A novel group transfer reaction is reported in which a drug molecule undergoes a thermally induced 2-methyl-2-yl-propionic acid group transfer from one drug molecule to the carboxylic acid functional group of another. The resulting product, the 2-carboxy isopropyl ester of the parent compound, can itself participate in further reactions to yield a series of homologous products. The structural requirements and solvent dependence of this reactivity were investigated, and the resulting implications for the reaction mechanism were discussed. The experimental data is consistent with solvent-assisted nucleophilic substitution reaction mechanism, where the solvent is a small molecule or a second drug molecule. Hydrogen bonding appears to play an important role in both intramolecular activation of the leaving group, as well as intermolecular interaction with the attacking nucleophile. The reactivity is found to be intrinsic to the 2-arenoxy-2-methylpropionic acid structure, which is common to the extended class of fibrate PPAR drug molecules, suggesting that the potential for this reactivity exists for many of these drug molecules as well.
(c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association.