CN109535065B - 一种长叶烯基季铵盐类化合物及其合成方法与应用 - Google Patents

一种长叶烯基季铵盐类化合物及其合成方法与应用 Download PDF

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CN109535065B
CN109535065B CN201811401125.XA CN201811401125A CN109535065B CN 109535065 B CN109535065 B CN 109535065B CN 201811401125 A CN201811401125 A CN 201811401125A CN 109535065 B CN109535065 B CN 109535065B
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quaternary ammonium
longifolene
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黄道战
林志楠
李庆永
蓝虹云
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Guangxi University for Nationalities
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Abstract

本发明属于精细化学品合成技术领域，具体涉及一种长叶烯基季铵盐类化合物及其合成方法与应用。该合成方法是基于药物合成设计的活性亚甲基拼接原理，以ω‑卤甲基长叶烯为原料，与有机叔胺进行季铵化反应，构建兼具亲水性和抑菌活性的季铵功能基，合成具有较强亲水性和抑菌活性的长叶烯基季铵盐类化合物，合成得到的长叶烯基季铵盐类化合物含有天然长叶烯的分子结构和季铵功能基，具有良好的表面活性和抑菌活性，能够抑制大肠杆菌、肺炎克雷伯菌、金黄色葡萄球菌、枯草芽孢杆菌、白色念珠菌、热带念珠菌和黑曲霉等细菌和真菌的生长，具有良好的应用前景。

Description

一种长叶烯基季铵盐类化合物及其合成方法与应用
技术领域
本发明属于精细化学品合成技术领域，具体涉及一种长叶烯基季铵盐类化合物及其合成方法与应用。
背景技术
长叶烯是一种倍半萜烯烃，广泛存于多种天然植物精油中，也是马尾松脂加工、联产松节油产品之一—重质松节油的主要成分。它具有良好的抗菌、抑藻、抗癌、抗炎、驱虫等生物活性，作为植物源医药、农药，对农、渔、医业具有重要的意义，然而其易挥发和弱亲水性的特性，不利于直接应用，难以商品化。为此，人们对长叶烯进行分子结构改造或衍生化，合成系列产物（分为长叶烯、异长叶烯以及四氢萘三系列衍生物），以改善使用性能、增强或拓展生物活性，例如ω-甲酰基长叶烯的炔肟醚能抑制桑蚕幼虫的生长，ω-氯甲基长叶烯具有比长叶烯、ω-乙酰氧甲基长叶烯、ω-羟甲基长叶烯和ω-甲酰基长叶烯更高的抑菌活性，异长叶烯酮具有较强的驱蚊活性，异长叶烯基吡唑类衍生物和异长叶烷噻唑类衍生物具有抗炎、抗肿瘤活性，其中ω-氯甲基长叶烯、ω-羟甲基长叶烯等长叶烯系列衍生物在分子结构中仍保留着天然长叶烯的分子结构，对植物源医药、农药等分子的设计合成更具理论研究和实际应用价值。然而，目前含有天然长叶烯的分子结构的长叶烯系列衍生物，无论是在品种、数量方面，还是在生物活性方面的研究较为欠缺，严重制约了其更广泛的应用推广。
发明内容
针对现有技术中存在的含有长叶烯分子结构的长叶烯衍生物在品种、数量、生物活性研究方面的不足，以及在亲水性、抑菌活性较弱的问题，本发明的目的是提供一种具有较强亲水性和抑菌活性的长叶烯基季铵盐类化合物及其合成方法与应用，即基于药物合成设计的活性亚甲基拼接原理，以ω-卤甲基长叶烯为原料，与有机叔胺进行季铵化反应，构建兼具亲水性和抑菌活性的季铵功能基，合成具有较强亲水性和抑菌活性的长叶烯基季铵盐类化合物，并提供该长叶烯基季铵盐类化合物在用作表面活性剂、抗菌杀菌剂方面的应用。
为了实现上述目的，本发明采用如下技术方案：
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
