A pyrazole cinnamaldehyde acylhydrazone compound, a preparation method thereof and applications thereof

Abstract

The present invention discloses a pyrazole cinnamaldehyde hydrazone compound, a preparation method and an application thereof. The structural general formula of the compound is shown as formula I. The preparation method of the pyrazole-substituted cinnamaldehyde hydrazone compound of the present invention comprises the following steps: in an organic solvent, mixing the compound shown as formula II and the compound shown as formula III, and carrying out a condensation reaction to obtain the compound shown as formula I. The compound of the present invention is applied to control plant pathogenic bacteria that cause harm to agricultural production, especially plant pathogenic oomycetes. The compound of the present invention has a novel structure and a simple preparation method, and has strong antibacterial activity and broad antibacterial spectrum; it is used as a potential bactericide for controlling the above-mentioned plant pathogenic fungi and oomycetes.

Description

Technical Field

[0001] The present invention belongs to the technical field of pesticides, and particularly relates to pyrazole cinnamaldehyde hydrazone compounds, a preparation method thereof, and an application in antibacterial aspects. Background Art

[0002] Pesticides play an important role in ensuring food security. However, with the large-scale use of traditional pesticides, a series of problems such as drug resistance and ecological environmental pollution have inevitably occurred. In order to meet the high-quality development of green agriculture in the new era, it is of great significance to discover new pesticide targets and develop new green pesticides with high efficiency, low toxicity, and low residues. The key to the creation of new green and efficient pesticides lies in the discovery of new structures.

[0003] In the prior art, pyrazole cinnamaldehyde hydrazone compounds with a structure as shown in general formula I of the present invention have not been reported. Summary of the Invention

[0004] The object of the present invention is to provide a class of pyrazole cinnamaldehyde hydrazone compounds with novel structures and a preparation method thereof.

[0005] The pyrazole cinnamaldehyde hydrazone compounds provided by the present invention have a general structural formula as shown in formula I:

[0006]

[0007] In formula I:

[0008] R 1 is selected from any one of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, nitro, C 1 -C 12 alkyl, halo C 1 -C 12 alkyl, C 1 -C 12 alkoxy, halo C 1 -C 12 alkoxy, C 3 -C 12 carbocyclic alkyl, C 1 -C 12 alkylamino, halo C 1 -C 12 alkylamino, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 2 -C 12 alkenyloxy, halo C 2 -C 12 alkenyloxy, C 2 -C 12 alkynyloxy, halo C2 -C 12 alkynyloxy; wherein the halogen in the halogen or the halogenated group is selected from F, Cl, Br, or I;

[0009] R 2 is selected from any of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, nitro, C 1 -C 12 alkyl, halogenated C 1 -C 12 alkyl, C 1 -C 12 alkyloxy, halogenated C 1 -C 12 alkyloxy, C 3 -C 12 carbocycloalkyl, substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted C 3 -C 30 heterocyclic group; wherein the halogen in the halogen or the halogenated group is selected from F, Cl, Br, or I;

[0010] R 3 is selected from any of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, nitro, C 1 -C 12 alkyl, halogenated C 1 -C 12 alkyl, C 1 -C 12 alkyloxy, halogenated C 1 -C 12 alkyloxy, C 3 -C 12 carbocycloalkyl, substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted C 3 -C 30 heterocyclic group; wherein the halogen in the halogen or the halogenated group is selected from F, Cl, Br, or I;

[0011] R 4 is selected from any of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, nitro, C 1 -C 12 alkyl, halogenated C 1 -C 12 alkyl, C 1 -C 12 alkyloxy, halogenated C 1 -C 12 alkyloxy, C 3 -C 12 carbocycloalkyl, C 1-C 12 alkylamino, halo C 1 -C 12 alkylamino, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 2 -C 12 alkenyloxy, halo C 2 -C 12 alkenyloxy, C 2 -C 12 alkynyloxy, halo C 2 -C 12 alkynyloxy; wherein the halogen in the halogen or the halo is selected from F, Cl, Br or I.

[0012] The substituents of the substituted C 6 -C 30 aryl, the substituents of the substituted C 3 -C 30 heterocyclyl are each independently selected from one or more of the following groups: halogen, hydroxy, amino, cyano, nitro, C 1 -C 12 alkyl, halo C 1 -C 12 alkyl, C 1 -C 12 alkoxy, halo C 1 -C 12 alkoxy, C 2 -C 10 ester group, halo C 2 -C 10 ester group;

[0013] The carbocycles of the C 3 -C 30 heterocyclyl are each independently selected from one or more of the following heterocycles: furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, quinoline.

[0014] Furthermore, the compound of formula I is specifically selected from the following compounds:

[0015] R 1 is selected from any of the following groups: H, 2-CH 3 、2-OCH 3 、2-Cl、2-Br、3-CH 3 、3-Cl、3-Br、4-CH 3 、4-OCH 3 、4-F、4-Cl、4-Br;

[0016] R 2Selected from any of the following groups: H, CH 3 , Cl, phenyl, 2-CH 3 -phenyl, 2-F-phenyl, 2-Cl-phenyl, 2-Br-phenyl, 2-Ph phenyl, 3-CH 3 -phenyl, 4-CH 3 -phenyl, 4-OCH 3 -phenyl, 4-Cl-phenyl, 4-NO 2 -phenyl, 3,4-Cl 2 -phenyl;

[0017] R 3 Selected from any of the following groups: H, CH 3 , Cl, Br;

[0018] R 4 Selected from 3-CHF 2 .

