CN110372533A - 一种阳离子型线性氯胺抗菌剂及其合成方法 - Google Patents

一种阳离子型线性氯胺抗菌剂及其合成方法 Download PDF

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CN110372533A
CN110372533A CN201910657798.XA CN201910657798A CN110372533A CN 110372533 A CN110372533 A CN 110372533A CN 201910657798 A CN201910657798 A CN 201910657798A CN 110372533 A CN110372533 A CN 110372533A
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李令东
王瀚德
贾冬雪
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Abstract

本发明属于氯胺抗菌剂的合成与应用技术领域，提供了一种阳离子型线性氯胺抗菌剂的合成方法，以N‑叔丁基‑氯烷基酰胺Ⅱ和化合物Ⅳ为原料，制得氯胺前体化合物Ⅲ，再与次氯酸叔丁酯在常温条件下反应制得氯胺化合物Ⅰ；其中化合物Ⅳ为携不同烷基链的叔胺化合物Ⅳ1、携不同烷基链的吡啶化合物Ⅳ2及三丁基膦中的一种。本发明的制备方法，在规避氰化钾使用的同时，向线性氯胺分子中引入不同阳离子结构以改善水溶性并提高抗菌活性；而且向阳离子中心引入的长烷基链的结构与氯胺结构可产生强大的协同抗菌作用，抗菌活性较海因类氯胺有显著的提高；其有望对高效阳离子型氯胺抗菌材料的制备提供理论基础。

Description

一种阳离子型线性氯胺抗菌剂及其合成方法
技术领域
本发明属于氯胺抗菌剂的合成与应用技术领域，具体涉及到一类阳离子型线性氯胺抗菌剂的合成。
背景技术
随着社会发展及人们生活水平的提高，由病原体引起的传染病越来越成为人类健康和社会福祉的重大威胁。诸多病原微生物已经对现代抗生素表现出较强的耐药性，如耐甲氧西林金黄色葡萄球菌及大肠埃希菌等,所以高效广谱抗菌剂的研发使用迫在眉睫。抗菌剂可在在一定时间内抑制细菌、真菌等微生物繁殖或杀死微生物，主要可分为无机类抗菌剂、有机类抗菌剂和天然类抗菌剂。其中有机类抗菌剂种类繁多，抗菌性能突出，主要有季铵盐类、季鏻盐类、氯胺类和酚类等，其中季铵盐和氯胺抗菌剂是研究较多应用较广的两类。
氯胺一般指结构中含有一个或多个N-Cl键的有机化合物，拥有杀菌速度快、稳定性好等优点，是一种高效广谱可再生的绿色抗菌剂。普遍认为其与菌体接触后氧化态的活性氯会迅速氧化/氯化细菌的胞内受体，从而破坏细菌酶催化体系和代谢进程进而致死细菌微生物。为改善氯胺抗菌分子水溶性，几类阳离子单元被引入到海因类氯胺化合物骨架中，从而制备了一系列阳离子型氯胺抗菌剂：季铵盐型氯胺化合物(Adv.Healthc.Mater.2012,1,609-620)(CN 104968655 A)、吡啶盐型氯胺化合物(Tetrahedron Lett.2017,58,321-325)(CN 104926787 A)和季鏻盐型氯胺化合物(RSCAdv.2017,7,13244-13249)(CN 104910208 A)。研究表明阳离子结构的引入改善了氯胺亲水性，同时亦显著提升了氯胺结构的抗菌性能。然而，海因化合物合成需要剧毒的氰化钾，这对环境危害极大。为此，制备不依赖于氰化钾的线性氯胺结构抗菌剂是一个非常好的选择。氯胺结构中α-H存在会脱除HCl成席夫碱结构造成分解，故本项目拟采用、多步化学合成策略制备一系列基于叔丁基胺的阳离子型线性氯胺抗菌剂。
发明内容
本发明的目的是提供一种基于叔丁基胺的线性阳离子型氯胺抗菌剂及其合成方法。
本发明的技术方案：
一种阳离子型线性氯胺抗菌剂，采用化学合成将基于叔丁基的氯胺单元和阳离子单元整合到一个分子中，分子的结构式为(Ⅰ)：
式(I)中，n＝1-8；R为其中R1为C1-C12烷基；R2，R3不存在或为(-OCH3)-(OC12H25)。
一种阳离子型线性氯胺抗菌剂的合成方法，以N-叔丁基-氯烷基酰胺(Ⅱ) 和(Ⅳ)为原料，制得氯胺前体化合物(Ⅲ)，再与次氯酸叔丁酯在常温条件下反应制得氯胺化合物(Ⅰ)；其中(Ⅳ)为携不同烷基链的叔胺化合物(Ⅳ1)、携不同烷基链的吡啶化合物(Ⅳ2)及三丁基膦中的一种；
