Substituted quinoline compound as well as preparation method and application thereof

Abstract

The invention discloses a substituted quinoline compound and a preparation method and application thereof, the substituted quinoline compound with bactericidal activity and herbicidal activity is successfully synthesized by a multi-step reaction method taking THF as a solvent, sodium hydride as a reducing agent and polyphosphoric acid as a cyclizing agent, the synthesized compound is confirmed by characterization means such as NMR (nuclear magnetic resonance) and the like, and the substituted quinoline compound has a good application prospect. 16 target compounds are subjected to bactericidal activity and herbicidal activity tests. Experimental results show that part of the compounds have a remarkable inhibiting effect on various phytopathogens, and particularly have a good sterilizing effect on alternaria solani, magnaporthe oryzae and fusarium graminearum at the concentration of 50 ppm. In addition, part of the compounds also have a certain weeding effect on dicotyledonous plants such as oilseed rape, and a new pesticide development direction is provided. The invention has a wide application prospect, and especially has important potential in agricultural pest control.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and pharmaceutical application, and particularly relates to a substituted quinoline compound, a preparation method thereof, and application thereof as a fungicide and a herbicide. Background Art

[0002] Heterocyclic compounds are widely present in nature and represent the largest class of organic compounds. The most common heteroatoms in heterocyclic structures are nitrogen, sulfur, and oxygen. They possess a wide range of biological activities and are easily modified, often resulting in new functionalities. In particular, novel nitrogen-containing heterocyclic compounds have become a hot topic in pesticide research and development. Using active natural products as lead compounds to develop novel compounds with high potency and broad-spectrum biological activity has also become one of the most actively developing areas in recent years.

[0003] Quinoline is a key structural element in nitrogen-containing compounds. Quinoline compounds, as a class of heterocyclic compounds with a quinoline skeleton, play a crucial role in the development of new pesticides. Currently, numerous new insecticides, fungicides, and herbicides containing quinoline heterocycles have been developed both domestically and internationally, including the new quinoline insecticide Flometoquin and the quinoline fungicide Ipflufenoquin.

[0004] Although existing quinoline compounds have some fungicidal or herbicidal activity in agriculture, their activity types are limited, their scope of action is narrow, and some compounds present difficulties in synthesis. Therefore, there is still a need to develop quinoline derivatives with novel structures, stronger activity, and simpler synthesis processes to meet the demand for new, highly effective and safe pesticide compounds. Summary of the Invention

[0005] In view of the problems existing in the prior art, the purpose of the present invention is to provide a substituted quinoline compound, a preparation method thereof, and its application as a fungicide and herbicide. The present invention uses Tebufloquin as a lead compound, keeps the quinoline ring and the methyl group at position 2 of Tebufloquin unchanged, performs structural derivatization, and designs and synthesizes novel substituted quinoline compounds.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] A substituted quinoline compound, the structural formula of which is shown in formula (I):

[0008]

[0009] In formula (I), the substituent R1 is an alkyl group; the R2 group is a halogen, an alkyl group or an alkoxy group.

[0010] Furthermore, the R2 group is 2-chloro, 2-fluoro, 2-bromo, 4-isobutyl, 2-methoxy or 2,4-difluoro.

[0011] Furthermore, the substituent R1 is n-hexyl, n-heptyl or n-octyl.

[0012] The present invention provides a method for preparing the substituted quinoline compound, comprising the following steps:

[0013] 1) using THF as solvent and sodium hydride as reducing agent, reacting ethyl acetoacetate with the compound represented by formula (II) to generate the compound represented by formula (III);

[0014] 2) using polyphosphoric acid as a cyclizing agent, reacting the compound of formula (III) obtained in step 1) with the compound of formula (IV) to obtain the substituted quinoline compound of formula (I);

[0015] The reaction process is as follows:

[0016]

[0017] The substituent R1 is an alkyl group; the substituent R2 is a halogen, an alkyl group or an alkoxy group.

[0018] Furthermore, in step 1), when synthesizing the compound represented by formula (III), the molar ratio of ethyl acetoacetate to sodium hydride and the substance of formula (II) is 1:1-1.5:1-1.5.

[0019] Furthermore, when synthesizing the compound represented by formula (I) in step 2), the molar ratio of the compound represented by formula (III) to the compound represented by formula (IV) is 1:1-1.5.

