CN113980027A - Fluorine-containing heterocyclic compound, preparation method and application thereof - Google Patents

Fluorine-containing heterocyclic compound, preparation method and application thereof Download PDF

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CN113980027A
CN113980027A CN202111413585.6A CN202111413585A CN113980027A CN 113980027 A CN113980027 A CN 113980027A CN 202111413585 A CN202111413585 A CN 202111413585A CN 113980027 A CN113980027 A CN 113980027A
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containing heterocyclic
heterocyclic compound
fluorine
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CN113980027B (en
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杨亦谋
李吉
李晓倩
向毅
黄华
项欣然
武文斌
郑绍军
陈磊
陈孝云
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Jiangsu University of Science and Technology
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    • 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
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    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
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Abstract

The invention relates to a fluorine-containing heterocyclic compound shown as the following formula and a preparation method thereof, wherein the fluorine-containing heterocyclic compound is prepared by using a nitrogen-containing heterocycle as a base

Description

Fluorine-containing heterocyclic compound, preparation method and application thereof
Technical Field
The invention aims to provide a fluorine-containing heterocyclic compound, a preparation method thereof and application thereof in ship antifouling.
Background
Since the human being engaged in marine activities, marine fouling organisms have brought a lot of harm to the marine industry and the marine industry. Marine fouling organisms are mainly classified into fungi, attached plants and attached animals, and are commonly attached to the surfaces of various ship bottoms and offshore facilities. For ships, the adhesion of marine fouling organisms can obviously increase the surface friction resistance, so that the fuel consumption of the ships is increased, and the sailing speed is reduced. The british international paint company has counted that the fouling of the ship bottom is more than 50% and the fuel consumption is increased by more than 40% according to the docking condition of more than 1500 ships. In addition, the underwater sonar equipment for ships is also degraded in sensitivity and acoustic characteristics due to accelerated corrosion and destruction by organic acids secreted from organisms and by biological action. Acidic substances generated by fouling organisms also influence the coating protection of metal materials in the offshore platform structure to a great extent. According to incomplete statistics, the economic losses caused by biofouling alone worldwide to various underwater engineering facilities and ship equipment can reach billions of dollars each year. The prevention and control of marine fouling organisms has been a major problem that is difficult for humans to solve. Therefore, effective methods are adopted to inhibit the attachment of marine fouling organisms in various countries in the world. Among the methods for preventing and controlling marine fouling organisms, the most convenient, effective and economical method is to apply the antifouling paint.
The traditional antifouling paint achieves the antifouling effect mainly by slowly releasing heavy metals such as copper, tin, mercury, lead and the like, but the antifouling agent has serious pollution to the coast and has certain potential safety hazards to marine ecology and human diet health. The antifouling paint is developing towards the direction of high performance and environmental protection, and the environmental-friendly antifouling paint becomes the key point of future development. The antifouling agent is an important component in the antifouling paint, and the antifouling paint plays a role in killing or avoiding marine fouling organisms by continuously seeping the antifouling agent from a paint film so as to inhibit the attachment of the marine fouling organisms. With the banning of organotin, natural product antifouling agents are receiving attention because of their non-toxicity and non-pollution. The natural product used as the antifouling agent has the advantages of no toxicity, high efficiency, quick degradation and no harm to the environment. In recent years, more and more natural products with antifouling activity are discovered, and efficient and environment-friendly natural product antifouling agents are always the research hotspots in the antifouling field. However, the low content of natural products and the insufficient supply are major problems in commercializing natural product antifouling agents. Chemical synthesis is the most direct method for ensuring supply, and a series of novel natural product antifouling agents can be developed according to the relation between antifouling activity and molecular structure. Thus, the synthetic approach to obtaining natural product antifoulants would help to effectively solve the yield difficulties in the commercialization of natural product antifoulants.
