Large-Scale Asymmetric Synthesis of a Cathepsin S Inhibitor
| Autor: | Nelu Grinberg, Xudong Wei, Chris H. Senanayake, Nizar Haddad, Joe Johnson, Earl Spinelli, Suresh R. Kapadia, Heewon Lee, Carl A. Busacca, Max Sarvestani, Jon C. Lorenz, Xingzhong Zeng, Rich Varsolona, Anjan Saha, XuWu Feng |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Vinyl Compounds Stereochemistry Strecker amino acid synthesis Alkenes Calorimetry Aldehyde Chemical synthesis Catalysis Side chain Urea Rhodium Enzyme Inhibitors chemistry.chemical_classification Molecular Structure Organic Chemistry Asymmetric hydrogenation Enantioselective synthesis Stereoisomerism Cathepsins Claisen rearrangement chemistry Cyclization Indicators and Reagents Palladium |
| Zdroj: | The Journal of Organic Chemistry. 75:1155-1161 |
| ISSN: | 1520-6904 0022-3263 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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