A quinazole heterocyclic compound for ship antifouling, preparation method and application thereof

Abstract

The present invention relates to a quinazole heterocyclic compound for ship antifouling and a preparation method thereof. The method comprises using 2-aminobenzamide as a substrate, dissolving it in DMSO, reacting it at 100°C for 6 hours, and detecting it with thin-layer chromatography. After the reaction is complete, water is added for quenching. The crude product is separated by column chromatography to obtain an intermediate a. The intermediate a then undergoes a nucleophilic substitution reaction with different halogenated hydrocarbons to obtain the target compound in just two steps. The synthesis process is simple, the product is highly pure, and it can effectively inhibit Escherichia coli and Staphylococcus aureus, showing promising application prospects in ship antifouling.

Description

Technical Field

[0001] The present invention provides a quinazole heterocyclic compound, a preparation method thereof and use thereof in ship antifouling. Background Art

[0002] Marine fouling refers to damage to underwater facilities caused by the attachment and invasion of marine organisms. Examples of underwater facilities or equipment susceptible to fouling include ships, docks, buoys, water pipes, oil platforms, and aquaculture facilities. The harm caused by fouling is diverse. For example, oysters, mussels, barnacles, and large algae attaching to and growing on ship bottoms can increase ship weight and navigation resistance, and corrode hulls. Marine boring animals can damage wooden ships and docks, and large-scale growth of marine organisms in suction and drainage pipes can clog them. Large-scale biofouling can damage oil platforms. Specifically, the damage caused by marine fouling primarily stems from three factors: 1. Surface corrosion. Thousands of species of marine organisms cling to the ocean, and their attachment increases ship resistance, leading to reduced speed, significantly increased fuel consumption, and increased mechanical wear. Furthermore, marine biofouling damages membranes, accelerating surface metal corrosion. This increases repair and maintenance costs for submerged structures like ships, and can even shorten the service life of ships and warships. 2. Increased environmental costs. Increased fuel consumption generates large amounts of greenhouse gases, placing a significant burden on the environment and incurring enormous environmental costs. This can cause significant damage to coastal defense, shipping, coastal industrial fisheries, and even the environment. It can also affect the normal operation of water-based facilities. For example, marine organisms can clog pipes and cause serious accidents. The prevention and control of marine fouling organisms has always been a major challenge for humanity. To this end, countries around the world have adopted effective methods to inhibit the attachment of marine fouling organisms. Among the many methods for preventing and controlling marine fouling organisms, the application of antifouling paint is the most convenient, effective, and economical method.

[0003] Traditional antifouling coatings achieve their antifouling effects primarily by slowly releasing heavy metals such as copper, tin, mercury, and lead. However, these antifouling agents cause serious coastal pollution and pose certain safety risks to marine ecology and human dietary health. Using natural products as antifouling agents has the advantages of being non-toxic, highly effective, rapidly degradable, and harmless to the environment, and has always been a research hotspot in the antifouling field. However, the low content and insufficient supply of natural products are the main problems in the commercialization of natural product antifouling agents. Chemical synthesis is the most direct way to ensure supply. Therefore, obtaining natural product antifouling agents through synthetic means can help effectively solve the production problem in the commercialization of natural product antifouling agents.

[0004] Currently, quinazole compounds have great application value as antifouling research targets, but the preparation process needs to be further simplified to obtain more active antifouling agents. Summary of the Invention

[0005] To develop novel antifouling agents, the present invention aims to provide a quinazole heterocyclic compound for ship antifouling and its preparation method. The synthesized compound exhibits excellent inhibitory effects against Escherichia coli and / or Staphylococcus aureus, demonstrating excellent antifouling activity. This invention utilizes a special catalyst, cesium carbonate, to synthesize a natural antifouling compound, eliminating the use of the highly toxic heavy metal cuprous oxide, reducing pollution, enhancing antifouling activity, and significantly simplifying the reaction process.

