Hydroxyl-containing heterocyclic compound as well as preparation method and application thereof
By introducing hydroxyl groups into 2-phenylindole and synthesizing hydroxyl-containing heterocyclic compounds using triethylamine catalysts, the problems of insufficient anti-fouling activity and environmental pollution of existing anti-fouling coatings are solved, and efficient ship anti-fouling effect is achieved and Environmentally friendly craftsmanship.
Patent Information
- Application Number
- CN202411128197.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-16
- Publication Date
- 2024-12-17
AI Technical Summary
The existing anti-fouling coatings have insufficient anti-fouling activity in ship anti-fouling, especially the complex structure is not conducive to industrialization, and the use of heavy metal copper oxide has serious pollution to the marine environment and cannot meet commercial needs.
Using hydroxyl-containing heterocyclic compounds, the hydroxyl group is introduced into 2-phenylindole, and the binding force with the coating is enhanced by hydrogen bonding, and the inexpensive and easy-to-get triethylamine is used as a catalyst to synthesize compounds with high antifouling activity. , avoid the use of heavy metals.
It significantly improves the anti-fouling activity of ships, reduces the loss rate of anti-fouling agents in seawater, extends the anti-fouling period by 24 months, and the process is simple and easy to industrialize, reducing pollution to the marine environment.
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Abstract
Description
Technical Field
[0001] The object of the present invention is to provide a hydroxyl-containing heterocyclic compound, a preparation method thereof and use thereof in ship antifouling. Background Art
[0002] The hull below the waterline of a ship is in contact with seawater for a long time. It is not only corroded by seawater, but also often has marine organisms attached to its surface, which reduces the ship's speed, increases fuel consumption, and accelerates the corrosion of the hull. In addition, it also endangers platform facilities and aquaculture in the water, and easily causes blockage of cooling water pipes in power plants.
[0003] At present, there are systematic technologies to prevent marine organisms from attaching and growing, among which antifouling coatings have developed the fastest and are the most widely used. Early antifouling coatings used compounds such as arsenic and mercury as antifouling agents, which have long been eliminated due to their high toxicity. Then came soluble antifouling coatings with cuprous oxide as the antifouling agent base material, and then developed into insoluble antifouling coatings with high copper compound base materials (with polymers as the main base material) and organic tin and organic tin, cuprous oxide composite toxic agent antifouling coatings, and then to high-performance, long-term, and excellent construction performance organic tin self-polishing antifouling coatings, which have made a big step forward in antifouling coating technology. However, heavy metals such as cuprous oxide are highly toxic, causing serious marine pollution, seriously affecting the growth and reproduction of marine organisms, and also causing genetic mutations in marine organisms. With the growing call for environmental protection, it is a general trend to develop new non-toxic antifouling coatings that do not pollute the environment.
[0004] Indole compounds have the advantages of low toxicity and high efficiency in antifouling, which is an important direction for the development of modern antifouling agents. The inventor submitted an invention patent application with application number CN201611113112.3 on December 7, 2016, disclosing a hexahydropyrroloindole compound having the structure of formula (I).
