Pyrimidine-substituted 1,2,4-triazole derivatives, methods of preparation, and uses

Abstract

The application discloses a kind of pyrimidine-substituted 1,2,4-triazole derivatives, it is characterized in that, with the structure expressed in general formula I or II:Wherein, R1 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amine group, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, ethyl formate;R2 is hydrogen, methyl, ethyl, methoxy, chlorine, fluorine, bromine, iodine, cyano, amine group, trifluoromethyl, ethyl formate;R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, cyano, amine group, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl.The compound of the application shows excellent activity against plant pathogens, such as rice sheath blight fungus, cucumber botrytis, blueberry botrytis, strawberry botrytis, tobacco botrytis, and sclerotinia sclerotiorum.

Description

Technical Field

[0001] This invention relates to the field of pesticide synthesis technology, specifically to a method for preparing pyrimidine-substituted 1,2,4-triazole derivatives, and their application in combating plant pathogens. Background Technology

[0002] Pyrimidines are an important class of nitrogen-containing heterocyclic compounds and are active structural units in many drugs. Pyrimidine compounds have attracted considerable attention from pharmacologists due to their high efficiency, low toxicity, diverse pharmacological activities, and the ability to change the position of substituents on their rings. Pyrimidines are not only crucial building blocks in biological activities, such as the three pyrimidine structures of nucleic acids—uracil, cytosine, and thymine—but also possess a wide range of biological activities, including antiviral, antitumor, antibacterial, insecticidal, and herbicidal effects, and have been widely used in the pharmaceutical and pesticide fields.

[0003] The 1,2,4-triazole ring is a five-membered aromatic heterocycle containing three nitrogen atoms. The molecule contains three nitrogen atoms and a π-π conjugated system, exhibiting a strong ability to complex metal ions and form hydrogen bonds. This unique structural property endows triazole compounds with broad-spectrum biological activities, such as insecticidal, fungicidal, herbicidal, anticonvulsant, and anticancer activities. Triazole compounds with different structures often possess different biological activities. Therefore, the research and development of new structural types of triazole compounds has become a research hotspot in pesticides and pharmaceuticals.

[0004] The above content is only used to help understand the technical solution of the present invention and does not represent an admission that the above content is prior art. Summary of the Invention

[0005] The purpose of this invention is to provide a class of pyrimidine-substituted 1,2,4-triazole derivatives and their preparation methods, and to use these derivatives to synthesize a series of drugs against plant pathogens.

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

[0007] Pyrimidine-substituted 1,2,4-triazole derivatives having structures expressed as general formula I or II:

[0008]

[0009] Wherein, R1 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, or ethyl formate; R2 is hydrogen, methyl, ethyl, methoxy, chlorine, fluorine, bromine, iodine, cyano, amino, trifluoromethyl, or ethyl formate; and R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, or difluoromethyl.

[0010] The present invention also provides a method for preparing pyrimidine-substituted 1,2,4-triazole derivatives, wherein pyrimidine-substituted 1,2,4-triazole derivatives are obtained by reacting an intermediate with a pyrimidine derivative;

[0011] The pyrimidine derivative has a structure expressed by general formula III:

[0012] Where R 10 The following are compounds: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, ethyl formate; R 20 The following are possible meanings: hydrogen, methyl, ethyl, methoxy, chlorine, fluorine, bromine, iodine, cyano, amino, trifluoromethyl, ethyl formate; R 30 The following are possible meanings: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl; R 40 The following are compounds: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, and ethyl formate.

[0013] The intermediate has a structure expressed by general formula IV:

[0014] N,N-diisopropylethylamine was used as a catalyst in the preparation of pyrimidine-substituted 1,2,4-triazole derivatives.

[0015] The intermediate was obtained by reacting 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole methanesulfonate with piperazine.

[0016] N,N-diisopropylethylamine was used as an acid-binding agent when preparing the intermediate.

[0017] The pyrimidine-substituted 1,2,4-triazole derivatives of this invention can be used to prepare drugs against plant pathogens. Detailed Implementation

[0018] It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0019] Example 1: Pyrimidine-substituted 1,2,4-triazole derivatives, whose general structural formulas are shown in Formula I or Formula II below:

[0020]

[0021] Wherein, R1 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, or ethyl formate; R2 is hydrogen, methyl, ethyl, methoxy, chlorine, fluorine, bromine, iodine, cyano, amino, trifluoromethyl, or ethyl formate; and R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, or difluoromethyl.

