WO2022135397A1 - 手性吲哚类化合物、其制备方法及船舶防污用途 - Google Patents

手性吲哚类化合物、其制备方法及船舶防污用途 Download PDF

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WO2022135397A1
WO2022135397A1 PCT/CN2021/140092 CN2021140092W WO2022135397A1 WO 2022135397 A1 WO2022135397 A1 WO 2022135397A1 CN 2021140092 W CN2021140092 W CN 2021140092W WO 2022135397 A1 WO2022135397 A1 WO 2022135397A1
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compound
chiral
room temperature
indole
antifouling
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郑绍军
林传颂
武文斌
谈祎
戴慧慧
方越
朱瑞
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Shanghai Shipbuiding Technology Research Institute Zhoushan Ship Engineering Research Center
Jiangsu University of Science and Technology
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Jiangsu University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

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  • the purpose of the present invention is to provide a novel chiral 3-cyclic indole compound, its preparation method and use in ship antifouling.
  • Marine biofouling refers to the phenomenon that micro-fouling organisms and large-scale fouling organisms in seawater adhere and accumulate on the surface of substrates soaked in seawater, which adversely affects human production activities and the marine ecological environment. Marine biofouling has always been a big problem for the shipping industry, costing an estimated $200 billion annually. Sea creatures not only cause additional fuel consumption and reduce the service life of ships, but also increase carbon dioxide emissions. According to Lloyd's Register, the world's annual increase in fuel consumption by 28% will result in an additional 250 million tons of carbon dioxide emissions.
  • the most important antifouling means is to apply antifouling coatings containing highly effective antifouling active compounds.
  • the commercial antifouling agents with heavy metals such as tributyl tin and cuprous oxide as the main anti-fouling components which were once widely used, are toxic to various organisms and are seriously enriched in the seabed silt. , posing a serious threat to the marine ecological environment and human health.
  • IMO International Maritime Organization
  • Cuprous oxide coatings have also been included in the "high pollution, high environmental risk” product list by the Ministry of Environmental Protection of my country, and have been banned from use in 2012. With the increasingly strict international environmental protection regulations and the requirements of developing a low-carbon economy, it is more and more important to develop antifouling coatings with high performance, saving energy and resources, convenient and efficient construction, environmental friendly and healthy. Therefore, exploring safe and effective environmentally friendly anti-fouling coatings (compounds) is an urgent problem to be solved in this field.
  • R1 and R2 represent mono- or polysubstituted benzyl groups, and R1 and R2 can be the same substituents.
  • the synthetic route selects indole-3-acetonitrile as the synthetic starting material. It has the advantages of high yield and easy separation. These compounds have varying degrees of inhibitory effect on Staphylococcus aureus and Escherichia coli, and can be developed into antifouling agents with potential application value in ship antifouling.
  • the application number CN201811465472.9 filed on 2018.12.03 discloses indole compounds, their synthesis methods and their antifouling uses.
  • the structural formula of this compound is: The preparation method is as follows: firstly, the reaction reagent is prepared to obtain the acid chloride product.
  • haloindole and its derivatives as marine antifouling agents.
  • one or more of the halogenated indole derivatives are mixed with the antifouling paint as an active ingredient and used as a marine antifouling agent, wherein the active ingredient is 1%-20% by weight of the antifouling paint.
  • the molecular formula of the haloindole derivative is C 8 H m NR 1 R 2 .
  • indole compounds as antifouling research objects have great application value.
  • most of the currently synthesized indole antifouling compounds are achiral isomer mixtures, that is, the mixture of levorotatory and dextrorotatory isomers.
  • multiple studies have shown that one of the isomers is responsible for the antifouling effect, while the other is not. Therefore, a lot of raw materials are wasted, the cost is increased, and the environment is polluted.
  • the purpose of the present invention is to provide a chiral indole compound, its preparation method and its antifouling activity on ships, and a variety of fungi have good antifouling activity.