按照物质的量之比ω-卤甲基长叶烯:有机叔胺为1:（1～1.2）的比例，将ω-卤甲基长叶烯和有机叔胺加入到安装有回流冷凝和搅拌装置的反应器中，加热回流搅拌反应4～6小时；反应结束，待反应混合物冷却至室温，加入有机溶剂加溶解、萃取2～3次，除去未反应的原料和副产物，经冷却、过滤、分液、溶剂脱除、干燥得到产品。所述的ω-卤甲基长叶烯是一种含有天然长叶烯分子结构的烯丙型卤代物，为ω-氯甲基长叶烯、ω-碘甲基长叶烯、ω-溴甲基长叶烯中的一种，是以长叶烯为原料，按文献[Ramdas Nayak U,等.Tetrahedron, 1963, 19(12): 2281 – 2292; 蓝虹云，等. 精细化工, 2018，35(7):1255-1260；姚丹姝，合成化学, 1998，(3):315-318; Snyder EI, J org. chem. 1972,37,212]中的方法，经Prins烯醛缩合、水解或醚化、卤代等多步反应制备得到的；其具有如下所示结构：
Figure 130227DEST_PATH_IMAGE001
上述的长叶烯基季铵盐类化合物的合成方法中，所述的有机叔胺为含氮杂环类叔胺或脂肪烷基叔胺中的一种，所述的含氮杂环类叔胺或脂肪烷基叔胺包括吡啶、N-甲基哌啶、1-甲基咪唑、N,N-二甲基苄胺、N,N-二甲基丁胺、N,N-二甲基辛胺、三甲胺、三乙胺、三正丙胺。
上述的长叶烯基季铵盐类化合物的合成方法中，所述的有机溶剂为乙酸乙酯、乙酸丁酯、石油醚和/或丙酮中的一种，有机溶剂的加入量为ω-卤甲基长叶烯质量的2～3.5倍。
所述的长叶烯基季铵盐类化合物的合成方法，合成得到的长叶烯基季铵盐类化合物具有良好的抑菌活性，能够抑制细菌（大肠杆菌、肺炎克雷伯菌、金黄色葡萄球菌、枯草芽孢杆菌等）和真菌（白色念珠菌、热带念珠菌和黑曲霉等）的生长，可用来制作抑菌、杀菌剂的原料或产品，应用于抑菌、杀菌等方面。
本发明合成得到的长叶烯基季铵盐类化合物易溶于水，具有良好的表面活性、乳化性能，可用来制作表面活性剂，应用于洗涤、乳化等方面。
按照本发明长叶烯基季铵盐类化合物的合成方法合成得到的长叶烯基季铵盐类化合物，其中部分长叶烯基季铵盐类化合物Ⅰa-f的分子结构如下所示。
Figure 377626DEST_PATH_IMAGE002
上述长叶烯基季铵类化合物Ⅰa-f的名称分别为：Ia，N-长叶烯甲基氯化吡啶；Ib，1-长叶烯甲基-3-甲基氯化咪唑；Ic，N-长叶烯甲基-N, N-二甲基-N-苄基氯化铵； Id，N-长叶烯甲基-N, N, N-三甲基氯化铵；Ie，N-长叶烯甲基-N,N,N-三乙基氯化铵；If，N-长叶烯甲基-N,N,N-三丙基氯化铵。
本发明合成的长叶烯基季铵类化合物，其分子结构经红外光谱（FT-IR）、核磁共振谱（1H-NMR和13C-NMR）的波谱分析手段确证；表面活性以对水的表面张力表示，通过吊环法测定；乳化性能测定采用分水法；抑菌、杀菌活性评价采用96孔板微量肉汤二倍稀释法。
本发明与现有技术相比较，具有以下优点：
（1）本发明合成得到的长叶烯基季铵类化合物具有良好的水溶性、表面活性和抑菌活性，能够抑制细菌（大肠杆菌、肺炎克雷伯菌、金黄色葡萄球菌、枯草芽孢杆菌等）和真菌（白色念珠菌、热带念珠菌和黑曲霉等）的生长，可用作抑菌、杀菌剂。
(2) 本发明的长叶烯基季铵类化合物含有天然长叶烯的分子结构，是一类植物源抑菌、杀菌剂，具有很好的应用前景。
附图说明
图1为本发明合成得到的长叶烯基季铵类化合物Ia的红外光谱（FT-IR）图；
图2为本发明合成得到的长叶烯基季铵类化合物Ia的1H核磁共振谱（1H-NMR）图；
图3为本发明合成得到的长叶烯基季铵类化合物Ia的13C核磁共振谱（13C-NMR）图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
实施例1
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯和1.90 g（24 mmol）吡啶加入到安装有回流冷凝和搅拌装置的反应器中，在85℃下加热回流搅拌反应6小时；反应结束，待反应混合物冷却至室温，加入10.1 g乙酸乙酯，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到4.97g酒红色粉末状固体N-长叶烯甲基氯化吡啶（化合物Ia），收率76.2%。
实施例2
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯和2.70 g（20 mmol）N, N-二甲基苄胺加入安装有回流冷凝和搅拌装置的反应器，在100℃下加热回流搅拌反应6小时；反应结束，待反应混合物冷却至室温，加入16 g乙酸丁酯，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到5.60g灰白色粉末状固体N-长叶烯甲基-N, N-二甲基-N-苄基氯化铵（化合物Ic），收率72.1%。
