Pyrazole compound as well as preparation method and application thereof

Abstract

The invention relates to a pyrazole compound as well as a preparation method and application thereof, and the pyrazole compound is prepared by the following steps: taking diethyl oxalate and butanone as raw materials, and reacting in an ice bath to obtain yellow liquid 1; reacting an ethanol solution of N2H4H2O with the compound 1 in an ice bath to obtain yellow liquid 2; adding thionyl chloride into the compound 3 and ethanol, refluxing, removing the solvent, dropwise adding a compound 6, and reacting at room temperature to obtain an intermediate 4; adding dichloromethane into the intermediate 4, wherein the ratio of dichloromethane to TFA is 1: 1, dissolving, and removing Boc to obtain an intermediate 5; and adding anhydrous tetrahydrofuran into the intermediate 5, adding a catalyst triethylamine in an ice-water bath, slowly dropwise adding different halogenated hydrocarbons, and transferring the reaction liquid to room temperature for reaction to obtain target compounds a1-a20. The preparation method is simple, the synthesis process is simple, the product purity is high, the bactericidal activity on staphylococcus aureus and escherichia coli is very high, and the marine antifouling application prospect is good.

Description

Technical Field

[0001] The object of the present invention is to provide a pyrazole compound, a preparation method thereof and use thereof in ship antifouling. Background Art

[0002] Marine fouling organisms, also known as marine attached organisms, are a general term for animals, plants and microorganisms that grow on the bottom of ships and the surface of all facilities in the sea. They attach to the surfaces of ships, floating docks, offshore oil platforms, submarine cables, buoys and mines, cooling pipes of coastal power plants and seawater aquaculture cages, etc., and cause huge losses in military activities, marine transportation, industry and aquaculture production by increasing ship resistance, blocking pipes and nets, accelerating metal corrosion, and increasing the weight of offshore facilities. The prevention and control of such organisms is called marine antifouling. At present, antifouling coatings containing toxic compounds (such as Cu2O, TBT, TPT) are generally used for prevention and control, but these toxic substances are continuously released into the marine environment, especially in military ports and civilian ports with intensive ship activities. The toxic substances often reach high levels, causing serious marine pollution problems. As a countermeasure, in recent years, there has been a wave of research on non-toxic and environmentally friendly marine antifouling coatings internationally. Among them, the antifouling agent in the bionic antifouling coating is a natural product or its chemically modified analogue, which is easy to degrade and does not harm the life of organisms. It is conducive to maintaining ecological balance and is one of the important ways to develop non-toxic and efficient antifouling coatings. The research on separation and purification of natural products and detection of their antifouling ability has become a hot topic for international scientific research institutions and enterprises. Foreign countries, especially the United States, the United Kingdom and Japan, have conducted a lot of research on this. However, there is very little research on the antifouling activity of natural products and its detection in China, and it is urgent to catch up. 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 attached to its surface by marine organisms, which reduces the speed of the ship, 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 later 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] The low toxicity and high efficiency of nitrogen-containing compounds are the important antifouling advantages that are the development direction of modern antifouling agents. The invention patent application with application number CN201611113112.3 submitted by the inventor on December 7, 2016, discloses 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, add triethylamine dropwise, add the dichloromethane solution of the chlorination product dropwise under ice-water bath conditions, wait for the addition to be complete, move the reaction solution to room temperature and stir, 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 Yantai Coastal Zone Research Institute of 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 nitrogen-containing 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 nitrogen-containing 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 pyrazole compound, a preparation method and application 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 triethylamine, which is cheap, easily available and easily recyclable, 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] Pyrazole compounds represented by formula (I)

[0011]

[0012] The R is any one of the following groups:

[0013]

[0014] The synthetic route of the above-mentioned pyrazole compounds is as follows:

[0015]

[0016] Specifically, the synthesis process of the pyrazole compound having formula (I) comprises the following steps:

[0017] Step 1, add diethyl oxalate and butanone into a 100 mL round-bottom flask, react for 2 h in an ice bath, extract with toluene, dry with MgSO4 and filter to obtain a yellow liquid 1;

[0018] Step 2: Add N2H4H2O dropwise to the ethanol solution, and then react compound 1 in an ice bath for 4 hours. Remove the solvent under reduced pressure. Extract with toluene, and obtain a yellow liquid 2 by column chromatography;