  • the present invention controls its stereoselective synthesis through a special catalyst, so that only a single isomer antifouling compound is generated, which improves the antifouling activity and reduces pollution.
  • Described catalyst structural formula is as follows:
  • Organo-Cation Catalyzed Asymmetric Homo/Heterodialkylation of Bisoxindoles Construction of Vicinal All-Carbon Quaternary Stereocenters and Total Synthesis of(-)-Chimonanthidine Si-Kai Chen, Wen-Qiang Ma, Zhi- Bo Yan, Fu-Min Zhang, Shao-Hua Wang, Yong-Qiang Tu*, Xiao-Ming Zhang, and Jin-Miao Tian J.Am.Chem.Soc.2018,140,10099-10103.
  • Phthalimide was dissolved in dimethylformamide, sodium hydride was added, the reaction was carried out at room temperature for 5 minutes, compound 4 was added, and the reaction was carried out at room temperature for 30 minutes. React in a sealed tube at 100 degrees for 4 hours. Then cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over sodium sulfate, and purified to obtain compound 6.
  • the present invention has the following advantages:
  • the chiral 3-cyclic indole compounds provided by the present invention have the advantages of simple structure, easy availability of raw materials, mild reaction conditions, simple process, antibacterial properties, and are suitable for antifouling of ships.
  • the chiral 3-cyclic indole compounds provided by the present invention not only have higher antifouling activity than traditional TBTO and cuprous oxide, but also have outstanding antifouling properties among similar indole antifouling compounds. fouling activity.
  • Example 2 Determination of bactericidal activity against synthetic compounds
  • the antibacterial activity of target product 10 against Staphylococcus aureus and Escherichia coli was determined by microdilution method.
  • the strains were purchased from the China General Microorganism Culture Collection Center.
  • test tube double dilution method take a sterilized test tube with 2 mL of liquid culture medium.
