Cephalosporin acetoxy displacement

Acetoxy displacement, cephalosporin C, I68,l69f ACTH-like material... 

Acetoxy displacement in broth prior to isolation of cephalosporin C (6,21,31,37,48-50) is compared schematically in Figure 12 with the more usual approach to cephalosporin C purification. Derivatization at C-3 can be used in conjunction with other methods such as non-ionic resin adsorption or N-derivatized extraction. However, no advantage in terms of reduced solubility or enhanced extractability is indicated for these derivatives. This alternative, however, does effectively eliminate one step in the chain and could result in an overall yield benefit. 

Substitution of the 7 -amino side chain is accomplished by non-aqueous cleavage of the a-aminoadipyl group to yield 7-aminocephalos-poranic acid (7ACA). Reacylation at the 7-amino site by the desired substituent is carried out in a subsequent step. By contrast, substitution at C 3 is usually accomplished by a direct displacement of the acetoxy by the new group. Obviously, neither desacetyl cephalosporin C nor cephalosporin C lactone can participate in that substitution reaction. 

As discussed earlier, cephalosporin C is an intermediate for other cephalosporin antibiotics. Although some of these retain the C -3 acetoxy group, for others the acetoxy is displaced by a thiol or pyridinium compound. Where this displacement is generally carried out at the 7ACA stage or beyond, it can be run earlier. As an example, Figure 11 illustrates the reaction of l-methyltetrazole-5-thiol, used in cefamandole synthesis, with cephalosporin C. 

Chemical acetylation of the 3-hydroxymethyl to reform cephalosporin C is complicated by the competing lactonization reaction. This problem is avoided by reacting a desacetyl cephalosporin C derivative salt with acetic anhydride in a non-aqueous system. In the example shown in Figure 15, the triethylamine salt of N-phthaloyl desacetyl cephalosporin C is converted to N-phthaloyl cephalosporin C in dimethylformamide. If the acetoxy group is to be subsequently displaced, other acid anhydrides can be used to prepare other C-3 esters (64). A variation of this approach, also shown in Figure 15, is to react the desacetyl derivative with diketene, which yields the acetoacetate ester (65). 

Earlier modifications at the 3-position were mostly concentrated on indirect, formal displacement of the lO-acetoxy group or involved chemical manipulations of the carbon atom at the 10-position. When 3-meth-yienecephams became accessible, a new era in B-lactam antibiotics research was opened for the preparation of cephalosporins bearing a heteroatom directly attached at the 3-position. Several industrial insti-... 

The determination of the structure of cephalosporin C allowed us to account for a reaction that was first observed at the Antibiotics Research Station after we had suggested the use of pyridine acetate as a volatile buffer. This was the displacement of the acetoxy group of cephalosporin C by certain nucleophiles to give compounds that were more active, in some cases, than cephalosporin C itself. 

Early work on the reactivity of the acetoxy grouping in (179) showed that displacement reactions occurred fairly readily with certain heterocyclic tertiary bases (139), while hydrolysis to deacetylcephalosporin C was readily effected using an acetyl esterase (140). The structure elucidation of this first cephalosporin derivative in 1961 has been followed by the discovery of a number of other natural metabolites produced by fungi and various actinomycete species. The various structures are listed in Table 6. Aspects of the history, chemistry and biology of the group are covered in the extensive review edited by Flynn (6). 

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