874289-13-1Relevant articles and documents
Development of a Practical Synthesis of Functionalized Azaxanthene-Derived Nonsteroidal Glucocorticoid Receptor Modulators
Conlon, David A.,Natalie, Kenneth J.,Cuniere, Nicolas,Razler, Thomas M.,Zhu, Jason,De Mas, Nuria,Tymonko, Steven,Fraunhoffer, Kenneth J.,Sortore, Eric,Rosso, Victor W.,Xu, Zhongmin,Adams, Monica L.,Patel, Anisha,Huang, Jun,Gong, Hua,Weinstein, David S.,Quiroz, Fernando,Chen, Doris C.
, p. 921 - 933 (2016/06/13)
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.