The development of compounds with antifouling activity as antifouling coatings is one of the most common means of controlling marine biofouling today. The indole antifouling agents have the advantages of low toxicity, high efficiency and the like, and the development of the modern antifouling agents is an important direction. However, the content of the active substance in nature is limited, and the yield from nature cannot meet the requirements of human society at all due to the limitation of a plurality of factors such as separation and purification technology, acquisition cost and the like. Therefore, according to the structural characteristics of the indole compounds, human beings can obtain the indole compounds with antifouling activity by a chemical synthesis method, and the industrial production requirements are met. The inventor of the invention, which is filed with 2016.12.07 and has the application number of CN201611113112.3, discloses hexahydropyrroloindole compounds with the structure of formula (I),
Figure BDA0003375196250000031
wherein the substituents R1 and R2 represent mono-substituted or poly-substituted benzyl, R1And R2 may be the same substituent. The synthetic route adopts indole-3-acetonitrile as the initial raw material for synthesis. Has the advantages of high yield, easy separation and the like. The compounds have unequal inhibition effects on staphylococcus aureus and escherichia coli, and can be developed into antifouling agents with potential application values in the aspect of ship antifouling. 2018.12.03, patent number ZL201811465472.9, discloses indole compounds, a synthesis method and antifouling application thereof. The structural formula of the compound is:
Figure BDA0003375196250000032
the preparation method is that the reaction reagent is prepared to obtain the acyl chloride product. Weighing an anhydrous dichloromethane solution of a substrate a, dropwise adding triethylamine, dropwise adding a dichloromethane solution of an acyl chloride product under the ice-water bath condition, after the dropwise adding is complete, moving a reaction solution to room temperature, stirring, detecting, completely reacting the substrate, quenching, extracting an organic phase with dichloromethane, combining the organic phases, concentrating under reduced pressure, and separating a crude product by column chromatography to obtain the indole compound. The synthesis process is simple, the product purity is high, the bactericidal activity on staphylococcus aureus, solanaceae ralstonia and bacillus cereus is high, and the application prospect is excellent. The patent application No. CN201310098503.2 filed by the research of the coast zone of the cigarette platform of the Chinese academy of sciences 2013.03.26 discloses the application of halogenated indole and derivatives thereof as marine antifouling agents. When in use, one or more of halogenated indole derivatives are used as an effective component to be mixed with an antifouling paint to be used as a marine antifouling agent, wherein the effective component accounts for 1-20% of the weight of the antifouling paint. Halogenated indole derivatives having the formula C8HmNR1R2。
The researches show that the indole compound has great application value as an antifouling research object. However, the antifouling active compounds of the present invention have not yet been fully developed in performance, and antifouling activity has not yet been able to meet the commercial demand, so further research on indole compounds is required, and it is desired to obtain antifouling agents with better activity.
Disclosure of Invention
In order to develop a novel antifouling agent, the invention aims to provide a fluorine-containing heterocyclic compound, a preparation method thereof and ship antifouling activity thereof, wherein the synthesized compound has a good inhibition effect on escherichia coli and staphylococcus aureus and has good antifouling activity. The invention synthesizes the antifouling compound through the special catalyst, improves the antifouling activity and reduces the pollution.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a fluorine-containing heterocyclic compound represented by the formula (I)
Figure BDA0003375196250000041
The nitrogen-containing heterocyclic ring is any one of the following groups:
Figure BDA0003375196250000051
the reagent related to the nitrogen-containing heterocycle is 5, 6-dichloronicotinic acid, 6-chloronicotinic acid, 2-picolinic acid, nicotinic acid, 2-fluoronicotinic acid, 1-naphthoic acid, 2-aminonicotinic acid, 5-methylnicotinic acid, 5-methylpyrazine-2-carboxylic acid, 6-methylnicotinic acid, p-methoxybenzoic acid, pyrazine-2-carboxylic acid, 3-chloroisonicotinic acid, 5-chloropyrazine-2-carboxylic acid, isonicotinic acid, 2-chloronicotinic acid, 2-chloropyridine-6-carboxylic acid, 2-chloroisonicotinic acid and 2-hydroxynicotinic acid.
The synthetic route of the compound is as follows:
Figure BDA0003375196250000052
specifically, the synthesis process of the fluorine-containing heterocyclic compound with the formula (I) comprises the following steps:
(1) dissolving the nitrogen-containing heterocyclic compound in anhydrous dichloromethane, adding thionyl chloride under the protection of nitrogen, refluxing for 30min, and distilling under reduced pressure to remove the solvent dichloromethane and the residual thionyl chloride to obtain an acyl chloride intermediate which is directly used for the next reaction.
(2) Dissolving 3a, 8-bis (3-fluorobenzyl) -1,2,3,3a,8,8 a-hexahydropyrrole [2,3-b ] indole (compound a) in dichloromethane, adding a catalyst of hexamethyldisilazane lithium amide (LiHMDS), adding a corresponding acyl chloride intermediate prepared in the previous step, reacting for 3 hours at room temperature, extracting with ethyl acetate, and desolventizing to obtain a corresponding target compound.
The obtained fluorine-containing heterocyclic compound has ship antifouling activity, and the 2 bacteria are escherichia coli and staphylococcus aureus.
