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Synthesis and structure confirmation of the impurity in crude roflumilast product

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Abstract

An impurity was detected in the roflumilast product which was supposed to be N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-3-methoxybenzamide. To further verify the impurity structure, this compound was synthesized from 4-difluoromethoxy-3-hydroxybenzaldehyde through O-alkylation, oxidation, chlorination, and amidation reaction and characterized by 1H NMR, 13C NMR, and HPLC–MS. Comparison of the HPLC–MS spectrum of the impurity and the synthesized compound confirmed that they were the same compound. The generation of the impurity was found to be attributed to acetone and iodine in the O-alkylation system.

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Authors and Affiliations

  1. Tianjin Chase Sun Pharmaceutical Co., Ltd, Tianjin, 301700, People’s Republic of China

    Chang-hai Sun

  2. School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, People’s Republic of China

    Yan Lin, Meng Sun & Li-gong Chen

  3. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, People’s Republic of China

    Dong-hua Wang

Authors
  1. Chang-hai Sun
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  2. Yan Lin
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  3. Meng Sun
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  4. Dong-hua Wang
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  5. Li-gong Chen
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Correspondence to Li-gong Chen.

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Sun, Ch., Lin, Y., Sun, M. et al. Synthesis and structure confirmation of the impurity in crude roflumilast product. Res Chem Intermed 41, 245–250 (2015). https://doi.org/10.1007/s11164-013-1187-z

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  • DOI: https://doi.org/10.1007/s11164-013-1187-z

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