A hydroxyquinoline compound, a preparation method thereof and application thereof

Abstract

The application relates to a hydroxyquinoline compound, a preparation method thereof and application thereof, which is prepared from 2-methylquinoline-8-ol as raw material, dissolved in dioxane, refluxed to obtain an aldehyde compound through selenium dioxide catalysis, then subjected to a Grignard reaction with an ethynyl magnesium bromide solution to obtain a key intermediate, finally, copper sulfate and sodium ascorbate are added as catalysts, and a corresponding azide compound R-N3 is added to carry out a reaction to obtain a target compound containing a hydroxyl group. The synthesis process is simple, the product has high purity, has high sterilization activity on staphylococcus aureus, bacillus, corynebacterium, micrococcus and escherichia coli, and has a good ship antifouling application prospect.

Description

Technical Field

[0001] The purpose of this invention is to provide a hydroxyquinoline compound, its preparation method, and its use in ship antifouling. Background Technology

[0002] Marine biofouling refers to harmful molecules, microorganisms, plants, and animals that adhere to the hull and seabed equipment. This is a significant global problem because biofouling on marine vessels can degrade hull surfaces, damage propellers, increase drag, lead to high fuel consumption, and excessive maintenance costs. To address this issue, countries worldwide are developing antifouling strategies, among which applying antifouling coatings to the surfaces requiring protection is a relatively efficient, simple, and economical method.

[0003] Currently, there are systematic technologies for preventing the attachment and growth of marine organisms, 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, but these have long been phased out due to their high toxicity. Subsequently, soluble antifouling coatings with cuprous oxide as the antifouling agent base were developed, followed by insoluble antifouling coatings with high copper compound bases (using polymers as the main base), and organotin and organotin-cuprous oxide composite antifouling agents. Further advancements have been made in high-performance, long-lasting, and easy-to-apply organotin self-polishing antifouling coatings, representing a significant step forward in antifouling coating technology. However, heavy metals such as cuprous oxide are highly toxic, causing serious marine pollution, severely impacting the growth and reproduction of marine organisms, and even leading to genetic mutations. With increasing environmental concerns, the development of new, non-toxic antifouling coatings that do not pollute the environment has become an inevitable trend.

[0004] Nitrogen-containing compounds possess advantages such as low toxicity and high efficiency in preventing fouling, making them an important direction for the development of modern antifouling agents. The inventor's patent application CN201611113112.3, filed on December 7, 2016, discloses a hexahydropyrroloindole compound having the following structure.

[0005]

[0006] In this synthesis, substituents R1 and R2 represent monosubstituted or polysubstituted benzyl groups, and R1 and R2 can be the same substituent. The synthetic route uses indole-3-acetonitrile as the starting material. It has advantages such as high yield and easy separation. These compounds exhibit varying degrees of inhibitory activity against Staphylococcus aureus and Escherichia coli, and can be developed into antifouling agents with potential applications in ship antifouling. Patent document ZL201811465472.9, submitted on December 3, 2018, discloses indole compounds, their synthetic methods, and their antifouling applications. The structural formula of this compound is: The preparation method involves first preparing the acyl chloride product from the reaction reagents. A solution of substrate a in anhydrous dichloromethane is weighed, and triethylamine is added dropwise. Under ice-water bath conditions, a dichloromethane solution of the acyl chloride product is added dropwise. After complete addition, the reaction solution is moved to room temperature and stirred. The reaction is detected; if the substrate has completely reacted, the reaction is quenched. The organic phase is extracted with dichloromethane, the organic phases are combined, and the mixture is concentrated under reduced pressure. The crude product is separated by column chromatography to obtain indole compounds. The synthesis process is simple, the product has high purity, and it exhibits high bactericidal activity against Staphylococcus aureus, Solanaceae Rawlstonella, and Bacillus cereus, showing excellent application prospects. Patent application CN201310098503.2, submitted by the Yantai Coastal Zone Research Institute of the Chinese Academy of Sciences on March 26, 2013, discloses the application of halogenated indoles and their derivatives as marine antifouling agents. In use, one or more haloindole derivatives are mixed with antifouling coatings as active ingredients for marine antifouling agents, wherein the active ingredient constitutes 1%-20% of the antifouling coating by weight. The molecular formula of the haloindole derivatives is C8H. m NR1R2.