具体步骤如下：
(1)将N-叔丁基-氯烷基酰胺Ⅱ溶于适量有机溶剂，再加入化合物Ⅳ，100℃回流12～18h，反应结束后经柱层析分离得到阳离子型氯胺前体化合物Ⅲ；
(2)将阳离子型氯胺前体化合物Ⅲ完全溶解于叔丁醇-水的混合溶液中，加入次氯酸叔丁酯，常温条件下避光搅拌24～48h，真空浓缩反应液即得到氯胺化合物Ⅰ；
合成路线如下：
步骤(1)中所述化合物Ⅳ为携不同烷基链的叔胺化合物Ⅳ1、携不同烷基链的吡啶化合物Ⅳ2或三丁基膦，其中n2＝0,8,10,12。
步骤(1)中所述的N-叔丁基-氯烷基酰胺Ⅱ与化合物Ⅳ的摩尔比是1:1～1.5。
步骤(1)中所述的有机溶剂为乙醇、乙腈、水、N,N-二甲基甲酰胺中的一种。
步骤(2)中所述的次氯酸叔丁酯与阳离子型氯胺前体化合物Ⅲ的摩尔比是 2.5～4:1。
步骤(2)中所述的叔丁醇-水混合溶剂中叔丁醇与水的体积比为4:1。
步骤(1)中所述的N-叔丁基-氯烷基酰胺Ⅱ的结构式为ClCO(CH2)n1Cl，其中n1＝1,2,3,4,5,6,7,8。
本发明有益效果：在规避氰化钾使用的同时，向线性氯胺分子中引入不同阳离子结构以改善水溶性并提高抗菌活性；而且向阳离子中心引入的长烷基链的结构与氯胺结构可产生强大的协同抗菌作用，抗菌活性较海因类氯胺有显著的提高；其有望对高效阳离子型氯胺抗菌材料的制备提供理论基础。
具体实施方式
下面通过实施例进一步说明本发明的特点，但本专利的保护范围不受实施例限制。
实施例1
参照文献(Cryst.Growth Des.2008,8,2364-2376.)的方法：在恒压漏斗中加入10mL二氯甲烷并加入氯丁酰氯(5.04g，4.00mL，35.7mmol)混合均匀。向100mL单口烧瓶中加入25mL二氯甲烷，再加入叔丁胺(2.62g，3.79mL， 35.7mmol)和三乙胺(4.03g，5.52mL，39.9mmol)，在冰水浴条件下搅拌直到温度降低至0℃后，向烧瓶内缓慢滴加氯丁酰氯溶液，控制滴加时间在30min 以上；滴加完毕后撤去冰水浴并在室温条件下搅拌6h。反应结束后过滤除去无机盐，真空浓缩去除溶剂后进行柱层析提纯，以乙酸乙酯/石油醚(15:85，v/v)为洗脱剂得到化合物1为白色片状固体(4.45g，70.1％)。
1H NMR(500MHz,CDCl3)δ5.31(s,1H),3.54(t,J＝6.2Hz,2H),2.21(t,J＝ 7.1Hz,2H),2.09-1.95(m,2H),1.28(s,9H)；13C NMR(126MHz,CDCl3)δ170.9, 51.3,44.6,34.1,28.8,28.2.
实施例2
将化合物1(0.70g,3.94mmol)溶于8mL乙醇中，再加入质量分数为30％的三甲胺水溶液(2.33g,3.11mL,11.8mmol)；在搅拌条件下充分回流过夜。真空条件下除去溶剂后进行柱层析分离，以甲醇/二氯甲烷(1/4，v/v)为洗脱剂得到化合物2为白色粉末状固体(0.70g,75.3％)。
1H NMR(500MHz,D2O)δ3.27-3.19(m,2H),3.06(s,9H),2.21(t,J＝7.2Hz, 2H),2.02-1.90(m,2H),1.24(s,9H)；13C NMR(126MHz,D2O)δ173.3,65.5,52.9, 51.2,32.5,27.7,18.8；HRMS calcd.for C11H25N2O[M-Cl]+201.1963,found: 201.1967.
实施例3
将化合物2(0.50g,2.11mmol)溶于3.60mL叔丁醇和0.9mL去离子水的混合溶液中，完全溶解后滴加次氯酸叔丁酯(0.80g,0.84mL,7.39mmol)，室温避光搅拌24h。减压浓缩后得化合物3为白色固体。
1H NMR(500MHz,D2O)δ3.31-3.22(m,2H),3.07(s,9H),2.68(t,J＝6.9Hz, 2H),2.02-1.91(m,2H),1.43(s,9H)；13C NMR(126MHz,D2O)δ176.2,65.6,65.5, 52.8,32.8,28.1,18.3；HRMS calcd.for C11H24N2OCl[M-Cl]+235.1577,found: 235.1817.
