Carbonic acid ester prodrugs, hydrolysis

The potential of carbamic acid ester prodrugs (R-O-CO-NR R") is well-established by a number of studies on their stability and metabolism. Upon hydrolysis, they liberate the active agent ROH and the carbamic acid R R"N-COOH, which, being unstable, breaks down to the amine R R"NH and C02 (see also Sect. 8.7). The mechanism of HCT-catalyzed hydrolysis of carbamates, summarized in Fig. 8.7,b, is more complex than that of carbonates [153][158][159]. In the case of N,N-disubstituted carbamates (R-O-CO-NR R"), the only possible mechanism is as for carbonates (Fig. 8.7,b, Reaction a), which is, presumably, also the mechanism of enzyme-catalyzed hydrolysis for all carbamates. 

Fig. 8.4. Postulated mechanism of the base-catalyzed activation of (2-oxo-l, 3-dioxol-4-yl)methyl ester prodrugs (8.62) of carboxylic acids [74] [75]. After hydrolysis, the pro-moiety is liberated as a nonisolatable carbonate monoester intermediate, which is decarboxylated rapidly to a diketone.

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