American Chemical Society
op4c00052_si_001.pdf (1.31 MB)

Development and Scale-Up of a Key Copper-Catalyzed Biaryl Ether Formation for the Multikilogram Synthesis of Emprumapimod

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journal contribution
posted on 2024-03-26, 13:06 authored by Christopher Brearley, Robert David Bright, James Clarke, Douglas J. Critcher, Susana Torres, Ingrid Edwards, Harriet Fenton, Shanjun Huang, Rebecca Amy Johnson, Ricky A. Jones, Suju P. Mathew, Rhys Norster, Kathryn Alice Starbuck, Amelia Taylor-Young, William Waddington, Robert Walton, Jimmy Wang
Emprumapimod was a p38α MAPK inhibitor developed for LMNA-related dilated cardiomyopathy. One key modification from the discovery synthesis to the manufacturing synthesis involved moving the biaryl ether formation toward the end of the synthetic sequence. Herein, we discuss the redesigned route to suit large-scale manufacture. The development of a copper-catalyzed biaryl etherification reaction is detailed, including high-throughput experiments, process development and optimization, and purification. Subsequent amide formation afforded desired emprumapimod, delivering 82 kg of API across three batches. We anticipate this report will further support the utilization of nonprecious metal catalysis in pharmaceutical manufacture processes.