Study On Synthesis Process Of Quinazoline Intermediates And Anti-tumor Activties Of Its Derivatives

EGFR-TK plays a vital role in the development of the tumor.It can lead to proliferation and differentiation of tumor cells by inducing autophosphorylation of receptors.Therefore,it has become the key target of targeted anti-tumor therapy.At present,there are a series of targeted antineoplasticdrugstargetingEGFRreceptors,Mostofthesecompoundsare4-chloro-6,7-disubstituted quinazoline as key intermediates,such as gefitinib,erlotinib,lappatinib and,et al.Among them,Lapatinib was developed and produced by GlaxoSmithKline in the UK.,Oral tyrosine Kinase Inhibitors targeting at both EGFR and HER2.Enzyme inhibitor,mainly used in the treatment of advanced or metastatic breast cancer patients,However,it has some disadvantages such as high oral dose and low bioavailability,Therefore,it is necessary to optimize the synthesis process of the intermediates and to modify the structure of Lapatinib in order to improve its biological activity and reduce the oral dose.6,7-disubstituted quinazolinone（A₂-C₂）selected as the starting material in this design.under the action of catalyst,Reaction with equal molar Dichlorosulfoxide.The optimum reaction conditions were obtained as follows:the yield of the product is more than 90%and the purity is more than 99%,when the reaction temperature is 70-80℃,the reaction time is 4-5 h,the amount of catalyst is 1.5%,the volume ratio of EA and PE is 1:10.The optimized reaction yield is high,economic and environmental protection,and has a certain universal applicability.Lapatinib was selected as the lead compound of the positive control drug,Combine the structure-activity relationship of the sites on the binding quinazoline ring system,modification the structure of Lapatinib,In this paper,9 novel compounds were synthesized from4-chloro-6-iodoquinazoline by chlorination,amination,Suzuki reaction and witting,and their structures were confirmed by IR and ¹H NMR.The preliminary pharmacological screening of novel compounds was carried out by MTT method.The results showed that the inhibition rate of compound FSH-c on human pancreatic cancer cell line SW-1990 was 37.56%,which was better than that of positive control drug,Superior to the positive control drug Lapatinib,The inhibitory rate of Lapatinib（29.86%）and lung cancer cell line A-549 was 30.78%,which was almost the same as that of Lapatinib（35.67%）,which was valuable for further study.