实施例4
将化合物1(0.97g,5.45mmol)溶解于10mL乙腈中，加入过量的吡啶(0.65 g,0.66mL,8.18mmol)，加热充分回流过夜。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(15/85,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物10为白色固体(1.08g，78.1％)。
1H NMR(500MHz,D2O)δ8.85-8.75(m,2H),8.50(t,J＝7.9Hz,1H),8.02(t, J＝7.1Hz,2H),4.56(t,J＝7.0Hz,2H),2.30-2.15(m,4H),1.19(s,9H)；13C NMR (126MHz,D2O)δ173.3,145.9,144.3,128.4,61.1,51.2,32.7,27.7,26.4；HRMS calcd.for C13H21N2O[M-Cl]+221.1654,found:221.1657.
实施例5
将化合物10(0.50g,2.81mmol)溶于4.5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.76g,0.80mL,7.04mmol)，常温条件下避光搅拌反应 24h，真空浓缩反应液可到化合物11为白色固体。
1H NMR(500MHz,D2O)δ8.85-8.75(m,2H),8.50(t,J＝7.8Hz,1H),8.02(t, J＝7.0Hz,2H),4.59(t,J＝7.3Hz,2H),2.71(t,J＝6.9Hz,2H),2.25-2.18(m,2H), 1.37(s,9H)；13C NMR(126MHz,D2O)δ176.2,145.8,144.3,128.4,65.4,61.1,32.9, 28.0,26.0；HRMScalcd.for C13H20N2OCl[M-Cl]+255.1262,found:255.1264.
实施例6
将化合物1(0.95g,5.35mmol)溶解于15mL乙腈中，在氮气氛围中加入三丁基膦(1.08g,1.34mL,5.35mmol)，加热充分回流24h。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(8/92,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物12为白色固体(1.50g，73.9％)。
1H NMR(500MHz,D2O)δ2.24(t,J＝6.8Hz,2H),2.18-2.02(m,8H), 1.82-1.70(m,2H),1.52-1.32(m,12H),1.24(s,9H),0.85(t,J＝7.2Hz,9H)；13C NMR(126MHz,D2O)δ173.7,51.2,36.7,27.8,23.3,23.2,22.7,17.7,17.3,12.6； HRMS calcd.for C20H43NOP[M-Cl]+344.3086,found:344.3082.
实施例7
将化合物12(0.60g,3.38mmol)溶于4.5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.60g,0.63mL,5.50mmol)，常温条件下避光搅拌反应 24h，真空条件下浓缩反应液可到化合物13为白色固体.
1H NMR(500MHz,D2O)δ2.73(t,J＝6.7Hz,2H),2.19-2.06(m,8H), 1.80-1.72(m,2H),1.56-1.31(m,12H),1.42(s,9H),0.86(t,J＝7.2Hz,9H).
实施例8
以金黄色葡萄球菌(S.aureus ATCC 25923)为模式菌株，以海因类季铵盐氯胺分子29和其前体28为对照测试所制备季铵盐型线性氯胺3的抗菌性能。具体方法为：分别取20μL 0.28mol/L的化合物29和化合物3与10mL菌液混合(约 106CFU/mL,Colony-FormingUnits)，振荡5min、10min后，分别取出1mL混合液与1mL硫代硫酸钠溶液混合均匀，然后逐级稀释并涂覆于营养琼脂平板上培养16～24h，最后以平板计数法确定活菌的数量。
表1是实施方案制备的季铵盐型线性氯胺抗菌剂3与29对金黄色葡萄球菌(S.aureus ATCC 25923)的抗菌活性测试结果。
表1.氯胺化合物2-3抗菌测试结果
a金黄色葡萄球菌菌液浓度为5.06×106CFU/mL(Colony-Forming Units)
表1中测试数据表明，本发明制备的线性氯胺化合物3整体上表现出比海因氯胺化合物29略差的抗菌活性：在相同活性氯浓度(20ppm)条件下，线性氯胺3 在5min内可实现21.7％(0.11Log减少量)的细菌减少，与海因氯胺化合物29杀死19.9％(0.10Log减少量)细菌的抗菌能力大约在同一水平；而接触10分钟时，线性氯胺分子的杀生物活性(0.18Log减少量)较差于海因类氯胺分子3(0.53Log 减少量)。
实施例9
以金黄色葡萄球菌(S.aureus ATCC 25923)为模式菌株，对比含有不同阳离子结构的阳离子型线性氯胺分子3、11、13和其氯胺前体2、10、12的抗菌性能。
表2.阳离子型线性氯胺化合物3、11、13抗菌测试结果
a金黄色葡萄球菌菌液浓度为3.60×106CFU/mL(Colony-Forming Units).