Has the advantages that: the fluorine-containing heterocyclic compound provided by the invention has the characteristics of simple structure, easily obtained raw materials, mild reaction conditions and simple process, and has the activity of inhibiting escherichia coli and staphylococcus aureus.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
Figure BDA0003375196250000061
Synthesis of (2)
Step one, preparing acyl chloride: using 5, 6-dichloronicotinic acid as an example, a 100mL dry round-bottomed flask was prepared, and 5, 6-dichloronicotinic acid (288.6mg,1.6mmol) was weighed in. Adding anhydrous DCM (10.0mL), stirring until the anhydrous DCM is dissolved, adding (867.5mg,7.3mmol) thionyl chloride, putting the mixture into an oil bath pot, building a cooling reflux device (the cooling water cannot be cut off), heating and refluxing for 2h at the set temperature of 60 ℃, cooling to the room temperature, and rotationally evaporating DCM and excessive thionyl chloride in the system to obtain an acyl chloride intermediate.
Second, preparation of compound 1: 3a, 8-bis (3-fluorobenzyl) -1,2,3,3a,8,8 a-hexahydropyrrolo [2,3-b ] is weighed (200.0mg,0.5mmol)]Indole (compound a), was placed in a prepared 50mL round bottom flask. Anhydrous DCM (dichloromethane 10mL) was added until complete dissolution. Then add dropwise (81.0mg,0.8mmol) of lithium hexamethyldisilazide (LiHMDS) in slight excess, stir for half an hour, place the system in a 0 deg.C cryofreezer, remove the previously prepared acid chloride, dissolve the acid chloride intermediate with anhydrous DCM (10mL), add slowly to the round bottom flaskIn the process of dropwise adding, smog is generated, the dropwise adding speed is controlled, and after the dropwise adding is completed, the reaction system is moved to room temperature for reaction for two hours. And (4) detecting by TLC, tracking and detecting until the reaction is complete. 1mL of saturated sodium bicarbonate solution is slowly dropped into the reaction system, and a proper amount of saturated sodium bicarbonate solution is added dropwise, so that the reaction is quenched when the reaction is stopped. Extracting the liquid with DCM for three times, combining the lower organic phases, washing with saturated NaCl for three times, collecting with 100mL conical flask, adding anhydrous Na2SO4Stirring and drying. After drying, the anhydrous Na is removed by suction filtration2SO4The liquid thus extracted was concentrated under reduced pressure. Separation using silica gel column (V)Petroleum ether：VEthyl acetate4:1) to obtain compound 1.
A white powder of a white color, a white powder,1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.1Hz,1H),8.15(d,J＝1.9Hz,1H),7.22–6.88(m,7H),6.75–6.59(m,5H),6.07(d,J＝7.8Hz,1H),5.85(s,1H),4.40(s,2H),3.49(dt,J＝15.1,7.5Hz,1H),3.17(d,J＝13.2Hz,1H),2.97(d,J＝13.2Hz,1H),2.19(d,J＝4.6Hz,2H)13C NMR(100MHz,DMSO-d6:)δ165.45,163.93,161.50,150.71,149.36,146.88,142.61,140.80,138.75,132.92,131.49,130.68,130.12,129.68,129.05,126.34,124.01,122.74,117.96,116.85,116.64,113.90,113.69,113.39,106.24,82.39,56.87,49.15,48.86,44.01.MS(ESI(+))calcd for C30H23Cl2F2N3O[M+H]+:550.1；found:550.1。
