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摘要：阿文巴坦（原NXL104，AVE1330A）是一种合成的非β-内酰胺类物质，β-内酰胺酶抑制剂抑制了Ambler A类、C类和部分Ambler D级酶的活性。虽然不是β-内酰胺类，阿文巴坦的化学结构近似于头孢烯二环环系统的部分，并且阿文巴坦已经显示以出共价结合键合至β-内酰胺酶类。阿文巴坦的潜在角色包括对于疑似或者以证明是由耐药革兰阴性杆菌产生的超广谱β-内酰胺酶（ESBL）、肺炎克雷伯菌碳青霉烯酶（KPC）和/或产AmpC型β-内酰胺酶的治疗。根据文献所述我们利用硫叶立德产生活性中间体来产生第三步所需要的亚胺，同时硫叶立德被氯取代，再在利用酸脱去boc的保护下、碱性条件下关环，利用丙基硼化钠选择还原我们需要的构型，利用草酸成盐，重结晶得到纯度较高的产品。本实验设计两条路线来合成关键中间体哌啶酮，一条是以5-羟基-2羧基吡啶、另一条是以L-谷氨酸二乙酯盐酸盐作为原料，两条线路同时注意反应温度和反应时间的控制，使合成中间体哌啶酮的过程中操作简便、环境污染小、易于工业化等方面从最大程度上优化反应路线.41001
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毕业论文关键词： 阿文巴坦；β-内酰胺类；广谱；哌啶酮
The study on synthesis the key intermediate of Avibactam
Abstract： Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam substances, within the β-lactamase inhibitor of Ambler A, class C and partially Ambler D grade enzymes active. Although not β-lactamase chemical structure, similar to part of Avibactam cephem bicyclic ring system, and Avibactam has been shown to the bonded covalently bound to β-lactamases. Avibactam potential roles include the suspected or to prove by resistant Gram-negative bacilli produce extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and / or produced within AmpC β-lactamase treatment. According to the literature we use sulfur ylide generation of reactive intermediates to produce the desired imine third step, a sulfur ylide substituted with chlorine, and then in an acid off under boc protection ring closure under basic conditions, the use of propyleneyl sodium borohydride reduction we need to choose the configuration, use oxalic acid salt formation, recrystallization, to obtain high purity product. We design two synthetic routes to synthesis the key intermediate piperidone, one is a 5-hydroxy-2-carboxy pyridine, and the other one is L-glutamic acid diethyl ester hydrochloride as starting materials, paying attention to controlling two lines'reaction temperature and reaction time at the same time, making the process of synthesis intermediate of piperidone more simple, less environmental pollution, easy industrialization and optimize the two routes in a way to the maximum extent.
KeyWords：Avibactam; β-lactamse; extended spectrum ; piperidone
目 录
1 绪论 1
1.1 课题背景与意义 1
1.2 阿文巴坦的简介 1
1.2.1 阿文巴坦的相关化学信息 2
1.2.2 阿文巴坦的应用价值 3
1.2.3 阿文巴坦的制备合成方法 3
1.3 本课题主要研究内容 4
1.3.1 阿文巴坦关键中间体合成路线的研究现状 4
1.3.2 阿文巴坦合成反应路线优化 6
2 实验部分 8
2.1 实验试剂和仪器 8
2.1.1 实验试剂 8
2.1.2 实验仪器 9
2.1.3 试剂的物理常数 10
2.2 主要反应原理 11
2.2.1 线路一 11
2.2.2 线路二 14
2.3 实验步骤 15
2.3.1 路线一 15