Substituted quinoline compound as well as preparation method and application thereof
By optimizing the synthesis method of substituted quinoline compounds, using specific solvents and reagents, simplifying the steps and improving biological activity, the problems of low efficiency and insufficient activity in the existing technology are solved, and a high-efficiency inhibitory effect on a variety of plant pathogens is achieved.
Patent Information
- Application Number
- CN202510767385.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-10
- Publication Date
- 2025-10-21
AI Technical Summary
Existing synthesis methods for substituted quinoline compounds are inefficient, lack activity, and have complicated synthesis steps, making it difficult to meet the development needs of the agricultural field, especially fungicides and herbicides.
Substituted quinoline compounds were prepared using DCM as solvent through the reaction of thionyl chloride with specific intermediates, combined with reagents such as pyridine, polyphosphoric acid, ethanol and acetyl chloride. The synthesis steps were optimized to improve biological activity.
The synthesized substituted quinoline compounds showed significant inhibitory effects on a variety of plant pathogens at a concentration of 50 ppm, especially against rice blast fungus and rapeseed sclerotinia fungus, with some compounds having an inhibition rate of 100% at a concentration of 50 ppm.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to substituted quinoline compounds, preparation methods and applications thereof. 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 an important structural member of nitrogen-containing compounds. Quinoline compounds, as a class of heterocyclic compounds with a quinoline skeleton, play an important role in the development of new pesticides. Currently, many new insecticides, fungicides, and herbicides containing quinoline heterocycles have been developed both domestically and internationally, such as the new quinoline insecticide Flometoquin and the quinoline fungicide Ipflufenoquin. However, existing synthesis methods and applications of substituted quinoline compounds suffer from low efficiency, insufficient activity, and cumbersome synthesis steps. The present invention provides a new synthesis method and enhances its biological activity, aiming to provide an effective solution for the agricultural sector, particularly for the development of fungicides and herbicides. Summary of the Invention
[0004] In view of the problems existing in the prior art, the purpose of the present invention is to provide substituted quinoline compounds and their preparation method and application. The preparation method of the present invention is simple and easy to operate, and the obtained product has certain antibacterial activity.
[0005] To achieve the above object, the technical solution of the present invention is as follows:
[0006] Substituted quinoline compounds, whose structural formula is shown in formula (I):
[0007]
[0008] In formula (I), the substituent R1 is an alkyl group; the substituent R2 is a halogen, an alkoxy group, a haloalkoxy group, a haloalkyl group or a halogen-containing aromatic group.
[0009] Furthermore, the substituent R2 is 2-fluoro, 2-methoxy, 2-trifluoromethoxy, 5-bromo-2-methoxy or 2-(4-chloro-2-fluorophenoxy).
[0010] Furthermore, the substituent R1 is n-butyl, pentyl, n-hexyl, n-heptyl, n-nonyl or n-undecyl.
[0011] The present invention provides a method for preparing the substituted quinoline compound, comprising the following steps:
[0012] 1) Using DCM as solvent, reacting thionyl chloride with the compound represented by formula (II) to generate the compound represented by formula (III);
[0013] 2) using DCM as solvent, reacting the compound of formula (III) obtained in step 1) with Melvin's acid and pyridine to produce a compound of formula (IV);
[0014] 3) heating the compound of formula (IV) obtained in step 2) under reflux using ethanol as a solvent to produce a compound of formula (V);
[0015] 4) using polyphosphoric acid as a cyclizing agent to react the compound of formula (V) obtained in step 3) with the compound of formula (VI) to produce the compound of formula (VII);
[0016] 5) using DCM as solvent and TEA as acid-binding agent, reacting the compound (VII) obtained in step 4) with acetyl chloride to obtain the substituted quinoline compound (I);
[0017] The reaction process is as follows:
[0018]
[0019] Wherein R1 is an alkyl group; R2 is a halogen, an alkyl group, an alkoxy group, a haloalkoxy group, a haloalkyl group or a halogen-containing aromatic group.
[0020] Furthermore, when synthesizing the compound represented by formula (III) in step 1), the molar ratio of formula (II) to thionyl chloride is 1:2-3.
