Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization
| Autor: | Marvin M. Hansen, Jennifer Kuehne-Willmore, Amy C. DeBaillie, Molly Harding, Joseph R. Martinelli, Daniel J. Jarmer, Michael J. McCulley, Dominique Huber, Michael E. Laurila, Thomas J. Martin, David W. Hoard, Theo Zweifel, Ryan J. Linder, Stanley P. Kolis, Nikolay Zaborenko, Enver Arslantas, Rachel N. Richey, Derek R. Starkey, Thomas Kull, Adrienne Hollister, Jeffrey A. Ward, Andrea L. Frederick |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Organic Process Research & Development. 19:1214-1230 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/op500327t |
| Popis: | An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by “pH cycles” to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided... |
| Databáze: | OpenAIRE |
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