表2中测试数据表明，在相同活性氯浓度(20ppm)条件下，分子中含有不同阳离子单元的季铵盐型线性氯胺3、吡啶盐型线性氯胺11和季鏻盐型线性氯胺 13的抗菌活性依次增强，例如：接触时间5min时，季铵盐型线性氯胺3实现了23.9％ (0.12Log减少量)的细菌减少，同时吡啶盐型线性氯胺11实现了31.1％(0.16Log 减少量)的杀灭能力，而活性最好的季鏻盐型线性氯胺分子13实现了44.3％(0.26 Log减少量)的细菌减少。
实施例10
参考文献(J.Am.Chem.Soc.2001,123,5614-561.)中的方法：将二甲胺盐酸盐(3.67g,45.0mmol)溶解于50mL乙醇-水混合溶剂(v/v＝95:5)，向体系中加入氢氧化钠(2.10g,52.5mmol)并搅拌溶解后，加入1-溴代正辛烷(2.89g, 2.59mL,15.0mmol)100℃条件下回流24h；真空浓缩除去溶剂后，加入40mL 质量分数为10％的氢氧化钠溶液搅拌，之后用20mL二氯甲烷萃取产物三次，真空浓缩后得到化合物22为淡黄色液体(2.01g,85.2％)。
1H NMR(500MHz,CDCl3):δ2.25(t,J＝7.6Hz,2H),2.22(s,6H),1.49-1.41 (m,2H),1.33-1.20(m,10H),0.87(t,J＝6.9Hz,3H)；13C NMR(126MHz,CDCl3)δ 60.0,45.6,31.9,29.6,29.3,27.8,27.6,22.7,14.2.
实施例11
将化合物1(1.06g,6.00mmol)溶于15mL乙腈中，再加入叔胺化合物22 (0.94g,1.24mL,6.00mmol)；在搅拌条件下充分回流过夜。真空条件下除去溶剂后进行柱层析分离，以甲醇/二氯甲烷(15/85，v/v)为洗脱剂得到化合物4为白色固体(1.53g,76.5％)。
1H NMR(500MHz,D2O)δ3.24-3.14(m,4H),2.99(s,6H),2.19(t,J＝7.0Hz, 2H),1.98-1.85(m,2H),1.71-1.60(m,2H),1.30-1.18(m,10H),1.24(s,9H),0.79(t, J＝6.9Hz,3H)；13C NMR(126MHz,D2O)δ173.3,64.1,62.5,51.2,50.7,32.6,31.0, 28.1,27.8,25.4,22.0,21.7,18.5,16.8,13.4；HRMS calcd.for C18H39N2O [M-Cl]+299.3062,found:299.3065.
实施例12
将化合物4(0.55g,1.70mmol)溶于5.4mL叔丁醇-水混合溶剂(v/v＝4:1)，完全溶解后滴加次氯酸叔丁酯(0.46g,0.48mL,4.25mmol)，室温避光搅拌24h。减压浓缩后得化合物5为粘稠状白色固体。
1H NMR(500MHz,D2O)δ3.24-3.18(m,4H),2.99(s,6H),2.66(t,J＝6.8Hz, 2H),1.94-1.87(m,2H),1.70-1.65(m,2H),1.42(s,9H),1.30-1.18(m,10H),0.78(t, J＝6.8Hz,3H)；13C NMR(126MHz,D2O)δ176.2,65.5,63.9,62.5,50.7,32.8,31.0, 28.1,28.1,25.4,22.0,21.7,18.5,17.9,13.4.
实施例13
参考文献(J.Am.Chem.Soc.2001,123,5614-561.)中的方法：将二甲胺盐酸盐(3.67g,45.0mmol)溶解于50mL乙醇-水混合溶剂(v/v＝95:5)，向体系中加入氢氧化钠(2.10g,52.5mmol)并搅拌溶解后，加入1-溴代正癸烷(3.32g, 3.10mL,15.0mmol)100℃条件下回流24h；真空浓缩除去溶剂后，加入40mL 质量分数为10％的氢氧化钠溶液搅拌，之后用20mL二氯甲烷萃取产物三次，真空浓缩后得到化合物23为黄色液体(2.53g,91.0％)。
1H NMR(500MHz,D2O)δ2.25(t,J＝7.7Hz,2H),2.22(s,6H),1.47-1.42(m, 2H),1.33-1.22(m,14H),0.87(t,J＝6.8Hz,3H)；13C NMR(126MHz,CDCl3)δ60.0, 45.6,31.9,29.6,29.3,27.8,27.6,27.3,27.0 22.7,14.2.