实施例3
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯和1.97 g（24 mmol）1-甲基咪唑加入安装有回流冷凝和搅拌装置的反应器，在100℃下加热回流搅拌反应6小时；反应结束，待反应混合物冷却，加入17.64g乙酸乙酯，溶解、萃取2次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到5.26g淡黄色粉末状状固体1-长叶烯甲基-3-甲基氯化咪唑（化合物Ib），收率78.3%。
实施例4
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯和1.42 g（24 mmol）三甲胺加入安装有回流冷凝和搅拌装置的反应器，在100℃下加热回流搅拌反应6小时；反应结束，待反应混合物冷却，加入16 g乙酸乙酯，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到5.61g淡黄色粉末状固体N-长叶烯甲基-N, N, N-三甲基氯化铵（化合物Id），收率89.8%。
实施例5
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.92 g（20 mmol）ω-溴甲基长叶烯、2.97 g（22 mmol）N, N-二甲基苄胺加入安装有回流冷凝和搅拌装置的反应器，在145℃下加热回流搅拌反应4小时；反应结束，待反应混合物冷却，加入14 g丙酮，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到7.76g白色粉末状固体N-长叶烯甲基-N, N-二甲基-N-苄基溴化铵，收率90.0%。
实施例6
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯和2. 43 g（24 mmol）三乙胺加入安装有回流冷凝和搅拌装置的反应器，在145℃下加热回流搅拌反应6小时；反应结束，待反应混合物冷却，加入16 g乙酸乙酯，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到6.09g淡黄色粉末状固体长叶烯甲基三乙基氯化铵（化合物Ie），收率86.2%。
实施例7
一种长叶烯基季铵盐类化合物的合成方法，其合成方法包括如下步骤：
将5.04 g（20 mmol）ω-氯甲基长叶烯、3.44 g（24 mmol）三正丙胺加入安装有回流冷凝和搅拌装置的反应器，在156℃下加热回流搅拌反应5小时；反应结束，待反应混合物冷却，加入16 g石油醚，溶解、萃取3次，除去未反应的原料和副产物，经过滤、溶剂脱除、干燥，得到7.01g白色粉末状产品长叶烯甲基三丙基氯化铵（化合物If），收率88.3%。
上述实施例中制备得到的化合物Ⅰa-f的HPLC-HRMS、FT-IR、1H NMR及13C NMR分析结果如下：
N-长叶烯甲基氯化吡啶（Ia）LC-HRMS: found 296.2372, calcd for [C21H30N]+,296.2378; IR υ：3036, 2951, 2865, 1671, 1570, 1504, 1453, 883cm-1; 1H NMR (600MHz, D2O) δH: 8.662~8.672 (2H, d, J=5.8 Hz, H-15, H-16), 8.363~8.389 (1H, t,H-19), 7.894~7.916 (2H, t, H-17,H-18), 5.250~5.276 (1H, t, H-13), 5.100~5.133(2H, t, H-14), 2.941~2.949 (1H, d, J=4.6 Hz, H-1), 2.023 (1H, s, H-2eq),1.636~1.676 (1H, m, H-3eq), 1.482~1.547 (3H, m, H-6eq, H-4a, H-8a), 1.381~1.438 (2H, m, H-6ax, H-2ax,), 1.220~1.328 (3H, m, H-3ax, H-5eq , H-7eq),1.065~1.109 (2H, m, H-5ax, H-7ax), 0.849 (3H, s, H-10), 