[0021] Furthermore, when synthesizing the compound represented by formula (IV) in step 2), the molar ratio of the compound represented by formula (III), McBride's acid and pyridine is 1:1-1.5:1.5-2.5.
[0022] Furthermore, when synthesizing the compound represented by formula (VII) in step 4), the molar ratio of the compound represented by formula (V) to the compound represented by formula (VI) is 1:1-1.15.
[0023] Furthermore, in step 5), when synthesizing the substituted quinoline compound, the molar ratio of acetyl chloride to TEA and the compound represented by (VII) is 1:1.5-2.5:1.5-2.5.
[0024] The present invention also proposes the use of the substituted quinoline compound prepared by the method as a fungicide.
[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0026] 1) The present invention first uses thionyl chloride to react with a specific intermediate, using a solvent such as DCM, and using reagents such as pyridine, polyphosphoric acid, ethanol, and acetyl chloride during the reaction process. The compound synthesized by this method is tested for fungicidal activity. The results show that at a concentration of 50 ppm, it has significant inhibitory effects on various plant pathogens, especially against rice blast fungus and rapeseed sclerotinia fungus, showing excellent fungicidal activity;
[0027] 2) The preparation method of the present invention is simple and easy to operate. The structures of the obtained products were confirmed by nuclear magnetic resonance spectroscopy, and the fungicidal activity of the 29 target products obtained was tested. Among the target compounds of series I, compound VII2 had an inhibition rate of 43.8% against tomato early blight at a concentration of 50 ppm; compound VII16 had an inhibition rate of 71.1% against wheat fusarium at a concentration of 50 ppm; compounds VII3 and VII7 had an inhibition rate of 90% against rice blast fungus at a concentration of 50 ppm, and compound I1 had an inhibition rate of 100% at a concentration of 50 ppm;
[0028] The inhibition rate of compound Ⅶ3 against pepper phytophthora at a concentration of 50 ppm reached 41.9%; the inhibition rates of compounds Ⅶ1, Ⅶ3, and Ⅶ10 against rapeseed sclerotinia disease at a concentration of 50 ppm all reached 60%, especially the inhibition rate of compound Ⅶ4 reached 100% at a concentration of 50 ppm; the inhibition rate of compound Ⅶ3 against cucumber gray mold at a concentration of 50 ppm was 60.9%; the inhibition rate of compound Ⅶ8 against rice sheath blight at a concentration of 50 ppm reached 71.4%; the inhibition rates of compounds Ⅶ3 and Ⅰ1 against cucumber wilt pathogen at a concentration of 50 ppm were 51.9% and 48.1%, respectively; the inhibition rate of compound Ⅶ2 against peanut brown spot disease at a concentration of 50 ppm was 61.1%; the inhibition rate of compounds Ⅶ2, Ⅶ3, and Ⅰ1 against apple ring rot pathogen at a concentration of 50 ppm reached 61.1%. DETAILED DESCRIPTION
[0029] The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.
[0030] definition:
[0031] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and may be a C1-6 alkyl group. In some embodiments, the alkyl group has 6 to 9 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, n-pentyl, n-hexyl, n-heptyl, and n-nonyl.
[0032] "Alkoxy" refers to an "alkyl" group attached to the parent molecular group through an oxygen atom, wherein "alkyl" has the meaning given above.
[0033] "Haloalkyl" refers to an alkyl group in which all hydrogen atoms are partially or fully replaced with a halogen selected from fluoro. In some embodiments, all hydrogen atoms are individually replaced with fluoro.
[0034] "Haloalkoxy" refers to a "haloalkyl" group attached to the parent molecular group through an oxygen atom, wherein "haloalkyl" has the meaning given above. Examples of haloalkyl groups include -OCF3 and the like.
[0035] Example 1 Preparation of the compound represented by formula (III)
[0036] In a 100 mL round-bottom flask, dissolve the compound represented by formula (II) (6 g, 58.75 mmol) in DCM (30 mL). Add thionyl chloride (14.00 g, 117.50 mmol) and add 1-2 drops of DMF as a catalyst. Reflux for 4 h, then spin-dry the solvent to obtain the compound represented by formula (III). This compound is ready for use without purification. The R1 group is butyl, pentyl, n-hexyl, n-heptyl, n-nonyl, or n-undecyl.
