包合反应手性萃取分离芳香酸对映体及其动力学研究

【作者】 苗家兵；

【导师】 周涛； 唐课文；

【作者基本信息】 中南大学 ， 化学工艺， 2010， 硕士

【摘要】 药物对映体的制备性分离研究是当前最热门的课题之一。手性溶剂萃取是药物对映体制备性分离的一种十分重要方法,相对于化学拆分法、酶或微生物法和色谱拆分法,手性溶剂萃取分离体系的选择有一定的规律可循,且适用范围也大大拓宽。包合反应手性萃取是近年发展起来的一种高效分离技术,受到众多研究者的重视。本论文主要工作是研究疏水性α-环己基扁桃酸(α-CHMA)和苯基琥珀酸(PSA)两种对映体在含有手性选择体的水—有机溶剂两相系统中的萃取分配行为；并在优化的萃取体系下用恒界面池法研究萃取过程的动力学,为药物对映体的萃取分离提供理论依据和技术参数。主要内容和结果如下：1.α-CHMA和PSA对映体手性萃取分离的研究：采用具有工业应用前景的亲水性β-环糊精衍生物(β-CDs)作为手性选择体,从分配系数和分离因子上考察有机溶剂的种类、萃取剂种类及其浓度、对映体浓度、pH及温度等因素对α-CHMA和PSA对映体萃取性能的影响。研究不同种类的β-CDs手性选择体的萃取性能及手性识别规律。结果表明：包合反应萃取具有很强的手性分离能力,水溶性萃取剂羟丙基-β-环糊精(HP-β-CD)、羟乙基-β-环糊精(HE-β-CD)、甲基-β-环糊精(Me-β-CD)均对S-α-CHMA的识别能力大于对R-α-CHMA的识别能力,而对PSA识别能力刚好相反；一级萃取分离后,S-α-CHMA和R-α-CHMA对映体的分配系数(ks和kR)分别为4.77和2.36,分离因子(α)达2.02；R-PSA和S-PSA对映体的分配系数(kR和kS)分别为2.38和1.00,分离因子(α)达2.38。同时有机溶剂、pH、温度、对映体和萃取剂浓度对手性分离能力有显著的影响。2.HP-β-CD对α-CHMA、PSA对映体的包合反应萃取动力学研究：通过恒界面池法研究β-CDs对α-CHMA和PSA对映体反应萃取的动力学特性；考察了搅拌速率、界面面积、对映体浓度和萃取剂浓度等操作参数对α-CHMA和PSA对映体萃取动力学的影响。实验结果表明：HP-β-CD萃取α-CHMA对映体的反应为“快反应”；HP-β-CD萃取PSA对映体的反应也为“快反应”；萃取反应是对映体浓度的—级反应,是萃取剂浓度的二级反应；反应速率常数对S-α-CHMA,R-α-CHMA而言分别为70584.8 L2/mol2·s,18079.4 L2/mol2·s；而对R-PSA,S-PSA而言分别为32011.8 L2/mol2·s,7408.7 L2/mol2·s。这些数据对萃取过程的设计是很重要的。更多还原

【Abstract】 Preparative techniques for the separation of drug enantiomers have a great interesting potential. Chiral extraction is a very important method for preparative separation of enantiomers. It has some regularity and a larger application range in contrasting to chemical resolution, fermentation and enzymatic transformation and chromatography. Reactive extraction is a very effective separation technique with great promise. In the thesis, distribution behaviors ofα-cyclohexyl-mandelic acid (α-CHMA) enantiomers and phenylsuccinic acid (PSA) enantiomers were examined in the aqueous-organic solvent of a two-phase systerm containing a chiral selector. And then, the extraction kinetics was studied using constant- interface area cell under the optimized system to provide theoretical bases and technique parameters for enantioseparation process. The main contents and results can be summarized as follows:1. Study on chiral extraction ofα-CHMA enantiomers and PSA enantiomers:The influence of the types of organic solvents and P-cyclodextrin derivatives (β-CDs), the concentrations of the extractants and enantiomers, pH and temperature on distribution ratio (k) and enantioselectivity (α) forα-CHMA and PSA enantiomers, was separately investigated using hydrophilicβ-CDs as chiral selectors. The extraction performance and chiral recognition mechanism were studied.The experimental results indicate that reactive extraction has strong chiral separation ability. hydroxypropyl-β-cyclodextrin(HP-β-CD), hydroxyethyl-β-cyclodextrin(HE-β-CD) and methyl-β-cyclodextrin (Me-β-CD) have higher recognition ability for S-α-CHMA enantiomer than that for R-α-CHMA enantiomer, among which HP-β-CD has the strongest separation ability. But theseβ-CDs have reversed recognition ability for phenylsuccinic acid enantiomers. In the optimized extraction process forα-CHMA enantiomers, the extraction performance ofα-CHMA is optimum by one stage extraction, and the distribution ratio for S-α-CHMAt(kS) and for R-α-CHMA(kR) and separation factor(α) are 4.77,2.36 and 2.02, respectively. In the extraction process for PSA enantiomers, the extraction performance of PSA is optimum by one stage extraction, and the distribution ratio for R-PSA (kR) and for S-PSA(kS) and separation factor(α) are 2.38,1.00 and 2.38, respectively. Meanwhile, organic solvents, concentration of extractants, pH and temperature have great effects on chiral separation ability.2. Study on the reactive extraction kinetics ofα-CHMA enantiomers, PSA enantiomers using HP-β-CD as extractant:The reactive extraction kinetics was determined in a stirred cell with a constant interfacial area. The extraction process was measured at various stirring speeds, interfacial areas, initial enantiomers concentration in organic phase as well as HP-β-CD concentration in aqueous phase. The experimental results demonstrate that, the exraction reaction kinetics is ’fast’ for HP-β-CD extractionα-CHMA enantiomers, and the reactions between HP-β-CD and PSA enantiomers are also fast. The reactions have been found to be first order with respect to enantiomers and second order with respect to HP-β-CD with forward rate constants of 70584.8 L2/mol2·s and 18079.4 L2/mol2·s for S-α-CHMA and R-α-CHMA, respectively. The rate constants of HP-β-CD extraction PSA enantiomers are 32011.8 L2/mol2·s and 7408.7 L2/mol2·s for R-PSA and S-PSA, respectively. These data will be useful in the design of extraction processes.更多还原