Heterocyclic 1,2,4-oxadiazole compounds and preparation methods and applications thereof

Abstract

The invention discloses a 1,2,4-oxadiazole compound containing a heterocycle, a preparation method thereof and an application thereof, wherein p-chlorobenzonitrile is used as a raw material to synthesize p-chlorobenzylamine oxime, and then p-chlorobenzylamine oxime reacts with heterocyclic acyl chloride to obtain a novel 1,2,4-oxadiazole compound containing a heterocycle. The preparation method of the invention is simple and easy to operate, and the obtained compound has certain bactericidal and insecticidal properties at a concentration of 50ppm.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and pharmaceutical application, and specifically relates to a 1,2,4-oxadiazole compound containing a heterocycle and a preparation method and application thereof. Background Art

[0002] Oxadiazole can be used as an important structure of drug molecules and has obvious biological activity. Oxadiazole compounds have good thermal stability, chemical stability and high electron affinity, and are widely used in medicine, fine chemicals, pesticides and other fields. For example, 1-2-4-oxadiazole compounds have insecticidal, acaricidal, bactericidal, herbicidal and antibacterial biological activities; 1,2,4-oxadiazole is an important heterocyclic skeleton in the creation of new drugs, often used as a biological electronic isostere of esters and amides, and the drug molecules of 1,2,4-oxadiazole heterocyclic structure show diverse biological activities; however, there are relatively few studies on the agricultural use of 1,2,4-oxadiazole compounds, and the only commercialized 1,2,4-oxadiazole nematicide is Tioxazafen. Summary of the invention

[0003] The invention uses p-chlorobenzylamine oxime synthesized from p-chlorobenzonitrile as a raw material as a raw material, and introduces a heterocyclic acid chloride to design and synthesize a novel heterocyclic 1,2,4-oxadiazole compound. The purpose of the invention is to provide a heterocyclic 1,2,4-oxadiazole compound, a preparation method and an application thereof.

[0004] A 1,2,4-oxadiazole compound containing a heterocyclic ring, the structural formula of which is shown in formula (I):

[0005]

[0006] In formula (I), the substituent R is The substituent R1 is selected from CH3, The substituent R2 is substituted or unsubstituted, and when substituted, R2 is selected from CF3; the substituent R3 is substituted or unsubstituted, and when substituted, R3 is selected from CF3, CHF2 or Br; the substituent R4 is substituted or unsubstituted, and when substituted, R4 is Cl; the substituent R5 is substituted or unsubstituted, and when substituted, R5 is selected from Cl or Br; the substituent R6 is substituted or unsubstituted, and when substituted, R6 is OCF3; the substituent R7 is substituted or unsubstituted, and when substituted, R7 is Cl; the substituent R8 is C2H6 or isopropyl; the substituent R9 is CH3; the substituent R10 is substituted or unsubstituted, and when substituted, R10 is OCHF2 or CH3.

[0007] A method for preparing a heterocyclic 1,2,4-oxadiazole compound comprises the following steps:

[0008] 1) using anhydrous ethanol as solvent, reacting p-chlorobenzonitrile with hydroxylamine hydrochloride in the presence of sodium carbonate to generate a compound as shown in formula (II);

[0009] 2) using glacial acetic acid as solvent and triethylamine as alkaline condition, adding the compound of formula (II) obtained in step 1) to react with heterocyclic acid chloride to generate a heterocyclic 1,2,4-oxadiazole compound of formula (I);

[0010]

[0011] The reaction process is as follows:

[0012]

[0013] Furthermore, in step 1), when synthesizing the compound represented by formula (II), the molar ratio of p-chlorobenzonitrile to hydroxylamine hydrochloride is 1:2.

[0014] Furthermore, in step 2), when synthesizing the heterocyclic 1,2,4-oxadiazole compound as shown in formula (I), the molar ratio of the compound as shown in formula (II) to the heterocyclic acid chloride is 1:1.1-1:1.2.

[0015] The application of the heterocyclic 1,2,4-oxadiazole compound in the preparation of fungicides and insecticides.

[0016] The beneficial effects of the present invention are:

[0017] 1) The preparation method of the present invention is simple and easy to operate. The structure of the obtained product is confirmed by nuclear magnetic hydrogen spectrum, and the fungicidal activity of the obtained 18 target products is tested. The results show that: at 50ppm, the 18 compounds have certain activity. The inhibition rates of Ⅰ-5, Ⅰ-9 and Ⅰ-12 on pepper phytophthora are all 64.5%. The inhibition rates of Ⅰ-17 and Ⅰ-18 on cucumber gray mold are 60% and 53.3%, respectively. The inhibition rate of Ⅰ-5 on rice blast fungus is 54.5%. The inhibition rates of Ⅰ-14 on rapeseed sclerotinia, cucumber gray mold and rice sheath blight are 66.7%, 63.3% and 53%. The inhibition rates of Ⅰ-13 on rapeseed sclerotinia and rice sheath blight are both 75%, the inhibition rates on cucumber gray mold and apple ring rot are above 61%, and the inhibition rate on wheat fusarium is 54.2%.