examples 2 to 19 are different from example 1 in the point that the nitrogen-containing heterocyclic reagent used is different, and are specifically shown in table 1:
experimental data for the Compounds of Table 1
Figure BDA0003375196250000081
Example 2
Figure BDA0003375196250000091
Synthesis of (2)
White powder, H NMR (400MHz, DMSO-d)6)δ8.46(d,J＝2.2Hz,1H),7.92(dd,J＝8.3,2.4Hz,1H),7.56(d,J＝8.3Hz,1H),7.25–6.61(m,12H),6.09(d,J＝7.8Hz,1H),5.92(s,1H),4.43(s,2H),3.53–3.45(m,1H),3.20(d,J＝13.1Hz,1H),3.01(d,J＝13.2Hz,1H),2.21(dt,J＝13.5,6.8Hz,2H).13C NMR(100MHz,DMSO-d6:)δ166.79,163.37,160.95,152.11,150.68,149.13,142.61,140.91,139.34,131.53,130.59,130.10,129.05,126.33,124.55,124.01,122.69,117.95,116.85,113.89,113.72,113.58,113.37,106.22,82.43,56.80,49.30,48.92,44.02,38.60.MS(ESI(+))calcd for C30H24ClF2N3[M+H]+:516.2；found:516.2。
Example 3
Figure BDA0003375196250000092
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,DMSO-d6)δ8.53(d,J＝4.7Hz,1H),7.88(td,J＝7.8,1.3Hz,1H),7.62(d,J＝7.8Hz,1H),7.49–7.42(m,1H),7.17(dd,J＝14.8,7.9Hz,3H),7.01–6.88(m,4H),6.76–6.63(m,5H),6.02(d,J＝7.9Hz,1H),5.91(s,1H),4.43(s,2H),3.65(dd,J＝11.4,6.9Hz,1H),3.16(d,J＝13.2Hz,1H),3.02–2.96(m,1H),2.14(ddd,J＝20.1,10.6,5.2Hz,2H).13C NMR(100MHz,DMSO-d6:)δ167.79,163.96,160.98,154.05,150.58,148.70,142.63,140.95,137.79,131.79,130.64,130.10,128.96,126.38,125.80,124.05,122.84,121.98,117.97,116.91,116.70,113.91,113.72,113.51,106.27,82.60,56.52,49.05,43.93,38.50.MS(ESI(+))calcd for C32H30FN3O[M+H]+:482.2；found:482.2。
example 4
Figure BDA0003375196250000101
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.48(d,J＝2.0Hz,1H),7.91(dd,J＝8.2,2.3Hz,1H),7.50(d,J＝8.2Hz,1H),7.27–7.15(m,3H),7.07–6.65(m,9H),6.16(d,J＝7.8Hz,1H),6.06(s,1H),4.57(d,J＝16.8Hz,1H),4.49(d,J＝16.8Hz,1H),3.72–3.61(m,1H),3.46(td,J＝10.9,6.4Hz,1H),3.32–3.23(m,1H),3.12–3.05(m,1H),2.38–2.27(m,2H)13C NMR(100MHz,:Acetone-d6)δ166.68,164.12,161.16,152.28,150.73,148.82,142.60,140.61,138.51,131.44,131.28,130.12,129.53,128.69,125.98,123.91,123.55,122.42,117.74,116.66,116.45,113.47,113.26,113.12,106.15,82.62,56.74,49.13,44.13,38.19.MS(ESI(+))calcd for C32H30FN3O[M+H]+:482.2；found:482.2。
example 5
Figure BDA0003375196250000111
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.31(ddd,J＝4.8,1.8,1.1Hz,1H),7.93(ddd,J＝9.3,7.4,2.0Hz,1H),7.41(ddd,J＝7.2,4.9,2.1Hz,1H),7.28–7.16(m,3H),7.05–6.92(m,3H),6.88–6.80(m,3H),6.76–6.66(m,2H),6.14(d,J＝7.9Hz,1H),6.00(s,1H),4.55(s,2H),3.48(ddd,J＝5.7,5.2,4.1Hz,1H),3.35–3.26(m,2H),3.10(d,J＝13.3Hz,1H),2.36–2.28(m,2H).13C NMR(100MHz,:Acetone-d6)δ163.99,161.17,160.03,157.67,150.74,149.20,149.05,140.47,131.26,130.10,129.62,128.70,125.94,123.54,122.46,122.07,117.85,116.65,116.44,113.47,113.36,113.26,113.15,106.20,82.56,57.08,49.29,47.82,44.15,38.02MS(ESI(+))calcd for C30H24F3N3O[M+H]+:500.2；found.:500.2。
example 6
Figure BDA0003375196250000112