[0020] The present invention also proposes the use of the substituted quinoline compound prepared by the method as a fungicide and a herbicide.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1) The present invention successfully synthesized substituted quinoline compounds with fungicidal and herbicidal activities through a multi-step reaction method using THF as a solvent, sodium hydride as a reducing agent, and polyphosphoric acid as a cyclizing agent. The synthesized compounds were characterized by nuclear magnetic resonance (NMR) and other methods.

[0023] 2) The present invention tested the fungicidal and herbicidal activities of 16 target compounds. The experimental results showed that all compounds had certain antibacterial activity. Among the substituted quinoline compounds, among the compounds of formula (Ⅰ), Ⅰ2, Ⅰ4, Ⅰ7, Ⅰ8, Ⅰ10, Ⅰ13, Ⅰ15 and Ⅰ16 had a fungicidal activity of 30.0% against tomato early blight at a concentration of 50 ppm; Ⅰ2, Ⅰ3, Ⅰ14 and Ⅰ15 had a fungicidal activity of 47.4% against wheat fusarium at a concentration of 50 ppm; Ⅰ2 had a fungicidal activity of 47.4% against rice blast fungus at a concentration of 50 ppm. The fungicidal activity reached 50.0%. For three pathogens, pepper phytophthora, cucumber wilt, and peanut brown spot, the inhibition rate of the compound of formula (I) was less than 30%. The inhibition rate of I1, I4, I5, I10, and I12 against rapeseed sclerotinia at a concentration of 50 ppm reached 30.0%. The inhibition rate of I2, I3, I5, I9, I12, I14, I15, and I16 against cucumber gray mold at a concentration of 50 ppm reached 30.0%. The inhibition rates of I4 and I15 against apple ring rot at a concentration of 50 ppm were 43.9% and 48.8%, respectively.

[0024] 3) The present invention tested the herbicidal activity of some of the target products obtained. The results showed that all compounds had certain antibacterial activity. Among the substituted quinoline compounds, at a concentration of 100 μg·mL-1, most treatment groups showed high growth inhibition rates, among which the inhibition rate of I5 reached 59.59%. DETAILED DESCRIPTION

[0025] The present invention will be further described below with reference to the embodiments, but the scope of protection of the present invention is not limited to the described scope.

[0026] definition:

[0027] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and may be a C1-6 alkyl. In some embodiments, the alkyl group has 4 to 11 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, -methyl, -n-butyl, -n-pentyl, and -n-hexyl.

[0028] "Alkoxy" refers to an "alkyl" group attached to the parent molecular group through an oxygen atom, wherein "alkyl" has the meaning given above.

[0029] Example 1 Preparation of the compound represented by formula (III)

[0030] In a 250 mL three-necked flask, ethyl acetoacetate (2.60 g, 20.00 mmol) was dissolved in THF (30 mL). NaH (0.58 g, 24.00 mmol) was added and the mixture was heated to 40°C with stirring at room temperature. The reaction progress was monitored by TLC (VEA / VPE = 1 / 11). After 2 h, the reaction was complete. The compound represented by formula (II) (3.96 g, 24.00 mmol) was then added and the mixture was heated to reflux. The reaction progress was monitored by TLC (VEA / VPE = 1 / 11). After 10 h, the reaction was complete. The mixture was cooled to room temperature and the solvent was evaporated. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was evaporated. The compound represented by formula (III) was purified by column chromatography. Wherein R1 is n-hexyl, n-heptyl, or n-octyl.

[0031] Table 1 Physicochemical data of the compound represented by formula (III)

[0032] <![CDATA[Substituent group R1]]> Appearance Yield % n-Hexyl Colorless transparent liquid 73.4 Zheng Gengji Colorless transparent liquid 77.6 n-octane Colorless transparent liquid 72.2

[0033] Table 2 Hydrogen spectrum data of the compound represented by formula (III)

[0034]

[0035] Example 2 Preparation of formula (I)

[0036] In a 50 mL three-necked flask, the compound represented by formula (III) (1.00 g, 4.67 mmol), the compound represented by formula (IV) (4.67 mmol), and polyphosphoric acid (3.27 g) were added in sequence. The temperature was raised to 150°C for reaction. The reaction progress was monitored by TLC (VEA / VPE = 1 / 1). The reaction was complete after 5 h. The flask was cooled to room temperature and placed in an ice-water bath. The pH was adjusted to 7-8 with 20% NaOH solution. A large amount of solid precipitated. After standing, the solid was filtered with suction. The filter cake was washed with water and ethyl acetate and dried to obtain target compounds I1-I5. Other target compounds I6-I16 were synthesized using the same method.