[0007] The above studies demonstrate that using nitrogen-containing compounds as the research target for antifouling has significant application value. However, the existing related antifouling active compounds still have considerable room for improvement in their antifouling activity, especially due to their complex structures, which hinder industrialization and cannot yet meet commercial needs. Therefore, further research on indole compounds is needed to obtain antifouling agents with superior activity. Summary of the Invention

[0008] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a hydroxyquinoline compound, its preparation method and its application, to solve the problem of unstable bonding between existing antifouling agents and coating base materials.

[0009] To achieve the above-mentioned objectives, the present invention employs the following technical solution:

[0010] The hydroxyquinoline-containing compound shown in formula (I)

[0011] Formula (I)

[0012] The R mentioned is any one of the following groups 1-10:

[0013]

[0014] R corresponds to the following in sequence: methyl, ethyl, n-propyl, phenyl, o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl. The resulting compounds correspond to compounds c1 to c10 in sequence.

[0015] The synthetic routes for the above-mentioned hydroxyquinoline-containing compounds are as follows:

[0016]

[0017] Specifically, the synthetic process for hydroxyquinoline-containing compounds of formula (I) includes the following steps:

[0018] (1) Weigh 159 mg (1 mmol) of 2-methylquinoline-8-ol and add it to a round-bottom flask (100 mL). Add 30 mL of dioxane and stir until completely dissolved. Add 222 mg (2 mmol) of selenium dioxide to the reaction solution and reflux for 24 h. Monitor the reaction with a TCL. Pour the reaction solution into a 250 mL beaker, dilute with water, extract with ethyl acetate, wash with saturated NaCl aqueous solution, and remove anhydrous Na2SO4. The product was dried and concentrated under reduced pressure. 156 mg (0.90 mmol, 90%) of crude compound a was obtained.

[0019] (2) Weigh 173 mg of compound a (1 mmol) into a 100 mL dry round-bottom flask and slowly add it to 30 mL of anhydrous tetrahydrofuran. Stir at room temperature for 10 min, and slowly add 187.5 mg (1.5 mmol, 0.5 M in THF) of ethynyl magnesium bromide solution in an ice-water bath. Transfer the reaction solution to room temperature and stir. Detect by TLC (petroleum ether: ethyl acetate = 4:1, v / v). Quench the reaction by slowly adding an appropriate amount of saturated ammonium chloride solution. Extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and rapidly separate the corresponding intermediate b 183 mg (0.86 mmol, 86%) by chromatography column.

[0020] (3) Weigh 213 mg of compound b (1 mmol) and dissolve it completely in 30 mL of DMF (N,N-dimethylformamide). Add 192 mg of CuSO4 (1.2 mmol), 432 mg of sodium ascorbate (sodium vitamin C, 2 mmol), and then add the corresponding azide compound (1.2 mmol). React at room temperature for 6 h, extract with ethyl acetate, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and rapidly separate by chromatography to obtain the target compounds corresponding to Examples c1 to c10.

[0021] The hydroxyquinoline compounds obtained above have good antifouling activity on ships, and the five bacteria involved are Staphylococcus aureus, Bacillus, Corynebacterium, Micrococcus and Escherichia coli.

[0022] Beneficial effects:

[0023] This invention is based on the active structure of the natural product quinoline. By introducing OH and nitrogen atoms into the compound, and utilizing the strong coupling effect of their lone pair electrons with the hydroxyl hydrogen in the resin, the binding force between the antifouling agent and the coating resin is significantly enhanced. This ensures the long-term stability of the antifouling component in the coating, preventing precipitation or loss, and fundamentally extending the antifouling effect. The product not only possesses excellent physical stability but also exhibits superior biofouling activity. This compound has a significant inhibitory effect on common marine fouling microorganisms such as Staphylococcus aureus, Bacillus, Corynebacterium, Micrococcus, and Escherichia coli, effectively preventing marine organism attachment, ensuring ship surface cleanliness, reducing navigation drag, and improving fuel economy. More importantly, this product, with the quinoline structure possessing natural antifouling activity as its core, successfully replaces traditional heavy metal antifouling agents such as cuprous oxide, completely eliminating the pollution risk of heavy metals such as copper and tin to the marine ecosystem, aligning with the current trend of green, environmentally friendly, and sustainable technological development. While achieving highly efficient antifouling, the product is also eco-friendly, making it an ideal choice for environmentally friendly marine antifouling coatings with excellent application prospects and social value. Detailed Implementation

[0024] The present invention will now be described in detail with reference to the embodiments.