[0006] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0007] Quinazole heterocyclic compound represented by formula (I)

[0008]

[0009] R is any one of the following groups, wherein when R is group 3 to group 8, it is a normal alkane.

[0010]

[0011] The synthetic route of the above compound is as follows:

[0012]

[0013] Specifically, the synthesis process of the quinazole heterocyclic compound having formula (I) comprises the following steps:

[0014] (1) 2-Aminobenzamide and furfural were added to a 100 mL round-bottom flask, and then DMSO was added to dissolve them. The mixture was heated to 100°C for 6 hours, quenched with water, and post-treated to obtain intermediate a.

[0015] (2) using tetrahydrofuran as a reaction solvent and reacting the intermediate compound a obtained in step (1) with different halogenated hydrocarbons to undergo a nucleophilic substitution reaction in the presence of cesium carbonate as a catalyst to obtain the target compound;

[0016] The different halogenated hydrocarbons are selected from any one of the following reagents: iodomethane, iodoethane, bromopropane, 1-bromobutane, 1-bromopentane, 1-bromohexane, 1-bromoheptane, 1-bromooctane, benzyl chloride, o-methylbenzyl chloride, m-methylbenzyl chloride, p-methylbenzyl chloride, o-chlorobenzyl chloride, m-chlorobenzyl chloride, 4-chlorobenzyl chloride, o-fluorobenzyl chloride, m-fluorobenzyl chloride, 4-fluorobenzyl chloride, and p-methoxybenzyl chloride.

[0017] The obtained quinazole heterocyclic compound has antifouling activity against ships, and the bacterial species involved are one or both of Escherichia coli and Staphylococcus aureus.

[0018] Beneficial Effects: The quinazole heterocyclic compounds provided by the present invention have simple structures, readily available raw materials, and mild reaction conditions. They can be obtained in just two steps, greatly simplifying the preparation process and facilitating industrialization. They also eliminate the use of the highly toxic heavy metal cuprous oxide, reducing environmental pollution and enhancing antifouling activity. The prepared compounds exhibit antibacterial activity against Escherichia coli and Staphylococcus aureus. DETAILED DESCRIPTION

[0019] The present invention will be described in detail below in conjunction with the embodiments.

[0020] Example 1 Synthesis

[0021] The first step was to prepare intermediate a: 2-aminobenzamide (680 mg, 5.0 mmol) and furfural (576 mg, 6.0 mmol) were added to a 100 mL round-bottom flask, followed by dissolution in 30 mL of DMSO. The mixture was heated to 100°C for 6 hours. After TLC, the starting material spot disappeared. The mixture was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated under reduced pressure to obtain 974 mg (4.55 mmol, 91%) of crude compound a.

[0022] The second step is to prepare compound 1a: 214 mg of compound a (1 mmol) was weighed into a 100 mL dry round-bottom flask and slowly added to 30 mL of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 10 min, and cesium carbonate (390 mg, 1.2 mmol) was added as a catalyst in an ice-water bath. Methyl iodide (169 mg, 1.2 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was moved to room temperature and stirred. The mixture was detected by TLC, and an appropriate amount of saturated ammonium chloride solution was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and quickly separated by chromatography to obtain the corresponding target compound 1a (219 mg, 96%).

[0023] 1 H NMR(400MHz, DMSO-d6)δ8.23(s,1H),7.64(d,J=4.8Hz,1H),7.54(d,J=5.3Hz,1H),7.35–6.42(m,5H),6.15(d,J=1.9Hz,1H),3.01(s,3H).MS(ESI(+))calcd forC 13 H 13 N2O2[M+H] + :229.26;found:229.25.

[0024] The difference between Examples 2 to 19 and Example 1 is that different halogenated hydrocarbon reagents are used, as shown below:

[0025] Example 2 Synthesis

[0026] Yield: 95%. 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.68(d,J=4.5Hz,1H),7.51(d,J=4.7Hz,1H),7 .37–6.46(m,5H),6.15(d,J=2.1Hz,1H),3.31(q,2H),1.11(t,3H).MS(ESI(+))calcd for C 14 H 15 N2O2[M+H] + :243.29;found:243.28.

