Study On The Synthesis Of N-substituted 2-pyridone Compounds

This thesis includes three parts.(1)Synthesis and mechanism study of 2,2-dimethoxyethanol reacting with 2-chloropyridine compounds.(2)Regioselective nucleophilic substitution reactions study of 2-(2,2-dimethoxyethoxy)pyridine compounds.(3)Synthesis and biological activity evaluation of the arylisoquinoline derivatives.In the first section,the 2-(2,2-dimethoxyethoxy)pyridine compounds were synthesized via the nucleophilic substitution reactions which performed with 2,2-dimethoxyethanol and different 2-chloropyridine compounds.To our surprise,we found that this kind of nucleophilic substitution reactions had good regioselectivity,which was controlled by nucleophilic substrates.Furthermore,we investigated the influence of the species and position of the substituents on nucleophilic substrates.Then the possible mechanisms of nucleophilic substitution reactions were discussed combining quantum chemical calculation and experimental verification.In the second section,the N-substituted 2-pyridone compounds were prepared via the acid-promoted reaction condition from 2-(2,2-dimethoxyethoxy)pyridine compounds.Then we investigated the selectivity of the reactions with different nucleophiles.The experiment results showed that the nucleophilic reactions had good regioselectivities.In the last section,ten arylisoquinoline compounds were synthesized through the established synthetic route in the second section.Then the antitumor activity was evaluated.The bioactivity results showed that six compounds have antitumor activity against A375 cell with inhibition rate more than 50%at 10 ?M,and the inhibition rate of five compounds against HCT-116 cell was more than 50%at 10?M.In this thesis,we first investigated the nucleophilic substitutional selectivity of 2,2-dimethoxyethanol to 2-chloropyridine compounds.Then we optimized the reaction conditions,screened different substrates,discussed the possible reaction mechanism combining with the quantum chemical calculation.Finally,this synthetic stategy was applied in preparing different N-substituent of arylisoquinoline compounds.A series of new compounds with antitumor bioactivity were discovered.It may lay the foundation of follow-up N-substituted 2-pyridones library establishment.