[0022] Its preparation method includes the following steps:

[0023] S1. Using 1-((2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole methanesulfonate and piperazine as raw materials, the intermediate 2-(2,4-difluorophenyl)-1-(piperazin-1-yl)-3-(4H-1,2,4-triazin-4-yl)prop-2-ol was prepared.

[0024] The specific reaction formula is as follows:

[0025]

[0026] This embodiment provides a specific operation flow description for step S1 as follows (those skilled in the art can also use other operation flows based on the above reaction formula):

[0027] To a 100 mL round-bottom flask, add 15 g of anhydrous piperazine, 3 mL of N,N-diisopropylethylamine, and 50.0 mL of isopropanol. Stir at room temperature until dissolved. Then, add 1,2,4-triazole methanesulfonate dissolved in isopropanol dropwise using a constant-pressure dropping funnel. Heat to 80 °C and react for 4 h, monitored by TLC (petroleum ether:ethyl acetate = 1:1, v / v). After stopping the reaction, concentrate under reduced pressure to obtain a pale yellow oily liquid. Add an appropriate amount of water, extract the organic layer with dichloromethane, and concentrate under reduced pressure to obtain the intermediate, yield: 71%.

[0028] In this embodiment, isopropanol (CH3CHOHCH3) is used as the solvent and N,N-diisopropylethylamine is used as the acid-binding agent. Those skilled in the art may use other solvents and acid-binding agents, which are not limited here.

[0029] S2. Using intermediates and pyrimidine derivatives as raw materials, a series of pyrimidine-substituted 1,2,4-triazole derivatives (target compound M) were prepared.

[0030] The specific reaction formula is as follows:

[0031]

[0032] The general structural formula of the pyrimidine derivatives is shown in Formula III below:

[0033]

[0034] Where R 10 The following are compounds: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, ethyl formate; R 20 The following are possible meanings: hydrogen, methyl, ethyl, methoxy, chlorine, fluorine, bromine, iodine, cyano, amino, trifluoromethyl, ethyl formate; R 30 The following are possible meanings: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl; R 40 The following are compounds: hydrogen, methyl, ethyl, methoxy, ethoxy, thiomethyl, chlorine, fluorine, bromine, iodine, cyano, amino, morpholine, triazole, pyrazole, trifluoromethyl, difluoromethyl, and ethyl formate.

[0035] This embodiment provides 27 specific pyrimidine derivatives reacting with intermediates to obtain 27 pyrimidine-substituted 1,2,4-triazole derivatives (target compound M), as shown in Table 1 below:

[0036] Table 1

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] This embodiment provides a specific operation flow description for step S2 as follows (those skilled in the art can also use other operation flows based on the above reaction formula):

[0046] In a 50 mL single-necked flask, 0.8 g of intermediate, 0.8 g of N,N-diisopropylethylamine, and 20 mL of isopropanol were added sequentially and stirred for 5 min. 0.6 g of the pyrimidine derivative was dissolved in 5 mL of isopropanol and added dropwise to the system. The temperature was raised to 85 °C and stirred for 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1, V / V). After the reaction was stopped, 20 mL of water was added, and the organic layer was extracted with ethyl acetate. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:2, V / V) to obtain the solid (the target compound M).

[0047] In this embodiment, N,N-diisopropylethylamine is used as a catalyst and isopropanol is used as a solvent. Those skilled in the art may use other catalysts and solvents, which are not limited here.

[0048] The physicochemical properties and high-resolution mass spectrometry data of the synthesized pyrimidine-substituted 1,2,4-triazole derivatives are shown in Table 2.

[0049] Table 2

[0050]

[0051]

[0052] The nuclear magnetic resonance (1H NMR) and carbon (13C NMR) data of the synthesized pyrimidine-substituted 1,2,4-triazole derivatives are shown in Table 3.

[0053] Table 3

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] Example 2: Antifungal activity test of pyrimidine-substituted 1,2,4-triazole derivatives against plant pathogenic fungi:

[0064] (1) Test method

[0065] The mycelial growth rate method was used to evaluate the in vitro activity of six plant pathogenic fungi: *Rhizoctonia solani* (Rs), *Cucumber Botrytis cinerea* (Cbc), *Blueberry Botrytis cinerea* (Bbc), *Fragaria vesca Botrytis cinerea* (Fbc), *Nicotiana Botrytis cinerea* (Nbc), and *Sclerotinia sclerotiorum* (Ss). The commercially available fungicide tebuconazole was used as a positive control. Details are as follows:

[0066] PDA medium: Weigh 40g of PDA medium and dissolve it in 1000mL of purified water. Heat and stir until dissolved into a clear liquid, then sterilize and set aside. Prepare a medium with a drug concentration of 50μg / mL, label it, and await inoculation.

