Cephalosporin ester

The bulky triphenylmethyl group has been used to protect a variety of amines such as amino acids, penicillins, and cephalosporins. Esters of N-trityl a-amino acids are shielded from hydrolysis and require forcing conditions for cleavage. The a-proton s also shielded from deprotonation, which means that esters elsewhere in the molecule can be selectively deprotonated. 

Prodrug approaches have been used to increase the oral bioavailabilities of cephalosporins. Ester prodrugs are formed by reversible esterification of the carboxyl group on these antibiotics [20], These prodrugs are more orally bio-... 

AN Saab, LW Dihert, AA Hussain. Isomerization of cephalosporin esters Implications for the prodrug ester approach to enhancing the oral bioavailabilities of cephalosporins. J Pharm Sci 77(10) 906-907, 1988. 

Cephalosporins Ester or lactone at the C(4) carboxy group /3-Lactam carbonyl C-atom more electrophilic, no intramolecular acylamido participation Increased up to 130-fold ... 

Imines derived from cephalosporin esters 4 can be alkylated in a similar manner4 (see Table 3). 

Miyauchi M, Kurihara H, Fujimoto K, Kawamoto I, Ide J, Nakao H. Studies on orally active cephalosporin esters. III. Effect of the 3-substituent on the chemical stability of pivaloyloxymethyl esters in phosphate buffer solution. Chem Pharm Bull 1989 37 2375-2378. 

About one-third of the commercial cephalosporins are derived from 7-ADCA. Due to the lower cost of penicillin, 7-ADCA is usually produced from penicillin G by ring expansion of a penicillin sulfoxide ester to yield a cephalosporin ester. The removal of the ester group is followed by cleavage of the phenylacetyl side chain to give 7-ADCA. Two-thirds of the commercial cephalosporins are derived from 7-ACA, that is produced from CPC by either chemical or enzymatic deacylation. 

Among the functional derivatives a great number of penicillin and cephalosporin esters have been synthesized to date. With the exception of the active esters, these derivatives have served only as protected intermediates for further chemical transformations. The 3(4)-carboxy group can usually be functionalized by more or less standard procedures, and instead of details, therefore, their preparations are summarized in Table 8.13. 

Table 8.13. METHODS FOR PREPARATION OF PENICILLIN AND CEPHALOSPORIN ESTERS...

Cephalosporin esters are widely used as intermediates in cephalosporin synthesis and as prodmgs for oral administration of parenteral cephalosporins. These esters undergo reversible base-catalysed isomerisation according to the mechanism shown in Scheme 4.8. A proton in the 2-position is abstracted by a base (B) and the resulting carbanion can be repro-tonated in the 4-postion, giving a A -ester. On hydrolysis, A -cephalosporin esters yield A -cephalosporins, which are biologically inactive. 

Scheme 4.8 Proposed mechanism for the base

The extractive esterification method mentioned earlier allows the desacetyl cephalosporin C derivative to be reacylated without lactone formation since the C-4 carboxyl ester does not readily participate in the lactonization reaction. For the same reason, it is possible to form a 3-halomethyl derivative of cephalosporin C from desacetyl cephalosporin ester, with the resulting halide readily displaced by the desired C-3 substituent. These reactions are shown in Figure 16. (41)... 

Reaction of cyanuric chloride with three equivalents of pyridine gives 2,4,6-tripyridinio-1,3,5-triazine (TPT), a new and mild esterification agent for the preparation of penicillin and cephalosporin esters (Scheme 75) <90H(3l)2055>. This esterification procedure has been successfully applied to the industrial production of diphenylmethyl 6) -(4-toluamido)penicillate, an important intermediate for the production of Shionogi )3-lactam antiobiotics Latamoxef, Flomoxef, and Ceftibuten. The use of cyanuric chloride with pyridine is safer and more economical on a large scale, with better product yield than other known esterification procedures. 

Similar 7(6)-spiro-(3-lactams were synthesized by 1,3-dipolar addition reactions. Imino chlorides 314 and 319 obtained from penicillin or cephalosporin ester with PCI5, in the presence of a strong organic base such... 

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