苯并三氮唑及喹诺酮类化合物的合成
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摘要
据统计09年最畅销的前10个药物中仅有一个不是小分子杂环化合物。随着可持续发展意识的普及,人们不断开发对于这些杂环化合物的更为经济、绿色、有效的合成方法。本论文主要报道了含氮杂环化合物的分子内氨化合成法,包括两部分:
第一部分是苯并三氮唑类化合物的合成,采用易得的三氮烯为底物,以CuI为催化剂,1,10-菲啰啉为配体，叔丁醇钠为碱在DMSO中氮气氛围下于130℃反应10小时高产率进行分子内氨化环合得到目标化合物。该法适用于给、吸电子及有位阻取代的底物,解决了之前的合成方法不能有效避免的由互变异构带来的异构体问题。
第二部分是4-喹诺酮类化合物的合成,采用相应的醛与胺于DMSO中先高产率形成希夫碱再于碳酸钾碱性条件下在一锅内进行分子内氨化环合生成相应的喹诺酮。该法反应过程无须分离,无需金属催化剂,适用官能团范围广,提供了一种适合组合化学合成喹诺酮类化合物库的方法。
Only one out of the top 10 bestseller prescription drugs is non-heterocyclic. With more and more people perceiving the idea of sustainable development, it’s imperative to develop greener synthetic methodologies, i.e. more economic and efficiency. The thesis consists of two parts, mainly on the establishment of nitrogen heterocycles via intramolecular amination reactions.
The first part centers on the synthesis of benzotriaozles which were obtained in high yield via the intramolecular amination cyclization of corresponding triazenes using CuI as the catalyst, 1,10-phenanthroline the ligand, and sodium tert-butoxide the base, in DMSO at 130℃for 10 h. The methodology addresses the issue of isomers caused by tautomerism, and is tolerant of EWGs, EDGs and steric hindered groups.
The second part describes a metal-free one pot strategy for the synthesis of 4-quinolones, via intramolecular amination cyclization of schiff base that is generated in situ from aldehydes and amines in DMSO. The strategy is characterized by high yield and wide functionality tolerance, e.g. electron-withdrawing, electron-donating and steric hindered groups, requires no isolation of intermediates and is therefore applicable to library synthesis.
第一部分是苯并三氮唑类化合物的合成,采用易得的三氮烯为底物,以CuI为催化剂,1,10-菲啰啉为配体，叔丁醇钠为碱在DMSO中氮气氛围下于130℃反应10小时高产率进行分子内氨化环合得到目标化合物。该法适用于给、吸电子及有位阻取代的底物,解决了之前的合成方法不能有效避免的由互变异构带来的异构体问题。
第二部分是4-喹诺酮类化合物的合成,采用相应的醛与胺于DMSO中先高产率形成希夫碱再于碳酸钾碱性条件下在一锅内进行分子内氨化环合生成相应的喹诺酮。该法反应过程无须分离,无需金属催化剂,适用官能团范围广,提供了一种适合组合化学合成喹诺酮类化合物库的方法。
Only one out of the top 10 bestseller prescription drugs is non-heterocyclic. With more and more people perceiving the idea of sustainable development, it’s imperative to develop greener synthetic methodologies, i.e. more economic and efficiency. The thesis consists of two parts, mainly on the establishment of nitrogen heterocycles via intramolecular amination reactions.
The first part centers on the synthesis of benzotriaozles which were obtained in high yield via the intramolecular amination cyclization of corresponding triazenes using CuI as the catalyst, 1,10-phenanthroline the ligand, and sodium tert-butoxide the base, in DMSO at 130℃for 10 h. The methodology addresses the issue of isomers caused by tautomerism, and is tolerant of EWGs, EDGs and steric hindered groups.
The second part describes a metal-free one pot strategy for the synthesis of 4-quinolones, via intramolecular amination cyclization of schiff base that is generated in situ from aldehydes and amines in DMSO. The strategy is characterized by high yield and wide functionality tolerance, e.g. electron-withdrawing, electron-donating and steric hindered groups, requires no isolation of intermediates and is therefore applicable to library synthesis.
引文
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[2]毕晓昕具有潜在生物活性的五元含氮杂环化合物的合成研究[D],扬州大学, 2010.
[3]李乐平含氮杂环化合物的合成研究[D],天津大学, 2004.
[4]刘天宝五元含氮杂环化合物的合成研究[D],苏州大学, 2005.
[5]明志会具有潜在生物活性的含氮杂环化合物的合成研究[D],华中师范大学, 2009.
[6]缪春宝含氮杂环化合物的合成方法研究[D],中国科学技术大学, 2006.
[7]吴晓进含氮杂环化合物的合成研究[D],苏州大学, 2010.
[8]叶方国具有潜在生物活性的含氮杂环化合物的合成研究[D],湖南大学, 2001.
[9] Joule, J. A.;Mills, K. Heterocyclic Chemistry; 5th ed.; [M] Wiley, 2010
[10] Jones, T. N. Development and exploration of nitrogen heterocycle methodologies: Experimental and theoretical investigations[D], Montana State University, 2003.
[11] Carpenter, R. D. Interfacing chemistry and medicine: The power of the heterocycle[D], University of California, Davis, 2008.
[12] Miller, B. Advanced Organic Chemistry Reactions And Mechanisms; [M] Prentice Hall, 2005.吴范宏,荣国斌译高等有机化学-反应和机理
[13] March, J. Advanced Organic Chemistry - Reactions, Mechanisms, and Structure 2nd ed.; [M] McGraw-Hill Book Company, 1977
[14] Kundig, P. CHEMISTRY: The Future of Organic Synthesis Science [J] 2006, 314, 430.
[15] Torborg, C.;Beller, M. Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries Adv. ccSynth. Catal. [J] 2009, 351, 3027.
[16] Butters, M., Catterick, D., Craig, A.et al Critical Assessment of Pharmaceutical Processes: A Rationale for Changing the Synthetic Route Chem. Rev. [J] 2006, 106, 3002.
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