【作者】 杨艳丽；

【导师】 主沉浮；

【作者基本信息】 山东大学 ， 化学工艺， 2009， 硕士

【摘要】 手性对映体的存在是自然界中的一种普遍现象,在药物化学领域表现尤为突出。手性药物对映体的分离具有非常重要的意义,已经成为现代分析化学领域广泛研究的课题之一。毛细管电泳(Capillary Electrophoresis,CE)技术因其分离效率高、需样量少、操作模式多样化、环境污染少、应用范围广等优点受到众多科学工作者的关注。使用手性选择剂分离药物对映体仍然是CE手性拆分的重要方法,发展和研究新型手性选择剂是手性分离领域的重点。目前,环糊精(Cyclodextrins,CD)及其衍生物是CE中应用最为广泛的手性选择剂。然而,天然环糊精受其分子键合能力和水溶性等物理化学性能的限制,在手性分离上具有一定的局限性,经改性的环糊精衍生物则具有以下特点:1.环糊精分子外缘的羟基衍生化后,其水溶性增加,空腔尺寸与物化性质也有所改变;2.能与客体分子产生不同的作用,配位能力提高;3.若衍生化取代基带电荷,则产生的静电作用也可使手性识别能力有所增强,即带电环糊精可分离电中性和带电的手性药物。因此,环糊精衍生物应用于手性药物的拆分研究是一项具有挑战意义的课题。本论文主要由三部分组成,其具体内容如下:首先,系统阐述了毛细管电泳在手性拆分方面的研究进展,并对手性拆分理论、应用及其操作模式等做了简单介绍。其次,参照有关文献合成了两种新型的环糊精衍生物。利用丙交酯的开环聚合反应,将低聚乳酸基团修饰于β-环糊精上,得到了水溶性良好、可生物降解的6-O-低聚乳酸基-β-环糊精(6-Oligo(D,L-lactic acid)-β-cyclodextrin,6-OLA-β-CD);采用“合成—脱保护—锅法”将完整的甜菜碱内盐结构连到β-环糊精上,得到了6-O-(2-羟基-3-甜菜碱基丙基)-β-环糊精(6-O-(2-hydroxyl-3-betainylpropyl)-β-cyclodextrin,6-HBP-p-CD)。最后,以β-CD、HP-β-CD及合成的两种新型环糊精衍生物为手性选择剂对酮替芬、扑尔敏、特布他林、普萘洛尔等药物对映体进行了手性拆分。研究了环糊精浓度对分离的影响,同时考察了运行电压和背景电解质pH值对手性拆分的影响。更多还原

【Abstract】 Chirality is one of prevalent characters in universe,involving biologic survival and evolvement.With further research done for pharmacological properties,differences have been recognized in physiological effect and metabolism of a pair of enantiomers of chiral drugs.Because of the exceedingly similar pharmacological properties, enantiomers have extraordinary difficulties in separation.Due to the virtues of high separation efficiency,rapid analysis,good selectivity and stability,low consumption of samples and automatization,high performance capillary electrophoresis(HPCE) has broad application in the analysis field of enantiomers of chiral drugs.Successful chiral separation lies in choosing accurate chiral selector,current research is still focus on finding and synthesizing new chiral selectors.Cyclodextrins (CDs) including native and derivatized CDs are among the widely used chiral additives in CE.However,there are some limits to the native CDs in their solubility and physico- chemical properties for chiral separation.CD derivatives exhibit different properties compared to the native ones in the following:1.Improved solubility;2.Possibility for different bonds with analytes that can improve the inclusioncomplexation;3.The charged CDs can separate uncharged and charged chiral drugs.So the chiral separation using CDs derivatives is one of the challenging subjects.The dissertation consists of three parts.In chapter one,the development of chrial separation by CE was reviewed,including theoretical studies,applications and different operating models.In chapter two,two modifiedβ-CD were synthesized and characterized.Based on the ring-opening polymerization of 3,6-dimethyl-1,4-dioxane-2,5-dione(lactide), 6-Oligo(D,L-lactic acid)-β-cyclodextrin(6-OLA-β-CD) was gotten by modification of oligo lactic acid group onβ-cyclodextrin.6-O-(2-hydroxyl-3-betainylpropyl)-β-cyclodextrin(6-HBP-β-CD) was prepared by a "synthesis-deprotection one pot" method with the intention of producing useful functional models and enhanced performance characteristics.In chapter three,β-CD,HP-β-CD and novelβ-CD derivatives were selected as the chiral selector for the separation of ketotifen,chlorphenamine,terbutaline, propranolol,etc.Effect of the concentration of the chrial seletors was reviewed,as while as the applied voltage and different pH of back ground electrolytes.更多还原