CN109627240B - 一种吲哚类化合物、其合成方法及其防污用途 - Google Patents

一种吲哚类化合物、其合成方法及其防污用途 Download PDF

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CN109627240B
CN109627240B CN201811465472.9A CN201811465472A CN109627240B CN 109627240 B CN109627240 B CN 109627240B CN 201811465472 A CN201811465472 A CN 201811465472A CN 109627240 B CN109627240 B CN 109627240B
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郑绍军
朱瑞
魏洋
韩珂
唐冰
蔡星伟
陈立庄
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Abstract

本发明涉及吲哚类化合物、其合成方法及其防污用途。该化合物的结构式是：

Description

一种吲哚类化合物、其合成方法及其防污用途
技术领域
本发明涉及一种吲哚类化合物及其防污活性，具体而言是在船舶、码头设备、海洋钻井平台支柱等防污方面的用途。
背景技术
海洋污损生物又称为海洋附着生物，通常是指生长在船舶外壳水线下部分和海洋人工设施表面上，并对人类的经济活动带来巨大损失的海洋生物，包括海洋动物、植物和微生物。海洋生物污损对被附着物的影响有三大类:(1)加速金属腐蚀；(2)降低海洋设施性能；(3)影响水产养殖业产量和质量。以船舶为例，海洋生物在船底的附着，使船舶的燃料消耗增加40％,航行代价高达77％,为此全球每年要多花掉大约30亿美元。此外，海洋生物污损对海洋码头设备、海水冷却管道、发电厂冷却塔、海洋钻井平台支柱等的腐蚀破坏亦很严重。船体防污涂料是一种具有特殊效用的涂漆材料，涂在船体上既能使船看上去美观，又能抵挡海洋的腐蚀，阻挡海洋生物对船体的碰撞和伤害。防污涂料一般涂装于海洋水下设施和船底防锈漆之上，位于最外层。其主要作用是通过漆膜中毒料的水解、扩散或渗出等方式逐步释放毒料，达到防止海洋生物附着于海洋水下设施或船底的目的。涂刷含有机锡等有毒防污剂的防污涂料能够有效防止海洋生物附着，然而这种防污涂料在高效防污的同时严重危害海洋生态环境。国际海事组织(IMO)明确规定，自2008年1月1日起，全球禁止使用含有机锡防污涂料。目前，含铜自抛光防污涂料是有机锡涂料的最好替代品，但研究发现铜离子也会在海洋中，特别是在海港中大量积聚，破坏生态平衡。因此，含铜防污涂料最终也将被禁用。
因此，开发出环境友好型海洋防污涂料成为当今海洋科学技术中急需解决的重大技术问题之一。天然产物活性物质是环境友好型防污剂，是未来防污剂的发展方向。天然产物防污剂具有低毒无污染的优点，但是提取活性物质不仅操作困难、步骤繁琐，而且含量特别低，难于工业化生产。因此，根据天然产物的结构特点，人类可以通过化学合成方法得到大量的具有防污活性的天然产物及其类似物，满足工业化生产需求。吲哚类防污剂是目前为止最具有发展前景的防污剂，对吲哚类化合物作为防污剂的研究已取得很大的进展，然而目前关于吲哚类防污剂的研究主要集中在3-位上有取代基的吲哚-3-甲醛类和芦竹碱类的化合物，而对于其他结构的吲哚化合物的防污活性的研究却未见详细的报道，因此发展一种经济、高效合成吲哚类化合物的方法对该领域的发展将带来重大的经济效益以及社会效益。
发明内容
为了克服现有技术的不足，本发明的目的是提供一种吲哚类化合物及其合成方法，其对多种细菌(海洋污损生物)具有良好的防污活性。
为了实现上述目的，本发明采用了以下的技术方案：
一种具有通式(I)的吲哚类化合物：
Figure BDA0001889690830000021
R1可选自以下1-6基团之任意一种，相应地所得化合物1-6；
Figure BDA0001889690830000031
具有通式(I)的吲哚类化合物的合成路线如下：
Figure BDA0001889690830000032
上述合成路线具体说明如下：
(1)取反应试剂于干燥的圆底烧瓶中，加入无水二氯甲烷，然后加入二氯亚砜，加热回流，减压蒸去二氯甲烷和过量的二氯亚砜，得到反应试剂的酰氯化产物。
(2)称取底物a，置于干燥的圆底烧瓶中，加入无水二氯甲烷搅拌溶解，向其中滴加三乙胺，搅拌后，将体系置冰水浴中，缓慢滴加步骤(1)制备的酰氯化产物的二氯甲烷溶液，待滴加完全，将反应液移至室温下搅拌，检测，底物反应完全。向反应液中滴加饱和NaHCO3淬灭反应，有机相用二氯甲烷萃取，合并有机相，减压浓缩，粗产物用柱层析分离得到吲哚类化合物。
所述的反应试剂是：邻氟苯甲酸、间氟苯甲酸、对氟苯甲酸、间甲苯甲酸、对甲苯甲酸、苯甲酸。
与现有技术相比，本发明具有下述优点和有益效果:
(1)本发明提供的吲哚类化合物结构简单原料易得，反应条件温和，工艺简单。
(2)本发明提供的化合物具有防污用途，例如六氢吡咯并吲哚类化合物比 TBTO具有更高的防污活性。
具体实施方式
下面结合实施例，对本发明作详细说明。
实施例1
Figure BDA0001889690830000041
步骤(1)、先将邻氟苯甲酸制备成邻氟苯甲酰氯：取146mg(1.2mmol)的邻氟苯甲酸于干燥的25mL的圆底烧瓶中，加入10mL无水二氯甲烷，然后加入二氯亚砜0.13mL(1.8mmol)，加热回流2h，减压蒸去二氯甲烷和过量的二氯亚砜，得到邻氟苯甲酰氯。
步骤(2)、称取200mg底物a，置于25mL干燥的圆底烧瓶中，加入10mL 的无水二氯甲烷搅拌溶解，向其中滴加三乙胺0.13mL(0.90mmol)，搅拌20min 后，将体系置于0℃的冰水浴中，缓慢滴加苯甲酰氯的二氯甲烷溶液，待滴加完全，将反应液移至室温下搅拌2h，TLC(PE:EA＝4:1)检测，底物反应完全。向反应液中滴加适量饱和NaHCO3淬灭反应，有机相用二氯甲烷萃取3次，合并有机相，用饱和NaCl溶液洗涤3次，无水NaSO4干燥。减压浓缩，粗产物用柱层析分离(PE:EA＝6:1)，得到217mg N位苯甲酸衍生物1(87％)。衍生物2- 6的合成方法与上述方法相同。
白色油状，1H-NMR(400MHz,CDCl3),δ8.16–6.96(m,6H),6.87–6.37(m, 2H),5.88–4.62(m,1H),4.53–4.01(m,1H),3.47–3.20(m,1H),3.06(ddd,J＝ 12.9,7.5,5.3Hz,1H),2.66(s,3H),2.09–1.68(m,2H),1.55–0.84(m,2H).13C NMR(100MHz,CDCl3)δ168.56(C),159.05(C),148.87(C),134.95(C), 133.28(CH),131.49(CH),129.61(C),129.42(CH),129.02(CH),124.85(CH), 124.39(CH),121.97(CH),119.31(CH),108.43(CH),87.02(C),42.37(CH2), 37.79(CH3),33.12(CH2),19.09(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0。
