“纳米拆分剂”的设计合成及氨基酸结晶拆分新策略

Selective crystallization is the most commonly used method for obtaining optically pure drugs, fragrances, and pesticides. However, the crystallization yield is quite low and only one enantiomer can be obtained at one time. Applicant and his research group have developed a kind of "self-reporting inhibitors". In the present of the additives, two enantiomeric crystals with different colors can be obtained. But it is still low efficiency and can only be applied to a few compounds. In this project, the selective crystallization of amino acids was chosen to be a model system to evaluate the separation results. A kind of magnetic "nano-splitters" were developed by co-assembling of chiral amphiphilic copolymers and magnetic nanoparticles. They are applied in the selective crystallization of typical amino acid, leading to a mixture of magnetic S-crystals and non-magnetic R-crystals, thereby two pure enantiomers can be obtained in a unit operation with quantitative yield through a magnetic separation process. New methods and new concepts for efficient chiral separation can be developed based on this strategy. The chemical structure of chiral groups and the proportion of two segments were adjusted, and the influence of morphologies and chemical structures on the resolution performance were discussed. A mass production method of "nano-splitters" based on the polymerization-induced co-assembly was established for potential industrial applications. Heteroarm star-shape "nano-splitters" were prepared to broaden the range of separable racemates through a synergistic effect. Therefore, new separation methods with high efficiency, high crystallization yield, wide range of applications and recycling ability can be realized.

结晶拆分法是大量获得光学纯药物、香料、农药等最为常用的方法。但存在结晶产率低，一次结晶仅能获得一种对映体的缺点。申请人及所在研究组曾开发一类“自警报抑制剂”，实现一次结晶获得两种不同颜色的对映体晶体。本项目在以上工作的基础上，围绕现有方案存在的拆分效率低、适用化合物少的问题，通过两亲性嵌段共聚物与磁性纳米粒子共组装，制备磁性“纳米拆分剂”；将其用于氨基酸结晶，赋予对映体晶体磁性差异，通过磁选矿的方式，实现在单元操作中高产率获得两种对映体纯品的目标，提供一种高效便捷的手性拆分新方法；改变手性官能团结构，调整亲疏水链段比例，深入了解分子结构、组装形貌对分离性能的影响；建立基于聚合诱导共组装的“纳米拆分剂”宏量制备方法；通过制备杂臂星形“纳米拆分剂”，实现手性链段协同作用，拓宽适用范围。为获得拆分效果好、结晶产率高、适用范围广、可循环使用的手性高分子对映体选择性结晶添加剂提供新的途径和理论依据。

结晶拆分法是大量获得光学纯药物、香料、农药等最为常用的方法。但存在结晶产率低，一次结晶仅能获得一种对映体的缺点。申请人及所在研究组曾开发一类“自警报”聚合物抑制剂，实现一次结晶获得两种不同颜色的对映体晶体。但是总晶体产率仍然仅为30%左右，且需要人工判断何时开始收集第二种晶体。本项目在以上工作的基础上，围绕现有方案存在的操作繁琐、拆分效率低、拆分剂结构受限、适用化合物少等问题，通过两亲性嵌段共聚物与磁性纳米粒子共组装，发展了一类磁性“纳米拆分剂”，将其用于氨基酸的选择性结晶，可以自发获得无磁性和磁性对映体晶体混合物，进而通过模拟磁选矿的方式，实现了光学纯对映体的高效拆分。结合蒸发结晶与冷却结晶两种方法，实现了近乎定量的手性分离；通过改变手性官能团结构，调整亲疏水链段比例，深入探索了分子结构、组装形貌对分离性能的影响；利用聚合诱导自组装制备了一类荧光“纳米拆分剂”，建立了“纳米拆分剂”宏量制备方法。同时利用荧光的低检测极限将添加剂的使用量降低至0.03 wt%，极大提高了该类材料的产出投入比；发展了一种聚合物拆分材料的模块化构筑策略，将非手性聚合物主体与手性小分子客体通过非共价键进行复合，制备了一系列超分子聚合物抑制剂，不仅丰富了拆分剂结构，同时拓宽了其适用范围，实现了在水相和有机溶剂体系中对多种簇集晶体及个别外消旋晶体的高效拆分。该系列工作为获得拆分效果好、结晶产率高、适用范围广、可循环使用的手性高分子对映体选择性结晶添加剂提供了新的途径和理论依据。