0.789 (3H , s, H-11),0.662 (3H, s, H-12); 13C NMR (150MHz, D2O), δC: 20.676 (C10), 25115 (C6),28.259 (C3), 29.551 (C4), 30.320 (C11), 30.320 (C12), 32.996 (C8), 36.350 (C2),42.125 (C7), 42.571 (C18), 43.023 (C5), 44.368 (C14), 44.542 (C1), 47.976 (C4a),62.107 (C8a), 106.900 (C13), 128.086 (C17, C18), 143.550 (C15, C16), 145.353(C19), 171.191(C9)。
1-长叶烯甲基-3-甲基氯化咪唑（Ib）LC-HRMS: found 299.2489, calcd for[C20H31N2]+, 299.2487; IR υ：3083, 2954, 2864, 1677, 1565, 1452, 1093~1207,860cm-1; 1H NMR (D2O, 600 MHz), δH 8.635~8.701 (1H, s, H-17), 7.348~7.351 (1H,d, H-17, J=1.9 Hz, H-16), 7.260~7.257 (1H, d, J=1.8 Hz, H-15), 5.128~5.153(1H, t, H-13), 4.700~4.712 (2H, dd, J=10.6 Hz, J=25.5 Hz, H-14), 3.752~3.766(3H, d, J=8.3 Hz, H-18), 2.939~2.946 (1H, d, J=4.1 Hz, H-1), 1.929 (1H, s, H-2eq), 1.629~1.669 (1H, m, H-3eq), 1.554~1.597 (3H, m, H-6eq, H-4a, H-8a),1.444~1.543 (2H, m, H-6ax, H-2ax,), 1.318~1.382 (3H, m, H-3ax, H-5eq , H-7eq), 1.199~1.282 (2H, m, H-5ax, H-7ax), 0.852 (3H, s, H-10), 0.780 (3H , s,H-11), 0.713 (3H, s, H-12); 13C NMR (D2O, 150MHz), δC 20.676 (C10), 25.115(C6), 28.259 (C3), 29.551 (C4), 30.320 (C11), 30.320 (C12), 32.996 (C8), 36.350(C2), 42.125 (C7), 42.571 (C18), 42.937 (C5), 44.368 (C14), 44.542 (C1), 47.976(C4a), 62.107 (C8a), 106.900 (C13), 121.675 (C15, C16), 123.665 (C17), 167.606(C9)。
N-长叶烯甲基-N, N-二甲基-N-苄基氯化铵（Ic）LC-HRMS: found 352.2996,calcd for [C25H38N]+, 352.3004; IR υ：3022, 2958, 2863, 1670, 1584, 1504, 1455,726, 706cm-1; 1H NMR (600 MHz, D2O) δH 7.391~7.421 (2H, m, H-21, H-22), 7.380(1H, s , H-23), 7.340~7.364 (2H, m, H-19, H-20), 5.111~5.137 (1H, t, H-13),4.303 (2H, s, H-17), 3.786~4.013 (2H, m, H-14), 2.813~2.861 (6H, m, H-15, H-16), 2.581 (1H, s, H-1), 1.909~1.972 (1H, d, J=37.9, H-2eq), 1.576~1.624 (1H,m, H-3eq), 1.473~1.521 (3H, m, H-6eq, H-4a, H-8a), 1.251~1.396 (2H, m, H-6ax,H-2ax,), 1.132~1.176 (3H, m, H-3ax, H-5eq , H-7eq), 1.016~1.093 (2H, m, H-5ax, H-7ax), 