双相（W/O）识别手性萃取药物对映体的研究
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摘要
本文采用一种新的手性分离技术——双相(W／O)识别手性萃取法对α-环己基扁桃酸和扁桃酸对映体进行萃取拆分研究。主要内容如下：
1、α-环己基扁桃酸和扁桃酸对映体的萃取拆分研究：考察了萃取剂(β-环糊精衍生物和酒石酸衍生物)优先手性识别方向，以及有机溶剂的种类、萃取剂浓度及pH等因素对萃取性能的影响。结果表明：双相(W／O)识别手性萃取具有很强的手性分离能力，水相萃取剂羟丙基β-环糊精、羟乙基β-环糊精、甲基β-环糊精均对S-对映体的识别能力大于对R-对映体的识别能力；而有机相中部分酒石酸衍生物的识别能力刚好相反；在羟丙基β-环糊精／D-酒石酸异丁酯萃取体系中，α-环己基扁桃酸外消旋体的萃取效果最佳，一次萃取分离后，R和S对映体的分配系数(k_R和k_S)分别为2.44和0.98，分离因子(α)达2.49。在羟丙基β-环糊精和D-二对甲基苯甲酰酒石酸萃取体系中，扁桃酸对映体萃取效果最佳，R和S对映体的分配系数(k_R和k_S)分别为2.11和1.38，分离因子(α)达1.53。同时pH和萃取剂浓度对手性分离能力有显著的影响。
2、β-环糊精衍生物对α-环己基扁桃酸和扁桃酸对映体的包结作用紫外光谱研究：通过紫外光谱法测定β-环糊精衍生物与α-环己基扁桃酸和扁桃酸的包结稳定常数；考察了羟丙基β-环糊精与α-环己基扁桃酸和扁桃酸的包结反应的热力学常数及乙醇浓度和溶剂的离子强度对包结作用影响。结果表明：在水溶液中，三种β-环糊精衍生物对α-环己基扁桃酸和扁桃酸都有较弱的包结能力，且包结比为1：1；此类包结反应的热力学常数AG、AH和AS均小于0，该过程为自发放热过程，低温下有利于包结反应的进行；溶剂组成及离子强度对包结反应有大的影响，离子强度大有利于包结反应的进行，溶剂组成中乙醇比例增大，羟丙基β-环糊精与α-环己基扁桃酸包结物的稳定常数随着增大，但与扁桃酸包结反应反而逐渐消失。
In this paper,α-cyclohexyl-mandelic acid (α-CHMA) enantiomers and mandelic acid enantiomers were separated by a new chiral separation technique—two-phase (W/O) recognition chiral extraction. The main contents can be summarized as follows:
1、Study on chiral extraction ofα-cyclohexyl-mandelic acid (α-CHMA) enantiomers and mandelic acid (MS) enantiomers. The preferentially chiral recognition ability of extractant (tartrate derivatives andβ-CD derivatives), the influence of the kind organic solute and concentration of extractant and pH on extraction performance was investigated. The experimental results indicate that two-phase (W/O) recognition chiral extraction is of strong chiral separation ability. HP-β-CD, HE-β-CD and Me-β-CD have higher recognition ability for S-enantiomers than that for R-enantiomers. But some tartaric-acid derivatives have reversed recognition ability for them. In the extraction system containing HP-β-CD and D-isobutyl tartrate, the extraction effect ofα-CHMA is optimum by one stage extraction, and the distribution ratio for R-CHMA(k_R) and for S-CHMA(k_S) and separation factor(α) are 2.44, 0.89 and 2.49, respectively. In the extraction system containing HP-β-CD and di-O, O'-P-toluyl-D-tartaric acid, the extraction effect of MS is optimum by one stage extraction, and the distribution ratio for R-MS(k_R) and for S-MS(k_S) and separation factor(α) are 2.11, 1.38 and 1.53, respectively. Meanwhile, pH and concentration of extractants have great effects on chiral separation ability.
2、Study on inclusion betweenβ-cyclodextrin derivatives andα-cyclohexyl-mandelic acid and mandelic acid, respectively. The inclusion stability constants ofβ-cyclodextrin derivatives ( HP-β-CD、HE-β-CD、Me-β-CD) withα-cyclohexyl-mandelic acid and mandelic acid were studied using UV spectrophotometry. Inclusion formation constants、the effects of alcohol and ironic strength on inclusion behavior were further investigated. The experimental results indicate allβ-cyclodextrin derivatives had weak binding ability withα-cyclohexyl-mandelic acid and mandelic acid in aqueous solution and host-guest complex with 1:1 molar ratio is formed;△G、△H and△S of those binding reaction are all less than 0, so the inclusion process is a spontaneous and exothermic process, and lower temperature is of benefit to reaction; Ionic strength greatly influence on binding ability of HP-β-CD with CHMA. Strong ionic strength is good for reaction; Increasing of alcohol concentration is in favor of inclusion between HP-β-CD with CHMA, whereas, is bad for that of HP-β-CD with MS.
