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1、 . 密级 硕士学位论文 泰利霉素关键中间体的合成 李树宾 罗爱芹 (教授) 导师姓名(职称) 姚国伟 (教授) 答辩委员会主席 刘虎威 申请学科门类 工学 论文答辩日期 2007.7.9 申请学位专业 生物化工 2007 年 7 月 日 . 研究成果声明 本人郑重声明: 所提交的学位论文是我本人在指导教师的指导下进行的研究工作获得的研究成果。 尽我所知, 文中除特别标注和致谢的地方外,学位论文中不包含其他人已经发表或撰写过的研究成果, 也不包含为获得北京理工大学或其它教育机构的学位或证书所使用过的材料。 与我一同工作的合作者对此研究工作所做的任何贡献均已在学位论文中作了明确的说明并表示了谢意
2、。 特此申明。 签名: 日期: 关于学位论文使用权的说明 本人完全了解北京理工大学有关保管、使用学位论文的规定,其中包括:学校有权保管、并向有关部门送交学位论文的原件与复印件;学校可以采用影印、缩印或其它复制手段复制并保存学位论文;学校可允许学位论文被查阅或借阅;学校可以学术交流为目的,复制赠送和交换学位论文; 学校可以公布学位论文的全部或部分内容(保密学位论文在解密后遵守此规定) 。 签 名: 日期: 导师签名: 日期: 北京理工大学硕士学位论文 摘 要 摘 要 本文对泰利霉素合成中的相关试剂和中间体进行了深入的研究, 全文分6个部分:绪论;3-羟基-6-O-甲基红霉素 A 9-肟的合成;3
3、-羟基氧化反应研究;3-酮基-6-O-甲基红霉素的合成;E-O-对甲苯磺酰-3-乙酰吡啶肟的合成和结论。 综述了红霉素的起源、 结构特点和分子修饰, 新型红霉素衍生物发展的三个阶段,特别是泰利霉素的合成进展以及其它第三代红霉素衍生物的发展状况。 研究了克拉霉素的前体 6-O-甲基-2,4-二(三甲基硅)-红霉素 A 9-(1-异丙氧基环己基)肟一步水解得到 3-羟基-6-O-甲基红霉素 A 9-肟的反应,发现产率与溶剂、温度、pH、后处理方式有关,产率 81%。 在 3-羟基-6-O-甲基红霉素 A 9-肟乙酰化反应中,发现温度、时间、乙酸酐用量、水分均能影响产物的收率,探讨了最佳反应条件,产
4、率高于 95%。分离鉴定了 3-OH氧化产物,研究发现温度高于 30时,副产物明显增加;6h 后,反应结束;二甲亚砜、乙酸酐用量的增加能加快氧化反应的速度,探讨了氧化反应机理,阐明了主要副产物生成的两条途径,产率 78%。在此基础上,开发了以二氯甲烷为溶剂,乙酰化、氧化“一锅煮”方法,产率达到 77%。 分离鉴定了脱乙酰保护基产物 3-酮基-6-O-甲基红霉素 A 9-肟, 研究了溶剂、 温度、时间以及碳酸钾用量对反应结果的影响。 分离鉴定了肟羟基还原产物 3-酮基-6-O-甲基红霉素,研究了温度、溶剂、pH 对反应结果的影响。试探了脱乙酰保护基、肟羟基还原“一锅煮”反应的方法,产率达到 90
5、%。 研究了 3-乙酰吡啶的肟化反应,分离鉴定了肟化产物 E-3-乙酰吡啶肟,研究了溶剂、温度、时间、碱种类及其用量对反应结果的影响,探讨了肟化反应机理;分离鉴定了 E-O-对甲苯磺酰-3-乙酰吡啶肟,研究了温度、时间、对甲苯磺酰氯用量以及水分对反应结果的影响,探讨了肟羟基还原原理。在此基础上,开发了以吡啶为溶剂肟化、对甲苯磺酰氯酯化反应一锅煮新工艺路线。产率稳定在 80.1以上。 关键词关键词:3-酮基-6-O-甲基红霉素,E-O-对甲苯磺酰-3-乙酰吡啶肟,中间体,合成 北京理工大学硕士学位论文 Abstract In this thesis, the related compounds
6、and reaction intermediates of telithromycin were studied. It is composed of five parts: introductions, the synthesis of 3-hydroxy-6-O-methylerythromycinA 9-oxime, oxidation of 3-OH, synthesis of 3-keto-6- O-methylerythromycin, synthesis of E-O-Ts-3-acetylpyridine oxime and conclusion. The discovery,
7、 structural chatacter, modification of erythromycin and the development of new erythromycin derivatives, including telithromycin and other third generation compounds were reviewed. The hydrolysis of 6-O-methyl-2,4-bis(trimethylsilyl)-erythromycin A 9-(isopropox- yclohexyl) oxime, a precursor of clar
8、ithromycin to yield 3-hydroxy-6-O-methylerythr- omycin A 9-oxime was studied. The results showed that the yield was influenced by the solvent, temperature, pH and the work-up procedure. It found out the yield exceeded 80%. In the acetylation of 3-hydroxy-6-O-methylerythromycin A9 oxime, the result s
9、howed that the yield was depended on temperature, time, the amount of acetic anhydride,moisture in solvent and the kind of organic base. The product was obtained in over 95% yield, it showed that side products increased quickly when the temperature was above 30, the reaction was completed in 6h in 7
10、8% yield, the rate of oxidation increased as the amount of DMSO and Ac2O increased. Additionally, the reaction mechanism was proposed. Therefore, we have developed a new route to synthesize 2-acetyl-3-keto-6-O-methylerythromycin A 9-(O-acetyl)oxime in one-pot in 77% yield. 3-keto-6-O-methylerythromy
11、cin A 9-oxime, was purified and identified by 1HNMR, 13CNMR and MS. The result showed that the yield was influenced on the solvent, temperature, time, amount of K2CO3. Also,3-keto-6-O-methylerythromycin was purified and indentified by 1HNMR, 13CNMR and MS. Variant conditions, such as temperature, so
12、lvent, pH were investigated. On this basis, deprotection of acetyl groups and reduction of 9-oxime were conducted in one-pot in 90% yield. The oximation of 3-acetylpyridine afforded E-isomer and Z-isomer oxime, and the 北京理工大学硕士学位论文 E-isomer was separated and identified by IR and 1HNMR.The result sho
13、wed the yield was influenced by the solvent, temperature, time and base. In addition, the raction mechanism was proposed. E-O-Ts-3-acetylpyridine oxime was purified and identified by IR and 1HNMR. The conditions related with esterafication, such as temperature, time, amount of TsCl and moisture in a
14、ir, were researched. On this basis, we developed a new route of one-pot synthesis of E-O-Ts-3-acetylpyridine oxime, which included oximation and esterfication. And the yield was enhanced to 80.1%. Keywords:3-keto-6-O-methylerythromycin,E-O-Ts-3-acetylpyridine oxime,intermediates,synthesis 北京理工大学硕士学位论文 目 录 摘 要.I Abstract.II 第一章 绪 论.1 1.1 大环内酯类抗生素.1 1.2 红霉素研究进展.