The synthesis and oxidation of N-hydroxy-derivatives of the β-adrenoceptor antagonists bufuralol and toliprolol

Abstract

The m-tolyloxy-epoxide (5) reacts with N-isopropylhydroxylamine to give the hydroxylamine (7). Similarly, the benzofuran epoxide (21) reacts with N-t-butylhydroxylamine to give the hydroxylamine (13). These N-hydroxyderivatives of the β-adrenoceptor antagonists toliprolol (6) and bufuralol (12) are possible metabolites involved in the in vivo degradation of the β-hydroxylamine side-chains of these compounds. The hydroxylamines (7) and (13), although stable in the form of their hydrochloride salts, undergo oxidation in solution. The hydroxylamine (7) is readily oxidised to the nitrone (8), whereas the hydroxylamine (13) gives a mixture of t-butylammonium salts of the acid (16) and (22). The synthesis of the oximes (29), (32), and (33) is also described.