[0037] Example 2 Preparation of the compound represented by formula (IV)
[0038] In a 250 mL round-bottom flask, dissolve Melvin's acid (8.47 g, 58.75 mmol) in DCM (30 mL). Pyridine (9.28 g, 117.50 mmol) was added dropwise over 5 min in an ice-water bath. After the addition was complete, the compound (III) prepared in Example 1 was added dropwise over 30 min in an ice-water bath. Stirring was continued in the ice-water bath for 1 h. Warm to room temperature and continue stirring. TLC (VEA / VPE = 1 / 2) was used to monitor the reaction progress. The reaction was complete after 3 h. The product was washed three times with 14% hydrochloric acid and water, respectively, and dried over anhydrous Na2SO4. The solvent was then evaporated to dryness to obtain the crude product (IV) of the compound, which was set aside without further purification.
[0039] Example 3 Preparation of the compound represented by formula (V)
[0040] To the flask containing the compound of formula (IV) prepared in Example 2 was added ethanol (30 mL) and refluxed. The reaction progress was monitored by TLC (VEA / VPE = 1 / 1). The reaction was complete after 4 h. The solvent was dried and purified by column chromatography to obtain the compound of formula (V) as a light yellow liquid in a yield of 62.5%-70.6%.
[0041] Table 1 Physicochemical data of the compound represented by formula (V)
[0042] <![CDATA[R1 group]]> Appearance Yield % n-Butyl Light yellow liquid 67.6 Pentyl Light yellow liquid 63.4 n-Hexyl Light yellow liquid 70.6 Zheng Gengji Light yellow liquid 67.1 n-nonyl Light yellow liquid 65.7 n-Undecyl Light yellow liquid 65.2
[0043] Table 2 Hydrogen spectrum data of the compound represented by formula (V)
[0044]
[0045] Example 4 Preparation of the compound represented by formula (VII)
[0046] To a 50 mL three-necked flask, the compound of formula (V) (1 g, 5.81 mmol) prepared in Example 3, the compound of formula (VI) (5.81 mmol), and polyphosphoric acid (4.07 g) were added in sequence. The temperature was raised to 150°C for reaction, and the reaction progress was monitored by TLC (VEA / VPE = 1 / 1). Heating was stopped after 5 h. After cooling to room temperature, the three-necked flask was placed in an ice-water bath and the pH was adjusted to 7-8 with 20% NaOH solution. A large amount of solid precipitated, and after standing, it was filtered. The filter cake was washed with ethyl acetate and water, and dried to obtain target compounds VII1-VII5. Other target compounds VII6-VII26 were synthesized using the same method.
[0047] Table 3(VII) Physicochemical data of the compounds
[0048]
[0049] Table 4 (VII) shows the hydrogen spectrum data of the compounds
[0050]
[0051]
[0052]
[0053]
[0054] Example 6 Preparation of formula (I)
[0055] Take three 50 mL round-bottom flasks, dissolve VII3 (0.1 g, 0.28 mmol), VII13 (0.1 g, 0.21 mmol) and VII23 (0.1 g, 0.24 mmol) in DCM (10 mL), add TEA (2 eq), place the round-bottom flask in an ice-water bath, and then slowly add acetyl chloride (2 eq) dissolved in DCM dropwise to the solution. After the addition is complete, stir at room temperature and monitor the reaction progress by TLC (VEA / VPE = 1 / 3). The reaction is complete after 4 h. The solvent is dried and purified by column chromatography to obtain the target compounds I1 to I3.
[0056] Table 5 Physical and chemical data of substituted quinoline compounds
[0057]
[0058] Table 6 Hydrogen spectrum data of substituted quinoline compounds
[0059]
[0060] Example 7 Bactericidal Activity Test
[0061] Test methods
[0062] (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).
[0063] (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.
[0064] (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.
[0065]
[0066] The activity test results are shown in Table 7:
[0067]
[0068]
[0069] The fungicidal activity results of substituted quinoline compounds (29) showed that at a concentration of 50 ppm, compound VII2 had a fungicidal activity of 43.8% against tomato early blight; compound VII16 had a fungicidal activity of 71.1% against wheat fusarium; compound VII3 had a fungicidal activity of 92.3% against rice blast; and compound VII4 had a fungicidal activity of 71.1% against wheat fusarium.
