Kinetics and mechanism of the acid-base equilibrium of mexazolam analogues: A modification of the mechanism proposed previously for mexazolam

Oxazolidine ring-opening and ring-closing (acid-base equilibrium) reactions of 3-methyl-11b-hydrogen (1) and −11b-methyl (2) analogues of mexazolam (3) have been studied kinetically in solutions of various pH values and at 25°C. Compound 2 isomerizes to the cis/trans isomers (referring to substituents at the 3- and 11b-position) in methanol-d4 withh a half-life of baout 50 min, and at equilibrium the ratio of the cis to trans isomers is 6.9:1. The acid-base equilibrium reactions of 1 and 2 proceed via two steps due to the cis and trans isomers, the reactions of the trans isomer being faster than those of the cis isomer. The large difference between the cis and trans isomers of 2 is ascribed to their conformational differences (normal boat X1 and flat form Y11, respectively). These results required a modification of the mechanism previously proposed for mexazolam (Kurono et al., Chem. Pharm. Bull., 35 (1987) 3831–3837).