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摘要：噁唑烷酮类抗菌药是继磺胺类和喹诺酮类后上市的又一类新型的全合成抗菌药，在治疗耐多种药物的革兰氏阳性菌和结核杆菌感染方面显示出极好的前景。此类药物中首个上市的新药为普强公司的利奈唑胺。近些年来，虽然未见有关利奈唑胺引起广泛耐药性的报道，但由于利奈唑胺的大量使用和滥用，临床上已发现其耐药菌株。同时我们了解到含氟烷基在医药领域具有特殊的性质，在有机化合物中引入氟原子可以极大的改变化合物的物理化学性质及在生物体内的生理活性,因而在杂环化合物中引入氟原子的研究引起了国内外化学工作者的广泛兴趣。10636
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为解决利奈唑胺的抗药性问题，我们以利奈唑胺为母体，设计合成了利奈唑胺的类似物，即含氟烷基的4-氟烷基-2-噁唑烷酮，并经过了核磁验证证实了该化合物。本论文主要研究了4-氟烷基噁唑烷酮的合成过程。首先以相应的芳基胺为原料，通过与氯甲酸烯丙基酯在碳酸钾的无水四氢呋喃的悬浊液中室温反应2小时得到相应的芳基氨基甲酸烯丙基酯，收率为89.5%.然后,在室温下，以乙腈：水 = 4:1(v/v)为溶剂，氟烷基碘与芳基氨基甲酸烯丙基酯发生自由基加成反应，得到相应的加成产物，加成产物的收率为29.3%。再在室温下，以THF为溶剂，氢化钠为碱，反应2小时，加成产物发生分子内的N-环合反应以29.3%的收率得到4-氟烷基-2-噁唑烷酮。
关键词： 利奈唑胺；4-氟烷基-2-噁唑烷酮；氟烷基；N-环合法
The design and synthesis of analog of difluoro-substituted linezolid
Abstract: oxazolidinone is another new class of synthetic antibacterial agents, listed after the sulfonamides and quinolones. It displayed an excellent prospect in the treatment of multi-drug-resistant Gram-positive bacteria and Mycobacterium tuberculosis infection．The first listed of such drugs is linezolid of the Pharmacia & Upjohn company.In recent years, although no linezolid caused of extensively drug-resistant by reports, due to the extensive use of linezolid and even abuse, it has been found clinically resistant strains. At the same time, we found that the fluoroalkyl group has a special nature in the field of medicine.
The introduction of fluorine atom into organic compouds may greatly change their biological activities and the physical、chemical properties of the compound. Thus, the introduction of fluorine atoms to the oxazole heterocyclic compounds caused chemists wide interest.
To solve the problem of linezolid resistance, we designed and synthesized the analogue of linezolid, 4-fluoroalkyl-2-oxazolidinones,and confirmed the compound by NMR.This dissertation is focused on the synthesis of 4-fluoroalkyl-2-oxazolidinones.First of all, the aromatic amine reacted with chloroformate allyl ester in THF in the presence of K2CO3 to give allyl arylcarbamates in 89.5% yields at room temperature. The allyl arylcarbamates reacted with fluoroalkyl iodide initiated by sodium dithionite in aqueous acetonitrile (CH3CN-H2O = 4:1) at room temperature to give the corresponding adducts in 29.3% yields. The intramolecular N-cyclization of adducts was carried out under sodium hydride in THF at room temperature to afforded corresponding 4-fluoralkyoxazolidin-2-one in 29.3% yields.
Keywords: Linezolid; 4-fluoroalkyl-2-oxazolidinones; Fluoroalkyl; N-cyclization
目 录
1 前言1
1.1 抗菌药概况1
1.2 细菌的耐药性现状1
1.3 噁唑烷酮类抗菌药2
1.4 利奈唑胺的介绍••3
1.5 含氟有机化合物的生物活性•4
2 文献综述与方案论证•6
2.1 文献综述••6
2.1.1 利奈唑胺的合成方式6
2.1.2 利奈唑胺的结构修饰6
2.1.3 N-环合法在合成杂环上的应用•8
2.1.4 N-环合法在合成含氟杂环上的应用9