喹啉多环系列化合物的一锅法合成

One-pot synthesis of quinoline polycyclic compounds

摘要:

喹啉作为药物改构的优势骨架，在创新药物设计及研发领域有着重要的应用价值，对其结构衍生的方法学研究也备受关注。鉴于此，本研究以5-氟取代-4-氯喹啉为母核结构，在双亲核试剂存在下，通过分子内氯、氟双取代构建了一锅法合成新型喹啉并多环衍生物的新方法。该方法的核心步骤以4-氯-5-氟喹啉-3-甲酸酯为原料，以N,N-二甲基甲酰胺作溶剂，在缚酸剂存在下与邻位取代苯胺等双亲核试剂在加热条件下反应，即可完成氯、氟联级取代，不需分离单取代中间产物最终以高收率获得具有结构多样性的喹啉并多环衍生物。该方法无需其他催化剂，简单高效，且对官能团的容忍性强。产物结构经1H NMR，13C NMR和高分辨质谱(HRMS)确证。

Abstract:

Quinoline, as an advantageous skeleton of drug modification, has important application value in the field of innovational drug research and development, and the methodological studies on its structural modification has also attracted much attention. In view of this, a one-pot method to synthesize a series of novel quinoline polycyclic compounds were constructed with 5-fluorosubstituted-4-chloroquinoline derivatives and binucleophilic reagents as the starting materials. The key step of this method is the reaction of 4-chloro-5-fluoroquinoline-3-carboxylates with ortho-substituted anilines (binucleophilic reagents) in N,N-dimethylformamide, and in the presence of deacid reagents to complete a cascade substitution of chlorine and fluorine under heating conditions, to afford diversified quinoline polycyclic derivatives without separating the mono-substituted intermediates. The method is simple and efficient, does not require any catalysts, and with good tolerance of various functional groups. The structures of the products were confirmed by 1H NMR, 13C NMR and high resolution mass spectrum (HRMS).