【作者】 潘春秀；

【导师】 徐秀珠；

【作者基本信息】 浙江大学 ， 分析及应用化学， 2005， 硕士

【摘要】 本论文是高效液相色谱手性固定相法用于色谱分离对映体的研究,在正相体系下对几组手性药物对映体和新型胃药拉呋替丁及其原料1,4-丁烯二醇顺反异构体进行分离研究,并探讨其分离机理。 论文中采用的手性固定相有小分子Pirkle型(S,S)-Whelk-O1和大分子聚合物型手性固定相。其中聚合物型手性固定相包括四种自制的纤维素衍生物手性固定相,即纤维素三苯甲酸酯)(CTB)、纤维素三(4-甲基苯甲酸酯)(CTMB)、纤维素三苯基氨基甲酸酯)(CTPC)、纤维素三(3,5-二甲基苯基氨基甲酸酯)(CDMPC)和聚酰胺型ChiraSpher手性色谱柱。 论文的第一、第二章对立体化学及其分离的研究背景、Pirkle型CSP(Chiral Stationary Phase)和纤维素衍生物类CSP的种类、影响手性选择的因素以及手性识别的机理进行了简要的评述。 论文的第三章对一组农药除草剂进行了对映体分离。即: (1)在四种自制的纤维素衍生物类手性固定相上对禾草灵进行了对映体分离研究。结果表明,禾草灵在CTMB上保留最强,但CDMPC对禾草灵手性识别能力最强,其次是CTMB,最大分离度分别达到6.60和2.60。通过考察不同醇类添加剂对对映体分离的影响,比较不同手性柱对该溶质的分离效果,发现流动相中的醇类添加剂可与固定相手性空腔附近或其中的手性或非手性点相结合,从而使得手性空腔的立体环境发生改变,不同醇所产生的这种改变不同,因而使得维素衍生物类手性固定相的手性识别能力也不同。大体积的异丙醇和正丁醇所产生的改变更有利于禾草灵在纤维素衍生物类手性固定相上的手性识别。 (2)利用自制的涂敷型纤维素三(3,5-二甲基苯基氨基甲酸酯)CDMPC手性柱及(S,S)-Whelk-O1手性柱,在高效液相色谱上对禾草灵,吡氟禾草灵,喹禾灵,噁唑禾草灵四种芳氧丙酸类除草剂进行了对映体分离研究。分别考察了在流动相正己烷中,极性醇类添加剂种类和浓度对手性分离的影响,研究了溶质的结构因素对手性分离的影响,并初步探讨了溶质在两种手性柱上的手性识别的机理。结果显示:除了噁唑禾草灵在(S,S)-Whelk-O1上获得了较好的分离,其它三种溶质均在CDMPC上获得了较好的分离,各溶质都达到基线以上的分离。两种手性柱的手性识别机理不同,溶质和固定相的结构是手性识别的关键。更多还原

