Preparation, Characterization and Crystal Structures of a Key Intermediate, and a Significant Impurity, in the Synthesis of Repaglinide

Abstract

The crystal structure of 2-(3-ethoxy-4-(methoxycarbonyl)phenyl) acetic acid (RGA), an important intermediate in the preparation of Repaglinide, has been carried out. Hydrogen bonds between the carboxylate groups link the molecules into dimers while weak C–H···π interactions link these dimers into a one-dimensional chain lying along the crystallographic b axis. 4-(Carboxymethyl)-2-ethoxybenzoic acid (RGAA), an impurity observed in the preparation of Repaglinide, has been simply synthesized by the hydrolysis of RGA under basic conditions. Hydrogen bonds between the carboxylate groups link the molecules into dimers while weak C–H···O interactions connect these dimers into a one-dimensional chain lying along the crystallographic c axis. The compound RGAA has also been characterized by FT-IR and UV–Vis spectra, and by 1H NMR analysis. RGA: monoclinic, P21/n, a = 12.848(3) Å, b = 4.5539(10) Å, c = 22.328(5) Å, α = 90°, β = 101.703(5)°, γ = 90°, V = 1279.2(5) Å3. RGAA: monoclinic, P21/n, a = 14.0877(11) Å, b = 5.1814(3) Å, c = 14.5857(11) Å, α = 90°, β = 91.578(3)°, γ = 90°, V = 1064.26(13) Å3. The thermal behaviors and fluorescence properties of RGAA were also investigated.

Graphic Abstract

The crystal structures of one key intermediate of Repaglinide and its derivative have been characterized, where their luminescence properties and thermal behavior have been investigated.

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Acknowledgements

This work was financially supported by the Project of Shandong Province Higher Educational Science and Technology Program (J09LB03), Shandong Distinguished Middle-aged Young Scientist Encouragement and Reward Foundation (BS2011CL034), and Shandong Province Natural Scientific Foundation (ZR2017MB041). We thanks to one of reviewers giving a lot of good comments.

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Correspondence to Yong-Tao Wang.

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Appendix: Supplementary Material

Appendix: Supplementary Material

Crystallographic data for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC references numbers are 1500755 and 1500756 for compounds RGA and RGAA, respectively. Copies of this information may be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).

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Tang, GM., Wang, YT. & Wu, YS. Preparation, Characterization and Crystal Structures of a Key Intermediate, and a Significant Impurity, in the Synthesis of Repaglinide. J Chem Crystallogr 50, 381–386 (2020). https://doi.org/10.1007/s10870-019-00811-7

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Keywords

  • Repaglinide
  • Intermediate
  • Infrared spectra
  • UV–Vis and NMR spectra
  • X-ray diffraction
  • Crystal structures
  • Thermal behavior
  • Photoluminescence