[0018] 2) The heterocyclic 1,2,4-oxadiazole compounds of the present invention have certain insecticidal activity against armyworms and mosquito larvae. The mortality rates of I-1, I-4, I-12, I-13 and I-16 on armyworms at 500 ppm all reached 100%, but at 200 ppm, the mortality rates on armyworms were reduced to 65%, 0%, 25%, 35% and 30%, and I-1 had the best insecticidal activity against armyworms.

[0019] The mortality rate of mosquito larvae caused by Ⅰ-4 at 10ppm, 5ppm and 2ppm reached 100%, but at 1ppm, it dropped to 45%. The mortality rate of mosquito larvae caused by Ⅰ-13 at 10ppm, 5ppm, 2ppm, 1ppm and 0.5ppm reached 100%, but at 0.25ppm, it dropped to 65%. DETAILED DESCRIPTION

[0020] 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.

[0021] The reaction process is as follows:

[0022]

[0023] Example 1 Preparation of the compound represented by formula (II)

[0024] Sodium carbonate (5.8 g, 55.0 mmol) solution was added to a 100 mL round-bottom flask, followed by 10 mL of anhydrous ethanol and p-chlorobenzonitrile 18 (6.9 g, 50.0 mmol), and stirred at room temperature. After stirring evenly, hydroxylamine hydrochloride (7.0 g, 100.0 mmol) was added in batches, and stirring was continued at room temperature for 2 h. The temperature was raised and refluxed for reaction for 4 h. After the reaction solution was cooled, sodium carbonate was removed by suction filtration. The filtrate was decompressed and rotary evaporated to remove the solvent to obtain 7.7 g of crude intermediate II (4-chlorobenzylamine oxime) with a yield of 90%.

[0025] Example 2-19 Preparation of Compounds Ⅰ-1 to Ⅰ-18

[0026] Add intermediate II (0.3 g, 1.7 mmol) to a 50 mL round-bottom flask, then add 10 mL glacial acetic acid and 1 mL triethylamine, stir evenly, then drop 1.9 mmol heterocyclic acid chloride (substituent R is shown in Table 1), stir at room temperature for 2 h, heat and reflux for 4 h, track the reaction by TLC (VEA / VPE=1 / 1), stop heating after the reaction is complete, cool to room temperature, add water to precipitate solids, filter and dry to obtain target compounds I-1 to I-18. Specific data are shown in Tables 1 and 2.

[0027] Table 1 Physical and chemical data of heterocyclic 1,2,4-oxadiazole compounds

[0028]

[0029]

[0030] Table 2 Hydrogen spectrum data of 1,2,4-oxadiazole compounds containing heterocyclic rings

[0031]

[0032]

[0033]

[0034] Example 20 Bactericidal activity test

[0035] Test methods

[0036] (1) Test subjects: Alternaria solani, Fusa Humgraminearum Sehw, Pyricularia Grisea, Phytophthora capsici Leonian, Sclerotinia sclerotiorum (Lib.) de Bary, Botrytis cinerea, Thanatephorus cucumeris, Fusarium oxysporum.sp.cucumebrium Owen, Cercospora arachidicola Hori, Botryosphaeria dothidea.

[0037] (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 also set up.

[0038] (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.

[0039]

[0040] The activity test results are shown in Table 3:

[0041] Table 3 Fungicidal activity of heterocyclic 1,2,4-oxadiazole compounds

[0042]

[0043]

[0044] At 50ppm, the heterocyclic 1,2,4-oxadiazole compounds all have certain activity. The inhibition rates of Ⅰ-5, Ⅰ-9 and Ⅰ-12 against pepper phytophthora reached 64.5%. The inhibition rates of Ⅰ-17 and Ⅰ-18 against cucumber gray mold reached 60% and 53.3% respectively. The inhibition rate of Ⅰ-5 against rice blast reached 54.5%. The inhibition rates of Ⅰ-14 against rapeseed sclerotinia, cucumber gray mold and rice sheath blight reached 66.7%, 63.3% and 53% respectively. Overall, the fungicidal activity of Ⅰ-13 is the best in the series, with the inhibition rates against rapeseed sclerotinia and rice sheath blight reaching 75%, the inhibition rates against cucumber gray mold and apple ring rot were above 61%, and the inhibition rate against wheat fusarium reached 54.2%.

