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Continuous synthesis of N-(3-Amino-4-methylphenyl)benzamide and its kinetics study in microflow system

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Abstract

N-(3-Amino-4-methylphenyl)benzamide (1) is a crucial building blocks of many drug candidates. In this paper, a continuous flow microreactor system was developed to synthesize 1 and determine intrinsic reaction kinetics parameters. By screening the acylating reagents and reaction conditions, 1 was obtained by the selective acylation of 4-methylbenzene-1,3-diamine (2) with benzoic anhydride (3). Since the two amine groups in 2 are in different chemical environments, parallel by-products and serial by-products coexist, which makes the selective monoacylation process relatively complicated. To reveal the reaction process clearly, reaction rate constants and their 95% confidence intervals, activation energies, pre-exponential factors were acquired by kinetics study in microflow system. The established kinetic model can calculate the selectivity and conversion of the acylation reaction, which are in good agreement with the experimental results. Subsequently, the kinetic model was used to optimize reaction conditions, as a result, 1 was synthesized in the microreactor with a yield of 85.7% within 10 min.

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Acknowledgements

We are grateful to High-Level Talent Project of West Anhui University (WGKQ2022030), Key Project of Natural Science Research in Universities of Anhui Province (KJ2021A0957), Natural Science Foundation of Anhui Province (2008085QB96), Postdoctoral Science Foundation of Anhui Province (2020B454) for financial support.

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Correspondence to Qilin Xu or Zhiqun Yu.

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Xu, Q., Li, G., Zhu, F. et al. Continuous synthesis of N-(3-Amino-4-methylphenyl)benzamide and its kinetics study in microflow system. J Flow Chem 12, 317–325 (2022). https://doi.org/10.1007/s41981-022-00241-1

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