Heck And Oxidative Heck Reactions For The Preparation Of 3-alkenylindazoles By Mechanochemistry

With the continuous improvement of drug synthetic methods,pharmaceutical researchers always hope to find a more efficient,convenient,and environmentally friendly synthetic route for the preparation of drugs.As a kind of interdisciplinary technology with great potential,mechanochemical technology has been successfully applied in many organic synthesis reactions.With its unique advantages,mechanochemical technology has attracted the attention of more and more chemical researchers.In this thesis,we mainly focued on Heck coupling reaction and the oxidized Heck coupling reaction by mechanochemistry to achieve efficient 3-position activation of inert 3-H indazoles and 3-X(X =Br,Cl)indazoles for the preparation of series 3-alkenyl indazole derivatives.The content consists of the following three chapters:The first chapter introduced the research progress of indazole compounds and summarized the application of mechanochemistry in Heck coupling reactions and oxidative Heck coupling reactions.In the second chapter,we mainly studied the Heck coupling reaction between 3-haloindazoles and olefins performed under mechanochemical conditions.The chemical reaction conditions,involing the catalysts,ligands,bases,additives and grinding auxiliaries,as well as the mechanical parameters such as rotation speed,milling time,milling ball filling degree,milling ball diameter were examined in detail to obtain optimum reaction conditions.The in-depth study of the reaction pathway under mechanochemical conditions helped directing the reaction optimization and further providing a simple,rapid,efficient and environmentally friendly synthetic method for the preparation of 3-alkenyl indazole derivatives.Ultimately,a solvent-free total mechanosynthetic route for the preparation of Axitinib was designed and optimized by taking the above reaction method.In the third chapter,the oxidative Heck coupling reaction between 1-methylcarbazole and olefin was mainly carried out by mechanochemistry.The chemical reaction conditions of catalysts,oxidants,additives,grinding aids,and the mechanical rotation speed were investigated in detail.The preferred reaction conditions and the preliminary substrate scopes were explored to give 3-alkenyl indazole derivative in a moderate yield.In summary,this dissertation successfully applied mechanochemical methods to the synthesis of various 3-alkenylated indazoles and Axitinib through Heck coupling reaction and oxidative Heck coupling reaction,broadening the application range of mechanochemical techniques in organic & pharmaceutical synthestic field.