8-substituted anilino chloroquinoline compound as well as preparation method and application thereof

Abstract

The invention discloses a 8-substituted anilino chloroquinoline compound and a preparation method and application thereof.The preparation method of the 8-substituted anilino chloroquinoline compound comprises the following steps that a compound III, a compound IV, alkali and ethyl alcohol are mixed, reaction liquid is obtained and refluxed for 5-10 h at the temperature of 70-80 DEG C, after the reaction is finished, an organic phase is obtained through extraction, drying, rotary evaporation and column chromatography purification are conducted, and the 8-substituted anilino chloroquinoline compound is obtained. The 8-substituted anilino chloroquinoline compound is obtained by taking a compound I and a compound II as raw materials, the 8-substituted anilino chloroquinoline compound has certain bacteriostatic activity, the bacteriostasis rate of the 8-substituted anilino chloroquinoline compound on sclerotinia sclerotiorum reaches up to 80% or above, the inhibition rate of the 8-substituted anilino chloroquinoline compound on rhizoctonia solani reaches up to 70% or above, and the compound I-15 shows the inhibition rate of 92.0% on the sclerotinia sclerotiorum. The inhibition rates of the compound I-11 and the compound I-15 on rhizoctonia solani reach 78.8% and 78.5% respectively.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and pharmaceutical application, and specifically relates to an 8-substituted anilinochloroquinoline compound and a preparation method and application thereof. Background Art

[0002] In the development of heterocyclic pesticides, quinoline compounds, as a class of nitrogen-containing heterocyclic compounds with a quinoline skeleton, play an important role in the development of new pesticides and are widely present in synthetic and natural products. The parent quinoline of quinoline compounds was first extracted from coal tar by Runge in 1834. It is a hygroscopic liquid with a strong odor. Later, people isolated an alkaloid, quinine, from the cinchona tree of the Rubiaceae family. This alkaloid is a diastereoisomer of quinoline compounds and is the earliest effective antimalarial drug.

[0003] At present, many new varieties of insecticides, fungicides and herbicides containing quinoline heterocycles have been developed at home and abroad. In 1989, the Shanghai Pesticide Institute successfully developed dichloroquinoline acid, with the trade name of Kebailing, which is mainly used to control post-emergence barnyard grass and has special effects on old barnyard grass. It has low requirements for soil moisture and is highly safe for rice. It can be mixed with other herbicides for single treatment. It has the advantages of low dosage and high efficiency, convenient and odorless application, safety for direct seeding and transplanting rice, and certain growth and growth effects. In 2011, Meiji Pharmaceutical Co., Ltd. of Japan and Nippon Kayaku Co., Ltd. jointly developed a new quinoline insecticide (Flometoquin). This insecticide has excellent control effects on thysanoptera pests (thrips), whiteflies, gall mites and small lepidoptera pests, and has a fast killing speed and long lasting effect. In 1989, Dow AgroSciences developed a commercial systemic fungicide, quinoxyfen, which is a highly effective agent for controlling powdery mildew. It is suitable for barley, watermelon, and sugar beets. It is safe for the environment and does not cause harm to crops, making it an ideal control agent. However, in 2013, quinoxyfen was identified by the European Union as a major risk to surface water and a priority hazardous substance. After 2019, the EU will no longer renew the registration of quinoxyfen. At the same time, due to the long-term use of these quinoline agents, many strains have developed drug resistance, and there is an urgent need to create new quinoline fungicides with new structures. Summary of the invention

[0004] In view of the deficiencies in the prior art, the object of the present invention is to provide an 8-substituted anilinochloroquinoline compound.

[0005] Another object of the present invention is to provide a method for preparing 8-substituted anilinochloroquinoline compounds.

[0006] Another object of the present invention is to provide an 8-substituted anilinochloroquinoline compound for use as a pesticide in antibacterial treatment.

[0007] The purpose of the present invention is achieved through the following technical solutions.

[0008] An 8-substituted anilinochloroquinoline compound, the general structural formula of which is:

[0009]

[0010] Wherein, R is phenyl or substituted phenyl, and the substituent on the substituted phenyl is alkyl, alkoxy, nitro, halogen or halogenated alkyl.

