Base‐catalyzed hydrolysis of 6‐aminopenicillanic acid. The kinetic and thermodynamic products

Abstract

In the presence of sodium hydroxide or a β‐lactamase, 6‐APA has been shown to hydrolyze rapidly at room temperature to penicic acid 3, the kinetic product of the reaction. In a subsequent equilibration 3 isomerizes at C‐5, by way of intermediate imine 4, affording 5‐epi‐penicic acid 6 as the major hydrolysis product (∼ 95% at equilibrium). The pH and temperature parameters of equilibration are discussed and HPLC, optical rotation, proton nmr and 13C nmr data are presented.

Degradation of Mecillinam in Aqueous Solution

“…These findings are consistent with observations for 6-aminopenicillanic acid (31) where no deuterium incorporation during basecatalyzed hydrolysis could be detected. Several mechanisms have been proposed for the 5-epimerization, either through different enamine-(21, 28,37) or azomethine-(31) type intermediates.…”

“…The penicilloic acid was the only primary degradation product, presumably as a 5-epimeric mixture (31).…”

“…In contrast, thiazolidines are known to be in equilibrium with their thiol precursors (35). 5-Epimerization of the p-lactam-opened compounds, e.g., the penicilloic acids, is well documented (21, 31,36,37).…”

“…From these results, C-6 cannot be involved in the epimerization process, excluding an enaminetype intermediate. Therefore, it must be concluded that at least the thiazolidines derived from I 5-epimerize like 6-aminopenicillanic acid (31) through intermediates of the azomethine type.…”

Structure and Reactivity of β‐Lactams

“…However, epimerization then occurs at C(5) to give a mixture of the (5R,6R)-and (5S,6R)-penicilloic acids (17) [64,[130][131][132][133]. The equilibrium constant for the ratio of the (5S,6R)-to that of the (5R,6R)-benzylpenicilloate is 4.…”