新型胸苷酸合成酶抑制剂喹唑啉酮衍生物合成

发布时间：2018-03-07 16:45

本文选题：胸苷酸合成酶抑制剂　切入点：喹唑啉　出处：《青岛科技大学》2014年硕士论文　论文类型：学位论文

【摘要】：胸苷酸合成酶（Thymidylate synthase，TS）是一种叶酸依赖性酶，其参与胸苷嘧啶核苷酸的起始合成过程，胸苷嘧啶核苷酸是脱氧核糖核酸（DNA）生物合成的所必需物质，抑制胸苷酸合成酶的活性将引起胞内胸苷嘧啶的缺失，这样会使肿瘤细胞内的DNA合成不能正常进行，随后会产生缺陷的DNA合成、裂解以及细胞凋亡。因此，胸苷酸合成酶已经成为化疗药物一个非常重要的作用靶点，，其抑制剂是抗肿瘤药物研究的重要方向。本研究的目的是合成新型的胸苷酸合成酶抑制剂喹唑啉酮类抗肿瘤先导药物，通过对其中间体及其衍生物中间体的合成筛选获得具有一定活性和自主知识产权的化合物，用于进一步的活性研究。本文主要进行了以下方面的工作： 1对新型喹唑啉-嘧啶酮类衍生物A2-氨基-5-[2-（二氢嘧啶-2,4（1H,3H）-二酮-5-基）乙基]喹唑啉-4-酮进行合成探索，通过逆向合成分析，设计了其合成路线。以苯为原料，经付克酰基化、硝化、酯化、硝基还原、羰基还原、缩合成肟、闭环成靛红开环等8步反应，全合成抑制剂A的重要中间体4-（3-氨基-2-羧基苯基）丁酸。对每一步的反应条件进行了优化，提高了各步反应的收率。所有合成的化合物都通过1HNMR确认。 2对新型喹唑啉-嘧啶酮类衍生物B5-[3-(2-氨基-4-氧代-3,4-二氢喹唑啉-5-基)丙基]-二氢嘧啶-2,4（1H,3H）-二酮进行合成探索，其主要合成路线和A相似，以苯和戊二酸酐为原料，经过对付克酰基化反应、硝化反应、硝基还原、酯化、羰基还原等反应的实验条件探索，掌握了化合物B的中间体5-（3-氨基苯基）戊酸乙酯的合成方法。 3对3,4-二氨基苯甲酸乙酯进行了合成探索。我们以对氨基苯甲酸为原料，经酰基化、硝化、水解、硝基还原、酯化合成了3,4-二氨基苯甲酸乙酯。对每一步的反应条件进行了优化，提高了各步反应的收率。所有合成的化合物都通过1HNMR确认。 4对6-(3-氨基苯基)-4,5-二氢-3(2H)-哒嗪-2-酮进行了合成探索。以3-(3-硝基苯甲酰基)-丙酸为原料，与水合肼在雷尼镍的催化下合成了目标化合物。此反应一步完成了硝基还原和成环，减少了反应步骤，提高了产率。目标产物经过通过1HNMR和红外确认。
[Abstract]:Thymidylate synthase (Thymidylate synthase) is a folic acid-dependent enzyme involved in the initiation of thymidine nucleotide synthesis, and thymidine nucleotides are essential for the biosynthesis of deoxyribonucleic acid (DNA). Inhibition of the activity of thymidine synthase will lead to the deletion of thymidine, which will lead to abnormal DNA synthesis in tumor cells, followed by defective DNA synthesis, cleavage and apoptosis. Thymidine synthase has become a very important target of chemotherapeutic drugs, and its inhibitor is an important research direction of antitumor drugs. The aim of this study was to synthesize novel antitumor drugs of thymidine synthase inhibitor quinazolinone, and to obtain some active and independent intellectual property rights compounds through the synthesis and screening of intermediates and their derivatives. The main work of this paper is as follows:. 1 A _ 2-amino-5- [2-( dihydropyrimidine-2-dihydropyrimidine) -4H (dihydropyrimidine) -3H _ (3H) -diketone] -ethyl] quinazoline-4-one derivative of quinazoline-pyrimidone was synthesized and explored. The synthetic route of quinazoline-pyrimidinone derivatives was designed by reverse synthetic analysis. Nitration, esterification, nitro reduction, carbonyl reduction, synthesis of oxime, closed-loop ring opening reaction of indirubin, etc. The main intermediate of the total synthesis inhibitor A, 4-Amino-2-carboxyphenyl) butyric acid. The reaction conditions of each step were optimized. All the synthesized compounds were confirmed by 1H NMR. 2 A new quinazoline pyrimidinone derivative B5- [3-butadiene-2-amino-4-oxo-4-oxo-4-dihydroquinazoline -5-yl] -dihydropyrimidine -4H _ 2H _ 3H _ 3-diketone was synthesized by using benzene and glutaric anhydride as raw materials. The synthetic method of ethyl valerate, the intermediate of compound B, was obtained by exploring the experimental conditions for the reaction of ketoacylation, nitration, nitro reduction, esterification, carbonyl reduction and so on. 3. The synthesis of ethyl 3o 4-diaminobenzoate was studied. We used p-aminobenzoic acid as raw material through acylation, nitration, hydrolysis and nitro reduction. The reaction conditions of each step were optimized and the yield of each reaction was improved. All the synthesized compounds were confirmed by 1H NMR. (4) the synthesis and exploration of 6-O3-Aminophenyl-4-Aminophenyl-5-dihydro-3H-Pa-pyridazine-2-one was carried out. The target compound was synthesized with hydrazine hydrate and hydrazine hydrate as raw materials, and the nitro reduction and ring formation were completed in one step. The reaction steps were reduced and the yield was increased. The target product was confirmed by 1H NMR and IR.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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