[0011] In the above technical scheme, when R is a substituted phenyl, the substituent on the substituted phenyl is 2-fluoro, 2,4-difluoro, 4-chloro, 4-methyl, 3-chloro, 3,4-dichloro, 2-bromo, 3-fluoro, 2-methyl-3-chloro, 2,6-difluoro, 4-bromo, 2-bromo-4-fluoro, 2-bromo-5-fluoro, 4-fluoro or 3-methyl.

[0012] A preparation method of 8-substituted anilino chloroquinoline compounds comprises the following steps: uniformly mixing compound III, compound IV, alkali and ethanol to obtain a reaction solution, refluxing at 70-80°C for 5-10h, extracting to obtain an organic phase after the reaction is finished, drying, rotary evaporating, and purifying by column chromatography to obtain 8-substituted anilino chloroquinoline compounds, wherein the ratio of compound III, compound IV and alkali is 1:(1-1.2):(1-1.1) in terms of the amount of the substance, the general structural formula of compound IV is RNH2, R is phenyl or substituted phenyl, and the substituent on the substituted phenyl is alkyl, alkoxy, nitro, halogen or halogenated alkyl; the structural formula of compound III is The base is potassium carbonate, triethylamine, pyridine or sodium hydroxide.

[0013] In the above technical solution, the ratio of the amount of compound III to the volume of ethanol is 1.16:(8-15), the unit of the amount of compound III is mmol, and the unit of the volume is mL.

[0014] In the above technical solution, the extraction includes: extracting with water, ethyl acetate and saturated brine in sequence.

[0015] In the above technical scheme, when R is a substituted phenyl, the substituent on the substituted phenyl is 2-fluoro, 3-chloro, 2,4-difluoro, 4-chloro, 4-methyl, 3,4-dichloro, 2-bromo, 3-fluoro, 2-methyl-3-chloro, 2,6-difluoro, 4-bromo, 2-bromo-4-fluoro, 2-bromo-5-fluoro, 4-fluoro or 3-methyl.

[0016] In the above technical scheme, the method for obtaining compound III comprises: adding phosphorus oxychloride to compound II, refluxing at 140-160° C. for 8-12 hours, monitoring the reaction by thin layer chromatography until completion, cooling to room temperature, precipitating a solid in an ice-water mixture, filtering, and drying to obtain compound III, wherein the mass fraction ratio of compound II to phosphorus oxychloride is 1.05:(10-100), the unit of mass fraction is g, and the unit of mass fraction is mmol, and the structural formula of compound II is

[0017] In the above technical scheme, the method for obtaining compound II comprises: mixing o-fluoroaniline, ethyl 2-methylacetoacetate and a cyclizing agent, reacting at 140 to 160° C., monitoring the reaction by thin layer chromatography (TLC) until completion, cooling to -10 to 0° C., adjusting the pH to 7 to 8 at -10 to 0° C. to precipitate a solid, filtering, and drying to obtain compound II, wherein the o-fluoroaniline has the structural formula: The structural formula of the ethyl 2-methylacetoacetate is The cyclizing agent is polyphosphoric acid (PPA), and the ratio of o-fluoroaniline, ethyl 2-methylacetoacetate and the cyclizing agent is 1:(1-1.5):1.5 in terms of the amount of the substance.

[0018] In the method for obtaining compound II, the reaction time is 4.5 to 5.5 hours.

[0019] In the method for obtaining Compound II, the pH is adjusted to 7 to 8 with a sodium hydroxide solution to precipitate a solid.

[0020] In the above technical solution, the sodium hydroxide solution is a mixture of sodium hydroxide and water, and the content of sodium hydroxide in the sodium hydroxide solution is 9-11wt%.

[0021] In the above technical solution, the drying is carried out under an infrared lamp for 4 to 6 hours.

[0022] The above 8-substituted anilinochloroquinoline compounds are used as pesticides in antibacterial activities.

[0023] In the above technical scheme, one or more of tomato early blight (Alternaria solani), wheat fusarium rust (Gibberella zeae), rice blast (Pyricularia oryae), pepper phytophthora capsici, rapeseed sclerotinia (Sclerotinia sclerotiorum), cucumber gray mold (Botrytis cinerea), rice sheath blight (Riziocotinia solani), cucumber wilt (Fusarium oxysporum) and apple ring rot (Botryosphaeria berengriana) are inhibited.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The preparation method of the 8-substituted anilinochloroquinoline compounds of the present invention is simple and easy to operate. The 8-substituted anilinochloroquinoline compounds all have certain antibacterial activity. The 8-substituted anilinochloroquinoline compounds have an inhibition rate of more than 80% on rapeseed sclerotinia pathogen at a concentration of 10 mg / L, and an inhibition rate of more than 70% on rice sheath blight pathogen. Among them, compound I-15 shows an inhibition rate of 92.0% on rapeseed sclerotinia pathogen, and the inhibition rates of compound I-11 and compound I-15 on rice sheath blight pathogen reach 78.8% and 78.5%, respectively. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the hydrogen spectrum of the 8-substituted anilinochloroquinoline compound prepared in Example 15. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments.