实施例14
将化合物1(0.98g,5.50mmol)溶于15mL乙腈中，再加入叔胺化合物23 (1.01g,1.30mL,5.50mmol)；在搅拌条件下充分回流过夜。真空条件下除去溶剂后进行柱层析分离，以甲醇/二氯甲烷(15/85，v/v)为洗脱剂得到化合物6为白色固体(1.45g,72.5％)。
1H NMR(500MHz,D2O)δ3.25-3.15(m,4H),3.02(s,6H),2.20(t,J＝6.7Hz, 2H),1.98-1.85(m,2H),1.71-1.60(m,2H),1.30-1.18(m,14H),1.25(s,9H),0.80(t, J＝6.7Hz,3H)；13C NMR(126MHz,D2O)δ173.0,63.6,61.9,51.1,48.8,32.3,31.6, 29.2,28.9,28.8,28.6,28.0,25.6,22.3,21.9,18.5,13.7；HRMS calcd.for C20H44N2O [M-Cl]+328.3454,found:328.3461.
实施例15
将化合物6(0.56g,1.54mmol)溶于5.4mL叔丁醇-水混合溶剂(v/v＝4:1)，完全溶解后滴加次氯酸叔丁酯(0.42g,0.44mL,3.89mmol)，室温避光搅拌24h。减压浓缩后得化合物7为粘稠状固体。
1H NMR(500MHz,D2O)δ3.26-3.14(m,4H),3.05(s,6H),2.68(t,J＝6.3Hz, 2H),1.94-1.86(m,2H),1.71-1.60(m,2H),1.43(s,9H),1.33-1.19(m,14H),0.80(t, J＝6.6Hz,3H)；13C NMR(126MHz,D2O)δ175.6,64.7,62.7,61.2,51.7,32.5,31.8, 29.6,29.5,29.2,29.1,28.4,25.7,22.5,21.8,18.0,13.8.
实施例16
参考文献(J.Am.Chem.Soc.2001,123,5614-561.)中的方法：将二甲胺盐酸盐(3.74g,45.9mmol)溶解于50mL乙醇-水混合溶剂(v/v＝95:5)，向体系中加入氢氧化钠(2.20g,53.4mmol)并搅拌溶解后，加入1-溴代十二烷(3.80g, 3.66mL,15.3mmol)100℃条件下回流24h；真空浓缩除去溶剂后，加入40ml 质量分数为10％的氢氧化钠溶液搅拌，之后用20mL二氯甲烷萃取产物三次，真空浓缩后得到化合物24为浅红色液体(2.59g,80.9％)。
1H NMR(500MHz,CDCl3):δ2.23(t,J＝7.6Hz,2H),2.21(s,6H),1.48-1.43 (m,2H),1.33-1.21(m,18H),0.87(t,J＝7.2Hz,3H)；13C NMR(126MHz,CDCl3)δ 60.1,45.6,31.9,29.6,29.3,27.9,27.6,27.3,27.0,26.5,26.1,22.7,14.2.
实施例17
将化合物1(0.91g,5.11mmol)溶于15mL乙腈中，再加入叔胺化合物24 (1.07g,1.51mL,5.11mmol)；在搅拌条件下充分回流过夜。真空条件下除去溶剂后进行柱层析分离，以甲醇/二氯甲烷(15/85，v/v)为洗脱剂得到化合物8为白色固体(1.40g,70.3％)。
1H NMR(500MHz,D2O)δ3.30-3.15(m,4H),3.04(s,6H),2.22(t,J＝6.5Hz, 2H),1.97-1.86(m,2H),1.70-1.55(m,2H),1.35-1.20(m,18H),1.26(s,9H),0.80(t, J＝6.8Hz,3H)；13C NMR(126MHz,D2O)δ172.7,63.1,61.3,51.5,50.8,32.1,31.9, 29.8,29.7,29.4,29.3,29.2,28.2,25.9,22.6,22.1,18.5,13.8；HRMS calcd.for C22H47N2O[M-Cl]+355.3682,found:355.3688.
实施例18
将化合物8(0.60g,1.55mmol)溶于5.4mL叔丁醇-水混合溶剂(v/v＝4:1)，完全溶解后滴加次氯酸叔丁酯(0.42g,0.44mL,3.89mmol)，室温避光搅拌24h。减压浓缩后得化合物9为粘稠状固体。
1H NMR(500MHz,D2O)δ3.30-3.15(m,4H),3.06(s,6H),2.68(t,J＝6.2Hz, 2H),1.97-1.86(m,2H),1.75-1.65(m,2H),1.43(s,9H),1.36-1.15(m,18H),0.80(t, J＝6.7Hz,3H)；13C NMR(126MHz,D2O)δ175.6,64.4,62.4,61.0,51.9,32.4,32.0, 29.9,29.7,29.5,29.4,29.1,28.5,25.9,22.6,21.9,18.0,13.8.
