Yang S K, Yang M S
Department of Pharmacology, F. Edward Hebert School of Medicine, Uniformed Services, University of the Health Sciences, Bethesda, MD 20814-4799.
J Pharm Sci. 1994 Jan;83(1):58-63. doi: 10.1002/jps.2600830114.
2-Oxoquazepam [7-chloro-1-(N-2,2,2-trifluoroethyl)-5-(2'-fluorophenyl)-1,3- dihydro-2H-1,4-benzodiazepin-2-one, OQZ], a major pharmacologically active metabolite of quazepam, was hydrolyzed in NaOH solution to form a sodium salt of 2-(N-2,2,2-trifluoroethyl)amino-5-chloro-alpha-(2'- fluorophenylbenzylidene)glycine. The hydrolysis product was formed via a rapidly established acid-base equilibrium, followed by a rate-determining, ring-opening reaction involving two negatively charged ions. Following neutralization, the hydrolysis product was isolated by reversed-phase HPLC and subsequently identified by its UV-vis absorption and MS analyses. Kinetics of the hydrolysis reaction in acetonitrile/water mixture was studied by reversed-phase HPLC analysis as a function of water content, NaOH concentration, temperature, and ionic strength. In acetonitrile:0.05 N NaOH (1:1, v/v), the hydrolysis of OQZ had an energy of activation of 14.4 kcal/mol and at 25 degrees C (delta H++ = 13.8 kcal/mol, delta S++ = -31.2 cal/K/mol, and delta G++ = 23.1 kcal/mol).
2-氧代夸西泮[7-氯-1-(N-2,2,2-三氟乙基)-5-(2'-氟苯基)-1,3-二氢-2H-1,4-苯并二氮杂卓-2-酮，OQZ]是夸西泮的主要药理活性代谢物，在氢氧化钠溶液中水解形成2-(N-2,2,2-三氟乙基)氨基-5-氯-α-(2'-氟苯基亚苄基)甘氨酸的钠盐。水解产物通过快速建立的酸碱平衡形成，随后是涉及两个带负电荷离子的速率决定的开环反应。中和后，通过反相高效液相色谱法分离水解产物，随后通过其紫外可见吸收和质谱分析进行鉴定。通过反相高效液相色谱分析研究了乙腈/水混合物中水解反应的动力学，该动力学是水含量、氢氧化钠浓度、温度和离子强度的函数。在乙腈:0.05 N氢氧化钠(1:1，v/v)中，OQZ的水解活化能为14.4千卡/摩尔，在25℃时(ΔH++ = 13.8千卡/摩尔，ΔS++ = -31.2卡/K/摩尔，ΔG++ = 23.1千卡/摩尔)。
