基于松节油的对孟胺衍生物合成及其生物活性研究

发布时间：2018-04-20 15:30

本文选题：松节油 + 对孟胺衍生物　；参考：《中国林业科学研究院》2017年博士论文

【摘要】：松节油是一类重要的可再生资源,具有独特的生物活性。我国是松节油生产大国,但其深加工产品种类还不够丰富,特别是高附加值绿色产品还有待深度开发。本研究致力于以松节油为原料合成系列具有高生物活性的对孟胺衍生物,为开发绿色农药和医药产品奠定基础。由松节油与乙腈合成了N,N'-二乙酰基-1,8-对孟烷二胺,进一步水解合成了顺/反-1,8-对孟烷二胺,发现了新化合物3-对孟烯-1-胺和N-乙酰基-1,2-环氮对孟烷。以3-对孟烯-1-胺和顺-1,8-对孟烷二胺为原料,通过系列反应合成了相应的酰胺类衍生物、席夫碱类衍生物及硫脲类衍生物等共计53个新化合物。通过FT-IR、ESI+-MS、HRMS、1H NMR及13C NMR等现代分析手段对新化合物进行了结构鉴定。测定了这些新化合物的抑菌、除草、细胞毒性等生物活性。得出主要结论如下:1、首次应用Ritter反应由松节油和乙腈通过一锅法直接合成了N,N'-二乙酰基-1,8-对孟烷二胺。在高沸点溶剂乙二醇中将N,N'-二乙酰基-1,8-对孟烷二胺进行高温、氢氧化钠催化水解得到了1,8-对孟烷二胺。反应混合物通过精馏很容易得到纯度达98%以上的1,8-对孟烷二胺。解决了现有NaCN及NaN3法合成1,8-对孟烷二胺工艺中存在副产物多、分离难、毒性大的弊端。解决了现有NaCN及NaN3法合成1,8-对孟烷二胺工艺中存在的弊端。通过铵盐分步结晶法成功实现了1,8-对孟烷二胺顺反两种异构体的有效分离。2、发现了N,N'-二乙酰基-1,8-对孟烷二胺在酸催化作用下消去C-8位乙酰胺基合成N-乙酰基-3-对孟烯-1-胺,及其进一步异构、闭环合成N-乙酰基-1,2-环氮对孟烷的重要反应。同时,将N-乙酰基-3-对孟烯-1-胺进行高温碱水解得到新化合物3-对孟烯-1-胺。3、通过酰胺化和亚胺化反应成功合成了顺-1,8-对孟烷二胺和3-对孟烯-1-胺的酰胺类和席夫碱类衍生物,酰胺类产率53%~100%,席夫碱类65%~99%。通过3-对孟烯-1-胺与硫代氯甲酸苯酯的亲核加成-消除和高温裂解反应合成了3-对孟烯-1-异硫氰酸酯,产率为97%。将3-对孟烯-1-异硫氰酸酯与胺反应,或者将3-对孟烯-1-胺与异硫氰酸酯反应合成了相应的硫脲,产率为53%~98%。4、对孟胺及其部分衍生物对肺炎克雷伯氏菌、金黄色葡萄球菌和白色念珠菌的抑菌活性研究证明:N-(5-硝基-2-噻吩羧基)-3-对孟烯-1-胺(7g)对肺炎克雷伯氏菌(革兰氏阴性菌)的抑菌活性最强,MIC(最小抑菌浓度)值仅为0.44μg/mL;3-对孟烯-1-胺(5)和N,N'-二(6-氯-2吡啶-羧基)-1,8-对孟烷二胺(12h)对金黄色葡萄球菌的抑菌活性最强,MIC值为56.25μg/m L;化合物5和N-(5-氯-2-噻吩羧基)-3-对孟烯-1-胺(7h)对白色念珠菌的抑菌活性最强,MIC值为112.5μg/mL。5、对孟胺及其席夫碱衍生物对一年生黑麦草均具有很强的除草活性。其中N,N'-二(4-溴苯亚甲基)-1,8-对孟烷二胺(13j)活性最强,对一年生黑麦草根长和茎长的抑制活性分别比现有最好的除草剂草甘膦高310.0%和583.3%。构效关系研究表明:3-对孟烯-1-胺的环内双键有助于提高除草活性;向含呋喃环和苯环的对孟胺席夫碱衍生物中引入氯元素或溴元素可显著提高其除草活性。6、细胞毒性研究表明:对孟胺及其衍生物对MDA-MB-231、ES-2和HepG-2等3种癌细胞没有明显的抑制活性,对正常细胞3T3和HUVEC-C也没有毒害作用,属于安全型新化合物。
[Abstract]:Turpentine is a kind of important renewable resources and has unique biological activity. China is a big producer of turpentine, but its deep processing products are not rich enough, especially the high value-added green products are still to be developed. This study is devoted to the synthesis of monciditic amines with high bioactivity by using turpentine as raw material. N, N'- two acetyl -1,8- was synthesized from moncidiylamine from turpentine and acetonitrile. The synthesis of cis / anti -1,8- pair monalkanine was further hydrolyzed, and the new compound 3- was found to montelene -1- amine and N- acetyl -1,2- cyclonitrogen to montelane. 3- is used as raw material for montelene -1- amines and shun -1,8- to montelanine. A total of 53 new compounds, such as amide derivatives, Schiff Base Derivatives and thiourea derivatives, were synthesized through a series of reactions. The new compounds were identified by modern analytical methods such as FT-IR, ESI+-MS, HRMS, 1H NMR and 13C NMR. The biological activities of these new compounds were determined, such as bacteriostasis, herbicide, cytotoxicity and so on. The main conclusions are as follows: 1, the first application of the Ritter reaction was N, N'- two acetyl -1,8- to mencidiamine by one pot method, and N, N'- two acetyl -1,8- at high boiling point solvent ethylene glycol at high temperature, and sodium hydroxide catalyzed by sodium hydroxide to moncidiamine. The reaction mixture was distilled through distillation. It is easy to get mencidiamine with the purity of more than 98% of 