Prodrugs of phosphonoformate: products, kinetics and mechanisms of hydrolysis of dibenzyl (methoxycarbonyl)phosphonate

Abstract

Dibenzyl (methoxycarbonyl)phosphonate (1) has been prepared by the reaction of benzyl alcohol with (methoxycarbonyl)phosphonic dichloride. The hydrolysis of 1 proceeded rapidly, with a half-life of 60 min at 36.4 °C and pH 7.4, by two main pathways. The dominant pathway (k₁, 6.56 × 10^–3 min^–1) yielded the diester, benzyl (methoxycarbonyl)phosphonate (2) and benzyl alcohol (3), with P–O cleavage. The second (k₂, 3.55 × 10^–3 min^–1) gave dibenzyl phosphite (4), possibly arising from hydrolysis of the carboxyl ester followed by decarboxylation. Benzyl phosphite (5) was also observed, which arises from the hydrolysis of 4 with P–O cleavage (k₅, 9.04 × 10^–4 min^–1). Other products formed in small amounts were, benzyl (benzyloxycarbonyl)phosphonate (6)(k₃, 3.59 × 10^–4 min^–1) and dibenzyl phosphate (7)(k₄, 4.24 × 10^–4 min^–1). The rapid and complicated hydrolysis of 1, involving four competitive reactions, two of which involve C–P bond cleavage, suggests that triesters of phosphonoformate are unlikely to be suitable prodrug forms.