[0005]
[0006] Wherein the substituents R1 and R2 represent monosubstituted or polysubstituted benzyl groups, and R1 and R2 can be the same substituents. Its synthesis route uses indole-3-acetonitrile as the starting material for synthesis. It has the advantages of high yield and easy separation. This type of compound has varying degrees of inhibitory effects on Staphylococcus aureus and Escherichia coli, and can be developed into an antifouling agent with potential application value in ship antifouling. The patent document with the patent number ZL201811465472.9 submitted on December 3, 2018 discloses indole compounds, their synthesis methods and their antifouling uses. The structural formula of the compound is: The preparation method is to first prepare the reaction reagent to obtain the chlorination product. Weigh the anhydrous dichloromethane solution of substrate a, drop triethylamine, drop the dichloromethane solution of the chlorination product under ice-water bath conditions, and after the dropwise addition is complete, move the reaction solution to room temperature for stirring, detect, the substrate reaction is complete, quench the reaction, extract the organic phase with dichloromethane, combine the organic phases, concentrate under reduced pressure, and separate the crude product with column chromatography to obtain an indole compound. The synthesis process is simple, the product purity is high, and it has high bactericidal activity against Staphylococcus aureus, Ralstonia solanacearum and Bacillus cereus, and has excellent application prospects. The patent application document with application number CN201310098503.2 submitted by the Yantai Coastal Research Institute of the Chinese Academy of Sciences on March 26, 2013 discloses the application of halogenated indole and its derivatives as marine antifouling agents. When used, one or more of the halogenated indole derivatives are mixed with antifouling paint as an effective ingredient to be used as a marine antifouling agent, wherein the effective ingredient is 1%-20% by weight of the antifouling paint. The molecular formula of the halogenated indole derivative is C8H m NR1R2.
[0007] The above studies show that indole compounds have great application value as antifouling research objects. However, the antifouling activity of existing related antifouling active compounds still has a lot of room for improvement, especially because of their complex structures, which are not conducive to industrialization and cannot meet the needs of commercialization. Therefore, further research on indole compounds is needed to obtain antifouling agents with better activity. Summary of the invention
[0008] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide a hydroxyl-containing heterocyclic compound and a preparation method thereof, wherein the synthesized compound has good antifouling activity for ships and has a good inhibitory effect on Staphylococcus aureus and Escherichia coli. The present invention selects cheap, easily available and easily recyclable triethylamine as a catalyst to synthesize an antifouling compound, improve the antifouling activity, eliminate the use of heavy metal cuprous oxide, and reduce pollution to the marine environment.
[0009] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:
[0010] Hydroxyl-containing heterocyclic compound represented by formula (I)
[0011]
[0012] The R is any one of the following groups 1-10:
[0013]
[0014] The synthetic route of the above-mentioned hydroxyl-containing heterocyclic compound is as follows:
[0015]
[0016] Specifically, the synthesis process of the hydroxyl-containing heterocyclic compound of formula (I) comprises the following steps:
[0017] (1) Under nitrogen protection, 2-phenylindole was dissolved in N,N-dimethylformamide solution, phosphorus oxychloride was added, and the mixture was reacted in an ice-water bath for 4 h to obtain the key intermediate aldehyde compound 1.
[0018] (2) In the presence of a catalyst, the key intermediate 1 obtained in step (1) undergoes a nucleophilic substitution reaction with different halogenated hydrocarbons to obtain a compound 2 having a mono- or di-substituted N-grafted benzyl group on 2-phenylindole.
[0019] The halogenated hydrocarbon is benzyl chloride, p-methylbenzyl chloride, m-methylbenzyl chloride, o-methylbenzyl chloride, 2-chlorobenzyl chloride, 4-chlorobenzyl chloride, 3-chlorobenzyl chloride, 2-fluorobenzyl chloride, 4-fluorobenzyl chloride or 3-fluorobenzyl chloride.
[0020] The catalyst is triethylamine, which is environmentally friendly and easily available.
[0021] (3) Compound 2 was then reduced with lithium aluminum hydride. After the reaction was completed, water was slowly added to the reaction solution to quench the reaction. The solution was then extracted with ethyl acetate, washed with saturated NaCl solution, dried without Na2SO4, filtered, concentrated under reduced pressure, and quickly separated and purified by chromatography to generate 10 target compounds.
[0022] The obtained hydroxyl-containing heterocyclic compound has good ship antifouling activity, and the two bacteria involved are Staphylococcus aureus or Escherichia coli.
[0023] Beneficial effects:
[0024] (1) The present invention uses 2-phenylindole as a raw material, introduces hydroxyl groups into its structure, and utilizes hydrogen bonding to increase the binding force with the resin in the coating, thereby significantly reducing the loss rate of the antifouling agent in seawater and increasing the antifouling effect (up to 24 months).