0.888 (3H, s, H-10), 0.765 (3H , s, H-11), 0.669 (3H, s, H-12);13C NMR (D2O, 150MHz), δC 20.549 (C10), 24.932 (C6), 27.915(C3), 29.386 (C4),29.659 (C11), 30.307 (C12), 32.985 (C8), 36.443 (C2), 42.349 (C7), 43.078 (C5),45.026 (C1), 48.943 (C4a), 61.055 (C15), 61.573 (C16), 62.222 (C8a), 67.138(C14),101.640 (C13), 127.297 (C23), 129.024 (C21), 129.210 (C22), 130.030 (C18),130.644 (C19), 132.728 (C20), 173.044 (C9)。
N-长叶烯甲基-N, N, N-三甲基氯化铵（Id）LC-HRMS: found 276.2691, calcdfor [C19H34N]+, 276.2691; IR υ：3004, 2956, 2864, 1670, 1479, 889cm-1; 1H NMR(CDCl3, 600 MHz) , δH 5.121~5.148 (1H, t, H-13), 4.171~4.222(2H, dd, J=17.1Hz, J=8.2 Hz H-14), 3.413~3.450 (9H, d, J=16.8 Hz, H-15, H-16, H-17), 2.939~3.116 (1H, t, H-1), 2.175~2.181 (1H, d, J=3.3 Hz, H-2eq), 1.709~1.750 (1H, m,H-3eq), 1.678~1.692 (3H, m, H-6eq, H-4a, H-8a), 1.654~1.659 (2H, m, H-6ax, H-2ax,), 1.570~1.584 (3H, m, H-3ax, H-5eq, H-7eq), 1.255~1.296 (2H, m, H-5ax,H-7ax), 1.030 (3H, s, H-10), 0.962 (3H , s, H-11), 0.877 (3H, s, H-12); 13CNMR (CDCl3, 150MHz), δC 20.583 (C10), 25.136 (C6), 28.654 (C3), 29.896 (C4),30.155 (C11), 30.982 (C12), 33.497 (C8), 36.600(C2), 42.661 (C7), 43.513 (C5),44.537(C1), 45.518(C4a), 52.491(C15, C16, C17), 62.548 (C8a), 65.613 (C14),101.472(C13), 174.500 (C9)。
长叶烯甲基三乙基氯化铵（Ie）LC-HRMS: found 318.3161, calcd for [C22H40N]+,318.3161; IR υ：2956, 2865, 1671, 1473, 890cm-1; 1H NMR (CDCl3, 600 MHz), δH4.994~4.970 (1H, t, H-13), 3.986~4.001 (2H, dd, J=14.2 Hz, J=6.8 Hz, H-14),3.413~3.899 (6H, m, H-15, H-16, H-17), 2.817~3.171 (1H, d, J=4.9 Hz, H-1),2.179~2.185 (1H, d, J=3.4 Hz, H-2eq), 1.851~1.879 (1H, m, H-3eq), 1.718~1.741(3H, m, H-6eq, H-4a, H-8a), 1.642~1.695 (2H, m, H-6ax, H-2ax,), 1.513~1.578(3H, m, H-3ax, H-5eq, H-7eq), 1.467~1.596 (2H, m, H-5ax, H-7ax), 1.420~1.444(9H, t, H-18, H-19, H-20), 1.006 (3H, s, H-10), 0.969 (3H , s, H-11), 0.891(3H, s, H-12); 13C NMR (CDCl3, 150MHz), δC 20.555 (C10), 25.137 (C6), 28.849(C3), 29.820 (C4), 30.173 (C11), 30.924 (C12), 33.468 (C8), 36.525 (C2), 42.872(C7), 43.526(C5), 44.468 (C1), 45.653 (C4a), 52.638 (C15, C16, C17), 56.728(C14), 62.591 (C8a), 100.271(C13), 173.722(C9)。
