【作者】 张丹丹；

【导师】 李发美； 玄明浩；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2005， 博士

【摘要】 本文研究了应用大环抗生素类手性固定相（Chimbiotic V，T和R）分离马布特罗、班布特罗、克伦特罗、克伦普罗、福莫特罗和特布他林六种β₂-受体激动剂对映体；应用Pirkle型手性固定相（Pirkle-1J和α-Burke-2）分离马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β₂-受体激动剂对映体；应用冠醚类手性固定相（Crownether-NH和N-CH₃）分离马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β₂-受体激动剂及普萘洛尔、阿替洛尔、醋丁酰洛尔、吲哚洛尔、烯丙洛尔、烯丙氧洛尔六种β-受体阻断剂对映体；一种新的Pirkle型手性固定相的合成及应用，并对分离机制分别进行了深入的探讨。1．大环抗生素类手性固定相分离β₂-受体激动剂对映体本文应用大环抗生素类手性固定相Chirobiotic V，T和R对六种β₂-受体激动剂对映体进行了分离，考察了洗脱模式、流动相组成和温度等因素对分离的影响，对分离结果进行了比较研究，并对其分离机制进行了探讨。六种β₂-受体激动剂对映体在Chirobiotic R手性固定相上均不能实现分离。在Chirobiotic V和T手性固定相上，分离β₂-受体激动剂对映体的最佳模式均为新极性有机相模式，最佳色谱条件为：甲醇-冰醋酸-三乙胺（100∶0.01∶0.01，v／v／v）。在此条件下，六种β₃-受体激动剂对映体均可得到较好的分离，并可实现多种β₂-受体激动剂对映体的同时分离。考察了此模式下β₂-受体激动剂对映体的热力学参数变化，证明了β₂-受体激动剂对映体与两种手性固定相之间的相互作用是焓控过程。β₂-受体激动剂与固定相之间的离子相互作用是实现对映体分离的最主要分离机制。2．Pirkle型手性固定相分离β₂-受体激动剂对映体本文应用Pirkle型手性固定相，Pirkle-1J和α-Burke-2，对马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β₂-受体激动剂药物对映体进行了分离，考察了流动更多还原

【Abstract】 The enantiomeric resolution of sixβ₂-agonists including bambuterol, clenbuterol, clenproperol, fumoterol, mabuterol and terbutaline was studied on three macrocyclic antibiotic chiral stationary phases （CSPs）: Chirobiotic V, T and R. The enantiomeric resolution of fiveβ₂-agonists including bambuterol, clenbuterol, clenproperol, fumoterol and mabuterol mentioned above was studied on two Pikle-type CSPs: Pirkle-1J andα-Burke-2. The enantiomeric resolution of fiveβ₂-agonists mentioned above except terbutaline and sixβ-blockers including propranolol, atenolol, acebutolol, pindolol, alprenolol and oxprenolol was investigated on Crown ether-NH and N-CH₃ CSPs. A new Pirkle-type CSP was prepared and applied to resolve a number of N-（3,5-dinitrobenzoyl）-α-amino amides and N-acyl-1-aryl-l-aminoalkanes and found to be effective. The chiral recognition mechanism for different enantioresolution was proposed. 1、Enantioresolution ofβ₂-agonists on macrocyclic antibiotic CSPsThe enantiomeric resolution of sixβ₂-agonists was studied on three macrocyclic antibiotic chiral stationary phases （CSPs）: Chirobiotic V, T and R. Factors affecting the enantioresolution, such as the separation mode, composition of mobile phase and column temperature were investigated. No enantioresolution was achieved for the sixβ₂-agonists on Chirobiotic R CSP. On Chirobiotic V and T CSPs, the polar organic mode （POM） was proved to be the best, with methanol-acetic acid-triethylamine （100:0.01:0.01, v/v/v） as the mobile phase, the enantiorners of all the sixβ₂-agonists were successfully separated, and the simultaneous enantioseparation ofβ₂-agonist mixture was achieved. The thermodynamic parameters ofβ₂-agonists in this mode were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed, ionic interaction between the CSPs andβ2-agonists was confirmed to be the dramatic interaction responsible for the chiral discrimination.2. Enantioresolution ofβ₂-agonists on Pirkle-type CSPsThe enantiomeric resolution of fiveβ₂-agonists was studied on two Pikle-type CSPs: Pirkle-1J and or-Burke-2. Factors affecting the enantioresolution, such as the type and concentration of the salts additives, the content of the organic solvents and temperature were investigated. Under the optimized chromatographic condition, enantiomers of fiveβ₂-agonists were successfully separated on or-Burke-2 CSE while only twoβ₂-agonist enantiomers were resolved on Pirkle-1J CSE The thermodynamic parameters ofβ₂-agonists on two CSPs were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed,π-πinteraction and hydrogen binding between the CSPs andβ₂-agonists were confirmed to be the interactions responsible for the chiral discrimination.3、Enantioresolution ofβ₂-agonists andβ-blockers on crown ether CSPsThe enantiomeric resolution of fiveβ₂-agonists and sixβ-blockers was investigated on Crown ether-NH and N-CH₃ CSPs. By varying the mobile phase composition and temperature, the enantiomers of all analytess were successfully separated on Crown ether-NH CSP, while only enantiomers ofβ-blockers were partly resolved on Crown ether-N-CH₃ CSP, the enantioresolution ofβ₂-agonists was not achieved on it. The thermodynamic parameters ofβ₂-agonists andβ-blockers on the CSPs were investigated, the enantioselectivity was proved to be entropically controlled. The chiral recognition mechanism was discussed, hydrogen binding, ionic interaction and inclusion interaction between the CSPs and the analytes were confirmed to be the interactions responsible for the chiral discrimination.4. Preparation and application of a new Pirkle-type ehiral stationary phaseA new high-performance liquid chromatographic Pirkle-type chiral stationary, phase was prepared starting from R-（+）-1,1’-binaphthyl-2,2’-diamine. The CSP thus prepared was successfully applied to resolve a number of N-（3,5-dinitrobenzoyl）-α-amino amides and N-acyl-1-aryl-1-amino alkanes and found to be effective. The chiral recognition mechanism was proposed to beπ-πinteraction and simultaneously hydrogen bonding interactions between the CSP and the analytes.更多还原