1,8-. It solves the disadvantages of the existing NaCN and NaN3 synthesis of 1,8- in the process of montelan diamine, which has many byproducts, difficult separation and great toxicity. It solves the drawbacks of the existing NaCN and NaN3 synthesis of 1,8- in the process of mencidiamine. The 1,8- pair of Mencius has been successfully realized through the fractional crystallization of ammonium salt. The effective separation of.2 from the two isomers of alkanes two amines found that N, N'- two acetyl -1,8- eliminated C-8 bit acetamidyl group under the catalysis of acid to synthesize N- acetyl -3- to montelene -1- amines, and their further isomerization, and closed loop synthesis of N- acetyl -1,2- cyclic nitrogen for montelane. A new compound 3- was obtained by alkaline hydrolysis of montelene -1- amine.3. Through amidation and imidization, the amides and Schiff Base Derivatives of CIS -1,8- to mencidiene and 3- against montelene -1- amine, the yield 53%~100% of amides, and the nucleophilic addition of Schiff base 65%~99%. through 3- to Mencius -1- amines and benzoate benzoate were eliminated. The reaction of 3- to montelene -1- isothiocyanate was synthesized with a high temperature cracking reaction. The yield was 97%., and 3- was used to react with montelene -1- isothiocyanate with amines, or 3- to react with montelene -1- amine and isothiocyanate to synthesize the corresponding thiourea, the yield of which was 53%~98%.4, and to monamine and some of its derivatives against Klebsiella pneumoniae, Staphylococcus aureus and white. The bacteriostatic activity of Candida albicans showed that N- (5- nitro -2- thiophene) -3- had the strongest inhibitory activity against Klebsiella pneumoniae (Gram-negative bacteria), and MIC (minimum inhibitory concentration) was only 0.44 u g/mL; 3- against Mencius -1- amines (5) and N, N'- two (chlorhexine carboxylic group) against M. aureus The bacteriostasis activity was the strongest, MIC value was 56.25 g/m L; compound 5 and N- (5- chloro -2- thiophene) -3- had the strongest antibacterial activity to monicraline Candida albicans, MIC value was 112.5 mu g/mL.5. Both meniamine and Schiff base derivatives had strong herbicidal activity to annual ryegrass. The activity of two amine (13j) is the strongest, and the inhibitory activity of the root length and stem length of the annual rye root and stem length is 310% and 583.3%. higher than the existing best herbicide glyphosate. The study shows that 3-'s double bonds in the moncienene -1- amine can help improve the herbicidal activity, and the chloride or bromine are introduced into the montelamine Schiff Base Derivatives containing the furan ring and the benzene ring. The element can significantly increase its herbicidal activity.6. Cytotoxicity studies show that Mencius and its derivatives have no obvious inhibitory activity on 3 kinds of cancer cells, such as MDA-MB-231, ES-2 and HepG-2, and have no toxic effects on normal cells, 3T3 and HUVEC-C, which belong to a new safe type compound.

【学位授予单位】：中国林业科学研究院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ351.472

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