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Double Heck Route to a Dibenzoxepine and Convergent Suzuki Cross-Coupling Strategy for the Synthesis of an MR Antagonist

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journal contribution
posted on 19.12.2016, 00:00 by Marvin M. Hansen, Neil J. Kallman, Thomas M. Koenig, Ryan J. Linder, Rachel N. Richey, John R. Rizzo, Jeffrey A. Ward, Hannah Yu, Tony Y. Zhang, David Mitchell
A practical pilot plant convergent synthesis of MR antagonist LY2623091 was established. For synthesis convergence, a vinyl bromide geometric isomer and chiral alaninol derivative were required building blocks. Key to the synthesis route development is a stereoselective synthesis of the E-vinyl bromide via a sequential double Heck reaction, Suzuki–Miyaura cross-coupling of the vinyl bromide, a selective nitro reduction, and a highly sensitive cyanamide hydrolysis to the urea. Improvements in yield and processing were accomplished by two sets of telescoping methods which decreased the manufacturing time and provided purity enhancements.