实施例19
对比含有不同烷基链长度的季铵盐型线性氯胺分子5、7、9及海因类氯胺分子29的抗菌活性。
表3.季铵盐型线性氯胺化合物5、7、9与海因类氯胺29的抗菌测试结果
a金黄色葡萄球菌菌液浓度为7.00×106CFU/mL(Colony-Forming Units).
表3中测试数据表明：由于携有长烷基链的季铵盐部分与氯胺部分的协同抗菌效应，携有十个以上碳原子烷基链的氯胺分子7与9展现了比海因类氯胺29 更强的抗菌活性。例如，接触时间5min时，海因类线性氯胺29实现了18.8％ (0.09Log减少量)的细菌减少，而携有长烷基链的线性氯胺7与9分别显现了 99.9％(4.18Log减少量)和100％(6.85Log减少量)的杀灭能力。
实施例20
将化合物1(0.82g,4.58mmol)溶解于10mL乙腈中，加入3-甲氧基吡啶 (0.50g,0.46mL,4.58mmol)，加热充分回流过夜。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(15/85,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物14为白色固体(0.99g，75.1％)。
1H NMR(500MHz,D2O)δ8.51(s,1H),8.41-8.35(m,1H),8.09-8.02(m,1H), 7.95-7.85(m,1H),4.62-4.47(m,2H),3.96(s,3H),2.27-2.17(m,4H),1.18(s,9H)；13C NMR(126MHz,D2O)δ173.3,158.8,136.7,132.0,130.6,128.6,61.4,57.2,51.2, 32.7,27.7,26.3；HRMS calcd.for C14H23N2O2[M-Cl]+251.1754,found:251.1760.
实施例21
将化合物14(0.50g,1.74mmol)溶于4.5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.47g,0.49mL,4.35mmol)，常温条件下避光搅拌反应 24h，真空浓缩反应液可到化合物15为白色固体。
1H NMR(500MHz,D2O)δ8.53(s,1H),8.45-8.35(m,1H),8.08-8.00(m,1H), 7.96-7.85(m,1H),4.60-4.49(m,2H),3.96(s,3H),2.71(t,J＝6.8Hz,2H), 2.26-2.16(m,2H),1.36(s,9H)；13C NMR(126MHz,D2O)δ176.1,158.8,136.8, 131.9,130.6,128.6,65.4,61.4,57.1,32.9,28.0,25.9；HRMS calcd.for C14H22N2O2Cl[M-Cl]+285.1364,found:285.1370.
实施例22
参照专利(CN 105968043A)中的方法：将3-羟基吡啶(1.49g,15.7mmol) 溶解于10mLN,N-二甲基甲酰胺中，加入氢氧化钾(1.76g,31.3mmol)和1-溴代正辛烷(3.03g,2.73mL,15.7mmol)，70℃条件下反应2h；反应结束后加入 20mL水稀释反应液，之后用10mL乙酸乙酯萃取水相三次，有机相真空浓缩后经柱层析分离，以乙酸乙酯/石油醚(20/80,v/v)为洗脱剂，收集含有产物的液体，浓缩后得到化合物25为红棕色油状液体(1.67g,51.7％)。
1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.21(s,1H),7.30-7.17(m,2H),4.01 (t,J＝6.6Hz,2H),1.93-1.68(m,2H),1.65-1.41(m,2H),1.42-1.17(m,8H),0.90(t, J＝6.8Hz,3H)；13C NMR(126MHz,CDCl3)δ155.3,141.9,138.0,123.8,121.0, 68.3,31.8,29.3,29.2,29.2,26.0,22.7,14.1.
实施例23
将化合物1(0.99g,4.76mmol)溶解于10mL乙腈中，加入化合物25(0.85 g,4.76mmol)，加热充分回流过夜。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(15/85,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物16为白色固体(1.33g,72.6％)。
1H NMR(500MHz,D2O)δ8.54(s,1H),8.50-8.44(m,1H),8.01-7.86(m,2H), 4.57(t,J＝6.4Hz,2H),4.17(t,J＝6.2Hz,2H),2.26-2.18(m,4H),1.78-1.69(m, 2H),1.45-1.34(m,2H),1.27-1.16(m,8H),1.12(s,9H),0.78(t,J＝6.8Hz,3H)；13C NMR(126MHz,D2O)δ172.8,158.0,137.3,131.7,131.2,128.9,70.5,61.7,50.8, 32.6,31.5,29.0,28.9,28.4,27.9,26.2,25.5,22.4,13.7；HRMS calcd.for C21H37N2O2 [M-Cl]+349.2854,found:349.2855.
