手性化合物结晶拆分用“量身定制”聚合物添加剂的高效制备

李婧; 王兆旭; 叶曦翀; 宛新华

doi:10.11777/j.issn1000-3304.2023.23091

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手性化合物结晶拆分用“量身定制”聚合物添加剂的高效制备

研究论文 | 更新时间：2023-09-25

- 手性化合物结晶拆分用“量身定制”聚合物添加剂的高效制备
  增强出版
- Efficient Preparation of "Tailor-Made" Polymeric Additives for the Selective Crystallization of Chiral Compounds
- 高分子学报 2023年54卷第10期页码：1498-1508
- 作者机构：
  
  1.北京分子科学国家研究中心高分子化学与物理教育部重点实验室北京大学化学与分子工程学院北京 100871
  2.山西浙大新材料与化工研究院太原 030032
  3.金属材料强度国家重点实验室陕西省软物质国际联合研究中心西安交通大学材料科学与工程学院西安 710049
- 作者简介：
  
  E-mail: xcye917@xjtu.edu.cn;
  E-mail: xhwan@pku.edu.cn
- 基金信息：
  
  国家自然科学基金(基金号 ┣51833001);51921002┫;山西浙大新材料与化工研究院资助项目(2022SX-TD024)
- DOI：10.11777/j.issn1000-3304.2023.23091
  中图分类号：
- 纸质出版日期：2023-10-20，
  
  网络出版日期：2023-07-26，
  
  收稿日期：2023-04-06，
  
  录用日期：2023-06-12
扫描看全文
李婧,王兆旭,叶曦翀等.手性化合物结晶拆分用“量身定制”聚合物添加剂的高效制备[J].高分子学报,2023,54(10):1498-1508.

Li Jing,Wang Zhao-xu,Ye Xi-chong,et al.Efficient Preparation of "Tailor-Made" Polymeric Additives for the Selective Crystallization of Chiral Compounds[J].ACTA POLYMERICA SINICA,2023,54(10):1498-1508.
李婧,王兆旭,叶曦翀等.手性化合物结晶拆分用“量身定制”聚合物添加剂的高效制备[J].高分子学报,2023,54(10):1498-1508. DOI： 10.11777/j.issn1000-3304.2023.23091.

Li Jing,Wang Zhao-xu,Ye Xi-chong,et al.Efficient Preparation of "Tailor-Made" Polymeric Additives for the Selective Crystallization of Chiral Compounds[J].ACTA POLYMERICA SINICA,2023,54(10):1498-1508. DOI： 10.11777/j.issn1000-3304.2023.23091.

摘要

高分子型“量身定制”结晶抑制剂可以在较低添加量下获得出色的结晶拆分效果，但受限于传统“单体—高分子”冗长的合成路线，成本高，结构优化困难. 前期工作中，我们发展了利用非共价相互作用模块化构筑添加剂的高效制备方法，通过聚(乙烯基吡啶)与多种酸性小分子的复合获得了一系列适合簇集晶体对映选择性结晶拆分的添加剂. 为了拓展模块化构筑策略的适用范围，在本工作中，我们选择廉价易得的聚(对乙烯基苯磺酸)与不同碱性手性小分子化合物静电复合制备了一系列高分子型“量身定制”对映选择性结晶抑制剂，其在添加量低至0.5 mol%时仍可以接近10%的产率获得对映体过量值(enantiomeric excess，

%)超过99%的天冬酰胺一水合物晶体. 得益于操作简便的制备过程，实现了添加剂结构的快速筛选和高效优化. 实验证明使用该方法制备的添加剂可以在水、甲醇、异丙醇、丙酮等溶剂中有效拆分多种氨基酸、降压药尼莫地平、止咳药愈创甘油醚、有机合成中间体氢化苯偶姻、1

4-苯并二𫫇

烷甲酸甲酯等手性化合物.

Abstract

Polymeric "tailor-made" inhibitors can accomplish excellent resolution performance with low adding amount. However

its large-scale application is limited by the tedious "chiral monomer to polymer" synthetic route. In a previous work

we have developed an efficient modular strategy of constructing "tailor-made" supramolecular additives by combining achiral poly(vinylpyridine) and a variety of small chiral molecules through non-covalent interactions. In order to expand the scope of the modular strategy

in this work

we choose the cheap and commercially available polystyrene sulfonic acid as platform macromolecules

and small chiral molecules with primary amine groups or guanidine groups as the side groups to prepare "tailor -made" inhibitors efficiently. Benefiting from the easy preparation

the rapid structure screening and efficient optimization of the polymeric additives have been achieved. It has been proven that additives prepared using this method can be used in water

methanol

isopropanol

and acetone with good performance for the resolution of amino acids

nimodipine

guaifenesin

and synthetic intermediate hydrobenzoin and methyl 2

3-dihydrobenzo[b][1

4]dioxine-2-carboxylate. Combined with molecular docking simulation

effective suggestions are put forward for the rational design of "tailor-made" additives. We recommend that a batch of alternative small molecules could be selected based on structural similarities

and the crystallization resolution should be performed using the molecule with the smallest binding energy value in the molecular docking calculation of conglomerates crystal plane. Therefore

the number of trial and error and the cost of crystallization additive screening are reduced

improving the effectiveness of inhibitor structure design greatly.

关键词

结晶拆分量身定制对映选择性模块化制备手性药物

Keywords

Crystallization resolutionTailor-made additivesEnantioselectivityModular preparationChiral medicine

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