[0027] Example 3 Synthesis

[0028] Yield: 94%. 1 H NMR(400MHz, DMSO-d6)δ8.58(s,1H),7.67(d,J=4.5Hz,1H),7.53(d,J=4.6Hz,1H),7.35–6.42 (m,5H),6.25(d,J=2.3Hz,1H),3.34(t,2H),1.53–1.51(m,2H),0.85(t,3H).MS(ESI(+))calcd for C 15 H 17 N2O2[M+H] + :257.31;found:257.32.

[0029] Example 4 Synthesis

[0030] Yield: 97%. 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.65(d,J=4.7Hz,1H),7.52(d,J=5.2Hz,1H),7.34– 6.40(m,5H),6.25(d,1H),3.35(t,2H),1.47–1.35(m,4H),0.91(t,3H).MS(ESI(+))calcd for C 16 H 19 N2O2[M+H] + :271.34;found:271.34.

[0031] Example 5 Synthesis

[0032] Yield: 95%. 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.63(d,J=4.4Hz,1H),7.51(d,J=5.2Hz,1H),7.33–6.40( m,5H),6.24(d,J=2.1Hz,1H),3.35(t,2H),1.47–1.35(m,6H),0.91(t,3H)..MS(ESI(+))calcd for C 17 H 21 N2O2[M+H] + :285.37;found:285.38.

[0033] Example 6 Synthesis

[0034] Yield: 92%. 1 H NMR(400MHz, DMSO-d6)δ8.58(s,1H),7.64(d,J=4.4Hz,1H),7.54(d,J=5.4Hz,1H),7.34–6.44 (m,5H),6.25(d,J=2.3Hz,1H),3.32(t,2H),1.50–1.30(m,8H),0.89(t,3H).MS(ESI(+))calcd for C 18 H 23 N2O2[M+H] + :299.39;found:299.38.

[0035] Example 7 Synthesis

[0036] Yield: 93%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.65(d,J=4.5Hz,1H),7.55(d,J=5.3Hz,1H),7.34–6.45( m,5H),6.23(d,J=1.8Hz,1H),3.33(t,2H),1.50–1.30(m,10H),0.90(t,3H).MS(ESI(+))calcd for C 19 H 25 N2O2[M+H] + :313.42;found:313.42.

[0037] Example 8 Synthesis

[0038] Yield: 95%. 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.66(d,J=4.6Hz,1H),7.56(d,J=5.6Hz,1H),7.36–6.46( m,5H),6.26(d,J=1.6Hz,1H),3.36(t,2H),1.54–1.33(m,12H),0.91(t,3H).MS(ESI(+))calcd for C 20 H 27 N2O2[M+H] + :327.45;found:327.46.

[0039] Example 9 Synthesis

[0040] Yield: 96%. 1 H NMR(400MHz, DMSO-d6)δ8.65(s,1H),7.67(d,J=4.8Hz,1H),7.57(d,J=5.7Hz,1H),7.37–6.47(m,10H),6.24(d,J=2.2Hz,1H),4.65(s,2H).MS(ESI(+))calcd for C 19 H 17 N2O2[M+H] + :305.36;found:305.36.

[0041] Example 10 Synthesis

[0042] Yield: 93%. 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),7.62(d,J=4.2Hz,1H),7.52(d,J=5.7Hz,1H),7 .32–6.43(m,9H),6.23(d,J=2.3Hz,1H),4.63(s,2H),2.30(s,3H).MS(ESI(+))calcd for C 20 H 19 N2O2[M+H] + :319.38;found:319.38.

