Green fishing of cephalosporin antibiotics

Cephalosporins are life-saving antibiotics that are on the market for approximately 25 years. Their markets will probably remain substantial for the next two decades. Accordingly, there is both the opportunity and the need for innovation of the processes by which these antibiotics are being manufactured. An important driving force behind these innovations is reduction of the amount of chemical waste.This can be achieved by replacing the chemical processes by "green" processes.
Cephalosporins are semi-synthetic antibiotics. They consist of a beta-lactam nucleus and a D-amino acid side chain. The final step in the preparation of these cephalosporins comprises the coupling of the beta-lactam nucleus and the D-amino acid side chain. The conventional method to achieve this coupling requires stoichiometric chemistry resulting in the formation of large amounts of chemical waste.
A contemporary method employs biocatalysis for the coupling of the nucleus and side chain (in water). An important drawback of the enzymatic coupling is secondary hydrolysis of the cephalosporin product by the enzyme. In addition, isolation of the product from the aqueous reaction mixture is hampered because product concentrations obtained by the enzymatic coupling are relatively low.
Selective complexation of the cephalosporins provides an efficient method for the isolation of these antibiotics from aqueous solutions. Moreover, the problem of secondary hydrolysis is strongly reduced by instantaneous withdrawal of the product.
Beta-naphthol was already known as a reasonable complexing agent for four cephalosporins. However, it is rather toxic and hence is not particularly suitable for application in a "green" enzymatic process. The antibiotics research in Nijmegen, a collaboration between Organic Chemistry, Chemical Crystallography and DSM, was aimed at acquiring fundamental knowledge about the selective complexation process and at a significant improvement of the complexation process with respect to both the efficiency and the toxicity of the complexing agents.

This is an example of Crystal Engineering research.
See also research in Chemical Crystallography.

An antibiotic moleculeX-raying a crystal
Cefradine/beta-naphthol/water complexA new green complexant

References

  1. Complexen van Beta-lactam antibiotica.
    G.J. Kemperman, R. de Gelder, P.C. Raemakers-Franken.
    NL1007827, 1997.

  2. Complexes of Beta-lactam antibiotics and 1-naftol.
    G.J. Kemperman, R. de Gelder, P.C. Raemakers-Franken.
    NL1007828, 1997; WO99/31109.

  3. Clathrate Type Complexation of Cephalosporins with Beta-naphtol.
    G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. Raemakers-Franken, A.J.H. Klunder, and B. Zwanenburg.
    Chemistry, a European Journal 5 (1999), 2163-2168.

  4. Molecular Challenges in Modern Chemometrics.
     R. Wehrens, R. de Gelder, G.J. Kemperman, B. Zwanenburg, and L.M.C. Buydens.
    Analytica Chimica Acta (1999), 400, 413-424.

  5. Selective Complexation of Cephalosporin Antibiotics.
    R. de Gelder, G.J. Kemperman, F.J. Dommerholt, A.J.H. Klunder, and B. Zwanenburg.
    IUCr XVIII Congress and General Assembly, Collected Abstracts, C.C. Wilson, K. Shankland and T. Csoka, Eds., (1999), 407.

  6. Induced Fit Phenomena in Clathrate Structures of Cephalosporins.
     G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. Raemakers-Franken, A.J.H. Klunder, and B. Zwanenburg.
    Journal of the Chemical Society-Perkin Transactions 2 (2000), 7, 1425-1429.

  7. Crystallographic and Thermodynamic Aspects of Cephalosporin Complexation .
    R. de Gelder, G.J. Kemperman, F.J. Dommerholt, A.J.H. Klunder, and B. Zwanenburg.
    19th European Crystallographic Meeting, Nancy, France, 25th - 31st August 2000, Abstracts book, 313.

  8. Efficiency of Cephalosporin Complexation with Aromatic Compounds.
     G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. Raemakers-Franken, A.J.H. Klunder, and B. Zwanenburg.
    Journal of the Chemical Society-Perkin Transactions 2 (2001), 4, 633-638.

  9. A Computational Model to Predict Clathration of Molecules with Cephradine.
     G.J. Kemperman, R. de Gelder, R. Wehrens, F.J. Dommerholt, A.J.H. Klunder, L.M.C. Buydens, and B. Zwanenburg.
    Journal of the Chemical Society-Perkin Transactions 2 (2001), 6, 981-987.

  10. Molecular Precision in the Chemistry of Cephalosporin type Antibiotics.
    B. Zwanenburg, G.J. Kemperman, J. Zhu, R. de Gelder, F.J. Dommerholt, G.T.M. Titulaer, R. Keltjens and A.J.H. Klunder.
    In: Synthesis of Beta-lactam Antibiotics. Chemistry, Biocatalysis & Process Integration. Chapter II, page 56-101. Edited by Alle Bruggink, Kluwer Academic Publishers, 2001.

  11. Complexants for the clathration mediated synthesis of the antibiotic cephradine.
     G.J. Kemperman, R. de Gelder, F.J. Dommerholt, C.G.P.H. Schroën, R. Bosma, and B. Zwanenburg.
    Green Chemistry (2001), 3, 4, 189-192.

  12. Cavities, Layers and Channels in the hosting framework of molecular complexes derived from Cephradine.
     G.J. Kemperman, R. de Gelder, F.J. Dommerholt, P.C. Raemakers-Franken, A.J.H. Klunder, and B. Zwanenburg.
    European Journal of Organic Chemistry (2001), 3641-3650.


  13. Clathrate Type Complexation of Cephalosporin Antibiotics - Function, design and application.
     G.J. Kemperman.
    Thesis (2001). University of Nijmegen. The Netherlands.

  14. Molecular selectivity and cooperativity in clathrate-type complexation of Cephradine.
     G.J. Kemperman, R. de Gelder, F.J. Dommerholt, A.J.H. Klunder, and B. Zwanenburg.
    European Journal of Organic Chemistry (2002), 345-350.