长叶烯甲基三丙基氯化铵（If）LC-HRMS: found 360.3631, calcd for [C25H46N]+,3603630; IR υ：2962, 2876, 1675, 1458, 881cm-1; 1H NMR (CDCl3, 600 MHz), δH5.036~5.112 (1H, t, H-13), 4.038~4.119 (2H, dd, J=8.7 Hz, J=7.1 Hz, H-14),3.208~3.220 (1H, d, J=10.0 Hz, H-1), 2.700~2.727 (6H, m, H-15, H-16, H-17),1.973~2.020 (1H, d, J=3.7 Hz, H-2eq), 1.649~1.664 (6H, m, H-18, H-19, H-20),1.611~1.645 (1H, m, H-3eq), 1.496~1.595 (3H, m, H-6eq, H-4a, H-8a), 1.431~1.488 (2H, m, H-6ax, H-2ax,), 1.306~1.377 (3H, m, H-3ax, H-5eq , H-7eq),1.115~1.273 (2H, m, H-5ax, H-7ax), 1.035~1.096 (9H, m, H-21, H-22, H-23),0.901 (3H, s, H-10), 0.881 (3H , s, H-11), 0.877 (3H, s, H-12); 13C NMR(CDCl3, 150MHz), δC 11.414 (C21, C22, C23), 17.779 (C18, C19, C20), 20.560 (C10),25.478 (C6), 28.827 (C3), 29.782 (C4), 30.170 (C11), 30.959 (C12), 33.478 (C8),36.519 (C2), 42.901 (C7), 43.106 (C5), 44.624 (C1), 49.552 (C4a), 54.615 (C14),62.138 (C8a), 60.507 (C14, C15, C16), 100.412 (C13), 173.542 (C9)。
以化合物Ⅰa为例，采用多种波谱分析手段进行结构分析。在电喷雾离子源质谱[ESI-MS]条件下，季铵盐发生裂解反应，生成相对稳定的季铵阳离子，化合物Ⅰa的液质联用高分辨率质谱存在[M-Cl]+的离子峰；该离子峰对应碎片的化学式为[C21H30N]+，荷质比实测值（296.2372）与理论值（296.2378）基本一致，即化合物Ⅰa具有化学式C21H30NCl。在红外光谱中，3036 cm-1处是吡啶环烯氢的C-H伸缩振动吸收峰；2951、2880 、2902 和2865 cm-1 处是甲基、亚甲基的C-H伸缩振动吸收峰；1671 cm-1 处是C=C伸缩振动吸收峰；1570 、1504 和1453 cm-1 是吡啶环的骨架振动吸收峰；1487 cm-1 是亚甲基的C-H弯曲振动吸收峰；883cm-1 是烯氢=C-H弯曲振动吸收峰。1H核磁共振谱显示，化合物Ⅰa含有30个氢原子，在7.897~8.672 ppm处出现吡啶环5个质子的吸收峰；长叶烯分子骨架结构的环外C=C双键烯氢质子吸收峰在5.250~5.276 ppm范围内。13C核磁共振谱显示，化合物Ⅰa含有21个C原子，在δ128.086~145.353ppm处出现吡啶环上碳原子吸收峰；在δ 105.956和171.191ppm处分别为长叶烯分子骨架结构的环外C=C双键两个碳原子的吸收峰。上述化学组成及波谱结构的分析结果，证实了N-长叶烯甲基氯化吡啶（Ⅰa）的分子结构。
实施例8
实施例中制备得到的化合物Ia–f 在水溶液中的表面张力和临界胶束浓度
表面张力采用吊环法测定。将化合物Ia-f、氯代十六烷基吡啶、十六烷基二甲基苄基氯化铵分别以超纯水溶解、配成系列浓度溶液，在25℃下，在BZY-2型全自动表面张力仪上测量不同浓度溶液的表面张力γ，重复测量5次，取其平均值，制作γ～ln（c）关系曲线，根据曲线转折点，推算临界胶束浓度（CMC）。