[0045] Example 21 Insecticidal Activity Test

[0046] Test methods

[0047] (1) Test subjects:

[0048] Test targets: second-instar armyworms, first-instar mosquito larvae. Instruments and equipment: electronic balance, insect immersion cage, volumetric flask, culture dish, beaker, pipette (pipette gun), tweezers, filter paper, marker pen, stopwatch, etc.

[0049] (2) Experimental preparations:

[0050] Test compound Ⅰ-1-Ⅰ-18 was diluted in DMSO or ethanol to prepare a 500 ppm stock solution, and then diluted to 200 ppm, 10 ppm, 5 ppm, 2 ppm, 1 ppm, 0.5 ppm, and 0.25 ppm.

[0051] (3) Experimental methods:

[0052] The second-instar armyworms were immersed in 500ppm solution for 10s, and the first-instar mosquito larvae were immersed in 10ppm solution for 10s, then the excess solution was sucked off with filter paper, and the insects were transferred to normal conditions for feeding. Each treatment was repeated three times, and 20 insects were immersed in each repetition. An organic solvent treatment was set as a blank control. The life status of the insects was recorded at 24 hours. An organism was judged to be dead if it did not respond to the tip detection of the pipette. The treatment with 100% mortality of the second-instar armyworms continued to test the insecticidal activity at 200ppm. The treatment with 100% mortality of the first-instar mosquito larvae continued to test the insecticidal activity at 5ppm, and so on.

[0053] The mortality rate (%) was calculated according to the following formula.

[0054]

[0055]

[0056] If the blank control mortality rate is less than 5%, no correction is required; if the control mortality rate is between 5-20%, correction should be made; if the blank control mortality rate is greater than 20%, repeat the test. The insecticidal activity test results are shown in Table 4:

[0057] Table 4 Insecticidal activity of heterocyclic 1,2,4-oxadiazole compounds

[0058]

[0059]

[0060] Heterocyclic 1,2,4-oxadiazole compounds have certain insecticidal activity against sticky insects and mosquito larvae. At 500ppm, the mortality caused by compounds Ⅰ-1, Ⅰ-4, Ⅰ-12, Ⅰ-13 and Ⅰ-16 on sticky insects reached 100%, but at 200ppm, their mortality on sticky insects dropped to 65%, 0, 25%, 35%, and 30%, and Ⅰ-1 had the best killing activity against sticky insects. The mortality caused by Ⅰ-4 on mosquito larvae at 10ppm, 5ppm, and 2ppm reached 100%, but at 1ppm, it dropped to 45%. The mortality caused by Ⅰ-13 on mosquito larvae at 10ppm, 5ppm, 2ppm, 1ppm, and 0.5ppm reached 100%, but at 0.25ppm, it dropped to 65%.

[0061] 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 1,2,4-oxadiazole compound containing a heterocyclic ring, characterized in that: The structural formula is shown in formula (I): In formula (I), the substituent R is The substituent R1 is selected from CH3, The substituent R2 is substituted or unsubstituted, and when substituted, R2 is selected from CF3; the substituent R3 is substituted or unsubstituted, and when substituted, R3 is selected from CF3, CHF2 or Br; the substituent R6 is unsubstituted, the substituent R7 is substituted or unsubstituted, and when substituted, R7 is Cl, and the substituent R8 is C2H6 or isopropyl; A method for preparing a heterocyclic 1,2,4-oxadiazole compound comprises the following steps: 1) using anhydrous ethanol as solvent, reacting p-chlorobenzonitrile with hydroxylamine hydrochloride in the presence of sodium carbonate to generate a compound as shown in formula (II); 2) using glacial acetic acid solvent and triethylamine under alkaline conditions to add the compound of formula (II) obtained in step 1) and a heterocyclic acid chloride to react to generate a heterocyclic 1,2,4-oxadiazole compound of formula (I); 2. The heterocyclic 1,2,4-oxadiazole compound according to claim 1, characterized in that: When synthesizing the compound shown in formula (II) in step 1), the molar ratio of p-chlorobenzonitrile to hydroxylamine hydrochloride is 1:

2.

3. The heterocyclic 1,2,4-oxadiazole compound according to claim 2, characterized in that: When synthesizing the compound of formula (I) in step 2), the molar ratio of the compound of formula (II) to the heterocyclic acid chloride is 1:1.1-1:1.

2.

4. Use of the heterocyclic 1,2,4-oxadiazole compound according to claim 1 in the preparation of fungicides and insecticides, characterized in that: The fungi of the fungicide are tomato early blight, wheat fusarium rust, rice blast, pepper phytophthora, rapeseed sclerotinia, cucumber gray mold, rice sheath blight, cucumber wilt, peanut brown spot and apple ring rot, and the insect of the insecticide is second-instar armyworm.

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