3-Substituent effect and 3-methylene substituent effect on the structure-reactivity relationship of 7.beta.-(acylamino)-3-cephem-4-carboxylic acid derivatives studied by carbon-13 and IR spectroscopy

Abstract

Relationships between the chemical reactivity of 3-substituted cephalosporins or 3-methylene-substituted cephalosporins and several parameters observed by 13C NMR and IR spectroscopies are described. Among 3-substituted cephalosporins, the values of delta (C-3) and delta (COO) of 13C NMR spectra are correlated with the logarithms of the rate constants for alkaline hydrolysis (log kobsd) when substituents at the 3-position are classified into two groups, i.e., OR substituents and others. Among the 3-methylene-substituted cephalosporins, the difference values of the 13C chemical shifts for C-3 and C-4, delta delta (4-3), are correlated with log kobsd. The beta-lactam vC = O value of the solution IR spectra is a good index for the prediction of a significant change of the beta-lactam reactivity resulting from modification of a 3-substituent or a 3-methylene substituent. From analysis of these observed parameters, both resonance and inductive effects of the substituent at the 3-position were found to affect the chemical reactivity of the beta-lactam ring in cephalosporin, while only the inductive effect of the substituent at the 3'-position was found to affect the beta-lactam reactivity.

Degradation of Cephaloridine on Alkaline Hydrolysis

“…I , we developed the kinetic sequence shown in Scheme 1. It assumes that cephaloridine (1) can react via three pathways in an alkaline medium, namely via reversible epimerization at C (7) to yield the 7-epimer 2, via nucleophilic attack of the OH- ion on the carbonyl group of the ,!I-lactam ring to give the methylidene compound 4 and pyridine, and oia a reversible base-catalyzed isomerization of the A'-double bond to give A*-cephaloridine (3). The isomerization of a A3to a A'-isomer introduces a new asymmetric center at C(4).…”

“…2 ) indicating an openedp-lactam ring [lo]. The 'H-NMR spectrum shows 2s's typical of olefin protons (6 5.65 and 5.60 (2 H, J = 0 Hz)) of an exocyclic double bond and 2d's (6 4.62 and 5.42 (2 H, J = 2.5 Hz)) for H-C(6) and H-C (7) of the open ring [lo]. The 3-methylidene compound 4 was previously reported to occur as a degradation product in the alkaline hydrolysis of cephalosporins with a good leaving group at position 3' [lo] [13] [14].…”

Alkaline Hydrolysis of Cefotaxime. A HPLC and 1HnmR Study

“…29 reported an estimated second-order kinetic constant of 6 X 103 mol-1 s-l (30 "C) for epimerization catalyzed by hydroxyl ions at C (6). Such a value corresponds to a pseudo-first-order constant roughly 25 times smaller than that obtained by us at pH 10.5.…”

“…Nucleophilic attack on the carbonyl group in the P-lactam ring of the 7-epimer of cefotaxime must give rise to another exocyclic methylene compound (6) which is a stereoisomer of 5. These two compounds will be in equilibrium.…”

Cephalosporins

“…Thus 3-deacetoxycephalosporins are found to be more stable than cephalosporins having 3substituents that can be readily lost. The 3 -substituents exert an electronic influence on the chemical reactivity of the β-lactam carbonyl group (67,68) which can be correlated with antibiotic activity within a series (69,70) and it has been claimed that cephalosporin antibacterial activity is related to the ease of C-3 group expulsion (71). The deacetoxy analogues generally show lower levels of activity in vitro than their 3 -functionalized analogues.…”