Development of a scalable process for DG-041, a potent EP3 receptor antagonist, via tandem Heck reactions

DG-041 is a small molecule antagonist of the EP3 receptor for prostaglandin E-2 that is in clinical development for treatment of peripheral artery disease (PAD). Originally produced using a six-step synthetic procedure, process optimization led to development of a four-step sequence that is readily scalable. The key step in the optimized sequence contains two sequential Heck reactions, involving an intramolecular Heck cyclization followed by an intermolecular Heck coupling, performed in one pot to produce a highly substituted indole core.