[0019] Step 3: Add compound 3 and ethanol to a three-necked flask, and stir to completely dissolve. Then, add thionyl chloride and reflux for 1 hour. After removing the solvent, add tetrahydrofuran, drip triethylamine and stir for 10 minutes, and then dropwise add compound 6. The reaction was carried out at room temperature for 3 h, and ammonium chloride was added for quenching, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and quickly separated by chromatography to obtain intermediate 4;

[0020] Step 4, weigh 4 into a round-bottom flask, add dichloromethane:TFA=1:1 to dissolve, remove Boc, follow up and detect with TLC, the reaction is completed in about 4 hours, remove part of TFA by distillation under reduced pressure, dissolve with dichloromethane, neutralize with saturated sodium bicarbonate under ice bath conditions to obtain crude product 5, and post-treat the crude product as follows: extract with dichloromethane, then extract with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and separate the crude product using silica gel column chromatography to finally obtain intermediate 5;

[0021] Step 5. Weigh compound 5 into a dry round-bottom flask, and slowly add anhydrous tetrahydrofuran, stir at room temperature, add catalyst triethylamine in an ice-water bath, slowly add iodomethane dropwise, and add completely. Move the reaction solution to room temperature and stir, detect by TLC, slowly add an appropriate amount of saturated ammonium chloride solution dropwise to quench the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and quickly separate by chromatography column to obtain the target compound a1.

[0022] Referring to the above preparation method, by adjusting the reaction of compound 5 in step 5 with the following different halogenated hydrocarbons, the target compounds corresponding to Examples a2 to a20 are obtained.

[0023] The halogenated hydrocarbons are methyl iodide, ethyl iodide, propyl bromide, 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, 4-tert-butylbenzyl chloride, and p-methoxybenzyl chloride.

[0024] The catalyst is triethylamine, which is environmentally friendly and easily available.

[0025] The pyrazole compounds obtained above have good ship antifouling activity, and the two bacteria involved are Staphylococcus aureus or Escherichia coli.

[0026] Beneficial effects: (1) The present invention uses diethyl oxalate and butanone as raw materials, introduces a piperazine group into the structure, and utilizes the lone electron effect on nitrogen to increase the binding force with the resin in the coating, significantly reducing the loss rate of the antifouling agent in seawater and increasing the antifouling effect (up to 24 months); (2) The pyrazole compound prepared by the present invention has the characteristics of simple structure, easy availability of raw materials, mild reaction conditions, simple process, and easy industrialization, and has the activity of inhibiting Staphylococcus aureus and Escherichia coli. DETAILED DESCRIPTION

[0027] The present invention is described in detail below in conjunction with embodiments.

[0028] The synthesis process of pyrazole compounds is as follows:

[0029] (1) Synthesis of intermediate 1

[0030]

[0031] Sodium (2.50 g), toluene (50 mL) and anhydrous ethanol (30 mL) were added to a 100 mL three-necked flask. Then, diethyl oxalate solution (14.63 g, 0.10 mol) was added dropwise at 0°C, butanone (7.25 g, 0.10 mol) solution was reacted for 5-6 hours under reduced pressure to remove the solvent, and then neutralized with HCl. Subsequently, the mixture was extracted with toluene, and the extract was dried with MgSO4 and filtered. The filtrate was concentrated to obtain 12.70 g of yellow liquid, which was labeled as intermediate 1. Yield: 73.9%.

[0032] (2) Synthesis of Intermediate 2

[0033]

[0034] N2H4H2O (4.40 g, 88.50 mmol) was added dropwise to a mixture of ethanol (60 mL), and intermediate 1 (12.70 g, 73.80 mmol) was added, and the mixture was reacted at 0°C for 4 hours. The solvent was removed under reduced pressure. The mixture was extracted with toluene and subjected to column chromatography to obtain 7.20 g of a light yellow liquid, which was labeled as intermediate 2. Yield: 58.2%.

[0035] (3) Synthesis of Intermediate 3

[0036]

[0037] The intermediate 2 (168 mg, 1 mmol) was completely dissolved in 30 mL of ethanol, and NaOH (80 mg, 2 mmol) was added, refluxed for 2 h, cooled, placed in an ice-water bath, quenched with water, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and quickly separated by chromatography to obtain the target compound 3 (136 mg, 97%).

