- Development of a scalable process for CI-1034, an endothelin antagonist
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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.
- Jacks, Thomas E.,Belmont, Daniel T.,Briggs, Christopher A.,Horne, Nicole M.,Kanter, Gerald D.,Karrick, Greg L.,Krikke, James J.,McCabe, Richard J.,Mustakis, Jason G.,Nanninga, Thomas N.,Risedorph, Guy S.,Seamans, Ronald E.,Skeean, Richard,Winkle, Derick D.,Zennie, Thomas M.
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p. 201 - 212
(2013/09/04)
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- Certain benzothiazine dioxide endothelin antagonists and processes for their preparation
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The instant invention is a series of benzothiazine dioxides, or a pharmaceutically acceptable salt thereof, which are potent endothelin A antagonists with profound in vitro activity, and improved syntheses for the Formula 1 The compounds are useful in treating elevated levels of endothelin, essential renovascular malignant and pulmonary hypertension, cerebral infarction, cerebral ischemia, congestive heart failure, and subarachnoid hemorrhage.
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