[0037] Table 3 Physicochemical data of the compound represented by formula (I)

[0038] Target compound <![CDATA[Substituent group R1]]> <![CDATA[Substituent group R2]]> Melting point / ℃ Ⅰ1 n-Hexyl 2-chloro 200-202 Ⅰ2 n-Hexyl 2-methoxy 140-142 Ⅰ3 n-Hexyl 4-isobutyl 163-165 Ⅰ4 Zheng Gengji 2-Fluoro 230-232 Ⅰ5 Zheng Gengji 2-Bromo 236-238 Ⅰ6 Zheng Gengji 2,4-difluoro 173-175 Ⅰ7 Zheng Gengji 4-isobutyl 231-233 Ⅰ8 Zheng Gengji 2-Fluoro 178-180 Ⅰ9 Zheng Gengji 2-Bromo 142-144 Ⅰ10 n-octyl 2-methoxy 189-191 Ⅰ11 n-octyl 2-chloro 228-230 Ⅰ12 n-octyl 2,4-difluoro 223-225 Ⅰ13 n-octyl 2-Fluoro 167-169 Ⅰ14 n-octyl 2-Bromo 165-167 Ⅰ15 n-octyl 4-isobutyl 236-238 Ⅰ16 n-octyl 2-methoxy 130-132

[0039] Table 4 Hydrogen spectrum data of the compound represented by formula (I)

[0040]

[0041]

[0042]

[0043]

[0044] Example 3 Bactericidal activity test

[0045] Test methods

[0046] (1) Test subjects: tomato early blight (Alternaria solani), wheat fusarium rust (Fusa Humgraminearum Sehw), rice blast (Pyricularia Grisea), pepper phytophthora capsici Leonian), rapeseed sclerotinia (Sclerotinia sclerotiorum (Lib.) de Bary), cucumber gray mold (Botrytis cinerea), rice sheath blight (Thanatephorus cucumeris), cucumber wilt (Fusarium oxysporum.sp.cucumebrium Owen), peanut brown spot (Cercospora arachidicola Hori), apple ring rot (Botryosphaeria dothidea).

[0047] (2) Test treatment: Each test compound was dissolved in DMSO to form a 1% EC stock solution. The inhibition zone method was used to evaluate the indoor bactericidal activity of the test compound against the test target at a dose of 50 ppm. Tebufloquin (CK) was also used as a control drug.

[0048] (3) Test method: Use a pipette to draw 150 μl of the above-prepared EC mother solution and dissolve it in 2.85 mL of Tween water to prepare a solution with an effective concentration of 500 ppm of the test compound. Use a pipette to draw 1 ml of the solution into a sterilized culture dish, then add 9 ml of PDA culture medium, shake well, and cool. Use a punch to punch out a round bacterial cake and use an inoculation needle to pick it to the center of the culture dish. Then place the culture dish in an incubator at 27°C and culture it. After 48 hours, measure the colony diameter. The pure colony growth is the difference between the average colony diameter and the diameter of the bacterial cake. The antibacterial rate (%) is calculated according to the following formula.

[0049]

[0050] The activity test results are shown in Table 5:

[0051] Table 5 Fungicidal activity of substituted quinoline compounds

[0052]

[0053] The fungicidal activity results of substituted quinoline compounds (16) are shown in Table 5. Among the substituted quinoline compounds, among the compounds of formula (I), I2, I4, I7, I8, I10, I13, I15 and I16 have a fungicidal activity against tomato early blight of more than 30.0% at a concentration of 50 ppm; I2, I3, I14 and I15 have a fungicidal activity against wheat fusarium of more than 47.4% at a concentration of 50 ppm; I2 has a fungicidal activity against rice blast of more than 50.0% at a concentration of 50 ppm; The inhibition rates of the compounds of formula (Ⅰ) against three pathogens, namely, pepper phytophthora, cucumber wilt and peanut brown spot, were all lower than 30%; the inhibition rates of Ⅰ1, Ⅰ4, Ⅰ5, Ⅰ10 and Ⅰ12 against rapeseed sclerotinia disease reached more than 30.0% at a concentration of 50 ppm; the inhibition rates of Ⅰ2, Ⅰ3, Ⅰ5, Ⅰ9, Ⅰ12, Ⅰ14, Ⅰ15 and Ⅰ16 against cucumber gray mold reached more than 30.0% at a concentration of 50 ppm; the inhibition rates of Ⅰ4 and Ⅰ15 against apple ring rot were 43.9% and 48.8%, respectively, at a concentration of 50 ppm.

