Kinetics and mechanisms of hydrolysis of 1,4-benzodiazepines I: chlordiazepoxide and demoxepam.
Differential absorbance spectroscopy was successfully used to follow the hydrolysis kinetics of chlordiazepoxide and demoxepam from pH 1 to 11. Loss of the methylamino group from chlordiazepoxide produced demoxepam. Demoxepam degraded by a parallel consecutive reaction to 2-amino-5-chlorobenzophenone and a glycine derivative. Two intermediates were observed by TLC for demoxepam hydrolysis. One was assigned the open-ring structure resulting from amide hydrolysis, which kinetically appears to be the major mechanistic route leading to the benzophenone product. The other intermediate, representing an alternative but minor pathway, presumably results from initial scission of the azomethine linkage. Protonation of the N-oxide slightly alters the importance of these two pathways. Recyclization of the carboxylic acid intermediate was facile at pH values below the pKa of this intermediate. The stability parameters involving buffer catalysis, ionic strength effects, and temperature dependence of rate constants are reported.
D001569:Benzodiazepines / Q000032:analysis; D002021:Buffers; D002707:Chlordiazepoxide / Q000032:analysis; D003497:Cyclic N-Oxides; D003500:Cyclization; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D013816:Thermodynamics
D002021:Buffers; D003497:Cyclic N-Oxides; D001569:Benzodiazepines; D002707:Chlordiazepoxide; C000869:demoxepam