[0038] (4) Synthesis of intermediate 4

[0039]

[0040] Compound 3 (186 mg, 1 mmol) and ethanol (30 mL) were added to a three-necked flask, and then stirred to completely dissolve. Subsequently, thionyl chloride (10 mL) was added and refluxed for 1 hour. After removing the solvent, 30 mL of tetrahydrofuran was added, and 0.5 mL of triethylamine was added dropwise (triethylamine plays a role in dehydrogenation and neutralization of the produced hydrogen chloride, equivalent to a catalyst), stirred for 10 minutes, and compound 6 (168 mg, 1.2 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours, and ammonium chloride was added for quenching, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and quickly separated by chromatography to obtain intermediate 4 (268 mg, 87%).

[0041] (5) Synthesis of Intermediate 5

[0042]

[0043] Then, intermediate 4 (308 mg, 1 mmol) was weighed into a round-bottom flask, and dichloromethane:TFA=1:1 (volume ratio) or dichloromethane:TFA=2:1 (volume ratio) was added to dissolve, and Boc was removed. TLC tracking detection was performed. The reaction was completed in about 4 hours, and part of TFA was removed by distillation under reduced pressure. The product was dissolved in dichloromethane and neutralized with saturated sodium bicarbonate under ice bath conditions to obtain crude product 5. The crude product was post-treated as follows: extracted with dichloromethane (3х25 mL), then extracted with saturated sodium chloride (2х20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was separated using a silica gel column to finally obtain intermediate 5 (187 mg, 90%).

[0044] (6) Synthesis of target compound a1

[0045]

[0046] Weigh 208 mg of compound 1 (1 mmol) into a 100 mL dry round-bottom flask, and slowly add it into 30 mL of anhydrous tetrahydrofuran, stir at room temperature for 10 min, add catalyst triethylamine (2 mmol) in an ice-water bath, slowly add iodomethane (170 mg, 1.2 mmol) dropwise, and after the addition is complete, move the reaction solution to room temperature and stir, detect by TLC, slowly add an appropriate amount of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and quickly separate by chromatography to obtain the target compound a1 (206 mg, 93%).

[0047] Referring to the above preparation method, by adjusting the reaction of compound 5 with different halogenated hydrocarbons in step (6), target compounds a2 to a20 corresponding to Examples 1-20 are obtained;

[0048] The halogenated hydrocarbon is methyl iodide, ethyl iodide, propyl bromide, 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, 4-tert-butylbenzyl chloride or p-methoxybenzyl chloride.

[0049] Example 1 Synthesis

[0050] Compound a1, 87% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.87 (s, 1H), 6.58 (s, 1H), 3.19 (t, J = 6.4Hz, 4H), 3.09 (t, J = 3 .4Hz,2H),2.27(t,J=5.5Hz,4H),2.17(s,3H),1.28(t,J=4.4Hz,3H).MS(API(+))calcd for C 11 H 19 N4O + [M+H] + :223.30;found:223.30.

[0051] Example 2 Synthesis

[0052] Compound a2, 87% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.81 (s, 1H), 6.52 (s, 1H), 3.14 (t, J = 6.1Hz, 4H), 3.06 (q, 2H), 2.47 ( t,J=3.6Hz,4H),2.38(q,2H),1.31(t,J=4.4Hz,3H),1.02(t,J=3.4Hz,3H).MS(API(+))calcd for C 12 H 21 N4O + [M+H] + :237.33;found:237.33.

[0053] Example 3 Synthesis

[0054] Compound a3, 86% Yield. 1H NMR (400MHz, CDCl3), δ: 12.83 (s, 1H), 6.53 (s, 1H), 3.13 (t, J = 6.3Hz, 4H), 3.06 (q, 2H), 2.45 (t, J=3.5Hz,4H),2.45-1.46(m,4H),1.31(t,J=4.4Hz,3H),1.02(t,J=3.4Hz,3H).MS(API(+))calcd for C 13 H 23 N4O + [M+H] + :251.35;found:251.35.

