PRODRUGS OF PHOSPHONOFORMATE - PRODUCTS, KINETICS AND MECHANISMS OF HYDROLYSIS OF DIBENZYL (METHOXYCARBONYL)PHOSPHONATE

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-degrees-C and pH 7.4, by two main pathways. The dominant pathway (k1, 6.56 x 10(-3) min-1) yielded the diester, benzyl (methoxycarbonyl)phosphonate (2) and benzyl alcohol (3), with P-O cleavage. The second (k2, 3.55 x 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 x 10(-4) min-1). Other products formed in small amounts were, benzyl (benzyloxycarbonyl)phosphonate (6) (k3, 3.59 x 10(-4) min-1) and dibenzyl phosphate (7) (k4, 4.24 x 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.