Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy

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• 作者：Stanley P. Kolis ; Marvin M. Hansen ; Enver Arslantas ; Lukas Br盲ndli ; Jonas Buser ; Amy C. DeBaillie ; Andrea L. Frederick ; David W. Hoard ; Adrienne Hollister ; Dominique Huber ; Thomas Kull ; Ryan J. Linder ; Thomas J. Martin ; Rachel N. Richey ; Alfred Stutz ; Michael Waibel ; Jeffrey A. Ward ; Alexandru Zamfir
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：September 18, 2015
• 年：2015
• 卷：19
• 期：9
• 页码：1203-1213
• 全文大小：492K
• ISSN：1520-586X

文摘

A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.