Figure 978371DEST_PATH_IMAGE003
由表1可知，化合物Ia-f都能够明显降低水的表面张力，即具有表面活性。对γcmc值的比较分析，发现，含N杂环季铵盐Ia和Ib在降低表面张力的能力明显强于化合物Ic-f 、氯代十六烷基吡啶和十六烷基二甲基苄基氯化铵。对于Id-f，随着与氮原子相连的烷基链长度增加，γcmc值减小，即降低表面张力的能力减弱。
实施例9
实施例中制备得到的化合物Ia–f的乳化性能
乳化性能的测定采用分水法。室温下，量取40mL质量分数为0.1%的样品水溶液倒入100mL的具塞量筒中，再加入40mL α-蒎烯或苯，塞紧塞子，上下振荡50次，然后静置，记录分出10mL水的时间，每个样品重复3次，取其平均值；分水时间越长，乳化能力越强。
由表2可知，化合物Ia-f对α-蒎烯和苯都有乳化作用，而且对α-蒎烯的乳化能力明显大于对苯的乳化能力。
Figure 238451DEST_PATH_IMAGE004
实施例10
实施例中制备得到的化合物Ia–f对细菌、真菌的抑菌和杀菌活性
采用96孔板微量稀释法评价化合物Ia -f对细菌和真菌的抑菌、杀菌活性。具体方法如下：
在无菌的96孔平板中1号孔和2号孔中用无菌微量移液器打入100 μL已配好的样品溶液，往2-12号孔中依次打入100 μL含2% DMSO的无菌液体培养基，并混匀。从2号孔中取100 μL样品溶液打到第3个孔中，从3号孔取100 μL样品溶液打到4号孔，依次类推进行二倍稀释，最终把12号孔的100 μL舍去，便得到1-12孔的浓度依次为1000、500、250、125、62.5、31.25、15.625、7.8125、3.9063、1.9531、0.9766、0.4833 μg/mL的样品溶液，最后往1-12号孔依次打入100 μL菌悬液，在1-12孔的样品最终浓度依次为500、250、125、62.5、31.25、15.625、7.8125、3.9063、1.9531、0.9766 、0.4833和0.2417 μg/mL。以100 μL 2% DMSO的液体培养基和100 μL菌悬液的混合液作为阴性对照，其中细菌以利福平作为阳性对照，真菌以酮康唑作为阳性对照。细菌于37℃生化箱生长24 h，真菌于30℃生化箱生长24 h。培养结束后，观察结果，阴性对照组全部变浑浊，再通过比较待测组的浑浊度，没有变浑浊的孔的最低浓度即为MIC，每个样品做3个平行实验，实验结果分别列于表3。
在测定MIC的基础上，将浓度高于MIC(包括MIC)的孔中溶液各吸取100 µL于96孔平板中，37℃培养24 h后观察，仍无菌生长的平板所对应的浓度即为最低杀菌浓度(MBC)，实验结果列于表4。
如表3所示，化合物Ia-f对常见细菌表现较好的抑菌活性。化合物Ia-f对4种细菌的抑菌活性稍低于阳性对照品（利福平），但明显高于原料ω-氯甲基长叶烯；化合物I a-f对肺炎克雷伯菌、金黄色葡萄菌的抑菌活性高于对大肠杆菌和枯草芽孢杆菌的抑菌活性。化合物If对金黄色葡萄菌的MIC为0.977 μg·mL-1,抑菌作用最强，抑菌活性优于阳性对照品利福平和ω-氯甲基长叶烯。
化合物I a-f对3种常见真菌也表现较好的抑菌活性。化合物I a-f对3种常见真菌的抑菌活性稍低于阳性对照品（酮康唑），但明显高于ω-氯甲基长叶烯。化合物Ia和If对白色念珠菌的MIC均为15.6μg·mL-1，化合物Ic对热带念珠菌的MIC为1.95μg·mL-1。
含N杂环类季铵类化合物对细菌、真菌的抑菌活性也高于脂肪烷基季铵类化合物；对于脂肪烷基季铵类化合物，随着脂肪烷基碳链的增长，即亲脂性增加，其对细菌、真菌的抑菌活性增强。
Figure 395894DEST_PATH_IMAGE005
如表4所示，化合物Ia-f对常见细菌表现较好的杀菌活性。与其它季铵盐化合物相比，化合物Ic对金黄色葡萄球菌的杀菌能力最强，其杀菌活性（MBC值）与阳性对照品利福平相当。化合物Ic和Ib对克雷伯氏菌的杀菌能力稍弱于阳性对照品利福平，其MBC(7.81μg·mL-1)是利福平（MBC=15.6μg·mL-1）的0.5倍。
另外，化合物I a-f对3种真菌也具有较好的杀菌活性。除了化合物Id和Ie外，化合物Ia、Ib、Ic和If对3种真菌的杀菌活性等于或高于阳性对照品酮康唑；化合物Ic和Ie对白色念珠菌的MBC均为125μg·mL-1，化合物Ib对热带念珠菌的MBC为7.81μg·mL-1。
