两种具有抗菌活性的药物阿扑西林和木犀草素的合成与纯化的相关研究
摘要
阿扑西林和木犀草素是具有良好的抗菌活性的两种药物。分属于青霉素类和黄酮类化合物。阿扑西林目前尚未在国内生产及使用,而依靠植物提取制备木犀草素已远远无法满足科学研究及临床应用上的需求。因此对这两种药物进行合成与纯化的相关研究,对提高我国人民的健康水平,改变国内抗菌药物耐药现象严重的现状,具有重要意义。
本文对两种具有抗菌活性和良好发展潜力的药物阿扑西林和木犀草素进行了合成研究,重新设计并改进了原有合成路线及工艺,针对产品合成及纯化过程中的出现的问题进行了相关探索,涉及活性酯制备机理的理论研究,及芦丁木犀草素固液平衡性质的研究。
本论文的主要内容如下：
论文第一章为绪论部分,对阿扑西林和木犀草素这两种具有抗菌活性的药物的相关背景与国内外的研究现状进行了介绍,在此基础上阐述了本论文研究的主要内容。
第二章分别尝试以叔丁氧羰基(BOC)和苄氧羰基(Cbz)作为D-天冬氨酸-β-甲酯的氨基保护基,经5步反应合成阿扑西林。成功以Cbz路线获得最终产物。对各步反应的产物进行了结构鉴定,并对部分反应的机理及试验进行了讨论。
第三章对阿扑西林合成过程中活性酯制备步骤的反应产物及副反应产物进行了结构鉴定,对该步反应的可能机理进行了推理,并用量子化学中密度泛函的方法研究了琥珀酰亚胺活性酯合成的反应历程,在6-31G(d)的水平上对反应各驻点及过渡态的结构进行了优化和频率分析,并对反应各阶段的活化能进行了计算。讨论了反应温度、EDC·HCl滴加速度及反应时间对反应进程的影响。
第四章以芦丁为原料,在Na2S2O4的存在下微波辅助加热,合成了木犀草素。采用微波加热技术辅助反应时间仅为传统加热工艺的1/8左右。为优化合成产品的精制纯化工艺,对芦丁和木犀草素的固液平衡性质进行了研究：分别建立了RP-HPLC对芦丁和木犀草素的含量测定方法。用化学分析法测定了芦丁在7种纯溶剂和乙醇+水混合体系、木犀草素在8种纯溶剂和乙醇+水混合体系中的溶解度,对各自溶解度数据所表现出的规律进行了分析和总结。针对芦丁在乙醇水溶液中溶解度所表现出来的特殊现象,以TG/DSc和SEM为手段,研究了芦丁在不同比例的乙醇+水混合溶剂中得到的晶体的物化性质。
第五章以半经验的三参数方程关联测得的芦丁和木犀草素的溶解度数据,关联结果令人满意。根据试验数据和理论分析,提出了一种较为理想的木犀草素产品纯化工艺。
在最后一章中,我们对所有的实验工作进行了总结,认识其中的不足,并提出了后续研究的思路。
Aspoxicillin and luteolin are two drugs and both of them exhibit strong antimicrobial activity. Aspoxicillin belongs to wild spectrum penicillin while luteolin is a kind of flavonoids. Both of them got some problems in preparing and application: Aspoxicillin has neither been produced nor applied in domestic. The research and application of luteolin has been limited by the low content in nature. In that case, the study on the synthesis and purification of aspoxicillin and luteolin is required.
In this thesis, aspoxicillin has been synthesized with new method, using two different NH2 protecting groups. The mechanism of preparing activable ester has been discussed. We also synthesized luteolin from rutin with the assistance of microwave and study the solid-liquid equilibrium of the reactant and the product.
The main content of this thesis is as following:
In the first chapter of this thesis, we summarize the references about our research and introduce the correlated research background. The current developments were summarized and the research contents of this thesis were described.
In the second chapter, aspoxicillin, a new kind of semi-synthetic penicillin, was successfully synthesized during 5 steps using tert-butyl ester (BOC) and benzyl ester (Cbz) as NH2 protecting group. Most of the intermediate products and end product were obtained and confirmed by MS and NMR.
In the third chapter, the mechanism of preparing the active ester of N-hydroxysuccinimide during the synthesis of aspoxicillin was studied by B3LYP method at the level of 6-31G(d). The geometric configurations of reactants, products, intermediates, and transition states in the reaction have been optimized and vibrational analysis has been performed. The single-point was calculated and the activation energy of the reactions has been discussed. Relatively low temperature, low concentration of EDC-HCl and a long-term reaction are favorable for the preparation of the products, which is.essentially consistent with the experimental results.
In the forth chapter, luteolin was synthesized from rutin with the assistance of microwave. To optimize the process for the purification of the synthetic product, the solid-liquid equilibrium of rutin and luteolin was studied by analytical method. Simple procedure to analyze rutin and luteolin with high performance liquid chromatography (HPLC) method was set up, respectively. The solubilities of rutin and luteolin in some commonly used solvents and ethanol+water mixed solvents were determined using HPLC at different temperatures.
