A quinoline compound containing piperidine heterocycle and its preparation method and application

Abstract

The present invention discloses a quinoline compound containing a piperidine heterocycle, a preparation method and an application thereof. The quinoline compound containing a piperidine heterocycle has a structural formula as shown in formula (I): 1 is hydrogen or 6-tert-butyl; the substituent R 2 is phenyl or p-bromophenyl; the substituent R 3 The structures of the 20 target products obtained by the present invention are 1 H NMR and HRMS confirmed that the present invention is the application of quinoline compounds containing piperidine heterocycles in resisting plant pathogenic fungi. The antibacterial activity test of the prepared new compounds was carried out, and the results showed that all the new compounds had a certain inhibitory effect on the ten plant pathogenic fungi tested.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and drug application, and specifically relates to a quinoline compound containing a piperidine heterocycle and a preparation method and application thereof. Background Art

[0002] The normal development of agriculture is inseparable from the use of pesticides. Plant diseases and insect pests have great harm to the healthy development of agriculture and food security. Due to the excessive and improper use of pesticides by humans, problems such as pesticide residues and crop resistance have occurred. With the development of the new era and the improvement of global environmental awareness, the requirements for pesticides are also increasing. Therefore, it is urgent to develop new green, safe and environmentally friendly pesticides.

[0003] Quinoline is a nitrogen-containing heterocyclic aromatic compound that can undergo both electrophilic and nucleophilic substitution reactions, and it plays an important role in the fields of pesticides and medicines. Accordingly, quinoline compounds have good biological and pharmacological activities. Many researchers have synthesized many compounds with good antimalarial, antibacterial, insecticidal, anticonvulsant, anti-inflammatory and analgesic activities using quinoline ring as the skeleton. Among all nitrogen-containing heterocyclic compounds, due to its relatively good biological activity, its molecular design, synthesis and biological activity research are a hot spot in the current pesticide creation in drug research and development. Summary of the invention

[0004] The purpose of the present invention is to provide a quinoline compound containing a piperidine heterocycle and a preparation method and application thereof. The mainstream development trend of the current market is green and efficient new pesticides. The present invention keeps the core skeleton of the quinoline ring unchanged and modifies its structure, designs and synthesizes a new quinoline compound containing a piperidine heterocycle, and conducts a fungicidal activity test.

[0005] A quinoline compound containing a piperidine heterocycle, the structural formula of which is shown in formula (I):

[0006]

[0007] In formula (I), the substituent R 1 is hydrogen or 6-tert-butyl;

[0008] Substituent R 2 is phenyl or p-bromophenyl;

[0009] Substituent R 3 It is a C1~C4 alkyl group or a C1~C2 alkoxy group.

[0010] Preferably, the substituent R 3 is cyclopropyl, isopropyl, n-butyl, methoxy or ethoxy.

[0011] A method for preparing a quinoline compound containing a piperidine heterocycle comprises the following steps:

[0012] 1) reacting substituted aniline with ethyl acetoacetate at 140-160° C. using polyphosphoric acid as a catalyst to generate a compound as shown in formula (III);

[0013] 2) Under reflux conditions, using 1,4-dioxane as solvent, reacting the compound of formula (III) obtained in step 1) with phosphorus oxychloride to obtain a compound of formula (IV);

[0014] 3) at 130-150° C., ammonium iodide provides an alkaline environment, and N-methylpyrrolidone is used as a solvent to react the compound of formula (IV) obtained in step 2) with the substituted formaldehyde of formula (V) to obtain the compound of formula (VI);

[0015] 4) reacting the compound of formula (VI) obtained in step 3) with 4-methylformate piperidine at 140-150° C. in an alkaline environment provided by DIPEA and using DMF as solvent to obtain a compound of formula (VII);

[0016] 5) Finally, at room temperature, the compound of formula (VII) obtained in step 4) is first subjected to alkaline hydrolysis, and then the pH is adjusted to obtain the corresponding carboxylic acid compound. Finally, using DMAP and EDCI as condensing agents and DCM as solvent, the carboxylic acid compound is reacted with a fatty amine to obtain a quinoline compound containing a piperidine heterocycle as shown in formula (1);

[0017]

[0018] In formula (I), (III), (IV), (VI) and (VII), the substituent R 1 is H or 6-tert-butyl, the substituent R in formula (II) 1 is H or 4-tert-butyl;

[0019] In formula (I), (V), (VI) and (VII), the substituent R 2 is phenyl or p-bromophenyl;

[0020] In formula (I), the substituent R 3 It is a C1~C4 alkyl group or a C1~C2 alkoxy group.