  • the test tube without the test compound and inoculated with bacteria is used as the positive control, and the test tube without the test compound or inoculated with bacteria is used as the negative control.
  • the initial mass concentration of the drug was 1 g/L, which was diluted by two times in turn and mixed evenly.
  • the minimum inhibitory mass concentration was determined according to the growth of bacteria in the test tube.
  • the chiral 3-cyclic indole compounds provided by the present invention not only have higher antifouling activity than traditional TBTO and cuprous oxide, but also have outstanding antifouling activity among similar indole antifouling compounds.
  • the performance of this product is better than that of commercial TBG (the minimum inhibitory mass concentration of TBG to two bacteria is 0.0625 and 0.1250g/L).

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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

本发明涉及式(I)所示手性3-环吲哚类化合物其以3-甲基羟基吲哚为原料，在手性催化剂的作用下，得到手性中间体，再经过4步反应获得具有防污潜力的手性化合物，提高了原子利用率。工艺简单、产品纯度高，对大肠杆菌和金黄色葡萄球菌具有很高的杀菌活性，具有优良的船舶防污应用前景。

Description

手性吲哚类化合物、其制备方法及船舶防污用途 技术领域
本发明的目的在于提供一种新型的手性3-环吲哚类化合物、其制备方法及在船舶防污方面的用途。
背景技术
海洋生物污损是指海水中的微型污损生物和大型污损生物附着聚积在被海水浸泡的基质表面，对人类生产活动和海洋生态环境带来不利影响的现象。海洋生物污损问题一直是困扰航运业的大问题，每年为此所付出的花费约达2000亿美元。海生物附着不仅引起额外的燃油消耗，降低船舶的使用寿命，同时增加了二氧化碳的排放。据劳氏船级社的数据，世界每年所增加的28％的燃油消耗将会带来额外2.5亿顿的二氧化碳排放。
目前最主要的防污手段为涂布含有高效抗污损活性化合物的防污涂料。但随着时间推移，科研工作者发现曾一度被广泛使用的以三丁基锡、氧化亚铜等重金属为主要抗污损成分的商品防污剂对多种生物具有毒性且在海底淤泥中严重富集，对海洋生态环境及人类健康构成严重威胁。根据国际海事组织(International Maritime Organization，IMO)规定，从2008年9月17日起，所有含三丁基锡的防污损油漆都已经禁止在船舶上使用。氧化亚铜涂料也已被我国环保部列入“高污染、高环境风险”产品名录，并已于2012年被禁止使用。随着 国际环保法规的日趋严格和发展低碳经济的要求，研制高性能、节省能源和资源、施工方便高效、环境友好健康的防污涂料越来越重要。因此，探索安全有效的环境友好型抗污损涂料(化合物)是目前该领域亟需解决的问题。
将具有抗污损活性的化合物开发成防污涂料是目前防治海洋生物污损的最常用手段之一。吲哚类防污剂具有的低毒、高效等优点正是现代防污剂发展的重要方向。然而这种活性物质在自然界中的含量毕竟有限，加上分离提纯技术，获取成本等诸多因素的限制，来自自然界的产量根本无法满足人类社会的需求。因此，根据吲哚类化合物的结构特点，人类可以通过化学合成方法得到具有防污活性的吲哚类化合物，满足工业化生产需求。
虽然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。发明人本人于2016.12.07提交的申请号为CN201611113112.3的发明专利申请，公开了具有式(Ⅰ)结构的六氢吡咯并吲哚类化合物，
Figure PCTCN2021140092-appb-000001
