Tomonari Kuwayama

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

Abstract Oxazolidine ring-opening and ring-closing (acid-base equilibrium) reactions of 3-methyl-11 b -hydrogen ( 1 ) and −11 b -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 11 b -position) in methanol-d 4 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 X 1 and flat form Y 11 , respectively). These results required a modification of the mechanism previously proposed for mexazolam (Kurono et al., Chem. Pharm. Bull. , 35 (1987) 3831–3837).

Stereochemistry of benzodiazepinooxazoles: crystal structure and NMR spectroscopic investigations of new conformational variants of mexazolam analogues

The varied stereochemistry of mexazolam analogues is described on the basis of six crystal-structure analyses of the 11b-hydro (2), methyl (3 and 4), phenyl (5) and 2′-chlorophenyl (6; mexazolam) derivatives of 3-methylbenzodiazepinooxazole and the benzodiazepinooxazole (1), all determined by X-ray diffraction techniques. Two new comformations for the benzodiazepinooxazole ring system have been found in these analyses, i.e., a flat conformation YII in the case of 2 and 3, and a skewed conformation YI in 1. The usual ‘boat-wing’ conformation XI has been found in compounds 4–6. The solution-state 1H NMR spectra of 1, 3 and 4 at room temperature have been examined by phenyl ring-current effects and support retention of the three types of solid-state conformation. In polar solvents, all these compounds (except for 1) show a diastereoisomeric equilibrium of trans↔cis interconversion through epimerization at the 11b position. The diastereoisomeric and conformational differences in these compounds are discussed along with the steric interaction of the substituents.