Nonenzymatic hydrolysis of cocaine via intramolecular acid catalysis

The spontaneous hydrolysis of the methyl-ester group of cocaine (1) in vivo contributes to the metabolic clearance of the drug in man. Neighboring-gro up participation by the tropane N-atom of cocaine in this hydrolysis was su ggested by the normal stability of the methyl-ester groups of pseudococaine and N-acylnorcocaine. For cocaine, the relative rate of methyl-eater to be nzoyl-ester hydrolysis was ca. 10:1 at pH less than or equal to 7.4, and, a lthough absolute rates increased with increasing pH, their ratio collapsed at pH > pK(a), (8.6). These data are consistent with intramolecular acid ca talysis of alkaline hydrolysis of the cocaine methyl-ester group under phys iologic conditions.