Continuous Flow Synthesis of a Key 1,4-Benzoxazinone Intermediate via a Nitration/Hydrogenation/Cyclization Sequence

Abstract

The preparation of a functionalized 4H-benzo-[1,4]-oxazin-3-one was completed via a three-step nitration/hydrogenation/cyclization sequence. The unstable nature of the nitro and amino intermediates, in addition to the hazards associated with the nitration of organic compounds in general, makes this procedure exceedingly difficult to perform on industrial scale. To overcome these limitations, we have developed a fully integrated continuous protocol in which the aromatic starting material (2,2-difluoro-2-(3-fluorophenoxy)-N,N-dimethylacetamide) is subjected to an initial continuous flow dinitration using 20% oleum in combination with 100% HNO3 (2.5 equiv) using a microstructured device heated to 60 °C. This was followed directly by continuous flow hydrogenation of the dinitrointermediate over a Pd/C fixed bed catalyst at 45 °C. The resulting air-sensitive diamino derivative was then directly cyclized to the desired 6-amino-2,2,7-trifluoro-4H-benzo-[1,4]-oxazin-3-one target compound via an acid-catalyzed cyc...