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Large-scale Asymmetric Synthesis Of A Cathepsin S Inhibitor.

J. Lorenz, C. Busacca, X. Feng, N. Grinberg, N. Haddad, J. Johnson, S. Kapadia, Heewon Lee, A. Saha, M. Sarvestani, Earl M Spinelli, Rich Varsolona, Xudong Wei, X. Zeng, C. Senanayake
Published 2010 · Medicine, Chemistry

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A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.



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