Cephalosporin, antibiotics synthetic routes

In spite of the considerable progress in developing methods for total synthesis, this route to cephalosporins cannot compete with fermentation or penicillin rearrangement (see Sections 5.10.4.1 and 2) for the industrial production of cephalosporin antibiotics. While total synthesis does provide access to nuclear analogs not readily obtainable from fermentation products, none of the totally synthetic materials have displayed sufficient advantages to Warrant their development as new drug products (b-81MI51000). 

Considerable work went into modification of the strain (through the use of X-rays or UV light to induce mutations) and improvements were made in the technology of isolation and purification. However, the mould was much more difficult to handle and would not accept alternative side-chain precursors as did Penicillium chrysogenum hence, it was impossible to prepare semi-synthetic cephalosporins by this route. In addition, the discovery of methicillin with its resistance to penicillinases negated the advantages of cephalosporin C, and for a while it appeared that this new class of antibiotics was doomed. 

A carbon analogue of penicillin V (Ic) was resistant to Bacillus cer-eus B l ctamase and moderately active against gram-positive organisms.6 ) Several 2-acetoxymethyl penicillins (2ja,y6 and 2-spirocyclopropyl cephalosporins (3 )65 vere prepared. Various chemical procedures were developed for the 7(6)a-methoxylation of B-lactam antibiotics.66-72 Conversion of penicillins to cephalosporins was achieved by new synthetic routes.73-76 Some [2,3]-fused tricyclic cephem derivatives (4a-c) were synthesized.77,78 Compound displayed significant antibiotic activity.78 Racemic cephalothin, 7-methoxycephalothin, and cefoxitin were obtained by total synthesis of a novel type.79-81 nuclear analogue of a 7-methylcephalosporin (5), prepared by total synthesis, lacked antibiotic activity,82... 

A consequence of the development of the large number of cephalosporins is that the molecular structures have become more and more complex. Alterations in the cephalosporin molecule have resulted in differences between cephalosporins in spectrum of activity, protein binding, peak serum level, serum half-life, route of excretion, cerebrospinal fluid levels and toxicity. Cephalosporins are semi-synthetic antibiotics derived from 7-aminocephalosporanic acid, which is also called the cephalosporin nucleus. The cephem ring ( nucleus") is composed of a (3-lactam ring fused with a dihydrothiazine ring (Figure 1). 

As a result of the build-up of antibiotic resistance, the demand for derivatives from penicillins and cephalosporins rather than for the natural fermentation products has increased. One of the problems in the manufacture of semi-synthetic penicillins and cephalosporins is that fhese are vulnerable compounds and chemical modification is elaborate and difficult. Modification of fhe initial fermentation products penicillin G/V and cephalosporin G by the use of enzymes has provided economically feasible routes to semi-synthetic penicillins and cephalosporins [31]. 

The total synthesis of cephalosporin C by Woodward was just one of the great achievements ofthis genial chemist. However, this route was much too comph-cated for an industrial synthesis. The yield of cephalosporin from its original source, Cephalosporium acremonium, was also too low to allow sufficient drug supply for medicinal use. Fortunately, various far more productive mutants were found. In addition, chemical modification of the natural product enabled the production of new semi-synthetic antibiotics. 

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