Control over selectivity for demethylation in dolutegravir synthesis in microreactors: Kinetics and mechanisms

Abstract

Demethylation of DTG-7 (i.e., an intermediate of an anti-HIV medication dolutegravir (DTG)) is the final step in the DTG synthesis, but its reaction network and kinetic investigations have not been reported yet. In this work, we established the reaction kinetic model of this system based on experimental data from microreactors, according with the demethylation mechanism of the complex ion formation and transformation examined by density functional theory (DFT) calculation. Due to limited solubility of the intermediate product (i.e., organolithium), various parameters were screened to reach a high DTG yield of 98.5 % at a residence time of 12 min without microreactor clogging. Detailed kinetic investigation of DTG-7 demethylation and ring-opening side reaction revealed that precise control over the temperature and residence time in the cascade microreactor system facilitated high selectivity and DTG yield with short residence times. Finally, an operating window was established for process optimization based on the kinetic model.