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ7.99–7.88(m,2H),7.69(d,J＝8.2Hz,1H),7.49(tt,J＝11.0,7.1Hz,3H),7.36–7.21(m,3H),7.15(d,J＝7.3Hz,1H),7.09–6.89(m,6H),6.80(d,J＝10.3Hz,1H),6.74–6.67(m,1H),6.28–6.18(m,2H),4.81–4.66(m,2H),3.28(t,J＝11.2Hz,1H),3.23–3.12(m,2H),3.12–3.00(m,1H),2.43–2.14(m,2H).13C NMR(100MHz,DMSO-d6:),)δ169.20,163.69,161.26,150.83,142.91,140.68,135.19,133.57,131.69,130.12,129.72,129.43,129.16,128.66,128.44,126.95,126.40,126.17,125.19,124.86,123.98,123.53,122.65,117.73,116.87,113.61,113.40,113.21,106.01,82.30,57.12,49.41,48.05,44.07,38.19.MS(ESI(+))calcd for C35H28F2N2O[M+H]+:531.3；found:531.3。
example 7
Figure BDA0003375196250000121
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝3.5Hz,1H),7.37–6.83(m,8H),6.79–6.42(m,6H),6.22–5.82(m,4H),4.37(s,2H),3.45(s,1H),3.18(d,J＝13.0Hz,1H),3.00(d,J＝13.1Hz,1H),2.16(s,2H).13C NMR(100MHz,DMSO-d6:)δ163.36,161.48,160.94,157.30,150.83,150.30,141.07,141.00,137.04,131.51,130.63,130.06,128.99,126.30,124.07,122.60,117.84,116.85,116.64,113.88,113.67,113.51,113.29,111.95,105.98,82.04,56.89,48.78,44.09,38.99.MS(ESI(+))calcd for C30H26F2N4O[M+H]+:497.2；found:497.2。
example 8
Figure BDA0003375196250000131
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝1.3Hz,1H),8.43(d,J＝1.5Hz,1H),7.67(s,1H),7.27–6.67(m,12H),6.12(d,J＝7.8Hz,1H),5.98(s,1H),4.48(s,2H),3.48(d,J＝6.1Hz,1H),3.24(d,J＝13.1Hz,1H),3.06(d,J＝13.2Hz,1H),2.33(s,3H),2.26–2.19(m,2H).13C NMR(100MHz,DMSO-d6:)δ167.99,163.38,161.51,151.83,150.69,145.72,142.76,140.88,135.70,133.24,131.60,130.67,130.09,129.03,126.35,124.00,122.72,117.89,116.88,113.91,113.70,113.56,113.34,106.15,82.34,56.76,49.38,48.91,44.01,38.63,18.18.MS(ESI(+))calcd for C31H27F2N3O[M+H]+:496.2；found:496.2。
example 9
Figure BDA0003375196250000132
Synthesis of (2)
A light yellow powder of the above-mentioned components,1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝1.2Hz,1H),8.54–8.50(m,1H),7.19(dd,J＝14.6,7.0Hz,3H),7.04–6.93(m,4H),6.79(d,J＝7.7Hz,1H),6.75–6.65(m,4H),6.07(t,J＝6.1Hz,1H),5.95(s,1H),4.46(s,2H),3.78–3.70(m,1H),3.18(d,J＝13.2Hz,1H),3.02(d,J＝13.1Hz,1H),2.54(s,3H),2.26–2.16(m,2H)13C NMR(100MHz,DMSO-d6:)δ166.18,163.39,160.98,155.80,150.48,146.34,145.17,144.28,142.92,142.57,141.60,140.88,131.74,130.57,130.12,129.00,126.39,123.95,122.84,118.04,116.92,113.93,113.71,113.49,106.33,82.69,56.49,48.99,43.85,21.80.MS(ESI(+))calcd for C30H26F2N4O[M+H]+:497.2；found:497.2。
example 10
Figure BDA0003375196250000141
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.54(s,1H),7.73(d,J＝6.3Hz,1H),7.31–7.12(m,4H),7.11–6.77(m,6H),6.77–6.64(m,2H),6.21–6.03(m,2H),4.63–4.40(m,2H),3.70–3.51(m,1H),3.50–3.36(m,1H),3.28(dd,J＝13.2,3.3Hz,1H),3.09(d,J＝11.3Hz,1H),2.55–2.43(m,3H),2.37–2.24(m,2H).13C NMR(100MHz,Acetone-d6:)δ168.01,163.58,161.16,160.31,150.78,148.06,142.72,140.69,135.40,131.36,130.02,129.59,129.26,128.66,126.00,123.55,122.31,117.65,116.67,116.46,113.45,113.24,113.09,106.10,82.50,56.67,49.22,48.96,44.18,38.25,23.67.MS(ESI(+))calcd for C31H27F2N3O[M+H]+:496.2；found:496.2。
example 11
Figure BDA0003375196250000151