[0028] In the following embodiment, the method for obtaining the PDA culture medium comprises: placing 200 g of peeled potatoes in 1 L of water and boiling for 30 minutes, filtering with gauze after boiling for 30 minutes, collecting the supernatant, fixing the volume to 1 L, adding 20 g of glucose and 20 g of agar and stirring continuously at 50° C. to ensure that the agar is completely melted, and sterilizing in a pressure cooker after melting for later use.

[0029] In the following examples, the chemical formula of the fungicide Tebufloquin is 6-tert-butyl-8-fluoro-2,3-dimethyl-4-quinolinyl acetate.

[0030] In the following embodiments, compound IV-1, compound IV-2, compound IV-3, compound IV-4, compound IV-5, compound IV-6, compound IV-7, compound IV-8, compound IV-9, compound IV-10, compound IV-11, compound IV-12, compound IV-13, compound IV-14 and compound IV-15 are respectively used as compound IV, and their structural formulas are shown below.

[0031]

[0032] Tomato early blight (Alternaria solani), wheat fusarium rust (Gibberella zeae), rice blast (Pyricularia oryae), pepper phytophthora capsici), rapeseed sclerotinia (Sclerotinia sclerotiorum), cucumber gray mold (Botrytis cinerea), rice sheath blight (Riziocotinia solani), cucumber wilt (Fusarium oxysporum) and apple ring rot (Botryosphaeria berengriana) are all derived from strains long-term preserved in the Sterilization and Bioassay Laboratory of the National Engineering Research Center for Pesticides of Nankai University.

[0033] In the following examples, the sodium hydroxide solution is a mixture of sodium hydroxide and water, and the content of sodium hydroxide in the sodium hydroxide solution is 10wt%.

[0034] In the following embodiments, the structural formula of o-fluoroaniline is The structural formula of ethyl 2-methylacetoacetate is

[0035]

[0036] Examples 1 to 15

[0037] The synthetic route of 8-substituted anilinochloroquinoline compounds is as follows:

[0038]

[0039] A method for preparing 8-substituted anilinochloroquinoline compounds comprises the following steps:

[0040] Step 1, o-fluoroaniline (11.11 g, 100.00 mmol), ethyl 2-methylacetoacetate (14.42 g, 100.00 mmol) and a cyclizing agent (50.69 g, 150.00 mmol) were placed in a 250 mL three-necked flask, mixed and stirred until uniform, heated to 150° C. for reaction, and monitored by thin layer chromatography (TLC). The reaction was completed after 5 h, and after cooling to room temperature, the three-necked flask was placed in an ice bath at 0° C., and the pH was adjusted to 7 with sodium hydroxide solution at 0° C. to precipitate a solid, and filtered to obtain a filter cake, and the filter cake was placed under an infrared lamp and dried for 5 hours to constant weight to obtain a white solid as compound II with a yield of 90%, wherein the cyclizing agent is polyphosphoric acid (PPA);

[0041] Step 2, compound II (0.20 g, 1.05 mmol) was placed in a 250 mL three-necked flask, phosphorus oxychloride (10 g) was added, and the mixture was refluxed at 150 ° C. The reaction was monitored by thin layer chromatography. The reaction was completed after 8 hours, cooled to room temperature, and precipitated in an ice-water mixture. The solid was filtered to obtain a filter cake, and the filter cake was placed under an infrared lamp and dried to constant weight to obtain a light yellow solid as compound III with a yield of 90%;

[0042] Step 3, compound III (1 mmol), compound IV (1.16 mmol), a base (the base is sodium hydroxide, 1.05 mmol) and ethanol (10 mL) are placed in a 250 mL round-bottom flask and mixed evenly to obtain a reaction solution, which is refluxed at 78° C. for 8 h, and the reaction solution is placed in a separatory funnel, and water (30 mL) is added to dilute it to form an aqueous phase. The aqueous phase is extracted three times with ethyl acetate (the volume used each time is 10 mL), and the organic phases are combined. The organic phases are extracted three times with saturated brine (the volume used each time is 10 mL), and the organic phases are collected. Anhydrous sodium sulfate is added to the organic phase for drying, and the phase is filtered and the filtrate is collected. The filtrate is rotary evaporated and purified by column chromatography (the eluent of the column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:2 by volume) to obtain a white solid as an 8-substituted anilinochloroquinoline compound (compound I).