[0025] The synthetic process for hydroxyquinoline-containing compounds consists of the following steps:

[0026] (1) Synthesis of compound a

[0027]

[0028] Weigh 159 mg (1 mmol) of 2-methylquinoline-8-ol and add it to a 100 mL round-bottom flask. Add 30 mL of dioxane and stir until completely dissolved. Add 222 mg (2 mmol) of selenium dioxide to the reaction solution and reflux for 24 h. Monitor the reaction with a TCL. Pour the reaction solution into a 250 mL beaker, dilute with water, extract with ethyl acetate, wash with saturated NaCl aqueous solution, and remove anhydrous Na2SO4. The product was dried and concentrated under reduced pressure. 156 mg (0.90 mmol, 90%) of crude compound a was obtained.

[0029] (2) Synthesis of compound b

[0030]

[0031] Weigh 173 mg (1 mmol) of compound a into a 100 mL dry round-bottom flask and slowly add it to 30 mL of anhydrous tetrahydrofuran. Stir at room temperature for 10 min, and slowly add 187.5 mg (1.5 mmol, 0.5 min THF) of ethynyl magnesium bromide solution in an ice-water bath. Transfer the reaction solution to room temperature and stir. Detect by TLC (petroleum ether:ethyl acetate = 4:1). Quench the reaction by slowly adding an appropriate amount of saturated ammonium chloride solution. Extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and rapidly separate the corresponding intermediate compound b 183 mg (0.86 mmol, 86%) by column chromatography.

[0032] (3) Synthesis of target compounds c1-c10

[0033]

[0034] 213 mg of compound b (1 mmol) was weighed and completely dissolved in 30 mL of DMF (N,N-dimethylformamide). 192 mg of catalyst CuSO4 (1.2 mmol), 432 mg of sodium ascorbate (2 mmol), and the corresponding azide compound R-N3 (1.2 mmol) were added. The mixture was reacted at room temperature for 6 h, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and rapidly separated by chromatography to obtain the target compounds c1 to c10 corresponding to Examples 1 to 10.

[0035] Example 1 Synthesis

[0036] Compound c1: Yellow solid, 87% yield. 1 H NMR (400 MHz, CDCl3), δ: 9.57(s, 1H),8.06(s, 1H), 7.75–7.26 (m, 4H), 6.75 –6.64 (m, 1H), 5.26 –5.16 (m, 2H), 3.78(s, 3H), 2.87- 2.65 (m, 2H). MS (API (+)) calcd for C 14 H 15 N4O2 + [M+H] + : 271.12;found: 271.12.

[0037] Example 2 Synthesis

[0038] Compound C2: pale yellow solid, 83% yield. 1 H NMR (400 MHz, CDCl3), δ: 9.52(s,1H), 8.03(s, 1H), 7.74–7.23 (m, 4H), 6.71 –6.63 (m, 1H), 5.24 –5.14 (m, 2H),3.89(q, 2H), 2.87- 2.65 (m, 2H), 1.51(t, 3H). MS (API (+)) calcd for C 15 H 17 N4O2 + [M+H] + : 285.13; found: 285.13.

[0039] Example 3 Synthesis

[0040] Compound C3: Yellow solid, 84% yield. Melting point: 128-130 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.48 (s, 1H), 8.05 (s, 1H), 7.73–7.21 (m, 4H), 6.73 –6.61 (m, 1H), 5.21 –5.11 (m, 2H), 4.43(t, 2H), 2.86- 2.62 (m, 2H), 1.72 –1.68 (m, 2H) ,0.85(t, 3H). MS (API (+)) calcd for C 16 H 19 N4O2 + [M+H] + : 299.15; found: 299.15.

