Development of a Practical Synthesis of Functionalized Azaxanthene-Derived Nonsteroidal Glucocorticoid Receptor Modulators

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• 作者：David A. Conlon ; Kenneth J. Natalie Jr. ; Nicolas Cuniere ; Thomas M. Razler ; Jason Zhu ; Nuria de Mas ; Steven Tymonko ; Kenneth J. Fraunhoffer ; Eric Sortore ; Victor W. Rosso ; Zhongmin Xu ; Monica L. Adams ; Anisha Patel ; Jun Huang ; Hua Gong ; David S. Weinstein ; Fernando Quiroz ; Doris C. Chen
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：May 20, 2016
• 年：2016
• 卷：20
• 期：5
• 页码：921-933
• 全文大小：509K
• 年卷期：0
• ISSN：1520-586X

文摘

An efficient route to two functionalized 2-aryl-5H-chromeno[2,3-b]pyridines (azaxanthenes) is reported. The addition of lithiated 2,6-dichloropyridine to salicylaldehyde followed by cyclization was a key process improvement identified for the formation of the azaxanthene core. Further elaboration of 2-chloro-5H-chromeno[2,3-b]pyridin-5-ol at the 5 position was accomplished via Lewis acid-catalyzed coupling with commercially available ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane. A partial classical resolution coupled with a preparative chiral supercritical fluid chromatography (SFC) separation was used to isolate the desired enantiomer of the azaxanthene carboxylic acid that is a common intermediate for both compounds 1 and 2. Suzuki–Miyaura cross-coupling with appropriately substituted boronic acids, followed by condensation with 2-amino-1,3,4-thiadiazole, provided the target compounds with an overall yield of approximately 10%. The use of stable, amorphous materials to support clinical comparison of functionalized azaxanthenes 1 and 2 is also discussed.