[0055] Example 4 Synthesis

[0056] Compound a4, 91% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.89 (s, 1H), 6.56 (s, 1H), 3.16 (t, J = 6.6Hz, 4H), 3.09 (q, 2H), 2.46 (t, J=3.6Hz,4H),2.49-1.44(m,6H),1.33(t,J=4.4Hz,3H),1.06(t,J=3.6Hz,3H).MS(API(+))calcd for C 14 H 25 N4O + [M+H] + :265.20;found:265.20.

[0057] Example 5 Synthesis

[0058] Compound a5, 89% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.88 (s, 1H), 6.57 (s, 1H), 3.18 (t, J = 6.7Hz, 4H), 3.07 (q, 2H), 2.47 (t, J=3.7Hz,4H),2.47-1.46(m,8H),1.37(t,J=4.7Hz,3H),1.07(t,J=3.7Hz,3H).MS(API(+))calcd for C 15 H 27 N4O + [M+H] + :279.22;found:279.22.

[0059] Example 6 Synthesis

[0060] Compound a6, 93% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.84 (s, 1H), 6.58 (s, 1H), 3.18 (t, J = 6.54Hz, 4H), 3.08 (q, 2H), 2.44 (t, J=3.4Hz,4H),2.48-1.44(m,10H),1.34(t,J=4.4Hz,3H),1.04(t,J=3.4Hz,3H).MS(API(+))calcd for C 16 H 29 N4O + [M+H] + :293.23;found:293.23.

[0061] Example 7 Synthesis

[0062] Compound a7, 84% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.84 (s, 1H), 6.58 (s, 1H), 3.18 (t, J = 6.54Hz, 4H), 3.08 (q, 2H), 2.44 (t, J=3.4Hz,4H),2.48-1.44(m,12H),1.34(t,J=4.4Hz,3H),1.04(t,J=3.4Hz,3H).MS(API(+))calcd for C 17 H 31 N4O + [M+H] + :307.25;found:307.25.

[0063] Example 8 Synthesis

[0064] Compound a8, 88% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.86 (s, 1H), 6.56 (s, 1H), 3.16 (t, J = 6.56Hz, 4H), 3.06 (q, 2H), 2.46 (t, J=3.6Hz,4H),2.46-1.46(m,14H),1.36(t,J=4.6Hz,3H),1.06(t,J=3.6Hz,3H).MS(API(+))calcd for C 18 H 33 N4O + [M+H] +:321.27;found:321.27.

[0065] Example 9 Synthesis

[0066] Compound a9, 85% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.78 (s, 1H), 7.21-6.84 (m, 3H), 6.94 (d, J = 2.6Hz, 2H), 6.54 (s, 1H), 3.2 6(t,J=6.26Hz,4H),2.98(t,J=6.21Hz,4H),3.07(q,2H),1.31(t,J=4.2Hz,3H).MS(API(+))calcd for C 16 H 21 N4O + [M+H] + :285.37;found:285.37.

[0067] Example 10 Synthesis

[0068] Compound a10, 92% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.72 (s, 1H), 7.11-6.60 (m, 2H), 70.2 (d, J = 2.3Hz, 1H), 6.93 (d, J = 2.4Hz, 1H), 6.56 (s, 1H) ,3.25(t,J=6.25Hz,4H),2.95(t,J=6.25Hz,4H),3.05(q,2H),2.02(s,1H),1.35(t,J=4.5Hz,3H).MS(API(+))calcd for C 17 H 23 N4O + [M+H] + :299.19;found:299.19.

[0069] Embodiment 11 Synthesis

[0070] Compound a11, 93% Yield. 1H NMR (400MHz, CDCl3), δ: 12.75 (s, 1H), 7.15-6.95 (m, 1H), 7.04 (d, J = 2.4Hz, 1H), 6.83 (d, J = 2.4Hz, 1H), 6.56 (s, 1H), 6.43 (d, J = 2.44Hz,1H),3.22(t,J=6.22Hz,4H),2.92(t,J=6.22Hz,4H),3.02(q,2H),2.25(s,3H),1.32(t,J=4.2Hz,3H).MS(API(+))calcd for C 17 H 23 N4O + [M+H] + :299.19;found:299.19.

