The First GMP Synthesis of MK-2118, a Small Molecule Agonist for Stimulator of Interferon Genes

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.