【作者】 陈春燕；

【导师】 陈小明；

【作者基本信息】 湘潭大学 ， 分析化学， 2009， 硕士

【摘要】 单一对映体手性药物的制备是当前国际药物研究最热门的课题之一。高效液相色谱法是应用最广泛、适用范围最宽的手性拆分技术,其中,手性流动相添加剂法拆分手性药物,由于拆分前无需衍生,操作起来更加简便,且成本较低,是进行对映体拆分及光学纯度检测的非常准确、简便的方法。手性液-液萃取法的分离体系有一定的规律可以遵循,有比较成熟的理论指导,适用范围比较宽,规模易于放大,是实现单一对映体药物的工业化制备的重要途径。中空纤维膜分离技术是近年发展起来的一种高效分离技术,克服了传统液液萃取的缺点,大大提高了分离的效率和立体选择性,受到众多研究者的重视,在日常生产生活中得到越来越广泛的应用。本论文主要工作是采用高效液相色谱手性流动相添加剂法对多巴对映体进行定量分析;研究了手性液液萃取分离多巴对映体的最佳条件;将手性液液萃取与中空纤维膜相结合,对多巴对映体的制备性分离进行初步的研究。主要内容如下:采用β-环糊精手性流动相添加剂法拆分多巴对映体。研究手性选择剂种类及浓度、有机改性剂种类及含量、缓冲盐种类、pH值、流速等对分离的影响,并对分离条件进行优化:流动相为甲醇/水=20/80(v/v,其中水中含β-环糊精浓度为5mmol/L),流速0.8mL/min,分离度为1.73。建立了多巴对映体的定量检测曲线。以疏水性L-酒石酸正己酯为手性选择剂,研究了多巴对映体在水-有机溶剂两相中的萃取分配行为,建立了实验中优化的手性萃取条件:1,2-二氯乙烷为有机相溶剂,L-酒石酸正己酯浓度为0.25mmol/L,水相pH值控制在2.5,萃取温度为10℃,分离因子可达1.16。以疏水性L-酒石酸正己酯为手性流动载体,采用中空纤维支撑液膜法萃取分离多巴对映体,考察膜相有机溶剂种类、手性流动载体浓度、料液相多巴外消旋体起始浓度、pH梯度对立体选择性分离的影响,建立优化的手性拆分条件。在多巴起始浓度为2mmol/L、L-酒石酸正己酯浓度为50mmol/L、料液相和接收相存在pH梯度时,多巴对映体能够被有效拆分,最大分离因子为1.42。更多还原

【Abstract】 Preparative separation of chiral drugs has a great interesting potential. High performance liquid chromatography chiral mobile phase additives is the most widely used separation mothed because of its simple and low cost compared to derivative method or chiral stationary phase method. Chiral extraction is a very important method for the preparative separation of drugs enantiomers. It has some regularity and a larger application range. Hollow fiber membrane extraction is a very effective separation technology with great development. In the thesis, the dopa enantiomers were separated and determinated by method of chiral mobile phase additives; the optimal parameters of resolution of dopa by chiral extraction were investigated; combined with chiral extraction, the resolution of dopa enantiomers by hollow fiber supported liquid membrane extraction were further investigated. The main content and results can be summarized as following:A method for chiral mobile phase additives enantiomeric resolution of racemic dopa has been established withβ-cyclodextrin as the chiral selector. The effects of type and concentration ofβ-cyclodextrin, sorts of organic solvents, buffer type and pH, velocity of mobile phase were investigated in detail, respectively. The appropriate conditions was: the mobile phase composed of methanol/water = 20/80 (v/v, in which containing 5mmol/Lβ-cyclodextrin), 0.8mL/min, the baseline separation could be obtained with resolution of 1.73. The quantitative ability of chiral mobile phase additives also be researched.The distribution behavior of dopa enantiomers was examined in the aqueous and organic phase containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral selector, in order to establish the optima chiral extraction conditions in this experiment. The influence of organic solvent, concentration of chiral selector, pH in aqueous phase and extraction temperature on performances of chiral resolution were investigated. The results show that the separation factor is 1.16 under the optima conditions of pH2.5 in aqueous phase with 0.25mmol/L L-di-n-hexyl-L-tartaric ester.Hollow fiber supported liquid membrane extraction containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral carrier was used for resolution of racemic dopa, the optima chiral separation conditions were established in this experiment. The effects of concentration of dopa, concentration of chiral carrier, pH in the strip phase, velocity of fluent on the extraction performance were investigated. The results show that the method of resolution of racemic dopa was effectively established under the optimal chiral separation conditions of 2mmol/Ldopa, 50mmol/L L-di-n-hexyl-L- tartaric ester, pH2.5 in the feed phase and pH7.5 in the strip phase. The separation factor is 1.42.更多还原