[0067] Inoculation: In a sterile operating table, using a sterilized 5mm punch, pre-activated colonies were broken into individual mycelial discs. These discs were then placed upside down in the center of the drug-containing culture medium, one disc per medium. Drug-free medium served as a blank control. The plates were incubated in a constant temperature incubator for 2–5 days. When the mycelial growth of the blank control colonies reached 3 / 4 of the entire diameter of the culture dish, the colony diameter was measured using a ruler according to the cross-sectional method. Each treatment was performed in triplicate. The inhibition rate was calculated as follows:

[0068] Inhibition rate I (%) = (C tur -T tur ) / (C tur -0.5)×100

[0069] C tur The control colony diameter is the same as the colony diameter treated with DMSO.

[0070] T tur : Colony diameter after chemical treatment;

[0071] 0.5: Diameter of the mushroom cake;

[0072] I: Inhibition rate.

[0073] (2) The results of the bioactivity test against plant pathogenic fungi are shown in Table 4.

[0074] Table 4

[0075]

[0076]

[0077] Note: Average of three replicates; tebuconazole was used as a positive control.

[0078] Table 4 shows that most compounds exhibit good biological activity. Specifically, 14 compounds showed 100% inhibition against *Gyroderma purpureus* (cucumber gray mold), 20 compounds against *Gyroderma purpureus* (strawberry gray mold), 21 compounds against *Sclerotium sclerotium* (rapeseed sclerotium), 4 compounds against *Gyroderma purpureus* (blueberry gray mold), 3 compounds against *Gyroderma purpureus* (tobacco gray mold), and 2 compounds against *Rhizoctonia solani* (rice sheath blight). Given the high antibacterial activity of this series of compounds, further research was conducted targeting *Gyroderma purpureus* EC. of cucumber gray mold and strawberry gray mold. 50 test.

[0079] Compounds M1 and M6 showed 100% inhibition rates against *Botrytis cinerea*, *Botrytis cinerea*, *Sclerotinia sclerotiorum*, and *Botrytis cinerea*; compounds M4, M11, M12, M13, M15, M17, M19, and M22 also showed 100% inhibition rates against *Botrytis cinerea*, *Botrytis cinerea*, and *Sclerotinia sclerotiorum*.

[0080] Based on the initial screening data, the compound exhibited good antibacterial activity, and was subsequently subjected to EC testing against *Gyromyces cucumeris*. 50 The test results are shown in Table 5:

[0081] Table 5

[0082] compound Toxicity regression equation Correlation coefficient r <![CDATA[EC 50 (μg / ml)]]> M1 y = 1.0464x + 6.2739 0.9507 0.06 M2 y = 0.9321x + 4.0683 0.9435 9.9 M3 y = 1.8765x + 4.8187 0.9741 1.25 M4 y = 2.6115x + 4.7946 0.9205 1.19 M5 y = 4.2581x - 1.516 0.9199 33.9 M6 y = 2.2x + 4.8863 0.9391 1.12 M7 y = 1.1887x + 6.1518 0.9527 0.11 M8 y = 3.1254x + 0.7725 0.9945 22.5 M9 y = 1.6734x + 5.9816 0.9927 0.25 M10 y = 1.2135x + 3.3402 0.9385 13.6 M11 y = 0.6642 x = 5.4177 0.883 0.23 M12 y = 1.3276x + 5.3263 0.9618 0.56 M13 y = 1.1949x + 5.9322 0.9812 0.16 M14 y = 3.332x - 0.6524 0.9627 49.7 M15 y = 2.0811x + 2.745 0.9521 12.1 M16 y = 1.0644x + 5.8593 0.939 0.29 M17 y = 3.281x + 2.9556 0.957 4.19 M18 y = 1.793x + 2.1954 0.9503 36.6 M19 y = 1.9017x + 2.9118 0.9613 12.53 M20 y = 0.8213x + 4.8601 0.9637 1.48 M21 y = 6.997x - 8.5144 0.9797 86.5 M22 y = 1.783x + 4.8187 0.9849 1.81 M23 y = 1.2535x + 5.4416 0.8594 0.44 M24 y = 5.250x - 4.3932 0.961 61.5 M25 y = 1.4796x + 6.9427 0.9649 0.05 M26 y = 1.434x + 6.4151 0.969 0.1 M27 y = 1.0420x + 5.0237 0.9524 15.39 Tebuconazole y = 1.3464x + 3.3928 0.8117 2.82

