Synthesis of a Pyridoazepine Scaffold via Rhodium-Catalyzed Ring Expansion and Nitroacetamide Condensation

• Published in: Organic process research & development Vol. 27; no. 2; pp. 248 - 255
• Main Authors: Yang, Eddie, Tucker, Joseph W., Chappie, Thomas A., Weaver, John D., Chapman, Caroline, Duzguner, Remzi, Humphrey, John M.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 17.02.2023
• Subjects: hazard assessment; rhodium catalyzed ring expansion; nitroacetamide; differential scanning calorimetry; thermal screening unit; pyridoazepine
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.2c00145

Pyridoazepines are privileged structures in the search for novel drug candidates. We present the synthesis of a versatile pyridoazepine scaffold employing a precedented rhodium­(II)-catalyzed ring expansion and subsequent double-condensation-cyclization with nitroacetamide. The reactions applied several potentially hazardous reagents and intermediates, including p-toluenesulfonyl azide and nitroacetamide, the latter of which was determined to be potentially explosive and shock-sensitive. Reactions employed were derisked for laboratory scale work through DSC and TS U analysis in concert with optimization of reaction conditions. The key rhodium-catalyzed ring expansion was shown by TS U analysis to occur in a controllable manner with manageable nitrogen evolution. A new procedure is presented that enables preparation of nitroacetamide without excessive manipulation (i.e., extractive isolation) or isolation of dry solid. This article describes early safety studies used to derisk the preparation of multi-gram quantities of the target pyridoazepine.