Synthesis of Imidazole Based p38 MAP (Mitogen-Activated Protein) Kinase Inhibitors under Buffered Conditions

• Published in: Organic process research & development Vol. 10; no. 3; pp. 556 - 560
• Main Authors: Magnus, Nicholas A, Diseroad, William D, Nevill, C. Richard, Wepsiec, James P
• Format: Journal Article
• Language: English
• Published: American Chemical Society 01-05-2006
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op060042t

This article describes chemistry that was developed to give access to multigram quantities of imidazole 479754 and several related analogues for Eli Lilly's p38 MAPK program targeting therapies to address inflammation. The molecules of interest have an isopropyl sulfonyl group present on the 2-aminobenzimidazole heterocycyle that was found to be labile when heated in polar solvents and/or exposed to high or low pH. Due to this instability issue, the syntheses of the target molecules required optimizing Sonogashira reaction conditions, employing a buffered oxidative method to produce α-diones, developing buffered reaction conditions to generate imidazoles, and developing final recrystallization conditions.