Kinetics and mechanisms of hydrolysis of 1,4-benzodiazepines III: nitrazepam

The hydrolysis of nitrazepam involves a two-step sequential mechanism. The intermediate is the ring-opened compound resulting from scission of the azomethine bond. The final products are glycine and 2-amino-5-ni-robenzophenone. Recyclization of the intermediate to nitrazepam occurs at pH values above the pKa of the intermediate, in the pH region where the amino group of the intermediate is not protonated. As opposed to chlordiazepoxide and oxazepam, the initial hydrolysis step occurs at the 4,5-bond, not at the 1,2-amide linkage. This difference is attributed to a preferential activation for hydrolysis of the azomethine linkage by the nitro group. The hydrolysis involves an uncatalyzed reaction, specific acid-base catalysis, and general acid-base catalysis for acetate and phosphate buffers.