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

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 s...

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Bibliographic Details
Published in:	Organic process research & development Vol. 28; no. 4; pp. 1253 - 1259
Main Authors:	Brearley, Christopher, Bright, Robert David, Clarke, James, Critcher, Douglas J., Torres, Susana, Edwards, Ingrid, Fenton, Harriet, Huang, Shanjun, Johnson, Rebecca Amy, Jones, Ricky A., Mathew, Suju P., Norster, Rhys, Starbuck, Kathryn Alice, Taylor-Young, Amelia, Waddington, William, Walton, Robert, Wang, Jimmy
Format:	Journal Article
Language:	English
Published:	American Chemical Society 19-04-2024
Subjects:	copper catalysis process development nonprecious metal catalysis ullmann-type coupling biaryl etherification
Online Access:	Get full text
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Summary:	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.
ISSN:	1083-6160 1520-586X
DOI:	10.1021/acs.oprd.4c00052