Biocatalysis cephalosporin

Bruggink (1996) has given an account of how the production of cefalexin, which is the largest cephalosporin in the market, can be converted from a ten-step process based on benzaldehyde and penicillin into a six-step process where biocatalysis is involved in three steps. The wastewater stream, containing 30-40 kg of unwanted materials in the conventional process, has been substantially reduced. Similarly, Van Loon et al. (1996) have given details of fermentation processes for cleaner and cheaper compared to the process practised so far. 

Cephalosporins are -lactam antibiotics that block microbial cell wall synthesis. The original cephalosporin. Cephalosporin C, has only weak antibiotic activity. Therefore much more powerful second generation cephalosporins were developed by side-chain modification. Modifications at Cl are most effective but modifications at position 3 are also important so as to increase in vivo activity. Synthesis of the second generation cephalosporin cefuroxime requires the replacement of the C3 acetoxy side-chain of the precursor with a caibamate group. Chemical methods proceed via a hydroxylated intermediate which causes problems due to a tendency to lactonise at low pHs. Therefore development of a biocatalysis step was initiated in order to achieve selective reaction nnder mild conditions. 

Birkett, J.A. and Robinson C. (1990) Biotransformation of cephalosporins an adjunct to chemistiy. In Real products from Industrial Biocatalysis, Royal Society of Chemistry. 

Biocatalysis with Undissolved Solid Substrates and Products Synthesis of cephalosporins... 

M Conder, N Almeida, S Behrens, L Crawford, S Delawder, T Hoerner, P McAda, J Rambosek, C Reeves, T Scimmel, T Stepan, R Stieber, V Vinci. Cephalosporin production in Penicillium chrysogenum the application of metabolic engineering to the development of a new biocatalytic process. Conference on Applied Biocatalysis, Brighton, UK, 1994, pp 20-24. 

ADCA (cephalosporins) Fermentation and biocatalysis metabolic engineering, acylase... 

Biotechnological processes can be divided into fermentation processes and biotransformations. In a fermentation process products are formed as primary or secondary metabolites by microorganisms or higher cells from components in the fermentation broth. Product examples are amino acids, vitamins or antibiotics such as penicillin or cephalosporine. In these cases co-solvents are sometimes used for m situ product extraction. The term biotransformation or biocatalysis is used for processes where a starting material (precursor) is converted into the desired product... 

Biocatalysis, as the name suggests, involves using enzymes or other natural catalysts to carry out chemical reactions. This tends to work well within the context of green chemistry since biological reactions are often catalyzed in water at mild temperatures emd pH values. Moreover, enzymes are themselves environmentally benign and obtained from natural sources. In addition to these benefits, biocatalyzed reactions typically proceed with high selectivity emd specificity and require relatively few synthetic steps, thus minimizing the amount of unwanted byproducts produced. Some examples of biocatalyzed syntheses are those of penicillins, cephalosporins (another class of antibiotics). 

This switch from a chemical to an enzymatic process marks in the 1990s the beginning of biocatalysis on an industrial scale for the synthesis of fine chemicals. Similar processes were also developed for cephalosporin production. 

The industrial manufacture of semi-synthetic penicillins and cephalosporins is an outstanding example of the integration of chemistry and biocatalysis. The impact of biocatalysis shortens the synthesis for Cefalexin from ten to six steps is a successful example (Fig. 16) [55,56]. 

Tramper, J., H. H. Beeftink, A. E. M. Janssen, L. P. Ooijkaas, J. L. van Roon, M. Strubel, and C. G. P. H. Schroen. 2001. Biocatalytic Production of Semi-Synthetic Cephalosporins Process Technology and Integration. In Synthesis of Beta-Lactam Antibiotics Chemistry, Biocatalysis and Process Integration, edited by A. Bruggink, 206-249. Springer-Verlag. 

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