[0041] Example 4 Synthesis

[0042] Compound C4: Yellow solid, 96% yield. Melting point: 132-134 °C. 1H NMR (400 MHz, CDCl3), δ: 9.53 (s, 1H), 8.04 (s, 1H), 7.75–7.23 (m, 9H), 6.75 –6.58 (m, 1H), 5.27 –5.15 (m, 2H), 2.84- 2.58 (m, 2H). MS (API (+)) calcd for C 19 H 17 N4O2 + [M+H] + : 333.13; found: 333.13.

[0043] Example 5 Synthesis

[0044] Compound C5: Yellow solid, 90% yield. Melting point: 131-133 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.70 (s, 1H), 8.05 (s, 1H), 7.78–7.21 (m, 8H), 6.76 –6.51 (m, 1H), 5.29 –5.17 (m, 2H), 2.86- 2.53 (m, 2H), 1.85(s, 3H). MS (API (+)) calcd forC 20 H 19 N4O2 + [M+H] + : 347.15; found: 347.15.

[0045] Example 6 Synthesis

[0046] Compound C6: White solid, 78% yield. Melting point: 125-127 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.72 (s, 1H), 8.07 (s, 1H), 7.77–7.23 (m, 8H), 6.78 –6.52 (m, 1H), 5.31 –5.19 (m, 2H), 2.87- 2.54 (m, 2H), 1.83(s, 3H). MS (API (+)) calcd forC 20 H 19 N4O2 + [M+H]+ : 347.15; found: 347.15.

[0047] Example 7 Synthesis

[0048] Compound C7: Yellow solid, 87% yield. Melting point: 133-135 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.76 (s, 1H), 8.07 (s, 1H), 7.76–7.24 (m, 8H), 6.79 –6.55 (m, 1H), 5.27 –5.15 (m, 2H), 2.86- 2.55 (m, 2H), 1.82(s, 3H). MS (API (+)) calcd forC 20 H 19 N4O2 + [M+H] + : 347.15; found: 347.15.

[0049] Example 8 Synthesis

[0050] Compound C8: Yellow solid, 84% yield. Melting point: 123-125 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.78(s, 1H), 8.07(s, 1H),7.76–7.23 (m, 8H), 6.73 –6.52 (m, 1H),5.27 –5.14 (m, 2H), 2.85- 2.51 (m, 2H). MS (API (+)) calcd for C 19 H 16 ClN4O2 + [M+H] + : 367.10; found: 367.10.

[0051] Example 9 Synthesis

[0052] Compound C9: Yellow solid, 88% yield. Melting point: 125-127 °C. 1H NMR (400 MHz, CDCl3), δ: 9.72(s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 8.14–7.28 (m, 7H), 6.79 –6.53 (m, 1H), 5.28 –5.13 (m, 2H), 2.87- 2.53 (m, 2H). MS (API (+)) calcd forC 19 H 16 ClN4O2 + [M+H] + : 367.10; found: 367.10.

[0053] Example 10 Synthesis

[0054] Compound C10: Yellow solid, 92% yield. Melting point: 129-131 °C. 1 H NMR (400 MHz, CDCl3), δ: 9.73(s, 1H), 8.07 (s, 1H), 7.72–7.18 (m, 8H), 6.75 –6.56 (m, 1H), 5.25 –5.12 (m, 2H), 2.89- 2.54 (m, 2H). MS (API (+)) calcd for C 19 H 16 ClN4O2 + [M+H] + : 367.10; found: 367.10.

[0055] Example 11: Determination of the antifouling activity of the compounds obtained in Examples 1-10

[0056] The method for determining the minimum inhibitory concentration (MIC) was as follows: The synthetic hydroxyquinoline-containing compound was diluted twofold sequentially in test tubes. The diluted bacterial suspensions were then added to the hydroxyquinoline-containing compound dilution solution and incubated with shaking for 24 hours for Staphylococcus aureus, Bacillus, Corynebacterium, Micrococcus, and Escherichia coli. Positive control tubes (tubes inoculated with bacteria but without the test compound) showed bacterial growth and became turbid, while negative control tubes (tubes without the test compound and without inoculation) showed no bacterial growth and remained clear. This method determined the minimum inhibitory concentration of the analyte against the two test strains. The results of the hydroxyquinoline-containing compound's effects on the two bacteria are shown in Table 2.