[0025] (2) The hydroxyl-containing heterocyclic compound prepared by the present invention has the characteristics of simple structure, readily available raw materials, mild reaction conditions, simple process, and easy industrialization, and has the activity of inhibiting Staphylococcus aureus and Escherichia coli. DETAILED DESCRIPTION
[0026] The present invention is described in detail below in conjunction with embodiments.
[0027] The synthesis process of the hydroxyl-containing heterocyclic compound is as follows:
[0028] (1) Synthesis of intermediate 1
[0029]
[0030] Weigh 193 mg (1 mmol) of 2-phenylindole and add it to a round-bottom flask (100 mL). Take 10 mL of N,N-dimethylformamide and add it to the reaction. Stir until it is completely dissolved. Put it in an ice-water bath at 0°C. Add 232 mg (1.5 mmol) of phosphorus oxychloride to the reaction solution. React for 4 hours and track the reaction by TCL. Pour the reaction solution into a 250 mL beaker, dilute with water, extract with ethyl acetate, wash with saturated NaCl aqueous solution, dry with anhydrous Na2SO4, and concentrate under reduced pressure. Obtain 192 mg (0.87 mmol, 87%) of crude product of compound 1.
[0031] (2) Synthesis of Intermediate 2
[0032]
[0033] 221 mg of compound 1 (1 mmol) was weighed into a 100 mL dry round-bottom flask, and slowly added into 30 mL of anhydrous tetrahydrofuran, stirred at room temperature for 10 min, catalyst triethylamine (2 mmol) was added in an ice-water bath, and halogenated hydrocarbon was slowly added dropwise. After the addition was complete, the reaction solution was moved to room temperature and stirred, and detected by TLC (petroleum ether: ethyl acetate = 4:1). An appropriate amount of saturated ammonium chloride solution was slowly added dropwise to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and quickly separated by a chromatography column to obtain the corresponding intermediate 2.
[0034] (3) Synthesis of target compounds a1-a10
[0035]
[0036] Compound 2 was completely dissolved in 10 mL of anhydrous tetrahydrofuran, LiAlH4 was added in an ice bath, refluxed for 2 h, cooled, quenched with water in an ice-water bath, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and quickly separated by chromatography column to obtain the target compounds a1-a10.
[0037] Referring to the above preparation method, by adjusting the reaction of compound 2 with different halogenated hydrocarbons in step (2), the target compounds corresponding to Examples 1 to 10 were obtained.
[0038] Example 1 Synthesis
[0039] Yellow solid, 87% Yield. Melting point: 128-130℃. 1H NMR(400MHz, CDCl3), δ:7.48-7.46(m,2H),7.38-7.19(m,10H),6.95-6.94(m,2H),5 .42(s,1H),4.22(s,2H),3.72(t,J=6.4Hz,1H),3.12-2.98(m,2H).MS(API(+))calcd for C 24 H 23 O + [M+H] + :327.17; found:327.14.
[0040] Example 2 Synthesis
[0041] Light yellow solid, 75% Yield. Melting point: 132-135°C. 1 H NMR(400MHz, CDCl3), δ:7.45-7.21(m,4H),7.13-6.91(m,9H),5.45(s,1H),4.26 (s,2H),3.82(t,J=6.4Hz,1H),3.02-2.95(m,2H),2.26(s,3H).MS(API(+))calcd for C 24 H 23 O + [M+H] + :327.17; found:327.14.
[0042] Example 3 Synthesis
[0043] Yellow solid, 78% Yield. Melting point: 128-130℃. 1 H NMR(400MHz, CDCl3), δ:7.41-7.19(m,4H),7.06-6.87(m,9H),5.40(s,1H),4.21 (s,2H),3.78(t,J=5.6Hz,1H),3.01-2.90(m,2H),2.23(s,3H).MS(API(+))calcd for C 24 H 23 O + [M+H] + :327.17;found:327.15.
