| Chiral drugs and pesticides have played an important role in medical and agricultural production due to their high activity.Usually only one enantiomer has high pharmacological activity,and the rest enantiomers are not only low in activity,but even harmful to human body.Therefore,it is necessary to prepare high-purity enantiomers and strictly monitor and control the content of harmful enantiomers.At present,highperformance liquid chromatography(HPLC)combined with various chiral stationary phases(CSPs)has been developed as one of the preferred methods for the separation and analysis of enantiomers,in which the performance of chiral separation materials is the key to the success or failure of enantiomeric separation.Therefore,the research content of this dissertation mainly focuses on the preparation,characterization,evaluation and application of a new type of bridged cyclodextrin CSPs.It is of great research significance to develop a new type of CSPs with independent intellectual property rights and to establish a new method for rapid and accurate detection and separation of enantiomers.Bridged cyclodextrins(BCDs)is a new type of supramolecular compounds composed of a bridge group connecting multiple cyclodextrin cavities.The synergistic inclusion of its adjacent cavities and the multiple action sites provided by the bridging linker make BCDs excellent molecular spatial recognition properties and strong chiral separation potential.In this study,three bridged bis(β-cyclodextrin)CSPs with different aromatic linker,including pyridinediamide,ferrocenediamide and perylenediimide groups,were designed and prepared,which resolve chiral compounds more efficiently and over a wider range than ordinary cyclodextrin stationary phases.So far,related research has not been reported.The first chapter reviews the applications and potential toxicity of chiral drugs and pesticides,as well as the development of various stationary phases.The problems faced in the separation application and development of derivatized cyclodextrin CSPs are summarized.The structural characteristics,molecular recognition properties and existing application fields of BCDs are briefly introduced,which provides a theoretical basis for the development and utilization of chiral separation functions of BCDs.In the second chapter,based on the condensation reaction between pyridine-2,3-dicarboxylic acid and 6-amino-β-cyclodextrin,a new type of pyridinediamide bridged bis(β-cyclodextrin)chiral stationary phase(Py CDP)was prepared.Its chromatographic properties were systematically evaluated by using flavanones,triazoles,amino acids,β-receptor blockers as chiral probes,and native cyclodextrin stationary phase(CDCSP)for compare research.The results showed that Py CDP could resolve all 38 kinds of chiral probes in reversed-phase and polar organic modes.The resolutions(Rs)of 2’-hydroxyflavanone,flutriafol,phenylalanine and esmolol reached at 2.36,1.98,1.86 and1.52,respectively,within 30 min.Py CDP could completely resolve a series of triazole pesticides by adjusting the proportion of acetonitrile(20%-35%)in the mobile phase over a temperature range of 15-30 ℃.It could also baseline resolve easily ionizable polar amino acid enantiomers in a wide p H range(5.0～6.5).In addition,Py CDP also successfully resolved various β-blockers in polar organic mode and realized the resolution of bevanolol on CD-based CSPs for the first time.However,under the optimized conditions,CDCSP could only resolve 20 kinds of chiral probes,and the resolution was relatively lower.Obviously,the synergistic inclusion of the two adjacent cavities on the Py CDP and the hydrogen bonding,π-π interactions provided by the pyridinediamide bridging linker contributed to the above chiral separations.In third chapter,a novel ferrocenediamide bridged bis(β-cyclodextrin)chiral stationary phase(Fe CDP)was prepared and characterized for the first time by utilizing the stable metallocene complex ferrocene with aromatic electron-rich π-conjugated system and sandwich structure as linker.The results showed that Fe CDP successfully resolved 44 kinds of tested analytes(Rs=0.66～4.38),of which 36 were completely separated(Rs≥1.5).The separation range of Fe CDP was wide,including basic,acidic,amphoteric and neutral chiral substances.The resolutions of hexaconazole,ketoprofen,3’-hydroxyflavanone,phenylalanine and arotinolol reached 3.06,1.90,4.38,1.89 and2.12 in a short time,respectively.Especially,Fe CDP could completely resolve imazalil(Rs=1.97),ketoprofen(Rs=1.90),arginine(Rs=1.50),pindolol(Rs=1.42),bevantolol(Rs=1.41),which were difficult to be resolved on the ordinary CDCSPs.Based on the above separation results,the satisfactory enantioselectivity of Fe CDP was mainly related to the cooperative inclusion of larger "pseudo-cavities".Meanwhile,the linker of π-conjugated ferrocenediamide could also provide hydrogen bonding,π-π stacking,dipole-dipole and hydrophobic interactions,which broaden the enantiomeric recognition range of Fe CDP.In the fourth chapter,a large π-conjugated perylenediimide was used as the linker,and a new type of chiral stationary phase(PBCDP)was prepared.Its chiral HPLC performance was systematically evaluated by using a series of acidic,basic,neutral and amphoteric substances as chiral probes,including profens(Rs=1.48～3.28),triazoles(Rs=1.25～2.85),flavanones(Rs=1.34～5.29),amino acids(Rs=1.66～4.58)and β-blockers(Rs=1.22～1.97)in reversed-phase and polar organic modes.The results showed that PBCDP could resolve 37 broad-spectrum chiral drugs,of which 32 were completely resolved(Rs≥1.5).Compared with CDCSP,the PBCDP had a better chromatographic performance in enantioselectivity.For example,PBCDP had ability to simultaneously resolve 5 pesticides within 60 min,which created conditions for the analysis of multiple chiral pesticide residues.On the other hand,PBCDP could systematically separate a variety of acidic profen drugs,and the current common CDbased CSP had no such separation ability.Obviously,the synergistic inclusion of the two cavities of cyclodextrin,as well as the π-π stacking,hydrogen bond,dipole and basic primary amine site(-NH-)provided by the conjugated perylenediimide bridging group contributed together to the improvement of the above chiral separations.However,the complex separation mechanism still needs to be confirmed by solid-state NMR and other related methods.In addition,we also used PBCDP to conduct preliminary application research,and established a new method for the determination of the enantiomer content of warfarin sodium in tablets by high-performance liquid chromatography(HPLC). |
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