[0071] Example 12 Synthesis

[0072] Compound a12, 87% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.81 (s, 1H), 7.02 (d, J = 2.4Hz, 2H), 6.91 (d, J = 2.4Hz, 2H), 6.54 (s, 1H), 3.24 (t, J=6.24Hz,4H),2.94(t,J=6.24Hz,4H),3.04(q,2H),2.34(s,3H),1.34(t,J=4.4Hz,3H).MS(API(+))calcd forC 17 H 23 N4O + [M+H] + :299.19;found:299.19.

[0073] Example 13 Synthesis

[0074] Compound a13, 92% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.87 (s, 1H), 7.32 (d, J = 2.3Hz, 1H), 6.69 (d, J = 2.5Hz, 1H), 7.08-6.63 (m, 2H), 6.57 ( s,1H),3.34(t,J=6.23Hz,4H),3.14(t,J=6.22Hz,4H),3.02(q,2H),1.31(t,J=4.1Hz,3H).MS(API(+))calcd forC 16 H 20 ClN4O+ [M+H] + :319.81;found:319.81.

[0075] Embodiment 14 Synthesis

[0076] Compound a14, 93% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.78 (s, 1H), 7.05-6.95 (m, 1H), 6.94 (d, J = 2.4Hz, 1H), 6.81 (d, J = 2.4Hz, 1H), 6.62 (s, 1H), 6.42 (d,J=2.42Hz,1H),3.23(t,J=6.32Hz,4H),2.93(t,J=6.32Hz,4H),3.03(q,2H),1.32(t,J=4.2Hz,3H).MS(API(+))calcd for C 16 H 20 ClN4O + [M+H] + :319.81;found:319.81.

[0077] Embodiment 15 Synthesis

[0078] Compound a15, 88% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.85 (s, 1H), 7.12 (d, J = 2.6Hz, 2H), 6.71 (d, J = 2.6Hz, 2H), 6.56 (s, 1H), 3. 34(t,J=6.23Hz,4H),3.11(t,J=6.21Hz,4H),3.05(q,2H),1.30(t,J=4.3Hz,3H).MS(API(+))calcd for C 16 H 20 ClN4O + [M+H] + :319.81;found:319.81.

[0079] Example 16 Synthesis

[0080] Compound a16, 94% Yield. 1H NMR (400MHz, CDCl3), δ: 12.83 (s, 1H), 7.33 (d, J = 2.3Hz, 1H), 6.63 (d, J = 2.3Hz, 1H), 7.03-6.63 (m, 2H), 6.53 ( s,1H),3.33(t,J=6.33Hz,4H),3.13(t,J=6.32Hz,4H),3.03(q,2H),1.33(t,J=4.3Hz,3H).MS(API(+))calcd forC 23 H 20 FO + [M+H] + :331.15; found:331.16.

[0081] Embodiment 17 Synthesis

[0082] Compound a17, 93% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.79 (s, 1H), 7.13-6.93 (m, 1H), 6.83 (d, J = 2.3Hz, 1H), 6.73 (d, J = 2.3Hz, 1H), 6.46 (s, 1H), 6.5 3(d,J=2.3Hz,1H),3.32(t,J=6.23Hz,4H),3.09(t,J=6.23Hz,4H),3.04(q,2H),1.32(t,J=4.2Hz,3H).MS(API(+))calcd for C 23 H 20 FO + [M+H] + :331.15; found:331.16.

[0083] Embodiment 18 Synthesis

[0084] Compound a18, 85% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.87 (s, 1H), 7.17 (d, J = 2.7Hz, 2H), 6.77 (d, J = 2.7Hz, 2H), 6.57 (s, 1H), 3. 37(t,J=6.26Hz,4H),3.14(t,J=6.27Hz,4H),3.07(q,2H),1.32(t,J=4.2Hz,3H).MS(API(+))calcd for C 23 H 20 FO + [M+H] +:331.15; found:331.16.

[0085] Embodiment 19 Synthesis

[0086] Compound a19, 96% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.86 (s, 1H), 6.96 (d, J = 2.6Hz, 2H), 6.67 (d, J = 2.6Hz, 2H), 6.56 (s, 1H), 3.26 (t, J=6.26Hz,4H),2.96(t,J=6.26Hz,4H),3.06(q,2H),1.34(s,9H),1.33(t,J=4.3Hz,3H).MS(API(+))calcd forC 20 H 29 N4O + [M+H] + :341.48;found:341.48.

