Design And Synthesis Of Novel 4-aryl Aminoquinazoline Compounds

In this paper,the design and synthesis of novel 4-aryl aminoquinazoline compounds as ferroptosis inducer were illustrated in detail.First,in this paper,the synthetic route of erastin was improved.The starting material of 2-aminobenzoic acid was cyclized with propionic anhydride to obtain intermediate 2.Intermediate 2 and 2-ethoxyaniline undergo two-step nucleophilic substitution reaction to obtain intermediate 3.Boron tribromide and intermediate 3 undergo bromination to give intermediate 4.Intermediate 4 was reacted with piperazine to give intermediate 5 at room temperature.p-chlorophenol was reacted with sodium chloroacetate to obtain intermediate6.Intermediate 6 was chlorinated with thionyl chloride to give intermediate 7.Intermediate 5 was reacted with intermediate 7 under the action of triethylamine to obtain a crude product.The crude product was recrystallized from ethanol to give erastin.The structure of erastin was confirmed by ¹H-NMR.Erastin was selected as the lead compound and referenced its structural features.According to the theory of bioisosterism and skeleton transition,the aryl was transferred from 3 to 4 on the parent nucleus of erastin,and oxygen atoms was replaced by nitrogen atoms.In order to ensure that the structure of the essential active group acetyl aryl ether was not affected,the remaining fragments of erastin were retained.Finally,a novel ferroptosis inducer with 4-aryl quinazoline as the mother nucleus was obtained.In order to investigate the effect of steric hindrance on the antitumor activity of the compound,substituents with different properties and volumes were introduced into the structure of parent nucleotide aryl amine group and side chain aryl ether.A series of 4-arylquinazoline compounds which add up to 32 new compounds were designed and synthesized.The synthetic route of novel 4-arylquinazoline compound was designed according to the literature.Methyl 2-aminobenzoate was the starting material,which was added to eliminate with chloroacetonitrile to give intermediate ZYL-A.This was followed by a chlorination reaction to give the intermediate ZYL-B.Intermediate ZYL-B was substituted with the substituted aniline to obtain intermediate ZYL-C.intermediate ZYL-C was subjected to nucleophilic substitution reaction with piperazine hydrate to obtain intermediate ZYL-D.After the substitution reaction of the substituted phenol with chloroacetic acid,intermediate ZYL-F was obtained by chlorination.Intermediate ZYL-D was reacted with intermediate ZYL-F under the action of triethylamine to obtain a novel4-arylquinazoline compound.The structures of the 32 target compounds synthesized were confirmed by ¹H-NMR,and some of the compounds were identified by mass spectrum and ¹³C-NMR...