【作者】 梁俊；

【导师】 肖新荣；

【作者基本信息】 南华大学 ， 应用化学， 2010， 硕士

【摘要】 至今已发现吗啉醇类化合物在抗抑郁症和抗菌方面有重要的作用,研制了一批疗效好、副作用小的新型药物,因此吗啉醇类化合物越来越受到人们的关注,加大了在此方面的研究。本文针对当前吗啉醇类化合物的研究现状,基于对2-芳基-2-吗啉醇结构进行改造的思想,设计合成了系列新结构吗啉醇化合物。所合成的目标化合物目的在于从中筛选具有抗抑郁活性或抑菌活性的化合物,为研制新型药物提供先导化合物。主要研究内容包括:(1)以2-芳基-2-吗啉醇为母核,通过引入不同的取代基,对其结构中取代基进行改造,获得了7个新型2-芳基-2-吗啉醇类化合物。目标化合物的结构经过IR、1HNMR和MS确证。(2)设计了由芳香烃制备2-芳基-2-吗啉醇盐酸盐的合成路线。整个过程经过Friedel-Crafts酰基化反应、芳香酮的α-溴代反应、氨化环合反应和酸化成盐四步反应,并对其中部分反应条件进行了优化,本合成路线反应时间短,反应收率高、操作方便,整个反应的平均总收率为74.2 %。(3)实验中采用N-甲基吡咯烷酮非质子极性溶剂替代现有工艺中使用乙腈、二甲吡啶、丙酮等毒性较大溶剂,使吗啉醇的合成条件得到改善,能在较低的温度下快速获得目标产物。(4)参照Porsolt法小鼠强迫游泳实验建立“行为绝望模型”,评价目标化合物的抗抑郁活性,从中筛选具有抗抑郁活性的2-芳基-2-吗啉醇类化合物。实验发现其中由D-2-氨基丙醇反应获得3,5-二甲基-2-(3-氟苯)-2-吗啉醇盐酸盐,能明显缩短小鼠游泳的不动时间,与空白对照组相比有显著性差异,说明此化合物具有良好的抗抑郁作用,得到新型抗抑郁先导化合物,有深入研究的价值。抗抑郁活性实验中数据还提示了由不同的手性源转化得到的产物,目标产物因在立体结构上有着差异,导致了生物活性有较大的差异。(5)通过“纸片扩散法”实验考察了目标产物对金色葡萄球菌、大肠杆菌、沙门氏菌的抑菌活性。实验发现3,5-二甲基-2-(4-叔丁基苯)-2-吗啉醇盐酸盐对金色葡萄球菌具有一定抑菌活性,最低抑菌浓度为0.625 g L-1。更多还原

【Abstract】 So far, the morpholinol compounds is known to have various functions and bioactivities such as antidepressant and antibacterial, which is getting attention by its treatment effective and opposite small side effect. It has been one of the directions to prevent and cure depression. According to research situation of morpholinol compounds, the new compounds synthesized by modification of 2-aryl-2-morpholinol structure.The aim of this dissertation is to synthesizes and screens 2-aryl-2-morpholinol with antidepressant active or antibacterial active, to provides the lead compounds for the new medicine. The major research contents are described as follows:(1)Retains the manufacture of 2-aryl-2-morpholino, we won seven new 2-aryl-2- morpholinol by bring the new substituent to the aromatic rings.The target compounds structure after IR, 1HNMR corroboration.(2)Design routes of synthetic 2-aryl-2-morpholinol hydrochloride with 2-aminopropanol. We got the target compound by four step reactions: Friedel-Crafts acylation, arylketones ofα-bromination, ammonification and acidification, and some reaction conditions has been optimized. The results showed the synthesis reaction is high selectivity, mild reaction conditions and high yield. The reaction of the average gross admission rate of 74.2 %.(3)The research uses N-dimethyl formamide to replace acetonitrile,pyridine, acetone and other solvents, can improve the reparation conditions of morpholinol,lower temperatures and quickly get to the target product.(4)We established a“behavioral despair”model by Porsolt forced swimming test in mice to evaluate and screen antidepressant activity of compunds from the target product.The result showed that 2-(2-fluorophenyl)-3,5-dimethyl-2-morpholinol hydrochloride get from D-2-aminopropanol,which compared to the blank control could significantly shorten mice immobility time in FST.The result suggested that this compound has good antidepressant effects, maybe is the new lead compounds in antidepressant drug, which makes sure that the compound is worth of research. The antidepressant activity experiment data also showed that target products from different Chiral source had different biological activity.(5)2-aryl-2-morpholinol hydrochloride compounds were examined for antimicrobial activities against Fschevichia coil, Staphylococcus aureus and Salmonella by the paper method. The result showed that 2-(4-tert butylphenyl)-3,5-dimethyl-2-morpholinol hydrochloride has certain antibacterial activity, its minimum inhibition concentration (MIC) was 0.625 g L-1.更多还原