[0043] The general structural formula of the compound IV used in Examples 1 to 15 is RNH2, the compound IV used and R in the general structural formula are shown in Table 1, the numbers and yields of the 8-substituted anilinochloroquinoline compounds prepared in Examples 1 to 15 are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum data thereof are shown in Table 2, and the hydrogen spectrum of the 8-substituted anilinochloroquinoline compounds prepared in Example 15 is shown in Table 2. Figure 1 shown.

[0044] Table 1

[0045]

[0046] Table 2

[0047]

[0048]

[0049] Example 16

[0050] The inhibition zone method was used to evaluate the indoor bactericidal activity of the 8-substituted anilinochloroquinoline compounds obtained in Examples 1 to 15 against the test target (pathogens) at a dosage of 10 mg / L.

[0051] Indoor bactericidal activity test:

[0052] Treatment group: 1) Weigh 3 mg of the test compound and dissolve it in 0.1 mL of DMSO to prepare a 30,000 mg / L stock solution. Use a pipette to draw a certain amount of the stock solution and evenly disperse it in sterile Tween water (sterile Tween water is a mixture of Tween-80 and water, and the content of Tween-80 in sterile Tween water is 1‰) to prepare a drug solution with a concentration of 100 mg / L of the test compound.

[0053] 2) Use a pipette to draw 1 mL of the drug solution into a sterilized culture dish, then add 9 mL of PDA culture medium, shake well, and cool to room temperature. Use a hole puncher to make a round bacterial cake and use an inoculation needle to pick it to the center of the above culture dish (the concentration of the test compound in the culture dish is 10 mg / L), then place the culture dish in an incubator at 25°C for 72 hours, and measure the colony diameter after 72 hours. The pathogen on the round cake is one of tomato early blight (Alternaria solani), wheat fusarium (Gibberellazeae), rice blast (Pyricularia oryae), pepper phytophthora (Phytophthora capsici), rapeseed sclerotinia (Sclerotinia sclerotiorum), cucumber gray mold (Botrytis cinerea), rice sheath blight (Riziocotinia solani), cucumber wilt (Fusarium oxysporum) and apple ring rot (Botryosphaeria berengriana), wherein the test compound is one of the 8-substituted anilinochloroquinoline compounds obtained in Examples 1 to 15 and the fungicide Tebufloquin.

[0054] Control group: The control group was basically the same as the treatment group, except for the drug solution. The drug solution in the control group was sterile Tween water, that is, the drug solution in the treatment group was replaced with sterile Tween water.

[0055] The inhibition rate (%) was calculated according to the inhibition rate formula. The inhibition rates of the 8-substituted anilinochloroquinoline compounds and the bactericide Tebufloquin obtained in Examples 1 to 15 against various pathogens are shown in Table 3. The inhibition rate formula is as follows.

[0056]

[0057] The pure growth of the colony is the difference between the average diameter of the colony and the diameter of the circular cake.

[0058] Table 3 Antibacterial rate (unit: %)

[0059]

[0060] As shown in Table 3, at a concentration of 10 mg / L, the inhibition rates of compounds I-4, I-11, I-12, I-13, I-14 and I-15 against tomato early blight exceeded 50.0%, and were better than Tebufloquin; the inhibition rates of compounds I-3, I-11 and I-14 against wheat fusarium exceeded 50%, and were better than Tebufloquin; the inhibition rates of compounds I-1, I-4, I-9, I-11, I-12, I-13, I-14 and I-15 against rice blast fungus exceeded 50%, among which the inhibition rate of compound I-4 (75.5%) exceeded the inhibition rate of the fungicide Tebufloquin (63.6%); compounds I-13 and I-15 The inhibition rate against pepper phytophthora is over 60%, which is also better than the inhibition rate of the fungicide Tebufloquin (58.1%); the inhibition rates of compounds I-4, I-6, I-11, I-13, I-14 and I-15 against rapeseed sclerotinia are all over 75%, among which the inhibition rate of compound I-15 is as high as 92.0%, and the fungicidal efficacy of these compounds also exceeds that of the fungicide Tebufloquin (55.0%); the inhibition rates of compounds I-4, I-13, I-14 and I-15 against rice sheath blight are all over 65.0%, and the inhibition rates against cucumber wilt are over 50%, which are all better than the inhibition rate of the fungicide Tebufloquin; the fungicidal activity of compound I-3 against apple ring rot reaches 82.3%.

