Development of a Scalable Process for CI-1034, an Endothelin Antagonist
Organic Process Research & Development2004Vol. 8(2), pp. 201–212
Citations Over TimeTop 21% of 2004 papers
Thomas E. Jacks, Daniel T. Belmont, Christopher A. Briggs, Nicole M. Horne, Gerald D. Kanter, Greg L. Karrick, James J. Krikke, Richard J. McCabe, Jason Mustakis, Thomas N. Nanninga, Guy S. Risedorph, Ronald E. Seamans, Richard W. Skeean, Derick D. Winkle, Thomas M. Zennie
Abstract
A concise, convergent multikilogram synthesis of CI-1034 (1), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o-vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl2 as a substitute for TiCl4 in a Dieckmann condensation to provide the benzothiazine dioxide core.
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