[0070] The fungicidal activity of compound Ⅶ4 against rapeseed sclerotinia virus reached 92.3%; the fungicidal activity of compound Ⅶ3 against cucumber gray mold reached 60.9%; the fungicidal activity of compound Ⅶ8 against rice sheath blight reached 71.4%; the fungicidal activity of compound Ⅰ1 against cucumber wilt reached 48.1%; the fungicidal activity of compound Ⅶ2 against peanut brown spot reached 61.1%; the fungicidal activity of compound Ⅰ1 against apple ring rot reached 72.2%.
[0071] Example 8 Herbicidal Activity Test
[0072] Test methods
[0073] (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.
[0074] (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.
[0075] (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.
[0076]
[0077] Where:
[0078] R——growth inhibition rate;
[0079] L0—control root length (or shoot length);
[0080] L1 - Processing root length (or shoot length).
[0081] The activity test results are shown in Table 8:
[0082] Table 8 Herbicidal activity of substituted quinoline compounds (%)
[0083]
[0084]
[0085] As shown in Table 8, at 100 μg·mL -1 At the concentration of 100 μg·mL, the inhibition of the VII series compounds on the roots of the dicotyledonous plant rapeseed is generally excellent. -1 At a concentration of 10 μg·mL, compounds VII1, VII2, VII3, VII4, VII7, VII11, VII16 and VII19 all showed 100% inhibition rate on rapeseed roots. -1 At the concentration of , compounds VII7, VII11 and VII19 still showed an excellent inhibition rate of 100% on rapeseed roots.
Claims
1. Substituted quinoline compounds, characterized in that Its structural formula is shown in formula (I): In formula (I), the substituent R1 is an alkyl group; the substituent R2 is a halogen, an alkoxy group, a haloalkoxy group, a haloalkyl group or a halogen-containing aromatic group.
2. The substituted quinoline compound according to claim 1, characterized in that The substituent R2 is 2-fluoro, 2-methoxy, 2-trifluoromethoxy, 5-bromo-2-methoxy or 2-(4-chloro-2-fluorophenoxy).
3. The substituted quinoline compound according to claim 1, characterized in that The substituent R1 is n-butyl, pentyl, n-hexyl, n-heptyl, n-nonyl or n-undecyl.
4. A method for preparing a substituted quinoline compound as claimed in claim 1, characterized in that The steps include: 1) Using DCM as solvent, thionyl chloride is reacted with the compound represented by formula (II) to generate the compound represented by formula (III); 2) using DCM as solvent, reacting the compound of formula (III) obtained in step 1) with Melvin's acid and pyridine to produce a compound of formula (IV); 3) heating the compound of formula (IV) obtained in step 2) under reflux using ethanol as solvent to produce a compound of formula (V); 4) using polyphosphoric acid as a cyclizing agent, reacting the compound of formula (V) obtained in step 3) with the compound of formula (VI) to produce the compound of formula (VII); 5) Using DCM as solvent and TEA as acid-binding agent, the compound (VII) obtained in step 4) is reacted with acetyl chloride to obtain a substituted quinoline compound (I); The reaction process is as follows: Wherein R1 is an alkyl group; R2 is a halogen, an alkyl group, an alkoxy group, a haloalkoxy group, a haloalkyl group or a halogen-containing aromatic group.
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 formula (II) to thionyl chloride is 1:2-3.
6. The method for preparing a substituted quinoline compound according to claim 4, wherein In step 2), when synthesizing the compound represented by formula (IV), the molar ratio of the compound represented by formula (III), McBride's acid and pyridine is 1:1-1.5:1.5-2.
5.
7. The method for preparing a substituted quinoline compound according to claim 4, wherein In step 4), when synthesizing the compound represented by formula (VII), the molar ratio of the compound represented by formula (V) to the compound represented by formula (VI) is 1:1-1.
15.
8. The method for preparing a substituted quinoline compound according to claim 4, wherein In step 5), when synthesizing the substituted quinoline compound, the molar ratio of acetyl chloride to TEA and the compound represented by (VII) is 1:1.5-2.5:1.5-2.
5.
9. Use of a substituted quinoline compound prepared according to the method according to any one of claims 4 to 8 as a fungicide.