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Preparation of N-Aryl Anthranilic Acid Drugs by Modified Ullmann Coupling Reaction in Ionic Liquids

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Abstract

N-Aryl anthranilic acid drugs have been synthesized by a simple, environmentally friendly, low-cost, and high-yielding modified Ullmann coupling reaction protocol using potassium 2-bromobenzoate, substituted anilines, and copper acetate in tetrabutylphosphonium chloride ([TBP]Cl) ionic liquid. The optimal conditions have been found and applied to the synthesis of N-aryl anthranilic acid drugs at 170°C. Mass spectrometry, X-ray crystallography, and proton nuclear magnetic resonance were used to describe the structure of the products. Copper(I) complex catalyst was used as a starting catalyst for the Ullmann reaction because of the good fluidity and homogeneity in [TBP]Cl ionic liquid. Meclofenamic, mefenamic, clofenamic, and flufenamic acids were synthesized efficiently using the proposed general procedure. The distinct advantages of the described protocol are operational simplicity, cleaner reaction, high selectivity, excellent yield, rapid conversion, easy preparation, and the use of a low-cost catalyst.

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Funding

This work was financially supported by the National Natural Science Foundation of China (grant no. U1407122).

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Authors and Affiliations

  1. College of Chemical Engineering, Nanjing Tech University, 211816, Nanjing, China

    Zhengyu Gu, Feng Xue, Jiale Yu & Shengui Ju

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  1. Zhengyu Gu
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  2. Feng Xue
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  3. Jiale Yu
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  4. Shengui Ju
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Correspondence to Feng Xue or Shengui Ju.

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Gu, Z., Xue, F., Yu, J. et al. Preparation of N-Aryl Anthranilic Acid Drugs by Modified Ullmann Coupling Reaction in Ionic Liquids. Russ J Org Chem 58, 837–843 (2022). https://doi.org/10.1134/S1070428022060124

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