Han W W, Yakatan G J, Maness D D
J Pharm Sci. 1976 Aug;65(8):1198-204. doi: 10.1002/jps.2600650817.
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.
差示吸收光谱法已成功用于跟踪氯氮卓和去甲西泮在pH值1至11范围内的水解动力学。氯氮卓失去甲氨基生成去甲西泮。去甲西泮通过平行连续反应降解为2-氨基-5-氯二苯甲酮和一种甘氨酸衍生物。通过薄层色谱法观察到去甲西泮水解有两种中间体。一种被认为是由酰胺水解产生的开环结构，从动力学上看，这似乎是导致二苯甲酮产物的主要机制途径。另一种中间体代表了一条替代但次要的途径，推测是由甲亚胺键的初始断裂产生的。N-氧化物的质子化略微改变了这两条途径的重要性。在低于该中间体pKa的pH值下，羧酸中间体的环化很容易。报道了涉及缓冲催化、离子强度效应和速率常数的温度依赖性的稳定性参数。
