NXL-104合成及苯胺衍生物单溴代反应的研究
发布时间：2019-01-18 11:27
【摘要】：本学位论文共分为两部分,包括新型β-内酰胺酶抑制剂阿维巴坦(NXL-104)的合成和苯胺及其苯环衍生物的单溴代反应。第一部分内容为新型β-内酰胺酶抑制剂阿维巴坦的合成研究。首先对β-内酰胺酶抑制剂的作用、种类和合成方法做了综述。然后在对国内外已有合成路线分析的基础上,我们设计了一条合成阿维巴坦的改进路线,以L-焦谷氨酸为起始原料,经保护、亲核取代开环、成肟、成环、加氢、磺化成盐等十二步反应合成了NXL-104。该合成路线提高了关键反应的产率、简化了多步反应产物提纯的方法,与文献报道方法相比较,具有总产率高、易实现放大的优点。第二部分内容为苯胺及其苯环衍生物的单溴代反应的研究。以丙酸、甲基叔丁基醚和三乙胺的缓冲体系为溶剂,在低温条件下用溴素直接对苯胺及其苯环衍生物进行溴代,高产率得到单溴代产物,产物结构均由~1H NMR确认无误。与文献报道方法相比较,该方法减少了副反应的发生,同时回收一半量的溴原子,避免了对环境的污染,也避免了浪费。该溴代方法简单、高效、经济、环保而且不用金属催化剂,易实现规模化生产。
[Abstract]:This dissertation is divided into two parts, including the synthesis of new 尾 -lactamase inhibitor Avibactam (NXL-104) and the monobromination of aniline and its benzene-ring derivatives. The first part is about the synthesis of new 尾-lactamase inhibitor Avibactam. Firstly, the effects, types and synthesis methods of 尾-lactamase inhibitors were reviewed. Then, based on the analysis of the existing synthetic routes at home and abroad, we designed an improved route for the synthesis of Avibartan, using L-pyroglutamic acid as the starting material, protected, nucleophilic substitution, ring opening, oxime formation, ring formation, hydrogenation. NXL-104. was synthesized by 12 steps reaction, such as sulfonation and salt formation. The synthetic route improves the yield of the key reaction and simplifies the method of purification of the multi-step reaction product. Compared with the method reported in the literature, it has the advantages of high total yield and easy amplification. The second part deals with the monobromination of aniline and its benzene-ring derivatives. With the buffer system of propionic acid, methyl tert-Ding Ji ether and triethylamine as solvent, bromine was directly brominated on aniline and its benzene-ring derivatives at low temperature. The monobrominated product was obtained in high yield, and the structure of the product was confirmed by ~ 1H NMR. Compared with the reported method, this method reduces the occurrence of side reactions and reclaims half of the bromine atoms, thus avoiding environmental pollution and waste. The bromination method is simple, efficient, economical, environmentally friendly and easy to scale production without metal catalyst.
【学位授予单位】：烟台大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O621.25
，
本文编号：2410665
[Abstract]:This dissertation is divided into two parts, including the synthesis of new 尾 -lactamase inhibitor Avibactam (NXL-104) and the monobromination of aniline and its benzene-ring derivatives. The first part is about the synthesis of new 尾-lactamase inhibitor Avibactam. Firstly, the effects, types and synthesis methods of 尾-lactamase inhibitors were reviewed. Then, based on the analysis of the existing synthetic routes at home and abroad, we designed an improved route for the synthesis of Avibartan, using L-pyroglutamic acid as the starting material, protected, nucleophilic substitution, ring opening, oxime formation, ring formation, hydrogenation. NXL-104. was synthesized by 12 steps reaction, such as sulfonation and salt formation. The synthetic route improves the yield of the key reaction and simplifies the method of purification of the multi-step reaction product. Compared with the method reported in the literature, it has the advantages of high total yield and easy amplification. The second part deals with the monobromination of aniline and its benzene-ring derivatives. With the buffer system of propionic acid, methyl tert-Ding Ji ether and triethylamine as solvent, bromine was directly brominated on aniline and its benzene-ring derivatives at low temperature. The monobrominated product was obtained in high yield, and the structure of the product was confirmed by ~ 1H NMR. Compared with the reported method, this method reduces the occurrence of side reactions and reclaims half of the bromine atoms, thus avoiding environmental pollution and waste. The bromination method is simple, efficient, economical, environmentally friendly and easy to scale production without metal catalyst.
【学位授予单位】：烟台大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O621.25
，
本文编号：2410665
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