[0043] Example 11 Synthesis

[0044] Yield: 97%. 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),7.63(d,J=4.3Hz,1H),7.54(d,J=5.5Hz,1H),7 .33–6.42(m,9H),6.25(d,J=2.2Hz,1H),4.65(s,2H),2.32(s,3H).MS(ESI(+))calcd for C 20 H 19 N2O2[M+H] + :319.38;found:319.37.

[0045] Example 12 Synthesis

[0046] Yield: 95%. 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.65(d,J=4.6Hz,1H),7.57(d,J=5.7Hz,1H),7 .37–6.45(m,9H),6.24(d,J=2.3Hz,1H),4.66(s,2H),2.35(s,3H).MS(ESI(+))calcd for C 20 H 19 N2O2[M+H] + :319.38;found:319.37.

[0047] Example 13 Synthesis

[0048] Yield: 92%. 1 H NMR(400MHz, DMSO-d6)δ8.67(s,1H),7.65(d,J=4.6Hz,1H),7.57(d,J=5.7Hz,1H),7.35–6.41(m,9H),6.21(d,J=2.3Hz,1H),4.61(s,2H).MS(ESI(+))calcd for C 19 H 16 ClN2O2[M+H] + :319.38;found:319.38.

[0049] Example 14 Synthesis

[0050] Yield: 93%. 1H NMR(400MHz, DMSO-d6)δ8.71(s,1H),7.69(d,J=4.9Hz,1H),7.59(d,J=5.7Hz,1H),7.38–6.43(m,9H),6.28(d,J=2.3Hz,1H),4.69(s,2H).MS(ESI(+))calcd for C 19 H 16 ClN2O2[M+H] + :319.38;found:319.37.

[0051] Example 15 Synthesis

[0052] Yield: 96%. 1 H NMR(400MHz, DMSO-d6)δ8.65(s,1H),7.69(d,J=4.4Hz,1H),7.53(d,J=5.6Hz,1H),7.34–6.49(m,9H),6.28(d,J=2.3Hz,1H),4.68(s,2H).MS(ESI(+))calcd for C 19 H 16 ClN2O2[M+H] + :319.38;found:319.36.

[0053] Example 16 Synthesis

[0054] Yield: 95%. 1 H NMR(400MHz, DMSO-d6)δ8.68(s,1H),7.65(d,J=4.6Hz,1H),7.56(d,J=5.6Hz,1H),7.36–6.45(m,9H),6.26(d,J=2.6Hz,1H),4.65(s,2H).MS(ESI(+))calcd for C 19 H 16 FN2O2[M+H] + :323.35;found:323.37.

[0055] Example 17 Synthesis

[0056] Yield: 96%. 1H NMR(400MHz, DMSO-d6)δ8.64(s,1H),7.63(d,J=4.4Hz,1H),7.53(d,J=5.3Hz,1H),7.33–6.44(m,9H),6.23(d,J=2.6Hz,1H),4.64(s,2H).MS(ESI(+))calcd for C 19 H 16 FN2O2[M+H] + :323.35;found:323.32.

[0057] Example 18 Synthesis

[0058] Yield: 94%. 1 H NMR(400MHz, DMSO-d6)δ8.63(s,1H),7.62(d,J=4.5Hz,1H),7.52(d,J=5.6Hz,1H),7.31–6.45(m,9H),6.24(d,J=2.4Hz,1H),4.63(s,2H).MS(ESI(+))calcd for C 19 H 16 FN2O2[M+H] + :323.35;found:323.38.

[0059] Example 19 Synthesis

[0060] Yield: 95%. 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),7.67(d,J=4.7Hz,1H),7.57(d,J=5.6Hz,1H),7 .37–6.43(m,9H),6.23(d,J=2.7Hz,1H),4.67(s,2H),3.73(s,3H).MS(ESI(+))calcd for C 20 H 19 N2O3[M+H] + :335.38;found:335.39.

[0061] Example 20: Determination of fungicidal activity of synthetic compounds

[0062] The microdilution method was used to determine the antibacterial activity of target products 1a-19a against Staphylococcus aureus and Escherichia coli. All strains were purchased from China General Microbiological Culture Collection.