[0057] Table 1. MICs of the compounds against five bacteria

[0058]

[0059] According to the antifouling activity screening, all synthesized compounds showed good antifouling activity. Among them, compound C8 showed outstanding antifouling activity, with the lowest MIC value of 0.016 mg / mL against Staphylococcus aureus, Bacillus, Corynebacterium, Micrococcus and Escherichia coli, which is superior to commercially available tributyltin (TBT) antifouling agent.

[0060] The target compound C8 provided by this invention exhibits higher antifouling activity than conventional TBTO. Compared with the antifouling activity disclosed in ZL201811465472.9, the compound's best activity is 250 ug / mL, i.e., 0.25 g / L; the antifouling activity of this invention is significantly improved (0.016 mg / mL). Compared with the invention patent CN201611113112.3, whose compounds have antifouling activities of 0.0625 g / L, 0.125 g / L, or 0.250 g / L respectively, the antifouling activity of this invention is also significantly improved. Patent application 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, with an activity range of 0.84 mg / L to 18.9 mg / L, whose antifouling activity is significantly lower than that of this invention (0.016 mg / mL).

[0061] Regarding the antifouling effect, the compound obtained in this application has a significantly longer duration than the compound disclosed above, specifically reaching 36 months.

[0062] The foregoing has shown and described the basic principles and main features of the present invention, as well as its advantages. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A hydroxyquinoline-containing compound, characterized in that, As shown in equation (I): Equation (I).

2. The hydroxyquinoline-containing compound according to claim 1, characterized in that, The R mentioned is any one of the following groups: 。 3. The method for preparing the hydroxyquinoline-containing compound according to claim 1 or 2, characterized in that, The process is as follows: 。 4. The method for preparing the hydroxyquinoline-containing compound according to claim 3, characterized in that, The specific steps are as follows: (1) Weigh 2-methylquinoline-8-ol, add dioxane, stir until completely dissolved, add selenium dioxide to the reaction solution, reflux for 24 h, pour the reaction solution into a beaker, dilute with water, extract with ethyl acetate, wash with saturated NaCl aqueous solution, dry with anhydrous Na2SO4, concentrate under reduced pressure to obtain compound a; (2) Weigh compound a into a dry round-bottom flask and slowly add it into an organic solvent. Stir at room temperature and slowly add acetylenyl magnesium bromide solution in an ice-water bath. Move the reaction solution to room temperature and stir. Detect by TLC, quench the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and quickly separate intermediate b by chromatography column. (3) Weigh out compound b and dissolve it completely in DMF. Add catalyst and then add the corresponding azide compound R-N3. React at room temperature for 6 h. Extract with ethyl acetate, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and rapidly separate with a chromatography column to obtain target compounds c1-c10.

5. The method for preparing hydroxyquinoline-containing compounds according to claim 4, characterized in that, In step (2), the developing solvent used for TLC detection is petroleum ether: ethyl acetate = 4:1 (v / v).

6. The method for preparing hydroxyquinoline-containing compounds according to claim 4, characterized in that, In step (2), the organic solvent used is anhydrous tetrahydrofuran.

7. The method for preparing hydroxyquinoline-containing compounds according to claim 4, characterized in that, In step (2), the reaction is quenched by slowly adding a saturated ammonium chloride solution to the reaction solution.

8. The method for preparing hydroxyquinoline-containing compounds according to claim 4, characterized in that, The catalysts used in step (3) are copper sulfate and sodium ascorbate, and the molar ratio of the two is 3:

5.

9. The use of the hydroxyquinoline-containing compound obtained in claim 1 for antifouling purposes on ships.

10. The use according to claim 9, characterized in that... The aforementioned ship antifouling measures target bacteria such as Staphylococcus aureus, Bacillus, Corynebacterium, Micrococcus, or Escherichia coli.

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