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Download fileDevelopment of a Factory Process for Omecamtiv Mecarbil, a Novel Cardiac Myosin Activator
journal contribution
posted on 2019-07-15, 16:35 authored by Seb Caille, Alan M. Allgeier, Charles Bernard, Tiffany L. Correll, Andrew Cosbie, Richard D. Crockett, Sheng Cui, Margaret M. Faul, Karl B. Hansen, Seth Huggins, Neil Langille, Steven M. Mennen, Bradley P. Morgan, Henry Morrison, Alexander Muci, Karthik Nagapudi, Kyle Quasdorf, Krishnakumar Ranganathan, Philipp Roosen, Xianqing Shi, Oliver R. Thiel, Fang Wang, Justin T. Tvetan, Jacqueline C.
S. Woo, Steven Wu, Shawn D. WalkerThe
development of a factory process to manufacture the novel cardiac
myosin activator omecamtiv mecarbil (1) is described.
Omecamtiv mecarbil is prepared via the convergent synthesis and coupling
of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access
to aniline 2, reduction of the corresponding nitroaromatic
was designed to control potential mutagenic impurities. Key to
the efficient preparation of 2 was the benzylic bromination
of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5-phosphate. Overall, the longest linear sequence consists
of six steps, including a final salt formation step to afford the
drug substance in 55% overall yield. Because of poor performance of
the original free-base form of the drug substance in modified-release
formulations, an improved dihydrochloride hydrate form was developed
to aid drug product performance and manufacturability.