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Development of a Factory Process for Omecamtiv Mecarbil, a Novel Cardiac Myosin Activator

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journal contribution
posted on 15.07.2019, 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. Walker
The 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.