Synthesize Of Novel Thymidylate Synthase Inhibitors-quinazolinone

Thymidylate synthase (TS), as a folate-dependent enzyme，which participate ininitiation of synthesis of thymidine nucleotides. The thymidine nucleotide is adeoxyribonucleic acid (DNA) of the biosynthesis essential substance that inhibitsthymidylate synthase activity will cause intracellular thymidine missing, so that DNAsynthesis in tumor cells would not be normal, then will produce defective DNA synthesis,cleavage, and apoptosis. Therefore, thymidylate synthase chemotherapy drug has becomea very important target, which is an important direction inhibitor anticancer drug research.The objectives of this research are to synthesis of novel thymidylate synthaseinhibitors-Quinazolinone, and obtain some compounds that have relatively activity andpossess independent intellectual property rights by means of synthesize and screening itsintermediate and derivatives intermediates, for further activity. Achievement of thisresearch is as follows:1The synthetic route to the designed Quinazolinone derivatives A6-[2-(2-Amino-4-oxo-3,4-dihydro-quinazolin-5-yl)-ethyl]-dihydro-pyrimidine-2,4-dionewas explored. The synthetic route was designed by analysis of reverse reaction. The totalsynthesis of2-Amino-6-(3-carboxy-propyl)-benzoic acid, the key intermediate for thesynthesis of thymidylate synthase inhibitor A, was completed from benzene via8stepssuch as Friedel-Crafts acylation, nitration, esterification, reduction of nitro, carbonylreduction, reduced synthesis of oxime, closed-loop and open-loop into2-Amino-6-(3-carboxy-propyl)-benzoic acid. The synthesis process and the yield of every step wereimproved. All compounds were confirmed by1HNMR.2The synthetic route to the designed Quinazolinone derivatives B was explored. Itsmain synthetic route is similar to A, was completed from benzene and Glutarie anhydridevia Friedel-Crafts acylation, nitration, reduction of nitro, carbonyl reduction, We haveMastered the intermediate of compounds B Ethyl5-(3-aminophenyl) pentanoate synthesis method.3The synthetic route to the designed3,5-binitro-cinnamaldehyde was explored.Thetartget caompound was obtained first via the reaction of benzaldehyde and amm-onia,then the3,5–binitro–cinnamaldehyde was obtained via nitration and aldolization.Wefound a new method of synthetic3,5–binitro–cinnamaldehyde through our experimentsand has been patented.All compounds were confirmed by1HNMR.4The synthetic route to the designed6-(3-aminophenyl)-4,5-dihydropyridazin-3(2H)-one was explored.Under catalytic of Raney Ni, β-m-nitrobenzoylpropionic acidreacted with hydrazine hydrate, the tartgetcompound was been synthesised by one step ofnitro reduction and ring closing.All compounds were confirmed by1HNMR.