THE LACTONIZATION OF 2'-HYDROXYHYDROCINNAMIC ACID-AMIDES - A POTENTIAL PRODRUG FOR AMINES

The lactonization of two hydroxy amides—4-methoxyaniline 3-(2-hydroxyphenyl)-3,3-dimethylpropionic acid amide (2b) and 4-methoxyaniline 3-(2-hydroxy-4,6-dimethylphenyl)-3,3-dimethylpropionic acid amide (3b)—was studied over a pH range of 1–8. Due to the slowness of its reaction, a third hydroxy amide—4-methoxyaniline 3-(2-hydroxyphenyl)propionic acid amide (1b)—was investigated only at pH values of 7.5 and 10. The lactonization of 2b and 3b, which was found to be subject to general catalysis by buffer components, was observed to be catalyzed concurrently but not concertedly by both the acidic and basic forms of the buffer. The buffer-independent pH rate profiles for the lactonization of 2b and 3b were found to obey the equation k0-KH+[H3O+] + KH2o + Koh-[oh-]indicating the the reaction is also subject to specific catalysis by hydronium and hydroxide ions. A Bronsted analysis of the rate constants for buffer catalysis gave a and β values of 0.30 ± 0.02 and 0.54 ± 0.04, respectively, for 3b. The rate constants for the accelerated lactonization of lb at 50, 70, and 90 °C and pH 10 were used to calculate values of 14.7 ± 0.8 kcal/mol and -9.5 ± 2.3 eu for the activation parameters, ΔH‡and AS*, respectively. Comparison of the observed rates of lactonization at pH 7.5 and 30 °C for the three hydroxy amides allowed an estimate of the extent of rate enhancement provided by addition of a partial or total “trimethyl lock” for the hydroxy amide lactonization reaction under near physiological conditions. The order of reactivity of the three hydroxy amides was found to be 3b >> 2b > lb with rate enhancement factors of 2.5 x 104, 44, and 1, respectively. This study was begun with the objective of generating a hydroxy amide of very high reactivity at physiological pH for development into amine prodrug forms. 3b, which exhibited a half-life of 65 s at pH 7.5, has been chosen for further development as an amine prodrug. © 1990, American Chemical Society. All rights reserved.