Cephalosporin amine substitution

A second purification strategy involves the substitution of the amine moiety on the a-aminoadipyl side chain at C-7. Two substituted derivatives, iV-2,4-dichlorobenzoyl CPC and tetrabromocarboxybenzoyl CPC, can be crystallized from the acidic aqueous solution. Alternatively, salts can be formed between the, /V-substituted derivatives and an organic base, such as dicyclohexylamine or dimethylbenzylamine, resulting in cephalosporin salts that are solvent extractable. Bristol-Myers Squibb uses a solvent-extractable process resulting in the isochlorobutylformate (ICBF) ester of CPC, termed cephalosporin D. Several extraction steps are usually necessary to achieve the desired final purity. iV-Substituted CPC salts containing small amounts of contaminants can be effectively converted to 7-ACA. 

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

Substitution of the amine on the a-aminoadipyl side chain of cephalosporin C (Figure 7), using many of the derivatization methods borrowed from classical peptide and amino acid chemistry, sufficiently alters the properties of cephalosporin C so as to, depending on the derivative, make it solvent extractable or insoluble in aqueous solutions. Figure 8 shows examples of many such derivatives which have been prepared and which have been reported to aid in the isolation of cephalosporin C (16-40). The utility of this approach lies in the fact that each of these cephalosporin C derivatives are able to be cleaved to 7ACA in yields equivalent to (and sometimes better than) yields achieved with cephalosporin C itself. 

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