[0061] The present invention is described above by way of example. It should be noted that, without departing from the core of the present invention, any simple deformation, modification or other equivalent replacement that can be made by those skilled in the art without inventive effort falls within the protection scope of the present invention.

Claims

1. An 8-substituted anilinochloroquinoline compound, characterized in that: Its general structural formula is: Wherein, R is phenyl or substituted phenyl, and the substituent on the substituted phenyl is alkyl, alkoxy, nitro, halogen or halogenated alkyl.

2. A method for preparing 8-substituted anilinochloroquinoline compounds, characterized in that: The method comprises the following steps: mixing compound III, compound IV, a base and ethanol to obtain a reaction solution, refluxing at 70-80°C for 5-10 hours, extracting to obtain an organic phase after the reaction is finished, drying, rotary evaporating, and purifying by column chromatography to obtain 8-substituted anilinochloroquinoline compounds, wherein the ratio of compound III, compound IV and the base is 1:(1-1.2):(1-1.1) in terms of the amount of the substance, the general structural formula of compound IV is RNH2, R is phenyl or substituted phenyl, and the substituent on the substituted phenyl is alkyl, alkoxy, nitro, halogen or halogenated alkyl; the structural formula of compound III is The base is potassium carbonate, triethylamine, pyridine or sodium hydroxide.

3. The preparation method according to claim 2, characterized in that: The ratio of the amount of compound III to the volume of ethanol is 1.16:(8-15), the unit of the amount of compound III is mmol, and the unit of the volume is mL.

4. The preparation method according to claim 2, characterized in that: Extraction includes: The product was extracted with water, ethyl acetate and saturated brine in sequence.

5. The preparation method according to claim 2, characterized in that: When R is substituted phenyl, the substituent on the substituted phenyl is 2-fluoro, 3-chloro, 2,4-difluoro, 4-chloro, 4-methyl, 3,4-dichloro, 2-bromo, 3-fluoro, 2-methyl-3-chloro, 2,6-difluoro, 4-bromo, 2-bromo-4-fluoro, 2-bromo-5-fluoro, 4-fluoro or 3-methyl.

6. The preparation method according to claim 2, characterized in that: The method for obtaining compound III comprises: adding phosphorus oxychloride to compound II, refluxing at 140-160° C. for 8-12 hours, monitoring the reaction by thin layer chromatography until completion, cooling to room temperature, placing in an environment of 0° C. to cool so that a solid precipitates, filtering, and drying to obtain compound III, wherein the mass fraction ratio of compound II to phosphorus oxychloride is 1.05:(10-100), the unit of mass fraction is g, and the unit of mass fraction is mmol, and the structural formula of compound II is 7. The preparation method according to claim 6, characterized in that: The method for obtaining compound II comprises: mixing o-fluoroaniline, ethyl 2-methylacetoacetate and a cyclizing agent, reacting at 140 to 160° C., monitoring the reaction by thin layer chromatography until completion, cooling to -10 to 0° C., adjusting the pH to 7 to 8 at -10 to 0° C. to precipitate a solid, filtering, and drying to obtain compound II, wherein the o-fluoroaniline has the structural formula The structural formula of the ethyl 2-methylacetoacetate is The cyclizing agent is polyphosphoric acid, and the ratio of o-fluoroaniline, ethyl 2-methylacetoacetate and the cyclizing agent is 1:(1-1.5):1.5 in terms of the amount of the substance.

8. The preparation method according to claim 7, characterized in that: In the method for obtaining compound II, the reaction time is 4.5 to 5.5 hours.

9. The preparation method according to claim 8, characterized in that: The pH value is adjusted to 7-8 with sodium hydroxide solution to precipitate solids, and the content of sodium hydroxide in the sodium hydroxide solution is 9-11 wt %.

10. Use of the 8-substituted anilinochloroquinoline compound according to claim 1 as a pesticide in antibacterial treatment.

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