[0021] Furthermore, when synthesizing the compound represented by formula (III) in step 1), the molar ratio of substituted aniline to ethyl acetoacetate is 1:1.5-1:2.

[0022] Furthermore, when synthesizing the compound represented by formula (IV) in step 2), the molar ratio of the compound represented by formula (III) to phosphorus oxychloride is 1:1.5-1:2.

[0023] Furthermore, when synthesizing the compound of formula (VI) in step 3), the molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:1-1:1.5.

[0024] Furthermore, when synthesizing the compound represented by formula (VII) in step 4), the molar ratio of the compound represented by formula (VI) to 4-methylpiperidinecarboxylate is 1:1-1:1.5.

[0025] Furthermore, when synthesizing the compound represented by formula (I) in step 5), the molar ratio of the compound represented by formula (VII) to the fatty amine is 1:1-1:1.5.

[0026] The invention discloses an application of a quinoline compound containing a piperidine heterocycle in the preparation of a fungicide.

[0027] The beneficial effects of the present invention are:

[0028] The preparation method of the present invention has a simple process, low cost of raw materials, can be mass-produced, and the structure of the target product obtained is 1 H NMR and HRMS were used to confirm the existence of the 20 new compounds. The antibacterial activity of the compounds was tested at a concentration of 50 ppm. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0030] The reaction equation is:

[0031]

[0032] Example 1-2 Preparation of compounds represented by formula (III)-11 and (III)-2

[0033] In a 100 mL round-bottom flask, add the substituted aniline (0.05 mol, substituent R 1 H or 4-tert-butyl), ethyl acetoacetate (0.1 mol), PPA (35 g), the reaction temperature was heated to 150 ° C, and TLC (V EA / V PE =3 / 1) to detect the progress of the reaction. The reaction was carried out for about 5 hours. After the reaction was cooled to room temperature, the reaction bottle was placed in an ice-water bath and the pH was adjusted to 7-8 with a 2 mol / L sodium hydroxide solution. A white solid was precipitated, which was filtered, washed and dried to obtain compounds (III)-1 to (III)-2 as white solids.

[0034] Example 3-4 Preparation of compounds shown in formula (IV)-1 and (IV)-2

[0035] In a 100mL round-bottom flask, add the compound (III)-1 to (III)-2 (0.029 mol) and 1,4-dioxane (30 mL), stir and dissolve, add phosphorus oxychloride (8.87 g, 0.058 mol), heat the reaction temperature to reflux, and react for about 5 hours. After the reaction stops, wait for the reaction solution to cool to room temperature, adjust the pH to 7-8 with 2mol / L NaOH aqueous solution, and precipitate a white solid. After suction filtration, washing and drying, obtain compound (IV)-1 to (IV)-2, a white solid.

[0036] Example 5-8 Preparation of Compounds (VI)-1 to (VI)-4

[0037] In a 100 mL round-bottom flask, NMP (20 mL), compound (IV)-1 to (IV)-2 (8.06 mmol), compound (V)-1 to (V)-2 (9.00 mmol, substituent R 2 is phenyl or p-bromophenyl) and ammonium iodide (1.17 g, 8.06 mmol), the reaction temperature was heated to 140°C, TLC (V EA / V PE =1 / 6) to track the reaction progress. After the reaction was completed, 100 mL of water was added, and then extracted with EA (20 mL×3), the organic phases were combined, washed twice with saturated brine, dried with anhydrous sodium sulfate, the solvent was dried, and purified by column chromatography to obtain compounds (VI)-1 to (VI)-4.

