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Synthesis of 5-fluoro-2-nitrobenzotrifluoride in a continuous-flow millireactor with a safe and efficient protocol

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A synthesis process of 5-fluoro-2-nitrobenzotrifluoride was achieved in a continuous-flow millireactor system through the nitration of 3-fluorobenzotrifluoride using the mixed acid as a nitrating agent. The process safety was evaluated based on the temperature rise with the use of Reaction Calorimeter and Differential Scanning Calorimetry. The mass transfer limitation for this nitration process in the millireactor was evaluated. Effects of the composition of the mixed acid, the molar ratio of nitric acid to the substrate, the residence time, and the temperature on the reaction performance in the millireactor were studied in order to obtain optimal operational conditions. A heat transfer assessment was made to discuss the effects of the residence time and the inner diameter on the temperature distribution and the substrate conversion. Compared with the traditional batch reactor, the flow reactor could achieve better control over impurity and higher process efficiency because of its enhanced mass and heat transfer rates under the optimized conditions. This continuous-flow synthesis strategy would be beneficial for the commercial manufacturing of fine chemicals and pharmaceutical intermediates with the involvement of nitration.


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We would like to acknowledge financial support from the National Natural Science Foundation of China (No. 21676164) and the Science and Technology Commission of Shanghai Municipality (No. 18520743500). We also thank a safety engineer Mr. Guoxiang Wei from Porton Pharma Solutions, Ltd. for his assistance on the analysis of reaction heat release.

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Correspondence to Yuanhai Su.

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Chen, P., Shen, C., Qiu, M. et al. Synthesis of 5-fluoro-2-nitrobenzotrifluoride in a continuous-flow millireactor with a safe and efficient protocol. J Flow Chem (2020). https://doi.org/10.1007/s41981-019-00068-3

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  • Flow reactor
  • Nitration
  • 5-fluoro-2-nitrobenzotrifluoride
  • Flow chemistry