The Design And Synthesis Of Novel 4-aminoquinazolines

Quinazoline compounds exhibit a variety of biological activities. For example, some show good activity in anti-tumor as the inhibitors of epidermal growth factor receptor(EGFR)and epidermal growth factor receptor tyrosine kinase(EGFR-TK), so far, five compounds have entered into clinical trials; some can be used for the treatment of benign prostatic hyperplasia and hypertrophy, neurological diseases and hypertension; some show good activities in anti-tobacco mosaic virus (TMV), anti-malarial, anti-microbial, anti-bacterial and anti-HIV, and so on. In recent years, Quinazoline compounds have been extensively studied in the field of organic synthesis and medicinal chemistry.We designed and synthesized six 4-amino-quinazoline compounds through introducing the pharmacophore of compounds GW 572016 and CGP 57148.Refering to the structure of ZD 1839 and other compounds which have good biological activities, through the analysis of structure-activity relationship, while maintaining quinazoline ring and 7-methoxy unchanged, we designed and synthesized a series of novel quinazoline compounds. First of all, by fixing the 4-position and changing the side chain of quinazoline 6-position, we reduced the length of side-chain through reducing the number of the carbon atoms between the nitrogen and oxygen atom from three to two. In addition, we introduced aminoethyl to extend the length of side chain and changed 4-arylamino, while fixing the side chain of quinazoline 6-position.The intermediate 4-chloro-7-methoxyquinazolin-6-yl acetate was synthesized using methyl 2-amino-4,5-dimethoxybenzoate as starting materials, via four steps(formamide cyclization, selective demethylation, acetyl protection and chlorination). Tert-butyl2-(4-(3-chloro-4-fluorophenylamino)-7-methoxy quinazolin-6-yloxy)ethylcarbamate(2-2a), tert-butyl2-(4-(4-(3-fluorobenzyloxy) -3-chlorophenylamino)-7-methoxyquinazolin-6-yloxy)ethylcarbamate(2-2b), tert- butyl2-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin–6-yloxy)ethyl2-aminoethylcarbamate(2-3a) and tert-butyl2-(4-(4-(3-fluorobenzyloxy)-3- chlorophenylamino)-7-methoxyquinazolin-6-yloxy)ethyl-2-aminoethylcarbamate(2-3b) were prepared through substitution, deprotection, halogenation and Gabriel reaction starting from the key intermediate 4-chloro-7-methoxyquinazolin-6-yl acetate. The overall yields were 6.8%, 14.2%, 1.4% and 3.7% respectively. Unfortunately, we encountered difficulties, when synthesizing tert-butyl 2-(7-methoxy-4-(2-methyl-5-(2-morpholinoisonicotinamido)phenylamino) quinazolin-6-yloxy)ethylcarbamate(2-2c) and tert-butyl2-aminoethyl(2-(7- methoxy-4-(2-methyl-5-(2-morpholinoisonicotinamido) phenylamino)quinazolin -6-yloxy)ethyl)carbamate(2-3c) via the same route, The intermediate N-(3-(6- (2-bromoethoxy)-7-methoxyquinazolin-4-ylamino)-4-methylphenyl)-2-morpholinoisonicotinamide(2-15c) is too polar, and its solubility in organic solvents such as methylene chloride, methanolare is too low, so the separation and purification are very difficult. Therefore, We synthesized the side chain, followed by connecting to the quinazoline skeleton. This route increased the overall yield and reduced the reaction steps. The desired compounds 2-1c and 2-2c were obtained in the yield of 24% and 18 % respectively.In this thesis, we designed and synthesized six novel 4-aminoquinazoline compounds based on the structure of a number of highly active compounds. It laid the foundation for finding highly active quinazoline compounds or new targets.