Method Optimization for Synthesis of Trisubstitued Quinazoline Derivatives

Abstract

A series of new 4-anilinoquinazoline derivatives (IV-XVI) were synthesized in convenient pathway with desirable yields. 4-Aminoquinazoline derivatives corresponding Erlotinib are more active compounds for inhibition of the epidermal growth factor receptor (EGFR) which are used as anticancer agents. Although these categories of compounds have widespread clinical use, most of the reported syntheses protocol for them require multistep and low-yielding reaction pathways. Here we tried a new method with only 3 or 4 steps to prepare 4-anilinoquinazoline derivatives. We synthesized our new compounds in two parts (part I with 3 steps and part II with 4 steps). In the first step of part I, we used ortho-diflouro or ortho-dimethoxy anthranilic acid to get the quinazoline ring with a carbonyl group at its 4 position. Then, in the second and third steps of this part, we replaced the carbonyl group of quinazoline ring by chlorine and amine group respectively (IV-X). In part II, we used dichloro anthranilic acid to get the quinazoline ring with a carbonyl group at its 4 position. In these cases, after synthesis of the quinazoline ring we could etherify it via its substitutions on the starting anthranilic acid (XI-XVI), in order to mimic the erlotinib structure as a tyrosine kinase inhibitor. The next steps of this part (replacing the carbonyl group by chlorine and then by amine) were the same as part I. Our new compounds contain different substitutions at orto (6,7) or meta (5,7) positions of the quinazoline ring.