其中取代基R1、R2代表单取代或多取代苄基，R1、R2可以为相同的取代基。其合成路线选用吲哚-3-乙腈为合成起始原料。具有产率高、易分离等优点。这类化合物对金黄色葡萄球菌和大肠杆菌具有程度不等的抑制作用，可开发成在船舶防污方面具有潜在应用价值的防污剂。2018.12.03提交的申请号为CN201811465472.9专利申请文件公开了吲哚类化合物、其合成方法及其防污用 途。该化合物的结构式是：
Figure PCTCN2021140092-appb-000002
制备方法是先将反应试剂制备得到酰氯化产物。称取底物a的无水二氯甲烷溶液中，滴加三乙胺，冰水浴条件下，滴加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。合成工艺简单、产品纯度高，对金黄色葡萄球菌、茄科罗尔斯通氏菌和蜡状芽孢杆菌均有很高的杀菌活性，具有优良的应用前景。中国科学院烟台海岸带研究于2013.03.26所提交的申请号为CN201310098503.2的专利申请文件，公开了卤代吲哚及其衍生物作为海洋防污剂的应用。使用时，卤代吲哚衍生物中的一种或几种作为有效成分与防污涂料混合作为海洋防污剂的应用，其中所述其有效成分为防污涂料重量的1％-20％。卤代吲哚衍生物的分子式为C 8H mNR 1R 2。
以上研究表明，以吲哚类化合物作为防污的研究对象，具有巨大的应用价值。然而，目前大多数所合成的吲哚类防污化合物，都是非手性的异构体混合物，即左旋体和右旋体的混合物。但多项研究表明是其中的一种异构体发挥防污作用，而另一种异构体并无效果。因此，造成了大量的原料浪费，增加了成本，也污染了环境。
发明内容
为了克服现有技术存在的不足，本发明的目的是提供手性吲哚类化合物、其制备方法及其船舶防污活性，多种菌类具有良好的防污活性。本发明通过特 殊催化剂，控制其立体选择性合成，使其只生成一种单一的异构体防污化合物，提升了防污活性，减少了污染。
为了实现上述发明目的，本发明采用了以下的技术方案：
式(I)所示的手性3-环吲哚类化合物
Figure PCTCN2021140092-appb-000003
上述化合物的合成路线如下：
Figure PCTCN2021140092-appb-000004
上述合成路线详细叙述如下：
(1)3-甲基羟基吲哚溶于DCM，加入(Boc) 2O，室温下搅拌，滴加少量三乙胺，反应30min，乙酸乙酯萃取，脱溶，Boc保护的3-甲基羟基吲哚；
(2)Boc保护的3-甲基羟基吲哚溶于[bpy][BF 4]中，在手性催化剂作用下，与化合物2发生迈克尔反应，室温下反应4h，乙酸乙酯萃取，脱溶，得到手性化合物3；
所述的催化剂结构式如下：
Figure PCTCN2021140092-appb-000005
合成方法是参照下列文献进行：Organo-Cation Catalyzed Asymmetric Homo/Heterodialkylation of Bisoxindoles:Construction of V icinal All-Carbon Quaternary Stereocenters and Total Synthesis of(-)-Chimonanthidine Si-Kai Che n,Wen-Qiang Ma,Zhi-Bo Yan,Fu-Min Zhang,Shao-Hua Wang,Yong-Qiang Tu*,Xiao-Ming Zhan g,and Jin-Miao Tian J.Am.Chem.Soc.2018,140,10099-10103。
(3)向手性化合物3和碘化钠的混合物中加入[bpy][BF 4]，40℃下反应8h，乙酸乙酯萃取，脱溶，得到化合物4；
(4)邻苯二甲酰亚胺溶于二甲基甲酰胺中，加入氢化钠，室温下反应5分钟，加入化合物4，室温下反应30分钟。100度下在封管中反应4个小时。然后冷却到室温，加水淬灭，乙酸乙酯萃取，硫酸钠干燥，纯化后得到化合物6。
(5)化合物6溶于DCM中，加入氢氧化钾，70℃下反应18h，得到化合物7，关环后生成化合物8。
(6)化合物8溶于无水吡啶中，冰水浴下加入化合物9，然后室温下反应半小时得到目标化合物10。
与现有技术相比，本发明具有下述优点：
(1)本发明提供的手性3-环吲哚类化合物具有结构简单原料易得，反应条件温和，工艺简单，具有抗菌性，适合用于船舶防污。
(2)利用催化剂，得到手性化合物，提高了原子利用率。
(3)本发明提供的手性3-环吲哚类化合物不仅比传统的TBTO和氧化亚铜具有更高的防污活性，而且在同类吲哚类防污化合物中，也体现了突出的防污活性。
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
(1)中间体化合物1的合成
Figure PCTCN2021140092-appb-000006
