The First GMP Synthesis of MK-2118, a Small Molecule Agonist for Stimulator of Interferon Genes
Thomas W. Lyons, David A. Thaisrivongs, Nadine Kuhl, Cheol K. Chung, Angie R. Angeles, Dietrich Steinhuebel, Erik D. Guetschow, Andrew P. J. Brunskill, Timothy J. Henderson, Brandon Cash, Andrew M. Haidle
Abstract
The first GMP synthesis of MK-2118, a small molecule agonist of the stimulator of interferon genes (STING) is described. The small molecule represents a dramatic change in the chemical matter from the more complex cyclic dinucleotides previously disclosed. In this article, we detail the route-scouting, decision-making, and development details of a first GMP campaign typical for a first delivery on an accelerated timeline. The route chosen involves a key copper-mediated Negishi coupling using a chiral organozinc reagent and subsequent direct isolation. Several unexpected challenges are outlined, which highlight the difficulty in developing a first scale-up process.