水溶性β-环糊精包合反应萃取药物对映体的研究

【作者】 张盼良；

【导师】 潘春跃； 唐课文；

【作者基本信息】 中南大学 ， 有机化学， 2011， 硕士

【摘要】 手性和手性技术是当今化学研究的前沿和热点之一。单一对映体的制备是制药和精细化学品工业急待解决的重大基础问题之一。手性溶剂萃取具有适用范围广、可连续操作、易于工业化生产、生产成本相对较低等优点,成为最具发展潜力和应用前景的一种单一对映体制备技术。手性溶剂萃取技术的发展很大程度上依赖于萃取剂的改进。水溶性β-环糊精衍生物因良好的手性选择性和亲水性,用于疏水性药物对映体的分离有着独特的优势,是一种极具潜力的手性萃取剂。本文采用水溶性β-环糊精衍生物作为萃取剂,研究了某些疏水性药物对映体的手性溶剂萃取分离。通过实验考查了萃取条件对萃取性能的影响。进行了萃取机理的研究,建立反应萃取模型。通过模型预测和实验结果的比较,对模型进行修正。运用分配系数、分离因子、对映体过量和萃取性能因子等参数表征萃取性能,综合模型预测和实验结果对萃取体系进行优化。第二章是理论研究部分,本文针对水溶性环糊精衍生物强亲水性及疏水性药物对映体能在两相间分配的特点,采用了水相均相反应机理。综合对映体的物理分配、离解平衡及对映体与萃取剂的包合反应平衡等,建立了反应萃取模型用于萃取体系的模拟。与已报道的模型建立过程不同,本文结合药理研究论文中关于离子态药物对映体也在两相间分配的报道,在建立的模型中引入了离子分配系数。第三章到第六章是对四种药物对映体的手性萃取研究。实验研究了有机溶剂、环糊精衍生物类型、水相pH值、萃取剂浓度、温度等因素对萃取性能的影响,并测定了模型的相关参数。在实验研究基础上,得到了每个对映体最合适的萃取体系。结合相关参数,将模型应用于每个对映体的最合适体系,通过实验结果和模型预测的比较,对模型进行修正。在修正后的模型基础上,构建多元函数模型。经多元函数模型的模拟和优化获取最佳操作条件和参数。结果表明水溶性β-环糊精衍生物对所研究的药物对映体都有一定的识别能力,对同一药物对映体,结构不同的萃取剂优先识别的对映异构体是一致的,但识别能力各不相同。有机溶剂、水相pH值、温度、萃取剂浓度等对萃取性能有显著的影响,但对不同的分离对象影响规律有差别。本文建立的反应萃取模型需要针对具体的药物对映体进行修正,修正后的模型对所研究的四个体系的模拟都很成功,表明本文的理论研究具有普遍的适用性。离子分配的引入使模型预测的准确性大大提高。四种药物对映体都得到了各自的最佳萃取操作条件和参数。以上研究结果表明本文建立的模型是模拟药物对映体手性溶剂萃取体系的有力工具,并能为工程计算和设计提供参考。更多还原

【Abstract】 Chirality and chiral technology play an important role in the field of chemical research, nowadays. The availability of enantiopure compounds is of primary importance in the pharmaceutical and fine chemical industry. Chiral solvent extraction is considered as a very promising technology for the production of enantiopure compounds because it possesses a wide range of applications, can be operated continuously and economically and can be scaled up to an industrial scale easily. The development of chiral solvent extraction requires efficient chiral extractants. Hydrophilicβ-cyclodextrin (β-CD) are a kind of very promising chiral extractant for the separation of hydrophobic drug enantiomers because of their good chiral recognition ability and hydrophility.This thesis deals with the enantioselective extraction of some hydrophobic drug enantiomers to an aqueous phase of hydrophilicβ-CD solution. The influence of process variables on extraction efficiency was investigated experimentally. The extraction mechanism was investigated and a reactive extraction model was established. The model was validated by comparison of the model predictions with the experimental results. Extraction performances were evaluated using distribution ratio, enantioselectivity, enantiomeric excess and performance factor and the extraction systems were optimized by modeling and experiment.In Chapter 2, the theory of chiral solvent extraction was studied. Consideringβ-CD derivatives are highly hydrophilic and the hydrophobic drug enantiomers can distribute over the organic and aqueous phases, homogeneous aqueous phase reaction mechanism is applied. An inclusion reactive extraction model was established involving equilibrium of physical distribution, dissociation and inclusion complexation between enantiomers andβ-CD extractant. Some pharmacological studies have reported the distribution of ionic species between organic and aqueous phases, the model in this thesis therefore contains the physical distribution coefficient of ionic enantiomers, which is different from the models that have been reported. In Chapters 3-6, chiral solvent extraction of four drug enantiomers was investigated. The effects of process variables such as types of organic solvents andβ-CD derivatives, concentration of selector, pH and temperature, on extraction efficiency were investigated and important parameters of the model were determined experimentally. The most suitable extraction system for each drug enantiomers was obtained by experiment. Reactive extraction model was applied for each drug enantiomers. The models were then validated by comparison of the model predictions with the experimental results. Multivariate function models were then established based on the validated models. Modeling and optimization based on the multivariate function models were carried out to obtained the optimal extraction conditions and coefficients. Results show thatβ-CD derivatives can recognize all the drug enantiomers studied. For typical drug enantiomers,β-CD derivatives with different chemical structures preferentially recognize the same enantiomer but with different recognition abilities. Organic solvents type, concentration of extractant, pH and temperature strongly influence the extraction efficiency, but the pattern of their influence is different on different enantiomers. Application of the reactive extraction model need to be adjusted to each specific system and all the four systems are modeled successfully after the adjustment, which indicate the theory investigation of this thesis can be generally applied. Addition of the ionic physical distribution greatly improve the accuracy of the model predictions. The optimum conditions and coefficients of the four enantiomers were srparately obtained. The presented data indicates that the model is a powerful tool for modeling chiral solvent extraction system and can provide information for the engineering calculation and design.更多还原