双相识别萃取、泡沫分馏手性拆分药物对映体研究

【作者】 李琳；

【导师】 陈晓青；

【作者基本信息】 中南大学 ， 分析化学， 2011， 硕士

【摘要】 本文采取双相识别手性萃取法,在两相分别加入不同的手性选择剂对氧氟沙星对映体进行了拆分并初步探讨了萃取机理；采用泡沫分馏联用双相识别溶剂萃取技术拆分氧氟沙星外消旋体；并用泡沫分馏法考察了β-环糊精对L-扁桃酸的包结作用。主要研究内容如下：(1)在水相中使用β-环糊精(β-CD)、有机相中使用L-(-)-二苯甲酰酒石酸(L-(-)-DBTA)和二(2-乙基己基)磷酸(D2EHPA)形成的复合物作为手性选择试剂,对氧氟沙星对映体进行萃取拆分,考察了pH、水相与有机相体积比、β-CD浓度、氧氟沙星对映体浓度、L-DBTA浓度及萃取试剂的组合方式等因素对分离因子和对映体过量值的影响。结果表明：当pH=7.0、相比为5、β-CD浓度为0.011g/mL、氧氟沙星的浓度为0.002 g/mL及L-(-)-DBTA浓度为0.055 g/mL时,分离因子(α)最高可达到2.48,水相对映体过量值(e.e%)可达40.4。同时,探讨了手性选择剂与氧氟沙星对映单体在两相中分别可能存在的作用机理。通过实验发现,二元手性选择剂复合萃取拆分能够实现药物外消旋体的高效拆分,这对于萃取体系的优化以及实现手性萃取拆分的工业化放大有一定的指导作用。(2)将泡沫分馏技术与溶剂萃取技术联用,对氧氟沙星外消旋体进行了立体选择性拆分,实验以L-(-)-DBTA为手性选择剂,D2EHPA为协同萃取剂,十二烷基硫酸钠(SDS)为起泡剂,正辛醇为有机溶剂,主要考察了回流时间、氧氟沙星的量、起泡剂SDS的量、pH、D2EHPA的量、L-DBTA的量对拆分性能的影响,确定了最优工艺条件：在泡沫分馏柱填料层高度一定时,调整空气流速形成稳定泡沫层,L-(-)-DBTA浓度为0.11g/mL,氧氟沙星浓度为1.67mg/mL, SDS浓度为0.42mg/mL,水相体积为120mL,有机相的体积为20mL(有机相中V正辛醇：VD2EHPA=14:6),水相的pH为7,回流时间为4h。同时,探讨了手性选择剂与氧氟沙星对映体在泡沫分馏过程中可能的作用机理。研究发现,该联用技术能有效提高手性拆分的立体选择性。(3)基于泡沫分馏技术利用紫外光谱法对β-环糊精与L-扁桃酸包结作用的影响进行研究。通过实验得出包结作用的最优条件是：β-环糊精与L-扁桃酸质量浓度比为10：1,回流时间30min,回流气速为37.5L/h,溶液的pH值为4.0。实验发现,β-环糊精与L-扁桃酸仅形成一种类型的包结复合物。更多还原

【Abstract】 In this paper, Biphasic recognition chiral extraction was used to separate OFLX through adding different chiral selectors in two phases, and ofloxacin(OFLX) enantiomers was separated by a co-technology—bubble fractionation, with the help of solvent extraction. Meanwhile, inclusion ofβ-Cyclodextrin (β-CD) and L-Mandelic acid (L-MA) based on bubble fractionation was studied. The main contents can be summarized as follows:(1) The distribution behavior of OFLX enantiomers was examined in a two-phase system containing di(2-ethylhexyl) phosphoric acid (D2EHPA) with dibenzoyl-l-tartaric (L-(-)-DBTA) as complex chiral selectors in n-octanol andβ-CD in aqueous phase. Factors affecting the extraction were investigated, including the pH of aqueous phase, volume ratio of aqueous to organicphase, concentration ofβ-CD, concentration of OFLX, concentration of L-(-)-DBTA and the combination of extracting agent. The results showed that the enantiomeric excess value (e.e.%) was 40.4 and the enantioselectivity (a) was 2.48 with the aqueous phase pH 7.0, volume ratio of aqueous to organicphase 5:1, concentration ofβ-CD 0.011g/mL, concentration of OFLX 0.002g/mL, concentration of L-(-)-DBTA 0.055g/mL. Meanwhile, the possible mechanisms of chiral selectors and OFLX in the two phases for reaction in the separation process was discussed. It was found that the formation of mixed complex chiral selectors by mixingβ-CD and L-(-)-DBTA with D2EHPA in different phases can improve the capacity of enantioselective extraction obviously. It may be very helpful to optimize the extraction systems and realize thel arge-scale production of pure enantiomers.(2) A method of bubble fractionation, with the help of solvent extraction, was developed for the resolution of racemic ofloxacin (rac OFLX). In this method, L-(-)-DBTA, D2EHPA and sodium lauryl sulfate (SDS) were used as chiral collector, co-extractant and foamer, respectively. Several important parameters influencing the resolution performances, such as pH in aqueous phase, concentration of OFLX, concentration of L-(-)-DBTA, concentration of SDS and volume ratio of D2EHPA to n-octanol in solution, were investigated. The optimal resolution conditions were obtained with the aqueous phase pH 7, volume ratio of D2EHPA to n-octanol 6/14 in organic phase, concentration of SDS 0.42mg/mL, concentration of OFLX 1.67mg/mL, and concentration of L-(-)-DBTA 0.11g/mL. Under the optimal extraction conditions, the enantiomeric excess value(e.e.%) was 60.08 and the enantioselectivity (a) was 5.58. Meanwhile, the possible mechanism of chiral selectors and OFLX for reaction in the separation process was discussed. It was found that the capacity of enantioselective separation can be greatly improved by the co-technology.(3) A method of fractionation is a new developed technology, which is widely used in industry. Inclusion ofβ-CD and L-MA based on bubble fractionation was studied in this paper. The optimal resolution conditions were obtained with the solution pH 4.0, mass concentration ratio ofβ-CD to L- MA 10:1, reflux equilibration time of 30min, pH of solution of 2.0, gas flow rate of 37.5L/h. It was found that only one kind of compound was formed byβ-CD and L- MA.更多还原