A New Multigram Synthetic Process to Cabotegravir

Cabotegravir, a long-acting integrase strand transfer inhibitor, is clinically used for HIV treatment and prevention. Current synthetic processes for cabotegravir are limited to either low scalability or prolonged reaction times. In response to the demand for a scalable synthesis method, we report a novel synthetic route enabling multigram-scale production of cabotegravir. Starting from commercially available 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid, we have developed a five-step synthetic route that offers improved synthetic efficiency compared to the literature method. Key improvements include the following: (1) a two-step deacetalization-cyclization avoids the strongly acidic conditions and raises the combined yield from 74% to 96%, (2) a one-pot esterification–transamidation eliminating moisture-sensitive reagents and imidazole byproduct, and (3) replacement of the final demethylation and recrystallization conditions, improving safety and purity (99.91%). The overall yield has increased from 65% to 72%, and the total reaction period has reduced from 52 to 31 h. The process is robust, reproducible, and well suited for laboratory-scale production.