[0087] Embodiment 20 Synthesis

[0088] Compound a20, 86% Yield. 1 H NMR (400MHz, CDCl3), δ: 12.87 (s, 1H), 6.77 (d, J = 2.4Hz, 2H), 6.66 (d, J = 2.4Hz, 2H), 6.54 (s, 1H), 3.81 (s, 3H),3.21(t,J=6.24Hz,4H),2.91(t,J=6.24Hz,4H),3.01(q,2H),1.31(t,J=4.1Hz,3H).MS(API(+))calcd for:C 17 H 23 N4O2 + [M+H] + :315.40;found:315.40.

[0089] Example 21: Determination of antifouling activity of the compounds obtained in Examples 1 to 20

[0090] Minimum inhibitory concentration (MIC) determination method: using the test tube double dilution method, the concentration of the synthesized pyrazole compounds a1-a20 was diluted twice in sequence, and then the diluted bacterial solution was added to the pyrazole compound dilution solution for culture, Escherichia coli and Staphylococcus aureus were cultured by shaking for 24 hours, and the positive control tube (test tube inoculated with bacteria without adding the test compound) was observed with the naked eye to have bacterial growth and turbidity, and the negative control tube (test tube without adding the test compound and not inoculating bacteria) had no bacterial growth and was 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 pyrazole compounds on the two bacteria are shown in Table 2.

[0091] Table 2 MIC values ​​of the test compounds obtained in Examples 1-20 against two bacteria (unit: g / L)

[0092]

[0093] According to the antifouling activity screening, the synthesized compounds all showed good antifouling activity, among which compound a3 and compound a17 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.

[0094] The target compounds a3 and a17 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 its compounds 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 its compounds 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).

[0095] 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.

[0096] 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. 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, which 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 pyrazole 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 pyrazole compound according to claim 1, characterized in that: The process is as follows: 。 3. The method for preparing the pyrazole compound according to claim 1, characterized in that: Here are the steps: Step 1: Add diethyl oxalate and butanone into a 100 mL round-bottom flask, react for 2 h in an ice bath, extract with toluene, dry with MgSO4 and filter to obtain a yellow liquid, which is marked as intermediate 1. Step 2: Add N2H4 H2O dropwise to the ethanol solution, then add intermediate 1, and react for 4 hours in an ice bath; remove the solvent under reduced pressure, extract with toluene, and obtain a yellow liquid by column chromatography, which is marked as intermediate 2; Step 3: Dissolve the intermediate 2 completely in ethanol, add NaOH, and reflux for 2 h. After the reaction is completed, quickly separate the intermediate 3 using a chromatography column; Step 4: Add intermediate 3 and ethanol to a three-necked flask, and then stir to completely dissolve; then, add thionyl chloride and reflux for 1 hour; after removing the solvent, add tetrahydrofuran, add triethylamine dropwise and stir for 10 min, add compound 6 dropwise, react at room temperature for 3 h, add ammonium chloride for quenching, extract with ethyl acetate, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and quickly separate by chromatography column to obtain intermediate 4; Step 5, weigh the intermediate 4 into a round-bottom flask, add dichloromethane:TFA=1:1 or dichloromethane:TFA=2:1 to dissolve, remove Boc, and use TLC tracking detection. After the reaction is complete, remove part of TFA by vacuum distillation, dissolve with dichloromethane, and neutralize with saturated sodium bicarbonate under ice bath conditions to obtain a crude product 5, and post-treat the crude product as follows: extract with dichloromethane, then extract with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated using a silica gel column to finally obtain an intermediate 5; Step 6. Weigh the intermediate 5 into a dry round-bottom flask, and slowly add anhydrous tetrahydrofuran, stir at room temperature, add the catalyst in an ice-water bath, slowly drop methyl iodide, and add completely. Move the reaction solution to room temperature and stir, detect by TLC, slowly drop an appropriate amount of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and quickly separate by chromatography to obtain the target compound a1; By adjusting the iodomethane in step six to different halogenated hydrocarbons, target compounds a2-a20 can be obtained.

4. The method for preparing a pyrazole compound according to claim 4, characterized in that: The catalyst used in step six is ​​triethylamine.

5. Use of the pyrazole 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.

Images