[0054] Example 4 Herbicidal Activity Test

[0055] Test methods

[0056] (1) Test objects: Select representative indicator plants that are easy to cultivate, propagate and preserve. The germination rate of the indicator plant seeds should be above 90%. This test uses rapeseed.

[0057] (2) Test treatment: Water-soluble agents were directly dissolved and diluted with water. Other agents were dissolved in a suitable solvent (acetone, dimethylformamide or dimethyl sulfoxide, etc.) and diluted with 0.1% Tween 80 aqueous solution. The test compound was evaluated at 100 μg mL -1 and 10 μg·mL -1 The indoor herbicidal activity against the test target was tested at the dose, and a control group was set up.

[0058] (3) Test method: Select 20 indicator plant seeds with uniform germination and place them in a culture dish (9 cm in diameter) lined with two filter papers. The direction of the radicle and plumule of the seeds should be consistent. Add 9 mL of a series of drug solutions to the culture dish and fully immerse the seeds in the solution. Use the control drug as a control. Place the treated culture dish in an artificial climate chamber or plant incubator and culture it in the dark at a temperature of (25±1)°C and a humidity of 80% to 90%. The inhibition rate (%) is calculated according to the following formula.

[0059]

[0060] Where:

[0061] R——growth inhibition rate;

[0062] L0—control root length (or shoot length);

[0063] L1 - Processing root length (or shoot length).

[0064] The activity test results are shown in Table 8:

[0065] Table 8 Herbicidal activity of substituted quinoline compounds

[0066]

[0067] At 100 μg·mL -1 and 10 μg·mL -1 At the concentration of 100 μg·mL, the I series compounds showed a certain inhibitory effect on the roots of the dicotyledonous plant rape. -1 At a concentration of 10 μg·mL, the inhibition rates of compounds I7, I8, I14, and I16 on rapeseed roots reached more than 90%, the inhibition rate of I5 on rapeseed roots reached 59.59%, and the inhibition rates of compounds I2, I4, I6, I10, and I11 were 31.35%, 35.49%, 33.68%, 32.12%, and 81.61%, respectively. -1 At the same concentration, except for compound I4 which showed an inhibition rate of 33.21%, the inhibition rates of the other compounds were relatively average. Compounds I2, I6, I7, I8, I9, and I11, on the contrary, promoted plant growth at this concentration.

Claims

1. A substituted quinoline compound, characterized in that The structural formula is shown in formula (I): In formula (I), the substituent R1 is an alkyl group; and the substituent R2 is a halogen, an alkyl group or an alkoxy group.

2. The substituted quinoline compound according to claim 1, characterized in that The R2 group is 2-chloro, 2-fluoro, 2-bromo, 4-isobutyl, 2-methoxy or 2,4-difluoro.

3. The substituted quinoline compound according to claim 1, characterized in that The substituent R1 is n-hexyl, n-heptyl or n-octyl.

4. A method for preparing a substituted quinoline compound as claimed in claim 1, characterized in that The steps include: 1) Using THF as solvent and sodium hydride as reducing agent, ethyl acetoacetate and the compound represented by formula (II) are reacted to produce the compound represented by formula (III); 2) using polyphosphoric acid as a cyclizing agent, reacting the compound of formula (III) obtained in step 1) with the compound of formula (IV) to obtain the substituted quinoline compound of formula (I); The reaction process is as follows:

5. The method for preparing a substituted quinoline compound according to claim 4, wherein When synthesizing the compound represented by formula (III) in step 1), the molar ratio of ethyl acetoacetate to sodium hydride and the substance represented by formula (II) is 1:1-1.5:1-1.

5.

6. The method for preparing a substituted quinoline compound according to claim 4, wherein When synthesizing the compound represented by formula (I) in step 2), the molar ratio of the compound represented by formula (III) to the compound represented by formula (IV) is 1:1-1.

5.

7. Use of a substituted quinoline compound prepared by the method according to any one of claims 4 to 6 as a fungicide and herbicide.

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