[0038] Example 9-12 Preparation of Compounds (VII)-1 to (VII)-4

[0039] In a 100 mL round-bottom flask, DMF (20 mL), compounds (VI)-1 to (VI)-4 (8.04 mmol), DIPEA (1.04 g, 8.06 mmol) and 4-methylpiperidine formate (1.15 g, 8.04 mmol) were added. The reaction temperature was heated to 140 °C. TLC (V EA / V PE =1 / 3) to track the reaction progress. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of water was added, and it was extracted with EA (20 mL×3). The organic phases were combined, washed twice with saturated brine, and dried with anhydrous sodium sulfate. The solvent was dried by spin drying, and purified by column chromatography to obtain compounds (VII)-1 to (VII)-4.

[0040] Example 13-32 Preparation of quinoline compounds containing piperidine heterocycles

[0041] In a 100 mL round-bottom flask, compounds (VII)-1 to (VII)-4 (0.69 mmol) and 6N NaOH aqueous solution (20 mL) were added in sequence and stirred at room temperature. TLC (V EA / V PE =1 / 1) to track the reaction progress. After the reaction was completed, the pH was adjusted to 3-4 with a dilute HCl solution to precipitate a yellow solid, which was filtered and washed and then dried. The obtained yellow solid, DMAP (0.085 g, 0.69 mmol), EDCI (0.132 g, 0.69 mmol) and dichloromethane (10 mL) were added to a round-bottom flask in sequence, and a fatty amine (0.69 mmol, R 3 See Table 1), TLC (V EA / V PE =1 / 2) to track the reaction progress. After the reaction was completed, the mixture was spin-dried and purified by column chromatography to obtain the target compounds Ⅰ~1-Ⅰ~20.

[0042] Table 1 Physical properties of quinoline compounds containing piperidine heterocycles

[0043]

[0044]

[0045] Table 2 Quinoline compounds containing piperidine heterocycle 1 H NMR and HRMS data

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] Example 33 Antibacterial Activity Test

[0053] Test methods

[0054] (1) Experimental subjects: Alternaria solani (AI), Gibberella zeae (GZ), Pyricularia oryae (PO), Phytophthora capsici (PC), Sclerotinia sclerotiorum (SS), Botrytis cinerea (BC), Riziocotinia solani (RS), Fusarium oxysporum (FO), Cercospora arachidicola (CA), and Botryosphaeria berengriana (BB).

[0055] (2) Test treatment: Each test compound was dissolved in DMSO to form a 1% EC stock solution for later use. 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, and a clear water control (QCK) was set up.

[0056] (3) Test method: Use a pipette to draw 150 microliters of the above-prepared EC mother solution, dissolve it in 2.85 mL of Tween water, and prepare a solution with an effective concentration of 500 ppm of the compound to be tested. Use a pipette to draw 1 ml of the solution into a sterilized culture dish, then put in 9 ml of PDA culture medium, shake well, and cool. Use a hole 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 growth of the colony is the difference between the average diameter of the colony and the diameter of the bacterial cake. The method for calculating the antibacterial rate (%) refers to the following formula.

[0057]

[0058] The activity test results are shown in Table 3:

[0059] Table 3 Antibacterial activity of quinoline compounds containing piperidine heterocycle

[0060]

[0061]

[0062] The fungicidal activity results of quinoline compounds (20) containing piperidine heterocycles showed (Table 3): At a concentration of 50ppm, the 20 new compounds designed and synthesized all showed certain antibacterial activity. The 20 new compounds showed good antibacterial activity against rice blast fungus, rapeseed sclerotinia and cucumber gray mold. Among them, I-11 and I-15 showed 71.4% antibacterial activity against rice blast fungus; I-10 showed 81.3% antibacterial activity against apple ring rot fungus; I-4 showed 70.7% antibacterial activity against rice sheath blight fungus. Most of the target compounds showed good antibacterial activity against rapeseed sclerotinia, among which I-1 and I-20 had an antibacterial activity of more than 90%.

