Development of a scalable and sustainable continuous-flow microreaction process for mononitration of aromatic compounds with high selectivity and yield

Abstract

Nitroaromatic compounds are extensively used in industries such as pharmaceuticals, pesticides, and dyes. However, traditional synthesis methods often face challenges, including high safety risks, significant environmental pollution, and poor selectivity in mononitration reactions. In this study, we developed an efficient and safe continuous-flow microreaction process for mononitration, which achieves high yield and excellent selectivity. This process is applicable for the continuous synthesis of various mononitro compounds, including nitro-p-xylene, nitro-o-xylene, nitro-chlorobenzene, and nitro-toluene. Furthermore, the process was successfully applied to the synthesis of a key intermediate in the anticancer drug erlotinib, achieving a yield of 99.3%. The process has also been scaled up for the continuous production of nitro-p-xylene and nitro-o-xylene, with a product output of 800 g h⁻¹. Under the same reaction conditions, the yield and selectivity were consistent with, or even improved over, those obtained in small-scale experiments, demonstrating the scalability and industrial potential of the process. Additionally, the process incorporates a waste acid recycling strategy, which has no significant impact on product yield, thus enhancing economic benefits and reducing environmental pollution. This continuous nitration process not only shows broad application potential but also offers a safe and efficient solution for nitration in the pharmaceutical and chemical industries.