Synthesis Of 2-Substituted Quinazoline-5-Substituted Pyrimdinones

Thymidylate synthase(TS) is the key enzyme catalyzing the synthesis of deoxyth-ymidine monophosphate(dTMP) which is the vital material to synthesize and repair DNA. Inhibiting TS leads to the lack of dTMP in cells and blocks the synthesis of DNA, and then results in cell death. Thus TS has become an important anticancer target and the research of its inhibitors has also become the focus of anticancer drugs. Most of TS inhibitors still have strong side effects and drug resistance, thus, searching for the new TS inhibitors which have strong selectivity and good effeet, low toxicity and side effects, has been the common goal of the global pharmaceutical researchers.The purpose of this paper is to synthesize 2-substituted quinazoline-5-substituted pyrimidinone compounds. The following works were accomplished:1 Synthesis of 2-substituted-3(4H)-quinazoline-4-ketone compounds:2-sub-stituted-5-mercaptomethyl-3(4H)-quinazoline-4-ketone were synthesized by 2-amino-6-methylbenzoic acid through cyclization, bromination, alkylhydrolyzation. 2-substituted-6,7-dimethyl-3(4H)-quinazoline-4-ketone were synthesized by 3,4-dimethylaniline through oximation, cyclization, alkaline hydrolysis. These compounds were the important intermediates providing for the synthesis of the target product.2 Synthesis of 2-substituted quinazoline-5-substituted pyrimidinone compounds: firstly, uracil-5-methylene-S-isothiuronium salts was synthesized by uracil through hydromethylation, chlorination, alkylhydrolyzation. Then the target compound were synthesized using the uracil-5-methylene-S-isothiuronium salts to react with 2-substituted-5-bromomethyl-3(4H)-quinazoline-4-ketone in alkaline condition.3 Synthesis of 5,10-methylenetetrahydrofolate:5,10-methylenetetrahydrofolate was synthesized by folic acid through reduction and formylation, then purifying by microcrystalline cellulose.