PS基手性固定相的制备及其手性拆分的初步应用

发布时间：2018-01-18 00:17

本文关键词：PS基手性固定相的制备及其手性拆分的初步应用　出处：《郑州大学》2017年硕士论文　论文类型：学位论文

【摘要】：目前,光学纯手性药物的需求日渐增加,人们对手性药物的有效拆分与制备越来越重视。高效液相色谱法(HPLC)中的手性固定相法(CSP)由于具有效率高、灵敏度高和再现性好等优势被广泛用于手性药物的拆分与分离,再加上其较高的柱容量,所以具有良好的工业化应用前景。虽然已经商业化的手性固定相有很多,但由于手性药物的种类繁多,所需相应的手性固定相的类型也非常多。因此,制备高效且多样化的手性固定相是当前手性药物拆分领域的重要发展方向。本课题以L-亮氨酸(L-Leu)为手性源,将L-Leu负载到十微米级的氯甲基化聚苯乙烯微球上,制备了新型的手性固定相,并以DL-苯丙氨酸(DL-Phe)为拆分对象,对所制备的新型手性固定相的手性拆分能力做了初步的应用研究。主要工作如下:(1)负载手性源的确定:使用模板化合物氯化苄来代替氯甲基化聚苯乙烯微球负载不同的L-氨基酸,探究其消旋化程度。研究表明,L-亮氨酸与氯化苄的反应产物在强碱环境下没有发生明显的消旋化;而L-色氨酸(L-Trp)和L-脯氨酸(L-Pro)与氯化苄的反应产物则发生了明显的消旋化作用。说明L-Leu相比于其它两种L-氨基酸更适合作为手性固定相的手性源。(2)手性固定相的制备:先使用介于分散聚合和悬浮聚合之间的聚合方法,采用苯乙烯(St)和氯甲基化苯乙烯(CMS)为共聚单体,在无水乙醇和水的混合反应介质中,制备了粒径在10~100μm之间的氯甲基化交联聚苯乙烯微球(该氯球的氯含量约为5.91%)。再以该种氯球为基体,以L-Leu为手性源,通过相转移催化法,成功地将L-Leu负载到氯球上制备出了聚苯乙烯基手性固定相,该条件下的亲核取代反应程度约为62.8%。(3)手性拆分的初步应用:利用液相色谱法拆分DL-苯丙氨酸(DL-Phe),初步探究了聚苯乙烯基手性固定相的手性拆分能力。分别考察了流动相的组成和流速对DL-Phe拆分结果的影响。结果显示,当流动相是水或者石油醚时,DL-Phe没有被拆分;当流动相是无水甲醇时,固定相对DL-Phe有拆分作用,但是很不明显;当流动相是无水甲醇/石油醚时,对DL-Phe的拆分效果比较好。接着考察了流动相中无水甲醇与石油醚的比例对拆分结果的影响,结果显示,当无水甲醇与石油醚体积比为7/3时,拆分效果更优。设定流动相的流速分别为1.0~3.0 mL/min,考察了流动相的流速对拆分结果的影响,结果显示,随着流动相流速的升高,其拆分程度随之降低。
[Abstract]:At present, the demand for optical pure chiral drugs is increasing. More and more attention has been paid to the effective resolution and preparation of chiral drugs. The chiral stationary phase method (CSP) in HPLC is highly efficient. The advantages of high sensitivity and good reproducibility are widely used in the resolution and separation of chiral drugs, plus their high column capacity. Although there are many chiral stationary phases which have been commercialized, there are many kinds of chiral stationary phases which need a lot of corresponding chiral stationary phases because of the variety of chiral drugs. The preparation of high efficient and diversified chiral stationary phase is an important development direction in the field of chiral drug resolution. In this paper, L-Leu (L-Leu) is used as chiral source. A novel chiral stationary phase was prepared by loading L-Leu onto chloromethylated polystyrene microspheres of ten micron size and DL-Phe-phenylalanine was used as the resolution object. The chiral resolution ability of the novel chiral stationary phase was studied in this paper. The main work is as follows: 1). Determination of the chiral source: the template compound benzyl chloride was used instead of chloromethylated polystyrene microspheres to load different L-amino acids. The results showed that the reaction products of L-leucine and benzyl chloride had no significant racemization in strong alkali environment. L- tryptophan L-Trp) and L-proline). The products of the reaction with benzyl chloride had a significant racemization, indicating that L-Leu was more suitable as a chiral source for chiral stationary phase than the other two L- amino acids. Preparation of chiral stationary phase: first, the polymerization method between dispersion polymerization and suspension polymerization was used. Styrene (St) and chloromethylated styrene (CMSs) were used as comonomers in the mixed reaction medium of anhydrous ethanol and water. Chloromethylated crosslinked polystyrene microspheres with a diameter of 10 渭 m or 100 渭 m were prepared. The chlorine content of the microspheres was about 5.91%. The chlorine spheres were used as matrix and L-Leu as chiral source. Poly (styrene-based) chiral stationary phase was successfully prepared by phase transfer catalysis (PTC) by loading L-Leu onto chlorine spheres. The initial application of chiral resolution of DL- phenylalanine (DL-PHE) by liquid chromatography was studied. The degree of nucleophilic substitution reaction was about 62.8%. The effects of the composition and flow rate of the mobile phase on the resolution results of DL-Phe were investigated. The results showed that the mobile phase was water or petroleum ether. DL-Phe was not split; When the mobile phase is anhydrous methanol, the fixed DL-Phe can be separated, but it is not obvious. When the mobile phase is anhydrous methanol / petroleum ether, the resolution effect of DL-Phe is better. Then, the effect of the ratio of anhydrous methanol to petroleum ether on the resolution result is investigated. When the volume ratio of anhydrous methanol to petroleum ether is 7/3, the resolution effect is better. The flow rate of mobile phase is 1.0 ~ 3.0 mL / min, respectively. The effect of mobile phase flow rate on the resolution result is investigated. The results showed that the resolution degree decreased with the increase of mobile phase flow rate.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1

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