The Behavior of 1, 4-Benzodiazepine Drugs in Acidic Media. XV. Contribution of Iminium Structure to the Proton Exchange Reaction of 11b-Methylbenzodiazepinooxazoles

Abstract

2-Ethyl-11b-methyl-2, 3, 7, 11b-tetrahydrooxazolo [3, 2-d] [1, 4] benzodiazepin-6 (5H)-one (Ie), its 2-phenyl derivative (If), and 1, 3-dihydro-5-methyl-2H-1, 4-benzodiazepin-2-one (III) were synthesized to elucidate the contribution of the iminium structure (II) to the proton exchange reaction of 11b-methylbenzodiazepinooxazoles. The 11b-methyl protons of Ie and If and the 5-methyl protons of III were exchanged with deuterium in methanol-d₄ solution at 23°C. The exchange rates were accelerated in the presence of trifluoroacetic acid-d₁. Methanol solutions of Ie, If, and III had fluorescence due to such iminium structures as II and III·H⁺ of these compounds, and the fluorescence was not observed in the original (oxazolidine ring-closed) structures of I and III. Percentages of iminium form in methanol solution were estimated by using fluorescence intensity. There found a relationship between the magnitude of the exchange rates and the fluorescence intensity. These results indicate that benzodiazepinooxazoles (including Ie and If) have the iminium form to some extent in the solution and diastereoisomerization of oxazolam occurs via a similar iminium intermediate.