实施例24
将化合物16(0.60g,1.55mmol)溶于5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.59g,0.62mL,5.45mmol)，常温条件下避光搅拌反应 24h，真空浓缩反应液可到粘稠状固体17。
1H NMR(500MHz,D2O)δ8.58(s,1H),8.56-8.53(m,1H),8.04-8.00(m,1H), 8.00-7.95(m,1H),4.64(t,J＝6.4Hz,2H),4.20(t,J＝6.1Hz,2H),2.68(t,J＝6.6 Hz,2H),2.28-2.18(m,2H),1.78-1.70(m,2H),1.42-1.34(m,2H),1.28(s,9H), 1.25-1.15(m,8H),0.76(t,J＝6.6Hz,3H)；13C NMR(126MHz,D2O)δ175.6,157.9, 137.6,131.6,131.2,129.0,70.4,64.5,61.6,32.8,31.7,29.6,29.2,29.0,28.2,25.8, 25.6,22.5,13.8.
实施例25
参照专利(CN 105968043A)中的方法：将3-羟基吡啶(1.20g,12.6mmol) 溶解于10mLN,N-二甲基甲酰胺中，加入氢氧化钾(1.42g,25.2mmol)和1-溴代正癸烷(2.80g,2.62mL,12.7mmol)，70℃条件下反应2h；反应结束后加入 20mL水稀释反应液，之后用10mL乙酸乙酯萃取水相三次，有机相真空浓缩后经柱层析分离，以乙酸乙酯/石油醚(20/80,v/v)为洗脱剂，收集含有产物的液体，浓缩后得到化合物26为红棕色油状液体(1.81g,54.6％)。
1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.20(s,1H),7.30-7.16(m,2H),4.00 (t,J＝6.5Hz,2H),1.82-1.80(m,2H),1.52-1.42(m,2H),1.40-1.22(m,12H),0.89(t, J＝6.8Hz,3H)；13C NMR(126MHz,CDCl3)δ155.3,141.9,138.1,123.8,121.0, 68.3,31.9,29.6,29.5,29.4,29.3,29.2,26.0,22.7,14.1.
实施例26
将化合物1(0.71g,3.99mmol)溶解于10mL乙腈中，加入化合物26(0.95 g,4.00mmol)，加热充分回流过夜。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(15/85,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物18为白色固体(1.33g,72.6％)。
1H NMR(500MHz,D2O)δ8.58(s,1H),8.52(t,J＝2.8Hz,1H),7.97-7.90(m, 2H),4.60(t,J＝6.3Hz,2H),4.17(t,J＝6.1Hz,2H),2.28-2.18(m,4H),1.77-1.66 (m,2H),1.42-1.34(m,2H),1.28-1.18(m,12H),1.10(s,9H),0.80(t,J＝6.8Hz,3H)；13C NMR(126MHz,D2O)δ172.6,157.8,137.6,131.5,131.2,129.0,70.4,61.8,50.7, 32.6,31.9,29.7,29.5,29.4,28.7,28.1,26.2,25.8,22.6,13.8；HRMS calcd.for C23H41N2O2[M-Cl]+377.3174,found:377.3168.
实施例27
将化合物18(0.6g,1.45mmol)溶于5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.55g,0.58mL,5.08mmol)，常温条件下避光搅拌反应 24h，真空浓缩反应液可到粘稠状固体19。
1H NMR(500MHz,D2O)δ8.64-8.53(m,2H),8.08-7.89(m,2H),4.65(t,J＝ 6.3Hz,2H),4.20(t,J＝6.1Hz,2H),2.68(t,J＝6.6Hz,2H),2.29-2.16(m,2H), 1.80-1.68(m,2H),1.43-1.33(m,2H),1.27(s,9H),1.22-1.14(m,12H),0.76(t,J＝ 6.7Hz,3H)；13C NMR(126MHz,D2O)δ175.5,157.8,137.7,131.5,131.2,129.1, 70.4,64.4,61.6,32.8,31.9,29.7,29.6,29.5,29.4,28.6,28.3,25.9,25.9,22.6,13.8.
实施例28
参照专利(CN 105968043A)中的方法：将3-羟基吡啶(1.20g,12.6mmol) 溶解于10mLN,N-二甲基甲酰胺中，加入氢氧化钾(1.42g,25.2mmol)和1-溴代十二烷(3.15g,3.03mL,12.6mmol)，70℃条件下反应2h；反应结束后加入 20mL水稀释反应液，之后用10mL乙酸乙酯萃取水相三次，有机相真空浓缩后经柱层析分离，以乙酸乙酯/石油醚(20/80,v/v)为洗脱剂，收集含有产物的液体，浓缩后得到化合物27为红棕色油状液体(1.56g,52.3％)。
1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.20(s,1H),7.20(s,2H),4.00(t,J ＝6.5Hz,2H),1.80(m,2H),1.52-1.43(m,2H),1.39-1.23(m,16H),0.89(t,J＝6.9 Hz,3H)；13CNMR(126MHz,CDCl3)δ155.2,141.9,138.1,123.7,121.0,68.3,31.9, 29.7,29.6,29.6,29.6,29.4,29.2,26.0,22.7,14.1.