【Abstract】 This thesis focuses on the enantioseparation using chiral stationary phases (CSPs) by high performance liquid chromatography (HPLC), including enantioseparation of a group of herbicides and a group of chiral antifungal drugs with similar structure under normal phase mode and discussion of the recognition mechanism. Besides, the cis and trans isomers separation of a novel anti-ulcer drug lafutidine and its intermediate 2-Butene-l,4-diol were studied.In this thesis, the chiral columns included small molecule Pirkle type (S,S)-Whelk-Ol, high molecule CSP ChiraSpher and four kinds of high molecule cellulose derivative CSPs, cellulose tribenzoate (CTB), cellulose tris(4-methyl benzoate) (CTMB), cellulose triphenylcarbamate (CTPC) and cellulose tris(3,5-dimethyl phenyl carbamate) (CDMPC).In chapter 1 and chapter 2, the literatures of the stereochemistry and its separation, the kinds of Pirkle type CSP and cellulose derivative CSP, the factor influencing chiral selectivity, the mechanism of chiral recognition were briefly reviewed.In chapter 3, the enantioseparation of a group of herbicides with similar structure was studied: (1) the enantioseparation of diclofop was investigated on four kinds of coated cellulose derivative chiral columns (CTB, CTMB, CTPC and CDMPC) for the first time. It was the result that the retention of diclofop was strongest on CTMB, but diclofop obtained better enantioseparation on CDMPC than on CTMB. By the investigation of the influence of different polar alcohol additive in the mobile phase on the chiral separation and the compared experiment on different column, it was found that the alcohol additive could change the solid environment of chiral cave by interacting with the chiral and non-chiral dot in or near the chiral cave of the CSP. Different alcohol has different change ability, which correspondingly leads to different chiral separation efficiency. Diclofop gained better enantioseparation on cellulose derivative CSP when large alcohol, isopropanol and n-butanol were used as the additive in the mobile phase; (2) The Enantioseparation of four aryloxyphenoxypropionic acid herbicides, diclofop, fluazifop, quizalofop-P and fenoxaprop by HPLC on self-prepared cellulose derivative CDMPC and (S, S)-Whelk-Ol.The mobile phase composition including the type and concentration ofthe alcohol modifier in hexane was varied, and the influence on the retention factor(k’), the separation factor( ) and the resolution (Rs) for each enantiomer was studied. The influence of the structure of the analytes on the chiral separation was investigated. And then their chiral recognition mechanism was discussed. The experiment results showed that fenoxaprop obtained best resolution on CDMPC, while the other three solutes obtained best separation on (S,S)-WheIk-Ol. It was concluded that the four aryloxyphenoxypropionic acid herbicides obtained excellent separation and the chiral recognition mechanisms of CDMPC and (S,S)-Whelk-Ol differs greatly. And the structure of solutes and CSP play a key role in the chiral recognition; (3) On (S, S)-Whelk-Ol and four kinds of self-prepared cellulose derivative columns (CTB, CTMB, CTPC, CDMPC), naproanilide and its intermediate -chloro-propionanilide were both experimented for enantioseparation. Naproanilide obtained best separation on CDMPC. On CTPC naproanilide just obtained part enantioseparation when isopropanol was used as the polar additive. As to -chloro-propionanilide, it obtained baseline enantioseparation on (S, S)-Whelk-Ol and CDMPC, but just obtained part enantioseparation on CTPC when ethanol was used as the polar additive. It is indicated that the difference of structure of naproanilide and -chloro-propionanilide led to different separation efficiency. The influence of volume and concentration of polar alcohol modifier in mobile phase on the enantioseparation of naproanilide and its intermediate on CDMPC was studied. Following are the results: (a) As to a determined alcohol additive, changing volume and concentration led to identical change trend of the separation efficiency; (b) But the order of the chromatographic parameters of the solutes under different alcohol changed. It is because that the density and molecular weight of the different alcohol is different.In chapter 4, the enantioseparation of a group of chiral antifungal drugs were investigated on (S,S)-Whelk-Ol and four different cellulose derivative columns (CTB, CTMB, CTPC, CDMPC). The drugs included three kinds of imidazole (tetramisole, miconazole, imazalil) and seven kinds of triazole (tebuconazole, hexaconazole, myclobutanil, diniconazole, uniconazole, paclobutrazol, triadimenol). For tetramisole, imazalil and uniconazole, it was the first time for enantioseparation. The enantioseparation of each solute on a CSP differed from its structural characteristic and the different CSP showed different chiral discrimination capability for each solute. Following are theconclusions: (1) The retention of most of the solutes was stronger on (S,S)-Whelk-Ol than on the cellulose derivative columns, but the enantioseparation capability was better on the cellulose derivative columns except CTB; (2) Tetramisole was not eluted except on CDMPC. As to other solutes: (a) On (S,S)-Whelk-Ol, just miconazole, hexaconazole and triadimenol obtained enantioseparation; (b) On CTB, the retention of the solutes was weakest and just miconazole, imazalil obtained part enantioseparation; (c) On CTMB, CTPC and CDMPC, the solutes obtained enantioseparation of different degree by changing the mobile phase. Imazalil and tebuconazole obtained best enantioseparation on CTMB. Uniconazole, paclobutrazol, and triadimenol obtained best enantioseparation on CTPC. And the others obtained best enantioseparation on CDMPC. Besides, the influence of mobile phase composition was studied: (a) The retention and resolution factors of the solutes increased with decreasing the alcohol concentration in mobile phase, while separation factors kept steady; (b) On (S,S)-Whelk-Ol, acid modifier in mobile phase had no obvious effect on the enantioseparation; (c) On the four cellulose derivative columns, the most favorable alcohol modifier of each solutes was different. It may be due to that while competing with hydrogen bond interaction between solute and CSP, the different polar alcoholic modifier will have different effect on the steric structure of solute and CSP, especially the chiral cavity of CSP. Thus, for different solute, the inclusion and the steric fitness of solute shape in chiral cavity of CSP may differ greatly, which resulted in different enantioseparation.In chapter 5, the cis and trans isomers separation of 2-butene-l,4-diol and lafutidine were studied by HPLC on two kinds of chiral columns: (S,S)-Whelk-0 1 and ChiraSpher. The isomers of 2-butene-l,4-diol can be separated on both chiral columns while the isomers of lafutidine can only be resolved on ChiraSpher column. The influence of different type and amount of mobile phase modifier on the isomers separation was extensively studied. The resolution of cis and trans isomers of 2-butene-l,4-diol was 2.61 on (S,S)-Whelk-0 1 column with hexane-ethanol (97:3, v/v) as the mobile phase. The resolution of lafutidine was 1.89 on ChiraSpher column with hexane-ethanol-THF-diethylamine (92:3:5:0.1, v/v/v/v) as the mobile phase. LC-MS methods were developed to identify the isomer peaks.更多还原