Kinetics and Mechanism of the Acid-Base Equilibrium and the Hydrolysis of Benzodiazepinooxaziines

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Ring-opening and ring-closing (acid-base equilibrium) reactions of the six-membered oxazine of benzodiazepinoxazines (BZINs) and the subsequent hydrolyses of the diazepine ring have been investigated kinetically and compared with the reactions of benzodiazepinooxazoles (BZOLs) which have the five-membered oxazolidine ring. The ring-closing reaction for BZINs is slower than that for BZOLs due to the increase in the degree of freedom for the moving molety of BZINs. The rates of the ring-opening reactions are almost independent of the substituents at 12b-position (H-(1), CH_3-(2), and C_6H_5-(3)), indicating that an attacking proton may approach equally (non-sterically) to the lone pair of N_5 atoms. Possible conformational aspects of BZINs in solution are proposed. Cleavages (hydrolyses) of the diazepine ring occur at the C_<12b>-N_5 (iminium) bond for 2 and 3 and are 10-100 times faster than those for the corresponding BZOLs. For 1,in contrast to 2 and 3,hydrolysis of the amide bond (N_8-C_7) of the diazepine ring takes place instead of the iminium bond, similar to the case of 11b-hydrogen BZOL.
社団法人日本薬学会の論文
1991-12-25