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ7.44(d,J＝7.4Hz,2H),7.18(ddd,J＝18.5,10.8,9.3Hz,3H),7.01–6.79(m,8H),6.71–6.64(m,2H),6.12–6.02(m,2H),4.54(d,J＝16.2Hz,1),4.41(d,J＝16.2Hz,1),3.80(s,3),3.72–3.56(m,1),3.36(s,1),3.23(d,J＝13.2Hz,1),3.05(d,J＝13.3Hz,1),2.30–2.17(m,2H).13C NMR(100MHz,Acetone-d6:)δ169.59,164.13,163.59,161.71,161.38,161.17,150.86,140.76,140.69,130.05,129.97,129.68,129.56,129.48,128.58,128.45,126.01,123.52,122.42,117.56,116.69,116.47,113.43,113.31,113.21,113.05,106.06,82.42,54.91,48.83,44.24,38.29.MS(ESI(+))calcd for C32H28F2N2O2[M+H]+:511.2；found:511.2。
example 12
Figure BDA0003375196250000152
Synthesis of (2)
A light yellow powder of the above-mentioned components,1H NMR(400MHz,DMSO-d6)δ8.87(d,J＝1.5Hz,1H),8.75(d,J＝2.6Hz,1H),8.64(dd,J＝2.5,1.5Hz,1H),7.22–7.17(m,3H),7.02–6.96(m,3H),6.81–6.65(m,6H),6.08(d,J＝7.8Hz,1H),5.94(s,1H),4.46(s,2H),3.76–3.67(m,1H),3.33–3.25(m,1H),3.18(s,1H),3.04(s,1H),2.23–2.14(m,2H).13C NMR(100MHz,DMSO-d6:)δ166.00,163.94,160.98,150.47,149.25,146.56,145.29,143.54,142.47,140.87,131.71,130.59,130.14,129.02,126.40,123.97,122.84,118.08,116.92,116.71,113.95,113.75,113.49,106.34,82.68,56.55,49.14,48.96,43.82.MS(ESI(+))calcd for C29H24F2N4O[M+H]+:482.2；found:482.2。
example 13
Figure BDA0003375196250000161
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.65(s,1H),8.57(d,J＝4.8Hz,1H),7.29–7.18(m,4H),7.04–6.93(m,3H),6.86(dd,J＝15.6,9.7Hz,3H),6.75–6.70(m,2H),6.18(d,J＝7.9Hz,1H),5.99(s,1H),4.60(q,J＝16.7Hz,2H),3.34–3.28(m,2H),3.21–3.09(m,2H),2.38–2.28(m,2H).13C NMR(100MHz,Acetone-d6:)δ164.65,163.64,161.21,150.69,149.62,148.58,143.54,142.55,140.48,131.32,130.15,129.70,128.71,127.16,126.05,123.52,122.57,121.83,117.92,116.53,113.59,113.37,113.21,106.18,82.35,57.26,49.28,47.31,43.94,38.20.MS(ESI(+))calcd for C30H24F2N3O[M+H]+:516.2；found:516.2。
example 14
Figure BDA0003375196250000171
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.69–8.60(m,2H),7.84(d,J＝7.9Hz,1H),7.41(dd,J＝7.7,4.9Hz,1H),7.21(ddd,J＝21.1,11.4,4.7Hz,3H),7.05–6.97(m,2H),6.86(dd,J＝12.1,4.9Hz,2H),6.80(d,J＝10.1Hz,1H),6.75–6.67(m,2H),6.15(d,J＝7.9Hz,1H),6.08(s,1H),4.59(d,J＝16.8Hz,1H),4.50(d,J＝16.8Hz,1H),3.66–3.57(m,1H),3.44(td,J＝10.8,6.5Hz,1H),3.28(d,J＝13.2Hz,1H),3.14–3.04(m,1H),2.35–2.27(m,2H)13C NMR(100MHz,Acetone-d6:)δ166.33,163.58,161.16,151.31,150.69,150.30,147.24,142.60,140.56,131.23,130.13,129.55,128.70,125.95,123.54,122.44,122.09,120.67,117.79,116.65,116.44,113.41,113.28,113.15,106.16,82.69,56.85,48.77,44.07,38.16.MS(ESI(+))calcd for C30H24F2N3O[M+H]+:516.2；found:516.2。
example 15
Figure BDA0003375196250000172
Synthesis of (2)
A light yellow powder of the above-mentioned components,1H NMR(400MHz,Acetone-d6)δ8.73–8.71(m,1H),8.69–8.67(m,1H),7.22(ddd,J＝8.1,5.0,2.1Hz,2H),7.17(dd,J＝7.3,0.8Hz,1H),7.02–6.97(m,2H),6.90–6.78(m,4H),6.75–6.67(m,2H),6.34–6.24(m,1H),6.16(d,J＝7.8Hz,1H),6.04(s,1H),4.58(d,J＝17.2Hz,2H),3.48–3.41(m,1H),3.26(d,J＝13.3Hz,1H),3.09(d,J＝13.3Hz,1H),2.35–2.27(m,2H).13C NMR(100MHz,Acetone-d6:)δ164.70,164.15,163.60,150.54,149.83,147.64,145.01,142.47,131.49,130.10,130.02,129.63,129.55,128.65,126.02,123.49,122.56,117.86,116.71,116.50,113.54,113.48,113.35,113.27,113.14,106.34,83.08,56.46,49.36,48.66,43.99,37.96.MS(ESI(+))calcd for C29H23ClF2N4O[M+H]+:517.2；found:517.2。
