What Does It Take to Develop Structurally Complex Molecules by Total Synthesis? Rapid Process Development and GMP Manufacturing of E7130 Drug Substance for First-in-Human Clinical Study

Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, is described. To accomplish rapid delivery of such a large and structurally complex drug substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process chemistry, and academia teams was required. The successful establishment of a suitable synthetic route in a concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction and Zr/Ni-mediated ketone coupling reaction) is described herein. Experience with the development of eribulin mesylate was helpful in anticipating and overcoming the chemical and logistical challenges encountered in the E7130 project. Based on this background, more than 10 g of E7130 Drug Substance has been successfully manufactured under Good Manufacturing Practice (GMP) controls within 1.5 years after the medicinal chemistry team succeeded in the first total synthesis.