A Streamlined, Safe and Sustainable Process for Gemlapodect

Abstract

The research efforts to attain a suitable process for the timely delivery of Gemlapodect for initial toxicological and phase 1/2 clinical studies are described. The original discovery chemistry route was hampered by considerable safety issues and low overall yield. The safety issues were solved by the introduction of a copper‐catalyzed oxidative cyclization while a novel process for the synthesis of the pyrazole building block as well as the implementation of a palladium‐catalyzed coupling between the pyrazole amide and the bromo‐triazolopyridine scaffolds contributed to improve the route efficiency. Overall, a safe and sustainable process was attained that allowed the production of up to 19.2 kg of drug substance with a reduced number of steps and an increased overall yield.

Diversification of Pharmaceutical Manufacturing Processes: Taking the Plunge into the Non-PGM Catalyst Pool

“…Recently, the Roche R&D group described another gram scale copper-catalyzed C–N bond-forming reaction, namely a selective monoamination reaction of an aryl bromide using gaseous NH 3 ( Scheme 23 ), as part of route scouting to synthesize gemlapodect. 97 Although impressive results were achieved, the toxicity associated with aniline intermediate 71 led the team to develop an alternative route.…”