[0044] Example 4 Synthesis
[0045] Yellow solid, 91% Yield. Melting point: 132-134℃.1 H NMR(400MHz, CDCl3), δ:7.45-7.21(m,4H),7.19-6.96(m,9H),5.47(s,1H),4.29 (s,2H),3.88(t,J=6.4Hz,1H),3.05-2.96(m,2H),2.18(s,3H).MS(API(+))calcd for C 24 H 23 O + [M+H] + :327.17; found:327.14.
[0046] Example 5 Synthesis
[0047] Yellow solid, 93% Yield. Melting point: 131-133℃. 1 H NMR (400MHz, CDCl3), δ: 7.77 (d, J = 3.4Hz, 1H), 7.38-6.89 (m, 12H), 7.19-6.96 (m, 9H), 5.52 (s ,1H),4.21(s,2H),3.81(t,J=4.9Hz,1H),3.00-2.93(m,2H),2.18(s,2H)..MS(API(+))calcd for C 23 H 20 C1O + [M+H] + :347.12; found:347.11.
[0048] Example 6 Synthesis
[0049] White solid, 78% Yield. Melting point: 125-127℃. 1 H NMR (400MHz, CDCl3), δ: 7.82 (d, J = 4.3Hz, 1H), 7.34–6.85 (m, 12H), 7.15–6.92 (m, 9H), 5.48 ( s,1H),4.18(s,2H),3.79(t,J=4.5Hz,1H),3.01-2.87(m,2H),2.15(s,2H).MS(API(+))calcd for C 23 H 20 C1O + [M+H] + :347.12;found:347.08.
[0050] Example 7 Synthesis
[0051] Yellow solid, 84% Yield. Melting point: 133-135℃. 1 H NMR (400MHz, CDCl3), δ: 7.72 (d, J = 3.4Hz, 1H), 7.42-6.91 (m, 12H), 7.12-6.94 (m, 9H), 5.47 ( s,1H),4.16(s,2H),3.77(t,J=4.9Hz,1H),3.02-2.87(m,2H),2.09(s,2H).MS(API(+))calcd for C 23 H 20 C1O + [M+H] + :347.12; found:347.11.
[0052] Example 8 Synthesis
[0053] Yellow solid, 87% Yield. Melting point: 123-125℃. 1 H NMR (400MHz, CDCl3), δ: 7.62 (d, J = 5.6Hz, 1H), 7.26-6.78 (m, 12H), 7.10-6.84 (m, 9H), 5.41 ( s,1H),4.13(s,2H),3.65(t,J=4.7Hz,1H),3.01-2.80(m,2H),2.06(s,2H).MS(API(+))calcd for C 23 H 20 FO + [M+H] + :331.15;found:331.12.
[0054] Example 9 Synthesis
[0055] Yellow solid, 81% Yield. Melting point: 125-127℃. 1 H NMR (400MHz, CDCl3), δ: 7.75 (d, J = 3.4Hz, 1H), 7.32-6.89 (m, 12H), 7.05-6.84 (m, 9H), 5.43 ( s,1H),4.13(s,2H),3.57(t,J=4.4Hz,1H),2.95-2.82(m,2H),2.04(s,2H).MS(API(+))calcd for C 23 H 20 FO + [M+H] +:331.15; found:331.14.
[0056] Example 10 Synthesis
[0057] Yellow solid, 86% Yield. Melting point: 129-131°C. 1 H NMR (400MHz, CDCl3), δ: 7.81 (d, J = 3.5Hz, 1H), 7.48-6.93 (m, 12H), 7.16-6.97 (m, 9H), 5.51 ( s,1H),4.19(s,2H),3.81(t,J=4.7Hz,1H),3.07-2.91(m,2H),211(s,2H).MS(API(+))calcd for C 23 H 20 FO + [M+H] + :331.15; found:331.16.