1、α-环己基扁桃酸和扁桃酸对映体的萃取拆分研究：考察了萃取剂(β-环糊精衍生物和酒石酸衍生物)优先手性识别方向，以及有机溶剂的种类、萃取剂浓度及pH等因素对萃取性能的影响。结果表明：双相(W／O)识别手性萃取具有很强的手性分离能力，水相萃取剂羟丙基β-环糊精、羟乙基β-环糊精、甲基β-环糊精均对S-对映体的识别能力大于对R-对映体的识别能力；而有机相中部分酒石酸衍生物的识别能力刚好相反；在羟丙基β-环糊精／D-酒石酸异丁酯萃取体系中，α-环己基扁桃酸外消旋体的萃取效果最佳，一次萃取分离后，R和S对映体的分配系数(k_R和k_S)分别为2.44和0.98，分离因子(α)达2.49。在羟丙基β-环糊精和D-二对甲基苯甲酰酒石酸萃取体系中，扁桃酸对映体萃取效果最佳，R和S对映体的分配系数(k_R和k_S)分别为2.11和1.38，分离因子(α)达1.53。同时pH和萃取剂浓度对手性分离能力有显著的影响。
2、β-环糊精衍生物对α-环己基扁桃酸和扁桃酸对映体的包结作用紫外光谱研究：通过紫外光谱法测定β-环糊精衍生物与α-环己基扁桃酸和扁桃酸的包结稳定常数；考察了羟丙基β-环糊精与α-环己基扁桃酸和扁桃酸的包结反应的热力学常数及乙醇浓度和溶剂的离子强度对包结作用影响。结果表明：在水溶液中，三种β-环糊精衍生物对α-环己基扁桃酸和扁桃酸都有较弱的包结能力，且包结比为1：1；此类包结反应的热力学常数AG、AH和AS均小于0，该过程为自发放热过程，低温下有利于包结反应的进行；溶剂组成及离子强度对包结反应有大的影响，离子强度大有利于包结反应的进行，溶剂组成中乙醇比例增大，羟丙基β-环糊精与α-环己基扁桃酸包结物的稳定常数随着增大，但与扁桃酸包结反应反而逐渐消失。
In this paper,α-cyclohexyl-mandelic acid (α-CHMA) enantiomers and mandelic acid enantiomers were separated by a new chiral separation technique—two-phase (W/O) recognition chiral extraction. The main contents can be summarized as follows:
1、Study on chiral extraction ofα-cyclohexyl-mandelic acid (α-CHMA) enantiomers and mandelic acid (MS) enantiomers. The preferentially chiral recognition ability of extractant (tartrate derivatives andβ-CD derivatives), the influence of the kind organic solute and concentration of extractant and pH on extraction performance was investigated. The experimental results indicate that two-phase (W/O) recognition chiral extraction is of strong chiral separation ability. HP-β-CD, HE-β-CD and Me-β-CD have higher recognition ability for S-enantiomers than that for R-enantiomers. But some tartaric-acid derivatives have reversed recognition ability for them. In the extraction system containing HP-β-CD and D-isobutyl tartrate, the extraction effect ofα-CHMA is optimum by one stage extraction, and the distribution ratio for R-CHMA(k_R) and for S-CHMA(k_S) and separation factor(α) are 2.44, 0.89 and 2.49, respectively. In the extraction system containing HP-β-CD and di-O, O'-P-toluyl-D-tartaric acid, the extraction effect of MS is optimum by one stage extraction, and the distribution ratio for R-MS(k_R) and for S-MS(k_S) and separation factor(α) are 2.11, 1.38 and 1.53, respectively. Meanwhile, pH and concentration of extractants have great effects on chiral separation ability.
2、Study on inclusion betweenβ-cyclodextrin derivatives andα-cyclohexyl-mandelic acid and mandelic acid, respectively. The inclusion stability constants ofβ-cyclodextrin derivatives ( HP-β-CD、HE-β-CD、Me-β-CD) withα-cyclohexyl-mandelic acid and mandelic acid were studied using UV spectrophotometry. Inclusion formation constants、the effects of alcohol and ironic strength on inclusion behavior were further investigated. The experimental results indicate allβ-cyclodextrin derivatives had weak binding ability withα-cyclohexyl-mandelic acid and mandelic acid in aqueous solution and host-guest complex with 1:1 molar ratio is formed;△G、△H and△S of those binding reaction are all less than 0, so the inclusion process is a spontaneous and exothermic process, and lower temperature is of benefit to reaction; Ionic strength greatly influence on binding ability of HP-β-CD with CHMA. Strong ionic strength is good for reaction; Increasing of alcohol concentration is in favor of inclusion between HP-β-CD with CHMA, whereas, is bad for that of HP-β-CD with MS.
引文
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