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摘要：本论文从对噁唑烷酮类抗菌化合物的抗菌机制，构效关系等方面的总结，主要设计合成了一种新的含氟吡唑环噁唑烷酮类化合物，以简单的烯醚，环氧氯丙烷以及含氟酸酐为原料，通过多步反应合成了一种噁唑烷酮杂环化合物，并对其进行了结构表征,利奈唑胺是它的代表性药物。35096
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本文以利奈唑胺为母体，对其进行结构修饰。以吡唑环取代原结构中的吗啉环，保持其他的基团不变，设计并合成得到了一个结构新颖的含吡唑环的噁唑烷酮类似物。合成主要反应为(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)氨基甲酸酯。烯醚与三氟甲基基团取代的乙酸酐在吡啶作用下生成中间体(E)-4-乙氧基-1,1,1-三氟丁-3-烯-2-酮并与取代的对硝基苯肼经乙醇回流，三氟乙酸(TFA)脱羟基生成中间体1-(4-硝基苯基)-5-9三氟甲基-1H-吡唑。再经过Pd/C催化氢化得到中间体产物4-(5-三氟甲基-1H-吡唑-1-基)苯胺。在高温条件下反应生成中间体并经羰基二咪唑(CDI)环合得到噁唑烷酮化合物，再经TFA脱Boc保护，与乙酸酐在三乙胺作用下，最终得到目标化合物。
目标产物经核磁以及高分辨质谱验证。
毕业论文关键词：利奈唑胺；噁唑烷酮类；吡唑环；抗菌性
Design and Synthesis of Novel Pyrazolyl-Containing Oxazolidinone Analog
Abstract: Oxazolidinones are a new class of synthetic antibacterial agents that have high activity against a broad range of Gram-positive bacteria. Linezolid was developed by Pharmacia and Upjohn Company and approved in 2000 for the treatment of serious infections caused by the above-mentioned strains. However, bacterial resistance to linezolid has been found recently in Gram-positive bacteria Staphylococcus aureus and Enterococcus faecium.Herein, we use Linezolid as lead compound, designed and synthesized a novel oxazolidinone derivatives bearing pyrazole as the C-ring structure. Below is the detail synthesis reaction: (S)-epichlorohydrin and benzaldehyde in aqueous ammonia was reacted to form the intermediate after the addition of hydrochloride acid. Then the intermediate was transfomred to (S)-tert-butyl (3-chloro-2-hydroxypropyl) carbamate via the Boc-protection. Enol ethers reacted with trifluoromethyl substituted acetic anhydride to form the intermediate (E)-4-ethoxy-1,1,1-trifluoro-pyridin-3-en-2-one, and then the intermediate reacted with p-nitrophenylhydrazone in the refluxing ethanol to generate 1-(4-nitrophenyl)-5- (trifluoromethyl) -1H- pyrazole after the dehydroxylation by trifluoroacetic acid (TFA). Then the Pd/C catalytic hydrogenation gave the intermediate 4-(5-(trifluoromethyl) -1H- pyrazol-1-yl) aniline. The intermediate was reacted under high temperature to afford the further intermediate, which was finally transformed to the target compound via the sequence carbonyldiimidazole (CDI) cyclization and deprotection of Boc group by TFA.
The target product was verified by NMR and high resolution mass spectrometry.
Key words: Linezolid, Oxazolidinone, Pyrazole, Antibacterial activity
目录
1引言 1
1.1 抗菌药概况 1
1.2 抗菌药物作用机制 2
1.3 细菌的耐药性现状 2
1.4 噁唑烷酮类化合物的概况 3
1.5 噁唑烷酮类药物的意义 4
1.6 噁唑烷酮类化合物的作用机制 4
1.7 利奈唑胺的介绍 5
1.8 利奈唑胺的作用机制 6
2文献综述与方案论证 7
2.1 文献综述 7
2.1.1 路线一 7
2.1.2 路线二 7
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