example 16
Figure BDA0003375196250000181
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,DMSO-d6)δ8.64(dd,J＝4.4,1.5Hz,2H),7.37(dd,J＝4.4,1.6Hz,2H),7.28–6.91(m,7H),6.72(ddd,J＝26.3,18.9,9.7Hz,5H),6.09(d,J＝7.8Hz,1H),5.91(s,1H),4.45(s,2H),3.45–3.37(m,1H),3.20(d,J＝13.1Hz,1H),3.03(d,J＝13.2Hz,1H),2.20(dd,J＝10.5,6.2Hz,2H).13C NMR(100MHz,DMSO-d6:)δ167.93,163.97,161.55,150.68,150.51,143.66,142.71,142.65,140.86,131.56,130.70,130.62,130.11,130.03,129.07,126.36,124.02,122.73,121.89,118.00,116.87,116.67,113.94,113.70,113.60,113.38,106.22,82.47,56.84,49.07,43.95.MS(ESI(+))calcd for C30H25F2N3O[M+H]+:482.2；found:482.2。
example 17
Figure BDA0003375196250000191
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ8.45(dd,J＝4.1,1.9Hz,1h),7.70(s,1H),7.52–7.42(m,1H),7.30–7.17(m,3H),7.02–6.85(m,5H),6.72(ddd,J＝7.3,3.7,0.8Hz,2H),6.17(d,J＝7.5Hz,1H),5.99(s,1H),4.61(dd,J＝38.0,16.7Hz,2H),3.38–3.28(m,2H),3.15(t,J＝21.4Hz,2H),2.37–2.26(m,2H),2.10–2.08(m,1H).13C NMR(100MHz,Acetone-d6:)δ165.42,164.18,161.76,150.76,150.24,146.36,142.56,140.53,137.14,133.03,131.36,130.06,129.61,128.69,126.04,123.52,123.20,122.57,117.85,116.53,113.59,113.40,113.19,106.12,82.29,57.28,49.21,47.45,44.00,38.22.MS(ESI(+))calcd for C30H24F2N3O[M+H]+:516.2；found:516.2。
example 18
Figure BDA0003375196250000192
Synthesis of (2)
The yellow oil is in the form of yellow oil,1H NMR(400MHz,Acetone-d6)δ7.99–7.91(m,1H),7.81–7.67(m,1H),7.61–7.50(m,1H),7.24–7.15(m,3H),6.98(ddd,J＝23.4,14.7,8.8Hz,3H),6.87–6.80(m,3H),6.71(dd,J＝9.8,6.8Hz,2H),6.13(dd,J＝7.4,3.0Hz,1H),6.06–5.98(m,1H),4.63–4.46(m,2H),3.88(t,J＝7.9Hz,1H),3.47–3.40(m,1H),3.26(dd,J＝13.2,3.4Hz,1H),3.12–3.07(m,1H),2.37–2.26(m,2H).13C NMR(100MHz,Acetone-d6:)δ165.85,163.59,161.17,154.41,150.60,149.33,142.60,140.39,131.53,130.09,129.61,128.62,126.01,125.82,123.48,122.84,122.55,117.78,116.71,116.50,113.47,113.33,113.11,106.31,82.99,56.44,49.29,48.82,44.05,38.02.MS(ESI(+))calcd for C30H24F2N3O[M+H]+:516.2；found:516.2。
example 19
Figure BDA0003375196250000201
Synthesis of (2)
A white powder of a white color, a white powder,1H NMR(400MHz,Acetone-d6)δ7.61–7.52(m,2H),7.26–7.18(m,2H),7.15(d,J＝7.3Hz,1H),7.00–6.78(m,7H),6.71–6.64(m,2H),6.31(t,J＝6.6Hz,1H),6.06(d,J＝7.9Hz,1H),5.94(s,1H),4.53(q,J＝16.7Hz,2H),3.58–3.51(m,1H),3.31–3.26(m,1H),3.06(d,J＝13.2Hz,1H),2.31–2.20(m,2H).13C NMR(100MHz,Acetone-d6:)δ171.51,166.53,163.55,161.13,159.50,150.88,142.74,141.09,140.73,137.05,131.45,130.02,129.54,128.48,125.98,123.41,122.61,117.46,116.64,113.56,113.34,112.98,105.98,105.09,82.33,56.97,49.24,47.31,44.21,38.49.MS(ESI(+))calcd for C30H25F2N3O2[M+H]+:498.2；found:498.2。
example 20: measurement of fungicidal Activity of synthetic Compound
And (3) determining the bacteriostatic activity of the target product 1-19 on staphylococcus aureus (staphylococcus aureus) and escherichia coli (escherichia coli) by adopting a microdilution method. The strains are purchased from China general microbiological culture Collection center.
