The Behavior of 1, 4-Benzodiazepine Drugs in Acidic Media. II. Kinetics and Mechanism of the Acid-Base Equilibrium Reaction of Oxazolam

Abstract

The oxazolidine ring-opening and ring-closing reactions (acid-base equilibrium reactions) of oxazolam were investigated by using a stopped-flow spectrophotometer. The cis and trans isomers of oxazolam were found to have distinct ring-opening rate constants and the constant of the cis isomer was 10 to 20 times larger than that of the trans isomer. The ring-opening is hydrogen ioncatalyzed at low pH region. The ring-closing occurs in a hydroxide ion-catalyzed reaction in the alkaline region and is affected by the deprotonation of the diazepinone ring. The individual intrinsic rate constants for the ring-opening and ring-closing reactions were determined from the rate-pH profile. These rate measurements are of value to distinguish between cis and trans isomers of oxazolam.