[0058] Example 11: Determination of antifouling activity of the compounds obtained in Examples 1 to 10
[0059] The method for determining the minimum inhibitory concentration (MIC) is as follows: the test tube double dilution method is used to dilute the concentration of the synthesized hydroxyl heterocyclic compound by two times in sequence, and then the diluted bacterial solution is added to the hydroxyl heterocyclic compound dilution solution for culture. Escherichia coli and Staphylococcus aureus are cultured with shaking for 24 hours. The positive control tube (the test tube inoculated with bacteria without adding the test compound) is observed with the naked eye to have bacterial growth and turbidity, and the negative control tube (the test tube without adding the test compound and not inoculating bacteria) has no bacterial growth and is transparent, so as to determine the minimum inhibitory concentration of the test substance for the two test strains. Based on this judgment, the test results of the hydroxyl heterocyclic compound on the two bacteria are shown in Table 1.
[0060] Table 1 MIC of compounds against two bacteria
[0061]
[0062] According to the antifouling activity screening, the synthesized compounds all showed good antifouling activity, among which compound a7 and compound a9 showed outstanding antifouling activity, with the lowest MICs value against Staphylococcus aureus and Escherichia coli reaching 0.016 mg / mL, which is superior to the commercial tributyltin (TBT) antifouling agent.
[0063] The target compounds a7 and a9 provided by the present invention have higher antifouling activity than traditional TBTO. Compared with the antifouling activity disclosed in ZL201811465472.9, the best activity of the compound is 250ug / mL, i.e. 0.25g / L; the antifouling activity of the present invention is significantly improved (0.004mg / mL). Compared with the invention patent of CN201611113112.3, the antifouling activity of the compound is 0.0625g / L, 0.125g / L or 0.250g / L respectively, and the antifouling activity of the present invention is also significantly improved. The patent application document CN201310098503.2 submitted by the Yantai Coastal Zone Research Institute of the Chinese Academy of Sciences discloses the application of halogenated indoles and their derivatives as marine antifouling agents. The activity range of the compound is 0.84mg / L to 18.9mg / L, and its antifouling activity is significantly lower than the antifouling activity of the present invention (0.004mg / mL).
[0064] In terms of antifouling effect, the compound obtained in the present application has a significantly longer antifouling effect than the compound disclosed above, specifically, it can reach 24 months.
[0065] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.
Claims
1. A hydroxyl-containing heterocyclic compound, characterized in that: As shown in formula (I): Formula (I) The R is any one of the following groups: 。 2. The method for preparing the hydroxyl-containing heterocyclic compound according to claim 1, characterized in that: The process is as follows: 。 3. The method for preparing a hydroxyl-containing heterocyclic compound according to claim 1, characterized in that: Here are the steps: (1) Under nitrogen protection, 2-phenylindole was dissolved in N,N-dimethylformamide, phosphorus oxychloride was added, and the mixture was reacted in an ice-water bath for 4 h. The reaction was followed by TCL. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the intermediate aldehyde compound 1; (2) using tetrahydrofuran as a reaction solvent and in the presence of a catalyst, reacting the intermediate aldehyde compound 1 obtained in step (1) with different halogenated hydrocarbons to undergo a nucleophilic substitution reaction to obtain a 2-phenylindole N-grafted mono-substituted or di-substituted benzyl compound 2; (3) Under ice bath conditions, the compound 2 obtained in step (2) is reduced with lithium aluminum hydride. After the reaction is completed, water is slowly added dropwise to the reaction solution to quench the reaction. The mixture is then extracted with ethyl acetate, washed with a saturated NaCl solution, dried without Na2SO4, filtered, concentrated under reduced pressure, and quickly separated and purified by a chromatography column to produce the target compound.
4. The method for preparing a hydroxyl-containing heterocyclic compound according to claim 3, characterized in that: The catalyst used in step (2) is triethylamine.
5. Use of the hydroxyl-containing heterocyclic compound obtained according to claim 1 for antifouling of ships.
6. The use according to claim 5, characterized in that The antifouling method is directed against Staphylococcus aureus or Escherichia coli.