新型多重识别位点的“双手性选择单元”HPLC手性固定相的构建及应用研究

The chiral stationary phases (CSPs) as core technology dominated by foreign company inhibit the development of chiral industry in our country seriously. Due to the drawbacks of traditional CSPs such as less recognition sites, low binding constants, and mono-chiral selectors, they cannot keep up with the trend of complex chiral samples analysis. Many studies indicate that CSPs containing two efficient chiral selectors not only increase chiral recognition sites but also exhibit good chiral separation performance. Currently, cyclic compounds including cellulose, cyclodextrin and cyclopeptides are the most efficient chiral selectors in CSPs; furthermore, cinchona alkaloids-derived chiral catalysts as excellent chiral selectors are attracted by their good structural modification and chiral recognition. Based on our previous synthesis and applications of new cinchona alkaloids-derived chiral catalysts, this project will firstly construct three novel types of CSPs (sum up to 12) which derived from the coupling of cinchona alkaloids-derived chiral catalysts with cellulose, cyclodextrin and L-phenylalanine cyclopeptides, respectively. These novel CSPs are featured by dual chiral selectors and multiple recognition sites with π-π, hydrogen bonding, hydrophobic and dipole-dipole interactions with analytes, and their applications in HPLC analysis of chiral drugs and intermediates are also investigated. Hopefully, this study can provide us practically used CSPs as well as facile access to novel CSPs.

手性色谱固定相(CSP)作为手性分离核心技术，长期被国外企业垄断，严重影响我国诸多相关领域的快速发展。传统CSP以涂敷型为主，且手性选择单元单一，结合常数偏低，难以高效分离大量涌现的复杂手性化合物。研究表明：①两种手性选择单元相结合的CSP，可增加手性识别位点，显著提高分离效果；②CSP最有效手性选择单元为纤维素、环糊精、环肽等环状物质；③金鸡纳碱手性催化剂具有出色手性识别功能和高度可修饰性，是优秀的CSP手性选择单元。为此，本项目在原有合成的金鸡纳碱手性催化剂研究基础上，拟将纤维素衍生物、环糊精衍生物和L-苯丙氨酸环肽分别与金鸡钠碱手性催化剂有机结合，再键合到硅胶表面，构建三类共12个结构新颖，且具有π-π、氢键、疏水和偶极-偶极等多重识别位点的“双手性选择单元”的新型键合型CSP，考察其手性分离能力，预期获得分离效果好、实用价值高的新型CSP，为新型CSP的合成及应用提供新途径。

本研究利用光学纯扁桃酸酰卤或光学纯扁桃酸衍生物酰卤代替常用的酰卤或异氰酸酯，作为纤维素衍生化试剂，发明了一种光学纯扁桃酸衍生物-纤维素固定相及其制备方法，并进一步展示该固定相在手性分离分析中的应用。.研究表明，衍生化试剂结构的微小变化，也会导致纤维素手性固定相分离效率发生重大改变。本研究使用光学纯扁桃酸酰卤或光学纯扁桃酸衍生物酰卤与微晶纤维素制备手性色谱柱前体，并涂覆或键合在硅胶表面，形成手性柱填料，再进一步制成不锈钢手性色谱柱，用于手性物质的分离与分析。本研究共合成两大类16种手性固定相，测试结果显示：制备的涂覆型固定相对环碳酸酯和硝基甲烷衍生物具有基线分离能力，对氨基酸衍生物没有达到基线分离；制备的键合型固定相对芳基取代的硝基甲烷衍生物和苯基取代的氨基酸衍生物具有基线选择分离能力，对芳基环碳酸酯没有达到基线分离。