称取1.47g(10mmol)的3-甲基羟基吲哚于250mL的干燥圆底烧瓶中，加入30mL DCM，室温下搅拌15min使其完全溶解，将反应液置于0℃的冰浴中，然后用恒压漏斗向其中缓慢滴加100mL Boc酸酐，待滴加完全后将反应液移至室温搅拌30min。加入50mL水稀释，用无水K 2CO 3或无水Na 2CO 3固体调pH值，边搅拌，边检测溶液的pH值，将溶液的pH值调制在7～8之间。将整个体系移至室温下，用乙酸乙酯萃取(3×100mL)，合并有机相，有机相分别用饱和氯化钠(3×50mL)洗涤，无水硫酸钠干燥，减压浓缩，得到2.24g的化合物1(产率91％)。
(2)中间体化合物3的合成
Figure PCTCN2021140092-appb-000007
称取247mg化合物1(1mmol)于100mL干燥的圆底烧瓶中，并缓慢加入于5mL的[bpy][BF 4]，搅拌10min,加入手性催化剂(0.1mmol,56mg)，然后加入化合物2(259mg,1.2mmol),室温下搅拌6h,用乙酸乙酯萃取(3×50mL)，合并有机相，有机相分别用饱和氯化钠(3×10mL)洗涤，无水硫酸钠干燥，减压浓缩，得到406mg的手性化合物3(产率87％)。
性能检测：无色液体。产率86％,ee 94％,[a] D 20-8.0(c 0.5,DCM)。m.p.86-88℃. 1H-NMR(CDCl 3,500MHz):δ7.92-7.88(d,J＝8.1Hz,1H),δ7.42-7.39(m,1H),δ7.26-7.20(d,J＝4.2Hz,2H),δ2.99-2.91(m,1H),δ2.85-2.73(m,1H),δ2.72-2.68(m,1H),δ2.45-2.39(m,1H),δ1.68(s,9H),δ1.46(s,3H).MS-ESI m/z:464.10[M+H] +。
(3)中间体化合物4的合成
Figure PCTCN2021140092-appb-000008
称取93mg(0.2mmol)的化合物3于100mL干燥的圆底烧瓶中，加入碘化钠(90mg,0.6mmol)，搅拌15min后加入[bpy][BF 4](0.5mL)，在40度下反应12h,用乙酸乙酯萃取(3×20mL)，合并有机相，有机相分别用饱和氯化钠(3×10mL)洗涤，无水硫酸钠干燥，减压浓缩，得到74mg的化合物3(产率90％)。
性能检测：无色液体。产率93％，ee 95％,[a] D 20-33.9(c 1.25,DCM)。 1H-NMR(CDCl 3,500MHz):δ7.90-7.93(s,1H；d,J＝1.2Hz,1H),δ7.81-7.83(d,J＝7.8Hz,1H),δ7.71-7.76(t,J＝7.2Hz,1H),δ7.62-7.67(t,J＝7.2Hz,2H),δ7.31-7.36(m,1H),δ7.19-7.24(m,2H),δ3.29-3.39(m,1H),δ3.14-3.23(m,1H),δ2.33-2.52(m,2H),δ1.64(s,9H),δ1.46(s,3H)。MS-ESI m/z:402.06[M+H] +。
(4)中间体化合物6的合成
Figure PCTCN2021140092-appb-000009
称取176mg(1.2mmol)的化合物5于100mL干燥的圆底烧瓶中，加入氢化钠(36mg,1.5mmol)，搅拌15min后加入化合物4(401mg,1mmol)，室温下反应8h,用乙酸乙酯萃取(3×20mL)，合并有机相，有机相分别用饱和氯化钠(3×10mL)洗涤，无水硫酸钠干燥，减压浓缩，得到328mg的化合物6(产率78％)。
(5)中间体化合物8的合成
Figure PCTCN2021140092-appb-000010
称取420mg(1mmol)的化合物6于100mL干燥的圆底烧瓶中，加入氢氧化钾(84mg,1.5mmol)，在50度下反应2h,用乙酸乙酯萃取(3×20mL)，合并有机相，有机相分别用饱和氯化钠(3×10mL)洗涤，无水硫酸钠干燥，减压浓缩，得到164mg的化合物8(产率94％)。
性能检测：浅黄色液体,产率86％,ee 97％,[a] D 20+132.1(c 1.1,DCM)。 1H-NMR(CDCl 3,500MHz):δ7.25-7.18(m,2H),δ6.81-6.75(t,J＝7.2Hz,1H),δ6.63-6.59(d,J＝7.8Hz,1H),δ4.91(s,1H),δ4.24(br,2H),δ3.15-3.11(m,1H),δ2.85-2.81(m,1H),δ2.15-2.11(m,1H),δ1.98-1.95(m,1H),δ1.52(s,3H)。MS-ESI m/z:197.11[M+Na] +。
(6)目标化合物10的合成
Figure PCTCN2021140092-appb-000011