[0063] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept. The protection scope of the present invention should not be regarded as limited to the specific forms described in the embodiments. The protection scope of the present invention is also limited to the equivalent technical means that can be thought of by those skilled in the art based on the inventive concept.

Claims

1. A quinoline compound containing a piperidine heterocycle, characterized in that: Its structural formula is shown in formula (I): In formula (I), the substituent R 1 is hydrogen or 6-tert-butyl; Substituent R 2 is phenyl or p-bromophenyl; Substituent R 3 It is a C1~C4 alkyl group or a C1~C2 alkoxy group.

2. The quinoline compound containing piperidine heterocycle according to claim 1, characterized in that: Substituent R 3 is cyclopropyl, isopropyl, n-butyl, methoxy or ethoxy.

3. A method for preparing a quinoline compound containing a piperidine heterocycle as claimed in claim 1, characterized in that: The method comprises the following steps: 1) reacting the substituted aniline of formula (II) with ethyl acetoacetate at 140-160° C. with polyphosphoric acid as a catalyst to generate a compound of formula (III); 2) Under reflux conditions, using 1,4-dioxane as solvent, reacting the compound of formula (III) obtained in step 1) with phosphorus oxychloride to obtain a compound of formula (IV); 3) at 130-150° C., ammonium iodide provides an alkaline environment, and N-methylpyrrolidone is used as a solvent to react the compound of formula (IV) obtained in step 2) with the substituted formaldehyde of formula (V) to obtain the compound of formula (VI); 4) reacting the compound of formula (VI) obtained in step 3) with 4-methylformate piperidine at 140-150° C. in an alkaline environment provided by DIPEA and using DMF as solvent to obtain a compound of formula (VII); 5) Finally, at room temperature, the compound of formula (VII) obtained in step 4) is first subjected to alkaline hydrolysis, and then the pH is adjusted to obtain the corresponding carboxylic acid compound. Finally, using DMAP and EDCI as condensing agents and DCM as solvent, the carboxylic acid compound is reacted with a fatty amine to obtain a quinoline compound containing a piperidine heterocycle as shown in formula (I); In formula (I), (III), (IV), (VI) and (VII), the substituent R 1 is H or 6-tert-butyl, the substituent R in formula (II) 1 is H or 4-tert-butyl; In formula (I), (V), (VI) and (VII), the substituent R 2 is phenyl or p-bromophenyl; In formula (I), the substituent R 3 It is a C1~C4 alkyl group or a C1~C2 alkoxy group.

4. The method for preparing a quinoline compound containing a piperidine heterocycle according to claim 3, wherein: When synthesizing the compound shown in formula (III) in step 1), the molar ratio of substituted aniline to ethyl acetoacetate is 1:1.5-1:

2.

5. The method for preparing a quinoline compound containing a piperidine heterocycle according to claim 3, characterized in that: When synthesizing the compound represented by formula (IV) in step 2), the molar ratio of the compound represented by formula (III) to phosphorus oxychloride is 1:1.5-1:

2.

6. The method for preparing a quinoline compound containing a piperidine heterocycle according to claim 3, characterized in that: When synthesizing the compound represented by formula (VI) in step 3), the molar ratio of the compound represented by formula (IV) to the compound represented by formula (V) is 1:1-1:1.

5.

7. The method for preparing a quinoline compound containing a piperidine heterocycle according to claim 3, characterized in that: When synthesizing the compound represented by formula (VII) in step 4), the molar ratio of the compound represented by formula (VI) to 4-methylpiperidinecarboxylate is 1:1-1:1.

5.

8. The method for preparing a quinoline compound containing a piperidine heterocycle according to claim 3, characterized in that: When synthesizing the compound represented by formula (I) in step 5), the molar ratio of the compound represented by formula (VII) to the fatty amine is 1:1-1:1.

5.

9. Use of the quinoline compound containing a piperidine heterocycle according to claim 1 or 2 in the preparation of a fungicide.

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