In the fifth chapter, a three-parameter equation was used to correlate the experimental data of the solubilities of rutin and luteolin in different solvent systems and showed satisfactory results. An appropriate method of luteolin purification was given.
In the last chapter, all of the experiment work was summarized. We find the deficiencies in the work and propose the idea of the latter research.
本文对两种具有抗菌活性和良好发展潜力的药物阿扑西林和木犀草素进行了合成研究,重新设计并改进了原有合成路线及工艺,针对产品合成及纯化过程中的出现的问题进行了相关探索,涉及活性酯制备机理的理论研究,及芦丁木犀草素固液平衡性质的研究。
本论文的主要内容如下：
论文第一章为绪论部分,对阿扑西林和木犀草素这两种具有抗菌活性的药物的相关背景与国内外的研究现状进行了介绍,在此基础上阐述了本论文研究的主要内容。
第二章分别尝试以叔丁氧羰基(BOC)和苄氧羰基(Cbz)作为D-天冬氨酸-β-甲酯的氨基保护基,经5步反应合成阿扑西林。成功以Cbz路线获得最终产物。对各步反应的产物进行了结构鉴定,并对部分反应的机理及试验进行了讨论。
第三章对阿扑西林合成过程中活性酯制备步骤的反应产物及副反应产物进行了结构鉴定,对该步反应的可能机理进行了推理,并用量子化学中密度泛函的方法研究了琥珀酰亚胺活性酯合成的反应历程,在6-31G(d)的水平上对反应各驻点及过渡态的结构进行了优化和频率分析,并对反应各阶段的活化能进行了计算。讨论了反应温度、EDC·HCl滴加速度及反应时间对反应进程的影响。
第四章以芦丁为原料,在Na2S2O4的存在下微波辅助加热,合成了木犀草素。采用微波加热技术辅助反应时间仅为传统加热工艺的1/8左右。为优化合成产品的精制纯化工艺,对芦丁和木犀草素的固液平衡性质进行了研究：分别建立了RP-HPLC对芦丁和木犀草素的含量测定方法。用化学分析法测定了芦丁在7种纯溶剂和乙醇+水混合体系、木犀草素在8种纯溶剂和乙醇+水混合体系中的溶解度,对各自溶解度数据所表现出的规律进行了分析和总结。针对芦丁在乙醇水溶液中溶解度所表现出来的特殊现象,以TG/DSc和SEM为手段,研究了芦丁在不同比例的乙醇+水混合溶剂中得到的晶体的物化性质。
第五章以半经验的三参数方程关联测得的芦丁和木犀草素的溶解度数据,关联结果令人满意。根据试验数据和理论分析,提出了一种较为理想的木犀草素产品纯化工艺。
在最后一章中,我们对所有的实验工作进行了总结,认识其中的不足,并提出了后续研究的思路。
Aspoxicillin and luteolin are two drugs and both of them exhibit strong antimicrobial activity. Aspoxicillin belongs to wild spectrum penicillin while luteolin is a kind of flavonoids. Both of them got some problems in preparing and application: Aspoxicillin has neither been produced nor applied in domestic. The research and application of luteolin has been limited by the low content in nature. In that case, the study on the synthesis and purification of aspoxicillin and luteolin is required.
In this thesis, aspoxicillin has been synthesized with new method, using two different NH2 protecting groups. The mechanism of preparing activable ester has been discussed. We also synthesized luteolin from rutin with the assistance of microwave and study the solid-liquid equilibrium of the reactant and the product.
The main content of this thesis is as following:
In the first chapter of this thesis, we summarize the references about our research and introduce the correlated research background. The current developments were summarized and the research contents of this thesis were described.
In the second chapter, aspoxicillin, a new kind of semi-synthetic penicillin, was successfully synthesized during 5 steps using tert-butyl ester (BOC) and benzyl ester (Cbz) as NH2 protecting group. Most of the intermediate products and end product were obtained and confirmed by MS and NMR.
In the third chapter, the mechanism of preparing the active ester of N-hydroxysuccinimide during the synthesis of aspoxicillin was studied by B3LYP method at the level of 6-31G(d). The geometric configurations of reactants, products, intermediates, and transition states in the reaction have been optimized and vibrational analysis has been performed. The single-point was calculated and the activation energy of the reactions has been discussed. Relatively low temperature, low concentration of EDC-HCl and a long-term reaction are favorable for the preparation of the products, which is.essentially consistent with the experimental results.
In the forth chapter, luteolin was synthesized from rutin with the assistance of microwave. To optimize the process for the purification of the synthetic product, the solid-liquid equilibrium of rutin and luteolin was studied by analytical method. Simple procedure to analyze rutin and luteolin with high performance liquid chromatography (HPLC) method was set up, respectively. The solubilities of rutin and luteolin in some commonly used solvents and ethanol+water mixed solvents were determined using HPLC at different temperatures.
In the fifth chapter, a three-parameter equation was used to correlate the experimental data of the solubilities of rutin and luteolin in different solvent systems and showed satisfactory results. An appropriate method of luteolin purification was given.
In the last chapter, all of the experiment work was summarized. We find the deficiencies in the work and propose the idea of the latter research.
引文
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