含N杂环类季铵类化合物对细菌、真菌的杀菌活性也高于脂肪烷基季铵类化合物；对于脂肪烷基季铵类化合物，随着脂肪烷基碳链的增长，即亲脂性增加，其对细菌、真菌的杀菌能力增强。
Figure 425030DEST_PATH_IMAGE006
上述可见，本发明合成得到的长叶烯基季铵类化合物具有良好的水溶性、表面活性和抑菌活性，能够抑制细菌（大肠杆菌、肺炎克雷伯菌、金黄色葡萄球菌、枯草芽孢杆菌等）和真菌（白色念珠菌、热带念珠菌和黑曲霉等）的生长，可用作表面活性剂、抑菌杀菌剂。

Claims (6)

1.一种长叶烯基季铵盐类化合物的合成方法，其特征在于，其合成方法包括如下步骤：
按照物质的量之比ω-卤甲基长叶烯:有机叔胺为1:（1～1.2）的比例，将ω-卤甲基长叶烯和有机叔胺加入到安装有回流冷凝和搅拌装置的反应器中，加热回流搅拌反应4～6小时；反应结束，待反应混合物冷却至室温，加入有机溶剂溶解、萃取2～3次，除去未反应的原料和副产物，经冷却、过滤、分液、溶剂脱除、干燥得到产品；所述的ω-卤甲基长叶烯是一种含有天然长叶烯分子结构的烯丙型卤代物，其具有如下所示结构：
Figure 214544DEST_PATH_IMAGE001
。
2.根据权利要求1所述的长叶烯基季铵盐类化合物的合成方法，其特征在于，所述的有机叔胺为含氮杂环类叔胺或脂肪烷基叔胺中的一种。
3.根据权利要求2所述的长叶烯基季铵盐类化合物的合成方法，其特征在于，所述的含氮杂环类叔胺或脂肪烷基叔胺为吡啶、N-甲基哌啶、1-甲基咪唑、N,N-二甲基苄胺、N,N-二甲基丁胺、N,N-二甲基辛胺、三甲胺、三乙胺或三正丙胺中的一种。
4.根据权利要求1所述的长叶烯基季铵盐类化合物的合成方法，其特征在于，所述的有机溶剂为乙酸乙酯、乙酸丁酯、石油醚和/或丙酮中的一种，有机溶剂的加入量为ω-卤甲基长叶烯质量的2～3.5倍。
5.根据权利要求1所述的长叶烯基季铵盐类化合物的合成方法，其特征在于，根据该方法合成得到的长叶烯基季铵盐类化合物含有天然长叶烯的分子结构和季铵功能基。
6.根据权利要求3所述的长叶烯基季铵盐类化合物的合成方法，其特征在于，合成得到的长叶烯基季铵盐类化合物在作为表面活性剂、抑菌剂和杀菌剂的原料或产品方面的应用。
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* Cited by examiner, † Cited by third party
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CN103951566A (zh) * 2014-04-30 2014-07-30 南京林业大学 一种N-烃基-1,2,3,4,5,6-六氢-1,1,5,5-四甲基-7H-2,4α-桥亚甲基萘-7-胺类化合物及其合成方法和应用
CN106565536A (zh) * 2016-07-15 2017-04-19 广西民族大学 异长叶烯酮肟醚衍生物及其制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951566A (zh) * 2014-04-30 2014-07-30 南京林业大学 一种N-烃基-1,2,3,4,5,6-六氢-1,1,5,5-四甲基-7H-2,4α-桥亚甲基萘-7-胺类化合物及其合成方法和应用
CN106565536A (zh) * 2016-07-15 2017-04-19 广西民族大学 异长叶烯酮肟醚衍生物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Addition of chlorosulfonyl isocyanate to some polycyclic sesquiterpenes, longifolene, isolongifolene, α-cedrene, caryophyllene and thujopsene;Goverdhan mehta，et al.;《Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry》;19781231;第16B卷(第2期);第87-91页 *
ω-氯甲基长叶烯的合成及其抑菌活性;蓝虹云等;《精细化工》;20180731;第35卷(第7期);第1255-1260页 *

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