Mechanism of Alkaline Hydrolysis of Diazepam

Diazepam (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‐2 H ‐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]‐2 H ‐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 .