准确称量174mg(1mmol)的化合物8，倒入50mL的干燥圆底烧瓶中并加入12mL的无水二氯甲烷，然后向反应液中滴加0.9mL的三乙胺并搅拌20min，把反应体系放入0℃的冰水浴并缓慢滴加485mg化合物9(2.5mmol)，室温条件反应3小时。向反应液中滴加适量的饱和碳酸氢钠溶液，二氯甲烷(3×20mL)萃取并用饱和氯化钠溶液(3×15mL)洗涤，无水硫酸钠干燥，减压浓缩，TLC点板判断化合物的极性，通过柱层析得到441mg的目标化合物(产率91％)。
性能检测：浅黄色固体,产率89％,[a] D 20+126.3(c 0.8,DCM)。 1H-NMR(CDCl 3,500MHz)：8.69(s,1H),8.67(s,1H),δ7.28-7.05(m,4H),6.35(s,1H),6.33(s,1H),5.67(s,1H),3.79(s,6H),3.54-3.51(m,1H),3.34-3.31(m,1H),2.21-2.18(m,1H),1.96-1.92(m,1H),1.46(s,3H)。MS-ESI m/z:491.18[M+H] +。
实施例2：对合成化合物的杀菌活性测定
采用微量稀释法测定目标产物10对金黄色葡萄球菌(staphylococcus  aureus)和大肠杆菌(escherichia coli)的抑菌活性。菌种均购自中国普通微生物菌种保藏中心。
采用试管二倍稀释法，取加有2mL液体培养基的灭菌试管，以不加受试化合物而接种菌的试管为阳性对照，以不加受试化合物也不接种菌的试管为阴性对照。药物初始质量浓度为1g/L，依次二倍稀释，混合均匀。分别向各试管中加入菌悬液200μL，使最终菌液浓度为10 4～10 5cfu/mL(cfu即菌落形成单位，1cfu是指经培养后在琼脂平板上形成的一个单菌落)。振荡培养24h后，根据试管中细菌的生长情况判断最小抑菌质量浓度。
据此判断，含吲哚类化合物对两种细菌的检测结果见表3。
表1 受试化合物对两种菌的MIC值(单位:g/L)
化合物 大肠杆菌 金黄色葡萄球菌
10 0.0625 0.0313
表1的结果说明具有手性的目标化合物10对大肠杆菌和金黄色葡萄球菌均具有很强的抑制作用。
本发明提供的手性3-环吲哚类化合物不仅比传统的TBTO和氧化亚铜具有更高的防污活性，而且在同类吲哚类防污化合物中，也体现了突出的防污活性，如本产品性能优于商品化的TBG(TBG对两种菌的最小抑菌质量浓度0.0625和0.1250g/L)。
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发 明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (6)

  1. 一种手性3-环吲哚类化合物，其特征在于：所述新型手性吲哚类化合物，如式(I)所示：
    Figure PCTCN2021140092-appb-100001
  2. 权利要求1所述的手性3-环吲哚类化合物的制备方法，其特征在于工艺如下：
    Figure PCTCN2021140092-appb-100002
  3. 权利要求2所述的手性3-环吲哚类化合物的制备方法，其特征在于包括如下步骤：
    (1)3-甲基羟基吲哚溶于DCM，加入(Boc) 2O，室温下搅拌，滴加少量三乙胺，反应30min，乙酸乙酯萃取，脱溶，得到Boc保护的3-甲基羟基吲哚；
    (2)Boc保护的3-甲基羟基吲哚溶于[bpy][BF 4]中，在手性催化剂作用下，与化合物2发生迈克尔反应，室温下反应4h，乙酸乙酯萃取，脱溶，得到手性化合物3；
    (3)向手性化合物3和碘化钠的混合物中加入[bpy][BF 4]，60℃下反应8h，乙酸乙酯萃取，脱溶，得到化合物4；
    (4)把邻苯二甲酰亚胺溶于二甲基甲酰胺中，加入氢化钠，室温下反应5分钟，加入化合物4，室温下反应30分钟；100度下在封管中反应4个小时；然后冷却到室温，加水淬灭，乙酸乙酯萃取，硫酸钠干燥，纯化后得到化合物6；
    (5)化合物6溶于DCM中，加入氢氧化钾，70℃下反应18h，得到化合物7，关环后生成化合物8；
    (6)化合物8溶于无水吡啶中，冰水浴下加入化合物9，然后室温下反应半小时得到目标化合物10。
  4. 根据权利要求2所述的手性3-环吲哚类化合物的制备方法，其特征在于步骤(2)中所述 的手性催化剂是：
    Figure PCTCN2021140092-appb-100003
  5. 权利要求1所述的手性3-环吲哚类化合物用于船舶防污用途。
  6. 根据权利要求5所述的用途，其特征在于所述的防污，所涉及的菌类是大肠杆菌和金黄色葡萄球菌。
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