【作者】 武光顺；

【导师】 李峻青；

【作者基本信息】 哈尔滨工程大学 ， 应用化学， 2011， 硕士

【摘要】 众所周知,光学纯对映体在生命体内的药理活性及毒性方面存在着较大的差异,因此拆分外消旋化合物,使之成为单一纯对映体的研究尤为重要。手性拆分法是获得光学纯化合物的主要手段,在生物医药学、农业化学和现代合成化学等领域均有重要意义。到目前为止,酶拆分法、结晶拆分法、化学拆分法、不对称转换拆分法、色谱拆分法等一些手性拆分方法已经成功应用于对映体的拆分及制备中,在这些手性体拆分的方法中,用固定相分离外消旋体的高效液相色谱法(HPLC-CSPs)是一种快速高效、有巨大发展潜力的拆分方法之一,在测试对映体的光学纯度及大规模拆分方面具有举足轻重的地位。在众多的手性固定相(CSPs)中,多糖(纤维素和直链淀粉)类衍生物CSPs使用最为广泛。通常将多糖酯类或氨基甲酸酯类衍生物固定相,涂覆在作为支撑材料的氨丙基硅胶表面上,以正己烷/异丙醇(90/10,v/v)为流动相下,在高效液相色谱中对大多数外消旋化合物都表现出很好的手性分离能力。然而,涂覆型固定相易溶解或溶胀于很多良好的有机溶剂中,限制其实际应用范围。键合型多糖类手性固定相则克服了流动相受限问题,通过加入极性溶剂(如氯仿或四氢呋喃),调整流动相配比,可获得更好的拆分效果,使其在对映体制备及分析方面具有更大的灵活性。本实验主要合成涂覆型和键合型多糖类手性分离固定相,并利用HPLC评价其手性拆分性能,本论文研究工作分为三部分：首先,利用苯胺和三光气,合成苯基异氰酸酯,利用普通硅胶和3-氨丙基三乙氧基硅烷,制备氨丙基化多孔硅胶,通过1H核磁共振和红外光谱表征其结构。然后,合成了纤维素-三(苯基氨基甲酸酯)(CSP-1)和直链淀粉-三(苯基氨基甲酸酯)(CSP-2)衍生物,制备HPLC用涂覆型手性固定相。在常规流动相正己烷/异丙醇(90/10,v/v)的条件下,考察两类色谱柱对7种典型的手性对映体的手性拆分能力。实验结果表明：这两类手性固定相对一些对映体都表现出很好的手性拆分性能,总体上来说,CSP-1和CSP-2在手性拆分性能方面相互补充,一些在CSP-1上不能拆分的对映体,在CSP-2上却得到很好的拆分,反之亦然。最后,通过“一锅法”合成了含有不同硅氧烷基团(1%、2%、3%)含量的纤维素和直链淀粉苯基氨基甲酸酯衍生物,利用1H核磁共振和红外光谱表征衍生物结构,利用热失重测试键合效率；通过硅氧烷基团在酸性条件下的水解、缩合,可简单、高效地实现在氨丙基硅胶表面的化学键合,制得键合型HPLC用手性分离固定相,可以使用强极性有机溶剂作为流动相,通过调整流动相中含有氯仿(CDC13)或者四氢呋喃(THF)的成分和配比,不但克服了涂覆型手性色谱柱流动相选择溶剂受限的问题,还可极大地提高手性拆分性能。一些在涂覆型固定相中无法分离的对映体,得到了很好的拆分,扩大了流动相的选择范围,实现外消旋化合物的最佳手性拆分,并且延长了手性柱的使用寿命。更多还原

【Abstract】 As is known to all, a pair of optically pure enantiomers may show great different pharmacological and toxicological activities, and therefore, the separation of enantiomers has been becoming increasingly important. Enantioseparation has been one of the important ways to obtain optical purity compounds, which plays an important role in modern synthetic chemistry, bio-medicine, and agricultural chemicals and so on. Numerous chiral separation methods have been successfully applied to enantiomeric resolution and preparation, such as biological separation, crystallization, chemical separation method, asymmetric conversion, chromatography and so on. Among these methods, the high-performance liquid chromatographic separation of enantiomers using chiral stationary phase (CSPs) is a direct-fast and great potential method, which is important for determining enantiomeric purities and preparing separation for a large scale. The polysaccharide such as cellulose and amylose derivatives are the most widely used in a great deal of CSPs.The esters and carbamates of polysaccharide coated on aminopropyl silica gel have been greatly studied and widely applied for the high-performance liquid chromatography (HPLC) as CSPs. Most of them which exhibit broad applicability to a large number of chiral racemates can be used for a long time with a hexane-isopropanol (90/10, v/v) as the eluent. However, they usually have the shortcomings of poor properties of resisting solvent. The CSPs of immobilized polysaccharide derivatives on aminopropyl silica gel overcome the strict solvent limitation of eluents and have greater flexibility in enantiomeric resolution and preparation.This paper mainly focus on the synthesis and resolution ability of polysaccharide-based coated-type and immobilized-type chiral separation stationary phase which include three parts as the following:Firstly, we prepared the raw materials phenyl isocyanate and aminopropyl silica gel, which structures were characterized by 1H NMR and IR spectrum.Secondly, cellulose and amylose tris(phenylcarbamate) derivatives were synthesized, respectively. 1H nuclear magnetic resonance (1H NMR) and infrared spectroscopy (IR) showed that most of the hydroxyl groups on glucose untis of the cellulose or amylose had been converted into carbamate groups. The chiral stationary phases (CSPs) were prepared by coating CSP-1 or CSP-2 on the aminopropyl silica gel. The chiral recognition abilities of obtained derivatives were evaluated by using 7 typical racemates and a hexane/isopropanol (90/10, v/v) mixture as the eluent. The experimental results show that some racemates were better resolved on the two CSPs. On the whole, CSP-1 and CSP-2 have different chiral resolution ability of some enantiomers. Although CSP-1 has better chiral recognition ability than CSP-2, some racemates which can not be resovled on CSP-1 were better resolved on CSP-2.Finally, the phenycarbamates of cellulose and amylose bearing different amounts of 3-(triethoxysilyl)propyl residues (1%,2%,3%) were synthesized by a one-pot process and efficiently immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups under acid condition. The structure of the synthesized polysaccharide derivatives was characterized by 1H NMR and IR. The obtained chiral packing materials (CPMs) were evaluated by HPLC. The immobilization efficiencies were calculated by TG. By using the eluents containing chloroform or tetrahydrofuran, which cannot be used with the conventional coated-type CPMs, most of the racemates could be better resolved on immobilized-type CSPs than coated-type CSPs. Many racemates, which can not be resolved on the coated-type CPMs, could be separated on immobilized-type CSPs.更多还原