[0083] Table 5 shows that the compounds exhibit good inhibitory activity against *Gyromyces cuspidatum*, with compounds M1, M3, M4, M7, M9, M11, M12, M13, M16, M20, M23, M24, M25, and M26 showing the best EC50 inhibitory activity against *Gyromyces cuspidatum*. 50 The effective concentrations of 0.06 μg / mL, 1.25 μg / mL, 1.19 μg / mL, 0.11 μg / mL, 0.25 μg / mL, 0.23 μg / mL, 0.56 μg / mL, 0.16 μg / mL, 0.29 μg / mL, 1.48 μg / mL, 1.81 μg / mL, 0.44 μg / mL, 0.05 μg / mL, and 0.1 μg / mL were all superior to the control drug tebuconazole (2.82 μg / mL).

[0084] Based on the initial screening data, the compounds exhibited good antifungal activity against *Botrytis cinerea*, and EC2 analysis was performed on some of the compounds with better activity. 50 The test results are shown in Table 6:

[0085] Table 6

[0086] compound Toxicity regression equation Correlation coefficient r <![CDATA[EC 50 (μg / mL)]]> M2 y = 0.549x + 5.0334 0.9895 0.86 M6 y = 0.6175x + 4.8466 0.9927 1.77 M7 y = 1.1013x + 7.7147 0.9839 0.003 M9 y = 0.9768x + 5.0796 0.9899 0.82 M10 y = 2.5283x + 9.2449 0.9654 0.02 M11 y = 0.3868x + 5.3675 0.9303 0.11 M15 y = 0.9775x + 5.7053 0.9633 0.18 M22 y = 0.5057x + 5.5551 0.9668 0.07 M26 y = 0.4118x + 5.4198 0.961 0.09 Tebuconazole y = 1.9174x + 5.7621 0.958 0.40

[0087] Table 6 shows that the compounds exhibited good inhibitory activity against *Botrytis cinerea*, and compounds M7, M10, M11, M15, M22, and M26 showed good EC50 activity against *Botrytis cinerea*. 50 The concentrations of 0.003 μg / mL, 0.02 μg / mL, 0.11 μg / mL, 0.18 μg / mL, 0.07 μg / mL, and 0.09 μg / mL were all superior to the control drug tebuconazole (0.40 μg / mL).

[0088] The above activity data indicate that pyrimidine-substituted 1,2,4-triazole derivatives have a certain inhibitory effect on plant pathogens. Some of the target compounds show excellent activity against plant pathogens and can be used as anti-plant pathogen drugs, showing good application prospects.

[0089] The above are merely preferred embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A pyrimidine-substituted 1,2,4-triazole derivative, characterized in that, Structures expressed by general formula I or II: The structural formula of the compound is as follows: M1: M2: M3: , M4: ,M5: ,M6: , M7: ,M8: ,M9: , M10: ,M11: ,M12: , M13: ,M14: ,M15: , M16: ,M17: ,M18: , M19: ,M20: ,M21: , M22: ,M23: ,M24: , M25: M26: M27: 。 2. The method for preparing pyrimidine-substituted 1,2,4-triazole derivatives as described in claim 1, characterized in that, By reacting intermediates with pyrimidine derivatives, pyrimidine-substituted 1,2,4-triazole derivatives are obtained; The pyrimidine derivative has a structure expressed by general formula III: , in The radicals are hydrogen, methyl, ethyl, methoxy, chlorine, amino, trifluoromethyl, and difluoromethyl. The groups are hydrogen, methoxy, chlorine, fluorine, bromine, iodine, amino, trifluoromethyl, and ethyl formate. It can be hydrogen, chlorine, cyano, or trifluoromethyl. It can be hydrogen, methyl, chlorine, amino, or morpholino. The intermediate has a structure expressed by general formula IV: .

3. The method for preparing pyrimidine-substituted 1,2,4-triazole derivatives as described in claim 2, characterized in that, N,N-diisopropylethylamine was used as a catalyst.

4. The method for preparing pyrimidine-substituted 1,2,4-triazole derivatives as described in claim 2, characterized in that, The intermediate is through It is obtained by reacting methanesulfonate with piperazine.

5. The method for preparing pyrimidine-substituted 1,2,4-triazole derivatives as described in claim 4, characterized in that, N,N-diisopropylethylamine was used as an acid-binding agent when preparing the intermediate.

6. An antifungal agent against cucumber gray mold, characterized in that, Its active ingredient includes any one of compounds M1-M20 and M22-M27 as described in claim 1.

7. An antifungal agent against gray mold of strawberries, characterized in that, Its active ingredient includes any one of compounds M1-M27 as described in claim 1.

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