实施例29
将化合物1(0.58g,3.26mmol)溶解于10mL乙腈中，加入化合物27(0.90 g,3.40mmol)，加热充分回流过夜。真空条件下除去溶剂后进行硅胶层析柱分离，以甲醇/二氯甲烷(15/85,v/v)为洗脱剂，收集含有产物的液体。在真空条件下除去溶剂，得到化合物20为白色固体(1.08g,75.1％)。
1H NMR(500MHz,D2O)δ8.60(s,1H),8.55-8.47(m,1H),7.96-7.89(m,2H), 4.60(t,J＝6.3Hz,2H),4.16(t,J＝5.9Hz,2H),2.26-2.18(m,4H),1.77-1.66(m, 2H),1.42-1.34(m,2H),1.26-1.18(m,16H),1.10(s,9H),0.81(t,J＝6.6Hz,3H)；13C NMR(126MHz,D2O)δ172.5,157.8,137.7,131.5,131.2,129.0,70.4,61.8,50.6, 32.6,32.0,29.9,29.8,29.8,29.6,29.5,28.8,28.1,26.2,25.9,22.6,13.9；HRMS calcd. for C25H45N2O2[M-Cl]+405.3483,found:405.3481.
实施例30
将化合物20(0.6g,1.36mmol)溶于5mL叔丁醇-水混合溶剂(v/v＝4:1)，之后加入次氯酸叔丁酯(0.52g,0.54ml,4.76mmol)，常温条件下避光搅拌反应 24h，真空浓缩反应液可到粘稠状固体21。
1H NMR(500MHz,D2O)δ8.64-8.56(m,2H),8.05-7.95(m,2H),4.60(t,J＝ 6.0Hz,2H),4.20(t,J＝6.2Hz,2H),2.28-2.17(m,2H),1.81-1.66(m,2H),1.42-1.33 (m,2H),1.27(s,9H),1.22-1.15(m,16H),0.78(t,J＝6.6Hz,3H)；13C NMR(126 MHz,D2O)δ175.5,157.8,137.8,131.5,131.2,129.2,70.4,64.3,61.6,32.9,32.0, 29.9,29.9,29.8,29.7,29.6,29.5,28.7,28.4,26.0,26.0,22.6,13.9。

Claims (8)

1.一种阳离子型线性氯胺抗菌剂，其特征在于，该阳离子型线性氯胺抗菌剂的分子的结构式为(Ⅰ)：
式(I)中，n＝1-8；R为其中R1为C1-C12烷基；R2，R3不存在或为(-OCH3)-(OC12H25)。
2.一种阳离子型线性氯胺抗菌剂的合成方法，其特征在于，步骤如下：
(1)将N-叔丁基-氯烷基酰胺Ⅱ溶于有机溶剂，再加入化合物Ⅳ，100℃回流12～18h，反应结束后经柱层析分离得到阳离子型氯胺前体化合物Ⅲ；
(2)将阳离子型氯胺前体化合物Ⅲ完全溶解于叔丁醇-水的混合溶液中，加入次氯酸叔丁酯，常温条件下避光搅拌24～48h，真空浓缩反应液即得到氯胺化合物Ⅰ；
合成路线如下：
3.根据权利要求2所述的合成方法，其特征在于，
步骤(1)中所述化合物Ⅳ为携不同烷基链的叔胺化合物Ⅳ1、携不同烷基链的吡啶化合物Ⅳ2或三丁基膦，其中n2＝0,8,10,12。
4.根据权利要求3所述的合成方法，其特征在于，
步骤(1)中所述的N-叔丁基-氯烷基酰胺Ⅱ与化合物Ⅳ的摩尔比是1:1～1.5。
5.根据权利要求2或3所述的合成方法，其特征在于，
步骤(1)中所述的有机溶剂为乙醇、乙腈、水、N,N-二甲基甲酰胺中的一种。
6.根据权利要求5所述的合成方法，其特征在于，
步骤(2)中所述的次氯酸叔丁酯与阳离子型氯胺前体化合物Ⅲ的摩尔比是2.5～4:1。
7.根据权利要求6所述的合成方法，其特征在于，
步骤(2)中所述的叔丁醇-水混合溶剂中叔丁醇与水的体积比为4:1。
8.根据权利要求7所述的合成方法，其特征在于，
步骤(1)中所述的N-叔丁基-氯烷基酰胺Ⅱ的结构式为ClCO(CH2)n1Cl，其中n1＝1,2,3,4,5,6,7,8。
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