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


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.

This is a preview of subscription content, log in to check access.

Scheme 1
Scheme 2
Fig. 1
Fig. 2


  1. 1.

    Culy CR, Jarvis B (2001) Drugs 61:1625–1660

    CAS  Article  Google Scholar 

  2. 2.

    Plosker GL, Figgitt DP (2004) Pharmacoeconomics 22:389–411

    Article  Google Scholar 

  3. 3.

    Scott LJ (2012) Drugs 72:249–272

    CAS  Article  Google Scholar 

  4. 4.

    Barbara JE, Kandel S, Stanley FA, Buckley DB (2014) Drug Metab Rev 45:179–180

    Google Scholar 

  5. 5.

    Gertz M, Sall C, Houston JB, Galetin A (2014) Drug Metab Rev 45:258

    Google Scholar 

  6. 6.

    Barbara JE, Muranjan S, Stanley F, Kollu C, Kandel S, Otwell C, Buckley DB (2015) Drug Metab Rev 47:120

    Google Scholar 

  7. 7.

    Salman M, Babu SJ, Ray PC, Biswas S, Kumar N (2002) Org Process Res Dev 6:184–186

    CAS  Article  Google Scholar 

  8. 8.

    Grell W, Hurnaus R, Griss G, Mark RSERM, Luger P, Nar H, Wittneben H, Muller P (1998) J Med Chem 41:5219–5246

    Article  Google Scholar 

  9. 9.

    Panelo A, Wing JR (2005) Diabetes Care 28:1789

    CAS  Article  Google Scholar 

  10. 10.

    Wolffenbuttel BHR, Nijst L, Sels J, Menheere P, Muller PG, Kruseman ACN (1993) Eur J Clin Pharmacol 45:113–116

    CAS  Article  Google Scholar 

  11. 11.

    Sundaram DTSS, Mitra J, Rajesh C, Islam A, Prabahar KJ, Rao BV, Douglas SP (2015) Synth Commun 45:2092–2098

    CAS  Article  Google Scholar 

  12. 12.

    Zhang Y, Liu TT, Niu ZH, Fu YJ, Yang JX, Song YX, Zhao SC (2016) J Chem Res 11:506–510

    Article  Google Scholar 

  13. 13.

    Zhou XY, Zhu J, Bao ZJ, Shang ZH, Wang T, Song JF, Sun J, Li W, Adelusi TI, Wang Y, Lv DM, Lu Q, Yin XX (2016) Sci Rep 6:28023

    Article  Google Scholar 

  14. 14.

    Amin MM, Arbid MS (2017) Appl Physiol Nutr Metab 42:181–192

    CAS  Article  Google Scholar 

  15. 15.

    Awasthi R, Kulkarni GT, Ramana MV, Pinto TDA, Kikuchi IS, Ghisleni DD, Braga MD, De Bank P, Dua K (2017) Int J Biol Macromol 97:721–732

    CAS  Article  Google Scholar 

  16. 16.

    Kassem AA, Abd El-Alim SH, Basha M, Salama A (2017) Eur J Pharm Sci 99:75–84

    CAS  Article  Google Scholar 

  17. 17.

    Okunlola A, Adebayo AS, Adeyeye MC (2017) Int J Biol Macromol 94:544–553

    CAS  Article  Google Scholar 

  18. 18.

    Prior SL, Dunseath GJ, Luzio SD, Stephens JW (2017) Diabetic Med 34:65–66

    Google Scholar 

  19. 19.

    Xu YT, Lu J, Zhou DD, Wang YD, Li JJ, Wang MY, Zhang HJ (2017) Drug Metab Pharmacok 32:S65–S66

    Article  Google Scholar 

  20. 20.

    Yamazaki T, Desai A, Goldwater R, Han D, Howieson C, Akhtar S, Kowalski D, Lademacher C, Pearlman H, Rammelsberg D, Townsend R (2017) Clin Pharm Drug Dev 6:54–65

    CAS  Article  Google Scholar 

  21. 21.

    Sheldrick GM (1996, 2003) SADABS. University of Göttingen, Göttingen

  22. 22.

    Bruker AXS Inc. (1998) SAINT software reference manual. Bruker AXS Inc., Madison

    Google Scholar 

  23. 23.

    Sheldrick GM (1997) SHELXTL NT version 5.1. Program for solution and refinement of crystal structures. University of Göttingen, Göttingen

    Google Scholar 

  24. 24.

    Sheldrick GM (2008) Acta Crystallogr A 64:112–122

    CAS  Article  Google Scholar 

  25. 25.

    Accelrys (2014) Material studio release notes, release 7.0. Accelrys Software

  26. 26.

    Montazerozohori M, Mojahedi Jahromi S, Masoudiasl A, McArdle P (2015) Spectrochim Acta A 138:517–528

    CAS  Article  Google Scholar 

  27. 27.

    Wang P, Zhao L (2015) Spectrochim Acta A 135:342–350

    CAS  Article  Google Scholar 

  28. 28.

    Wang JH, Tang GM, Wang YT, Qin TX, Ng SW (2014) CrystEngComm 16:2660–2683

    CAS  Article  Google Scholar 

  29. 29.

    Wen YH, Dou RT, Yao K, Xu GF (2015) J Coord Chem 68:38–54

    CAS  Article  Google Scholar 

  30. 30.

    Chang XH, Zhao Y, Han ML, Ma LF, Wang LY (2014) CrystEngComm 16:6417–6424

    CAS  Article  Google Scholar 

  31. 31.

    Cheng L, Wang JQ, Gou SH (2011) Inorg Chem Commun 14:1201–1203

    CAS  Article  Google Scholar 

  32. 32.

    Wang CC, Wang JH, Tang GM, Wang YT, Cui YZ, Ng SW (2015) J Coord Chem 68:3918–3931

    CAS  Article  Google Scholar 

  33. 33.

    Tang G-M, Chi R-H, Wan W-Z, Chen Z-Q, Yan T-X, Dong Y-P, Wang Y-T, Cui Y-Z (2017) J Lumin 185:1–9

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Yong-Tao Wang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 286 kb)

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: or www:

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


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