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摘要：由于全世界范围内抗菌药物的广泛使用、甚至滥用，导致大量细菌出现严重耐药性问题，从而给临床医疗带来巨大难题。经过科学家们的不懈努力探索，开发出具有新型抗菌机制的抗菌化合物。其中，利奈唑胺(Linezolid)就是噁唑烷酮类抗菌药的代表。29444
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本文根据噁唑烷酮类抗菌化合物的构效关系，设计并合成了一个新的含二氟甲基噁唑烷酮类化合物。以简单的烯醚，环氧氯丙烷以及二氟乙酸酐为原料，通过几步反应合成了噁唑烷酮杂环化合物，并对其进行了结构表征。主要反应为(S)-环氧氯丙烷和苯甲醛在氨水中反应，后加入盐酸生成胺的盐酸盐再经Boc保护生成中间体(S)-叔丁基(3-氯-2-羟基丙基)氨基甲酸叔丁酯。烯醚二氟乙酸酐在吡啶作用下生成中间体，经过一系列反应合成中间体4-(5-(二三氟甲基-1H-吡唑-1-基)苯胺。两中间体经羰基二咪唑(CDI)环合得到含二氟甲基噁唑烷酮化合物，经TFA脱Boc保护，再与乙酸酐在三乙胺作用下，得到目标化合物(S)-N-((3-(4-(5-(二氟甲基)-1H-吡唑-1-基)-3-氟苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺。
毕业论文关键词：二氟甲基；利奈唑胺；噁唑烷酮类抗菌药；合成
The Synthesis of oxazolidinone containing difluoromethyl group
Abstract: Due to the widespread use of antibiotics in the world, and even abuse, resulting in a large number of serious bacterial drug resistance, thereby giving enormous clinical problem. Many chemists have devoted to developed novel antibacterial compounds with novel biological mechanism. Among them, linezolid is representative of oxazolidinone antibacterial agents.
According to the structure-activity relationship of oxazolidinones, in this thesis we designed and synthesized a novel difluoromethyl-containing oxazolidinone analoge. We used enol ether, epichlorohydrin and difluoropropylene acetic anhydride as stating materials to finally prepare the target compound via a few synthetic steps. The target compound has been verified by NMR and HRMS spectrum. Main reaction (S) - epoxy chloropropane and benzaldehyde in ammonia reaction, after add the hydrochloric acid to generate amine hydrochloride, then through Boc protection generated (S) - tert-butyl (3 - chloro - 2 - hydroxy propyl) carbamate tert-butyl ester. Difluoro alkenyl ether acetic anhydride effect in pyridine to form an intermediate , through a series of reactions generated intermediate 4- (5- (bis-trifluoromethyl--1H- pyrazol-1-yl) aniline. Two intermediate by carbonyl diimidazole (CDI) cyclized to give difluoromethyl containing oxazolidinone compound,After remove protect of the Boc by TFA,then with acetic anhydride under the action of triethylamine, get the target compounds S) -N - ((3- (4- (5- (difluoromethyl) -1H- pyrazol-1-yl) -3-fluoro-phenyl) -2-oxo-oxazolidin-5-yl) methyl) acetamide.
Keywords: difluoromethyl; linezolid; oxazolidinone antibacterial agents; synthesis
目录
1 绪论 1
1.1 抗菌药简介 1
1.1.1 抗菌药的分类 1
1.1.2 各类合成抗菌药简介与作用机制 2
1.2 噁唑烷酮类化合物的概况 4
1.2.1 噁唑烷酮类化合物的简介 4
1.2.2 利奈唑胺简介 5
1.2.3 噁唑烷酮类化合物的作用机制 6
1.2.4 噁唑烷酮类药物的意义 6
1.3含氟化合物 7
1.4二氟甲基的性质及其应用 7
1.4.1 二氟甲基噻唑类 8
1.4.2 二氟甲基磺酰胺类 8
1.4.3 二氟甲基的金雀花碱衍生物 8
2 文献综述 9
2.1 利奈唑胺的合成路线综述 9