemometric tools for kinetic investigations of a homogeneously catalysed Sonogashira cross-coupling reaction in flow

“…[20][21][22][23] Additionally, microreactors have recently been widely used for precise kinetic studies of various other reactions. [24][25][26] Performing crosscoupling reactions in flow offers several advantages including nearly isothermal reaction conditions, rapid mixing and enhanced heat and mass transfer. Furthermore, reaction control is improved regarding temperature, pressure and residence time.…”