Mechanism of Alkaline Hydrolysis of Diazepam

Abstract

AbstractDiazepam (1) is a frequently prescribed hypnotic/anxiolytic drug in worldwide use. Compound 1 is hydrolyzed in alkaline medium to form 2‐methylamino‐5‐chlorobenzophenone imine (2) and 2‐methylamino‐5‐chlorobenzophenone (3); the ratio of 2:3 increases with increasing NaOH concentration (J. Pharm. Sci. 85, 745–748, 1996). The mechanism in the conversion of 1 to 2 and 3 via various intermediates is the subject of this report. Results of hydrolysis kinetics and structural identification of some intermediate products indicated an initial hydroxide attack at the C2‐carbonyl carbon of 1, resulting in the formation of a dioxide (7, 7‐chloro‐1,3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1,4‐benzodiazepin‐2,2‐dioxide). Compound 7 was characterized by proton NMR spectroscopy and via its monomethyl ether (8, 7‐chloro‐1,3‐dihydro‐2‐hydroxy‐2‐methoxy‐l‐methyl‐5‐pheny]‐2H‐1,4‐benzodiazepine). The seven‐member diazepine ring of 7 opened at the N1‐C2 bond to form a glycinate [5, 2‐methylamino‐5‐chloro‐α‐(phenylhenzylidene)glycinate]. Compound 7 (and/or 5) underwent an additional hydroxide attack at the C5‐N4 imine bond to form a tetrahedral intermediate, which decomposed to form 2 and 3.