实施例2-6所采用的反应试剂、所得吲哚类化合物的分子式以及形状，如表1所示：
表 1
Figure BDA0001889690830000051
所得化合物的形状具体说明如下：
实施例2
Figure BDA0001889690830000052
白色油状，1H-NMR(400MHz,CDCl3),δ7.98–6.99(m,6H),6.88–6.39(m, 2H),5.86–4.72(m,1H),4.44–4.01(m,1H),3.66–3.17(m,1H),3.10(dt,J＝12.9, 6.1Hz,1H),2.64(s,3H),2.12–1.72(m,2H),1.56–0.84(m,2H).13C NMR(100 MHz,CDCl3)δ171.52(C),164.58(C),148.86(C),137.62(C),132.30(C),129.70(CH), 125.85(CH),123.58(CH),122.10(CH),120.40(CH),119.43(CH),117.06(CH), 115.01(CH),108.24(CH),86.74(C),43.19(CH2),38.25(CH3),34.19(CH2), 18.29(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0。
实施例3
Figure BDA0001889690830000061
无色油状，1H-NMR(400MHz,CDCl3),δ7.74–7.37(m,2H),7.25–6.95(m, 4H),6.88–6.32(m,2H),5.28(s,1H),4.43–4.00(m,1H),3.64–3.16(m,1H),3.14 –2.79(m,3H),2.60(m,2H),2.09–1.67(m,1H),1.57–1.22(m,1H).13C NMR (100MHz,CDCl3)δ172.16(C),163.35(C),148.92(C),133.43(C),132.32(C), 131.63(CH),130.24(CH),130.15(CH),129.64(CH),129.39(CH),122.15(CH), 119.32(CH),115.65(CH),108.13(CH),86.84(C),43.31(CH2),38.35(CH3), 34.16(CH2),18.24(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0。
实施例4
Figure BDA0001889690830000071
白色油状，1H-NMR(400MHz,CDCl3),δ7.33–7.08(m,6H),6.86–6.40(m, 2H),5.93–4.83(m,1H),4.44–4.01(m,1H),3.66–3.16(m,1H),3.08(dt,J＝12.7, 6.1Hz,3H),2.81–2.28(m,3H),2.05–1.94(m,1H),1.94–1.69(m,2H),1.55– 1.19(m,1H).13C NMR(100MHz,CDCl3)δ173.20(C),148.98(C),138.31(C), 135.63(C),132.46(C),130.39(CH),129.61(CH),128.34(CH),127.55(CH), 124.79(CH),123.84(CH),122.10(CH),119.19(CH),108.06(CH),86.69(C), 43.13(CH2),38.03(CH3),34.15(CH2),21.41(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1。
实施例5
Figure BDA0001889690830000072
淡黄色固体，1H-NMR(400MHz,CDCl3),δ7.99–7.51(m,1H),7.38(dd,J＝ 13.3,7.5Hz,2H),7.30–7.10(m,4H),6.84–6.37(m,2H),5.35(s,1H),4.43–3.52 (m,1H),3.28–2.95(m,1H),2.61(s,3H),2.43–2.28(m,3H),2.03–1.70(m,2H), 1.54–0.83(m,2H).13CNMR(100MHz,CDCl3)δ173.37(C),148.98(C), 144.10(C),139.80(C),132.68(C),130.16(CH),129.10(CH),129.07(CH), 127.90(CH),127.15(CH),127.00(CH),122.14(CH),119.16(CH),108.01(CH), 86.69(C),43.27(CH2),38.16(CH3),34.18(CH2),21.39(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1。
实施例6
Figure BDA0001889690830000081
白色固体，1H-NMR(400MHz,CDCl3),δ7.51–7.03(m,7H),6.88–6.39(m, 2H),5.78–4.56(m,1H),4.44–4.14(m,1H),3.95–3.17(m,1H),3.09(dt,J＝12.7, 6.1Hz,1H),2.89–2.45(m,3H),2.08–1.93(m,1H),1.87–1.70(m,1H),1.45– 1.21(m,1H),0.99–0.82(m,1H).13C NMR(100MHz,CDCl3)δ173.04(C), 148.94(C),135.67(C),132.43(C),130.03(CH),129.69(CH),129.61(CH), 129.38(CH),128.47(CH),127.76(CH),126.97(CH),122.11(CH),119.24(CH), 108.10(CH),86.69(C),43.18(CH2),38.09(CH3),34.17(CH2),18.37(CH2)。
MS(ESI(+))calcd for C19H20N2O2[M+H]+:308.4；found:309.1。
实施例7：杀菌活性测定
微量稀释法：将样品溶解于浓度为1％的DMSO中，初始样品浓度配制成1 mg/mL，经2倍系列浓度稀释，得到系列浓度分别为250.00、125.00、62.50、 31.25、15.63、7.81、3.91、1.96、0.98、0.59μg/mL的样品溶液。向96孔板中每孔加入100μL液体培养基，实验组每孔加入100μL样品溶液进行二倍稀释，再加入100μL浓度为1×106spores/mL的菌液，对照组则只加入100μL菌液，将96孔加盖，用膜密封，置于恒温培养箱中，细菌在37℃条件下培养24h，植物病原真菌和人体病原真菌在28℃条件下培养48～72h，将96孔板取出，然后读取最小抑制浓度(MIC)值。含吲哚类化合物对两种细菌的检测结果见表2。
表2化合物对革兰氏阴性细菌的MIC
Figure BDA0001889690830000091
通过活性分析发现实施例6所得化合物对茄科罗尔斯通氏菌的MIC为62.50 μg/mL与阳性对照庆大霉素(62.50μg/mL)相当，优于阳性对照链霉素(250.00 μg/mL)。

