Study On The Construction Of C6 Alkylation Purine Reaction Based On Free Radical Reaction

Purine bases and purine nucleoside derivatives are an important class of nitrogen-containing heterocyclic compounds,which play an important role in the fields of biology,chemistry and medicine.In particular,6-alkylpurine compounds have attracted the attention of scientific researchers because of their unique cell growth inhibitory activity and anti-tumor activity.The traditional methods of constructing C6substituted purine derivatives are mainly through nucleophilic substitution reaction and metal-catalyzed coupling reaction.Although these methods have achieved remarkable results,there are still problems such as poor substrate tolerance,low yield,and the need for expensive metal catalysts.Therefore,it is of great value to develop a green and efficient method for constructing C6 alkylated purine derivatives.In recent years,radical oxidative coupling reactions have made significant progress,especially the star reaction-Minisci reaction in the radical reaction type.The Minisci reaction that can directly selectively catalytically activate the inactive C-H bonds in aromatic compounds and avoid the pre-functionalization of the reaction substrate is a green and efficient way to construct C-C bonds.Although the classic Minisci reaction（carboxylic acid-mediated,Ag⁺-catalyzed alkylation of N heterocycles）is a good starting point,harsh reaction conditions limit its scope.Based on characterization of C-C bond construction of Minisci reactionon on heterocyclic compounds,the alkyl oxalate as the precursor of alkylation radicals was used in this thesis,and the following synthetic strategies were designed and implemented:The radical precursor-alkyl oxalate was induced by ammonium persulfate to homo-cleavage to produce alkyl radicals,which then reacted with the 6-hydropurine substrate,successfully realizing the alkylation reaction at the C6 position of the purine.First,6-chloropurine and alcohol compounds were used as starting materials to prepare purine substrates and alkyl oxalate through nucleophilic substitution,hydrazation,hydrogenation reduction and alcoholysis reactions.The optimal reaction conditions of the alkylation reaction were screened out through single-factor control experiments.Next,under the optimal reaction conditions,the electronic effects of the N9/N7substituents and the influence of the primary,secondary and tertiary alkyl oxalates on the route were explored,followed by through free radical capture experiments and kinetic isotope effect experiments,the reaction mechanism of the alkylation process was verified,and the possible mechanism of the method was proposed based on previous experience.Finally,the gram-level experiment verified the industrial production potential of this method.This method avoided the metal ion catalysis and the generation of toxic and harmful by-products required by the classic Minisci reaction,and had extremely high regioselectivity and good functional group compatibility.Through this method,we had successfully synthesized 28 new C6 alkylated purine derivatives,and the structure of the target compounds were characterized by¹H NMR、¹³C NMR、HRMS and other means.In summary,we had successfully developed a method for constructing C6 alkylated purine derivatives by free radical reaction without metal catalysis.This method enriched the synthetic routes of alkylated purines and had high academic value and application prospects.