Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach

AMG 176 is a drug candidate in our
oncology pipeline. Ring-closing
metathesis (RCM) is a key reaction in the AMG 176 synthesis that is
used to construct the 16-membered macrocycle. Process intensification
was executed on a compressed timeline by combining high-throughput
experimentation and computational analysis using density functional
theory, which led to the identification of an optimal 4-bromobenzoate
protecting group on the allylic alcohol moiety. Comprehensive process
improvements led to a reduction in reaction volume from 800 to 50
L/kg with a >20% yield improvement compared with the discovery
route.
The RCM process developed from these studies was instrumental in the
clinical advancement of the AMG 176 program.