Claims (5)

1.通式(I)的吲哚类化合物：
Figure FDA0002976249350000011
R1可选自以下1-6基团之任意一种：
Figure FDA0002976249350000012
2.权利要求1所述的具有通式(I)的吲哚类化合物的合成路线如下：
Figure FDA0002976249350000013
3.权利要求1所述的吲哚类化合物的合成方法，其特征在于，步骤如下：
(1)制备反应试剂的无水二氯甲烷溶液，加入二氯亚砜，加热回流，减压蒸去二氯甲烷和过量的二氯亚砜，得到反应试剂的酰氯化产物；
(2)称取底物a
Figure FDA0002976249350000014
置于干燥的圆底烧瓶中，加入无水二氯甲烷搅拌溶解，向其中滴加三乙胺，搅拌后，将体系置冰水浴中，缓慢滴加步骤(1)制备的酰氯化产物的二氯甲烷溶液，待滴加完全，将反应液移至室温下搅拌，检测，底物反应完全，淬灭反应，有机相用二氯甲烷萃取，合并有机相，减压浓缩，粗产物用柱层析分离得到吲哚类化合物。
4.权利要求3所述的吲哚类化合物的合成方法，其特征在于所述的反应试剂是：邻氟苯甲酸、间氟苯甲酸、对氟苯甲酸、间甲苯甲酸、对甲苯甲酸、苯甲酸。
5.权利要求1所述的吲哚类化合物是针对海洋污损生物的防污用途。
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