, Volume 44, Issue 9–10, pp 465–472 | Cite as

Synthesis of new stable aliphatic isothiocyanate-based chiral derivatizing agent and application to indirect separation of chiral amino and thiol compounds

  • O. P. Kleidernigg
  • W. Lindner


A new chiral derivatizing agent (CDA) (1S, 2S) N-[(2-isothiocyanato)-cyclohexyl)-pivalinoyl amide ((S,S)-PDITC) is described. The CDA is available from 1,2-diamino cyclohexane (DACH) via a straightforward synthesis in both the (R,R) and (S,S)-configuration and can serve as a highly selective, stable reagent for the indirect resolution of chiral primary and secondary amines, amino acids and thiol compounds. The resulting diastereomeric thioureas and dithiocarbamates can be separated by simple RP-HPLC as demonstrated with a number of pharmaceutically important examples of amines and amino alcohol-type drugs. The latter diastereomers are compared with the well-established GITC derivatized compounds. The separation factors (α) of the diastereomeric thioureas range between 1.03 and 2.08 and were usually higher than those of the GITC derivatives. The chemical stability of the PDITC derivatives is excellent due to the absence of hydrolyzable ester groups— considered an advantage compared to GITC derivatives.

Key Words

Column liquid chromatography Indirect separation Chiral derivatization Stable CDA 


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  1. [1]
    G. Egginger, W. Lindner, C. Vandenbosch, D. L. Massart, Biomed. Chromatogr.7, 277 (1993).CrossRefGoogle Scholar
  2. [2]
    J. Gal, J. Liquid Chromatogr.9, 673 (1986).Google Scholar
  3. [3]
    T. Kinoshita, Y. Kasahara, N. Nimura, J. Chromatogr. A210, 77 (1981).CrossRefGoogle Scholar
  4. [4]
    M. Lobell, M. P. Schneider, J. Chromatogr. A633, 287 (1993).CrossRefGoogle Scholar
  5. [5]
    K. Stoschitzky, W. Lindner, W. Klein, The Lancet340, 696 (1992).CrossRefGoogle Scholar
  6. [6]
    K. Stoschitzky, G. Egginger, G. Zernig, W. Klein, W. Lindner, Chirality5, 15 (1993).CrossRefGoogle Scholar
  7. [7]
    V. Schurig, Angew. Chem.96, 733 (1984).Google Scholar
  8. [8]
    V. Davankov, Adv. Chromatogr.18, 139 (1980).Google Scholar
  9. [9]
    F. Gasparrini, D. Misiti, C. Villan, F. La Torre, J. Chromatogr. A539, 25 (1991).CrossRefGoogle Scholar
  10. [10]
    H. Nishi, K. Nakamura, H. Nakai, S. Terabe, Chromatographia40, 638 (1995).CrossRefGoogle Scholar
  11. [11]
    W. H. Pirkle, J. M. Finn, J. Org. Chem.47, 4037 (1982).CrossRefGoogle Scholar
  12. [12]
    C. Vogt, A. Georgi, G. Werner, Chromatographia40, 287 (1995).CrossRefGoogle Scholar
  13. [13]
    H. Ruyters, S. J. Van Der Val, J. Liquid Chromatogr.17, 1883 (1994).Google Scholar
  14. [14]
    R. Bonfichi, C. Dallanoce, S. Lociuro, A. Spada, J. Chromatogr. A707, 355 (1995).CrossRefGoogle Scholar
  15. [15]
    W. Lindner, B. Böhs, V. Seidel, J. Chromatogr. A697, 549 (1995).CrossRefGoogle Scholar
  16. [16]
    F. Li, S. F. Cooper, M. Cote, J. Chromatogr. B668, 67 (1995).Google Scholar
  17. [17]
    S. S. Chen, M. Pawlowska, D. W. Armstrong, J. Liq. Chromatogr.17, 483 (1994).Google Scholar
  18. [18]
    T. Toyo'oka, Y. M. Liu, J. Chromatogr. A689, 23 (1995).CrossRefGoogle Scholar
  19. [19]
    S. Terabe, K. Otsuka, H. Nishi, J. Chromatogr. A666, 295 (1999).CrossRefGoogle Scholar
  20. [20]
    J. Liu, Y.-Z. Hsieh, D. Wiesler, M. Novotny, Anal. Chem.63, 408 (1991).CrossRefGoogle Scholar
  21. [21]
    I. S. Lurie, J. Chromatogr. A605, 269 (1992).CrossRefGoogle Scholar
  22. [22]
    H. Wan, P. E. Andersson, A. Engström, L. G. Blomberg, J. Chromatogr. A704, 179 (1995).CrossRefGoogle Scholar
  23. [23]
    J. Gal, J. Chromatogr. A331, 349 (1985).CrossRefGoogle Scholar
  24. [24]
    D. B. Goodnough, M. P. Lutz, P. L. Wood, J. Chromatogr. A672, 290 (1995).Google Scholar
  25. [25]
    T. Toyo'oka, Y. M. Liu, Analyst120, 385 (1995).CrossRefGoogle Scholar
  26. [26]
    T. Toyo'oka, Y.-M. Liu, Chromatographia40, 645 (1995).CrossRefGoogle Scholar
  27. [27]
    K. C. Chan, G. M. Muschik, H. J. Issaq, Electrophoresis6, 504 (1995).CrossRefGoogle Scholar
  28. [28]
    A. L. L. Duchateau, H. Knuts, J. M. M. Boesten, J. J. Guns, J. Chromatogr. A623, 237 (1992).CrossRefGoogle Scholar
  29. [29]
    O. P. Kleidernigg, W. Lindner, GIT1, 42 (1995).Google Scholar
  30. [30]
    W. Lindner, O. P. Kleidernigg, PCT Patent Application PCT/EP96/02258(1996).Google Scholar
  31. [31]
    O. P. Kleidernigg, K. Posch, W. Lindner, J. Chromatogr. A729, 33 (1996).CrossRefGoogle Scholar
  32. [32]
    S. G. Davies, A. A. Mortlock, Tetrahedron49, 4419 (1993).CrossRefGoogle Scholar
  33. [33]
    M. Fujimaki, Y. Murakoshi, H. Hakusui, J. Pharm. Sci.79, 568 (1990).Google Scholar
  34. [34]
    O. P. Kleidernigg, M. Lämmerhofer, W. Lindner, Enantiomer1, 387 (1996).Google Scholar
  35. [35]
    S. Ito, A. Ota, K. Yakamoto, Y. Kawashima, J. Chromatogr. A626, 187 (1992).CrossRefGoogle Scholar
  36. [36]
    W. C. Chan, R. Micklewright, D. A. Barrett, J. Chromatogr. A697, 213 (1995).CrossRefGoogle Scholar

Copyright information

© Friedr. Vieweg & Sohn Verlagsgesellschaft mbH 1997

Authors and Affiliations

  • O. P. Kleidernigg
    • 1
  • W. Lindner
    • 1
    • 2
  1. 1.Institute of Pharmaceutical Chemistry Karl-Franzens University of GrazGrazAustria
  2. 2.Institute of Analytical ChemistryUniversity of ViennaViennaAustria

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