The two-fold dilution in tube was performed by taking a sterilized tube containing 2mL of liquid medium, and using a tube inoculated with neither the test compound nor the test compound as a positive control and a tube inoculated with neither the test compound nor the test compound as a negative control. The initial mass concentration of the medicine is 1g/L, and the medicine is diluted twice in sequence and mixed evenly. Adding 200 μ L bacterial suspension into each test tube respectively to obtain final bacterial liquid concentration of 104～105cfu/mL (cfu is a colony forming unit, 1cfu means one single colony formed on an agar plate after incubation). After shaking culture for 24h, judging the minimum bacteriostatic mass concentration according to the growth condition of bacteria in the test tube.
Accordingly, the results of detecting two kinds of bacteria with the fluorine-containing heterocyclic compound are shown in Table 2.
TABLE 2 MIC values (unit: g/L) of the test compounds for both bacteria
Figure BDA0003375196250000211
The results in table 2 illustrate that: most of the prepared compounds show good inhibitory activity, wherein the target compounds 1,7 and 16 have strong inhibitory action on escherichia coli and staphylococcus aureus.
The target compounds 1,7 and 16 provided by the invention not only have higher antifouling activity than the traditional TBTO and cuprous oxide, but also show outstanding antifouling activity in similar indole antifouling compounds, for example, the product performance is superior to the commercial TBG (the minimum inhibition mass concentration of the TBG to two bacteria is 0.0625 and 0.1250 g/L). Compared with the antifouling activity disclosed in a patent (ZL201811465472.9, the compound has the best activity of 250ug/mL, namely 0.25g/L) granted by the inventor in 2018, the antifouling activity of the invention is obviously improved (0.0313 g/L). Compared with the invention patent of CN201611113112.3 disclosed by the inventor 2016.12.07 (the antifouling activity of the compound is 0.0625g/L,0.125g/L or 0.250g/L respectively), the antifouling activity of the invention is also obviously improved. CN201310098503.2 patent application document filed by research on the coast zone of the cigarette platform of China academy of sciences discloses application of halogenated indole and derivatives thereof as a marine antifouling agent, wherein the activity range of the compounds is 0.84 mg/L-18.9 mg/L, and the antifouling activity of the compounds is obviously lower than that of the antifouling activity (0.0313g/L) of the invention.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (6)

1. A fluorine-containing heterocyclic compound characterized by: the fluorine-containing heterocyclic compound is shown as a formula (I):
Figure FDA0003375196240000011
the nitrogen-containing heterocyclic ring is any one of the following groups:
Figure FDA0003375196240000012
2. the process for producing a fluorine-containing heterocyclic compound according to claim 1, characterized by comprising the steps of:
Figure FDA0003375196240000013
3. a process for producing a fluorine-containing heterocyclic compound according to claim 1, characterized by comprising the steps of:
(1) dissolving a nitrogen-containing heterocyclic compound in anhydrous dichloromethane, adding thionyl chloride under the protection of nitrogen, refluxing for 30min, and distilling under reduced pressure to remove the dichloromethane and the residual thionyl chloride to obtain an acyl chloride intermediate which is directly used for the next reaction;
(2) dissolving 3a, 8-bis (3-fluorobenzyl) -1,2,3,3a,8,8 a-hexahydropyrrole [2,3-b ] indole in THF, adding a catalyst, adding the corresponding acyl chloride intermediate prepared in the previous step, reacting for 3h at room temperature, extracting with ethyl acetate, and desolventizing to obtain the corresponding target compound.
4. A process for preparing a fluorinated heterocyclic compound according to claim 4, characterized in that the catalyst is lithium hexamethyldisilazide.
5. Use of the fluorine-containing heterocyclic compound obtained in claim 1 for marine antifouling.
6. Use according to claim 5, characterized in that, in order to prevent fouling, the bacteria involved are Escherichia coli and Staphylococcus aureus.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111019097A (en) * 2019-12-19 2020-04-17 河南大学 Alkenyl side chain conjugated indacenodifuranyl polymer material, preparation method and application thereof
CN112724146A (en) * 2020-12-22 2021-04-30 江苏科技大学 Chiral indole compound, preparation method thereof and ship antifouling application

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111019097A (en) * 2019-12-19 2020-04-17 河南大学 Alkenyl side chain conjugated indacenodifuranyl polymer material, preparation method and application thereof
CN112724146A (en) * 2020-12-22 2021-04-30 江苏科技大学 Chiral indole compound, preparation method thereof and ship antifouling application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHAOJUN ZHENG: "Synthesis and biological evaluations of a series of calycanthaceous analogues as antifungal agents", 《NATURAL PRODUCT RESEARCH》 *

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