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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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Abstract

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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Acknowledgments

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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Authors and Affiliations

  1. Department of Chemical Engineering, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China

    Peng Chen, Chong Shen, Min Qiu & Yuanhai Su

  2. Porton Pharma Solutions Ltd. (Shanghai) R&D center, Shanghai, 200241, People’s Republic of China

    Peng Chen & Yingjun Bai

  3. Key Laboratory of Thin Film and Microfabrication (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China

    Yuanhai Su

  4. Porton Pharma Solutions Ltd. (Chongqing) R&D center, Chongqing, 400714, People’s Republic of China

    Jing Wu

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  1. Peng Chen
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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 10, 207–218 (2020). https://doi.org/10.1007/s41981-019-00068-3

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