[0063] The test tube double dilution method was used. Sterile test tubes were added with 2 mL of liquid culture medium. The test tubes without test compound but inoculated with bacteria were used as positive controls, and the test tubes without test compound or inoculated with bacteria were used as negative controls. The initial concentration of the drug was 1 g / L. The mixture was diluted twice in sequence and mixed evenly. 200 μL of bacterial suspension was added to each test tube to make the final bacterial suspension concentration 10 4 ~10 5 cfu / mL (cfu stands for colony forming unit; 1 cfu refers to a single colony formed on an agar plate after culture). After 24 hours of shaking culture, the minimum inhibitory concentration (MIC) was determined based on bacterial growth in the test tube. Based on this determination, the test results of the obtained quinazole compounds against the two bacteria are shown in Table 1.

[0064] Table 1 MIC values ​​of the tested compounds against two bacteria (unit: g / L)

[0065]

[0066]

[0067] The results in Table 1 show that most of the prepared compounds exhibited good inhibitory activity, among which the target compounds 3a and 14a had strong inhibitory effects on Escherichia coli and Staphylococcus aureus.

[0068] The target compounds 3a and 14a provided by this invention not only exhibit higher antifouling activity than traditional TBTO and cuprous oxide, but also demonstrate outstanding antifouling activity among similar indole antifouling compounds. For example, these products outperform commercially available TBG (TBG's minimum inhibitory concentrations against two bacteria were 0.0625 and 0.1250 g / L, respectively). Compared to the antifouling activity disclosed in my patent granted in 2018 (ZL201811465472.9, with a maximum activity of 250 μg / mL, or 0.25 g / L), the antifouling activity of compound 14a of this invention was significantly improved (0.0313 g / L). This also significantly enhances the antifouling activity of the compound disclosed in my invention patent CN201611113112.3, published on December 7, 2016, which showed antifouling activities of 0.0625 g / L, 0.125 g / L, or 0.250 g / L, respectively. The patent application document CN201310098503.2 submitted by the Yantai Coastal Zone Research Institute of the Chinese Academy of Sciences discloses the use of halogenated indole and its derivatives as marine antifouling agents. The activity range of its compounds is 0.84 mg / L to 18.9 mg / L, and its antifouling activity is significantly lower than the antifouling activity of the present compound 14a (0.0313 g / L).

[0069] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention.

[0070] The present invention may be subject to various changes and modifications within the spirit and scope of the present invention.

[0071] Improvements are all within the scope of the invention claimed for protection. The scope of the invention claimed for protection is determined by the attached

[0072] The following claims are intended to define the scope of the present invention:

Claims

1. A quinazole heterocyclic compound for ship antifouling, characterized in that: The structural formula is shown in formula (I): Formula (I) Wherein, R is any one of the following groups: .

2. The method for preparing a quinazole heterocyclic compound for ship antifouling according to claim 1, characterized in that The process is as follows: ； RX is a halogenated hydrocarbon selected from p-methylbenzyl chloride, m-chlorobenzyl chloride or p-methoxybenzyl chloride.

3. The method for preparing a quinazole heterocyclic compound for ship antifouling according to claim 2, characterized in that: The steps include: (1) 2-Aminobenzamide and furfural were added to a round-bottom flask, and then dissolved in DMSO. The mixture was heated to 100°C for 6 hours, quenched with water, and post-treated to obtain intermediate a. (2) Using tetrahydrofuran as the reaction solvent, the intermediate compound a obtained in step (1) undergoes a nucleophilic substitution reaction with RX in the presence of cesium carbonate as a catalyst to obtain the target compound.

4. Use of the quinazole heterocyclic compound according to claim 1 in preparing a ship antifouling agent, characterized in that: The compounds inhibit either or both Escherichia coli and Staphylococcus aureus.

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