[0019] More specifically, such as:

[0020] Compound IA-02: In formula I, R 1 = 4-CH 3 , R 2 = H, R 3 = H, R 4 = 3-CHF 2 compound;

[0021] Compound IA-05: In formula I, R 1 = 4-Cl, R 2 = H, R 3 = H, R 4 = 3-CHF 2 compound;

[0022] Compound IA-06: In formula I, R 1 = 4-Br, R 2 = H, R 3 = H, R 4 = 3-CHF 2 compound.

[0023] The inhibition rates of the above compounds IA-02, IA-05, and IA-06 against Phytophthora capsici can reach 100%.

[0024] The preparation method of the compound shown in formula I provided by the present invention includes the following steps:

[0025]

[0026] Mix the compound shown in Formula II with the compound shown in Formula III in a solvent and carry out a condensation reaction to obtain the compound shown in Formula I;

[0027] In the compound shown in Formula II, R 1 , R 2 , R 3 are defined the same as in Formula I;

[0028] In the compound shown in Formula III, R 4 is defined the same as in Formula I.

[0029] The above solvent can be an alcohol solvent, including methanol, ethanol or n-propanol.

[0030] The above condensation reaction can be carried out without a catalyst or under the condition of adding an acid catalyst; the preferred acid catalyst is glacial acetic acid.

[0031] The reaction temperature of the above condensation reaction can be 18 - 50 °C, preferably 20 - 40 °C, and the reaction time can be 0.5 - 24 hours, preferably 1 - 3 hours; in the above condensation reaction, the molar ratio of the compound shown in Formula II to the compound shown in Formula III can be 1:(1 - 2).

[0032] The present invention also provides an application of the compound shown in Formula I above.

[0033] The application of the compound shown in Formula I provided by the present invention is its application in preventing and controlling plant pathogenic bacteria (including fungi and oomycetes) that cause harm to agricultural production and its application in preparing fungicides for plant pathogenic bacteria.

[0034] The plant pathogenic bacteria can be selected from at least one of the following: Alternaria solani, Rhizoctonia solani, Gibberella zeae, Valsa mali, Fusarium moniliforme, Magnaporthe oryzae, Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, Phytophthora nicotianae, Peronophythora litchi, Pythium aphanidermatum, Pythium ultimum, etc.

[0035] The compound shown in Formula I shows good antifungal (oomycete) activity against plant pathogenic bacteria that cause serious harm in agricultural production, and its inhibitory activity against Phytophthora capsici and Phytophthora nicotianae is better than that of the control agent cyazofamid. Preferably, the concentration of the active ingredient in the fungicide is 0.1 μg / mL - 500 μg / mL.

[0036] The present invention discloses a pyrazole cinnamaldehyde acylhydrazone compound with a novel structure and simple preparation. This type of compound has broad-spectrum antifungal and oomycete activities, and particularly has obvious inhibitory activities against pathogenic fungi such as Alternaria solani, Rhizoctonia solani, Magnaporthe oryzae, etc. and pathogenic oomycetes such as Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, Phytophthora nicotianae, Peronophythora litchi, Pythium aphanidermatum, etc.; and can be used as a potential fungicide for the prevention and control of the above plant pathogenic fungi and oomycetes. Detailed implementation manners

[0037] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments. The methods are all conventional methods unless otherwise specified. The raw materials can be obtained from public commercial channels unless otherwise specified.

[0038] The compound of formula II used in the following examples can be synthesized with reference to the following literature: [1] Long, Z.-Q., et al. (2021). Journal of Agricultural and Food Chemistry 69(30):8380 - 8393. [2] He, J., et al. (2019). Angewandte Chemie,International Edition 58(51):18513 - 18518. [3] Tessier, P.-E., et al. (2003). Organic Letters 5(17):2989 - 2992. [4] Romagnoli R, et al. (2008) Bioorganic&Medicinal Chemistry 16(10):5367 - 5376.

[0039] Example 1: Preparation of Compound IA-02

[0040]

[0041] In a 250 mL single-necked flask, (0.36 g, 2.50 mmol) of the intermediate (E)-3-(p-tolyl)acrolein was dissolved in 10 mL of anhydrous ethanol and stirred at room temperature (25 °C); (0.48 g, 2.50 mmol) of the intermediate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide (1) was dissolved in 15 mL of anhydrous ethanol and added to the reaction system of the single-necked flask at one time. 3 drops of glacial acetic acid were added as a catalyst and stirred at room temperature. It can be observed that the solution gradually becomes turbid and solids are produced; after monitoring by TLC plate until the reaction is complete, the ethanol was removed by rotary evaporation, and the obtained solid was recrystallized with ethyl acetate to obtain 0.43 g of white solid IA-02, with a yield of 53.7% and a melting point of 205.9 - 206.7 °C. 1 H NMR(500MHz,DMSO-d 6 )δ:11.50(s,1H),8.51(2s,1H),7.99(2d,J=8.7Hz,1H),7.50(2s,2H),7.47~7.24(m,1H),7.21(2s,2H),7.12~6.94(m,2H),3.97(2s,3H),2.32(s,3H).

[0042] Example 2: Preparation of Compound IA-05

[0043]

[0044] In a 250 mL single-necked flask, (0.42 g, 2.50 mmol) of the intermediate (E)-3-(4-chlorophenyl)acrolein was dissolved in 10 mL of anhydrous ethanol and stirred at room temperature (25 °C); (0.48 g, 2.50 mmol) of the intermediate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide (1) was dissolved in 15 mL of anhydrous ethanol and added to the reaction system of the single-necked flask at one time. 3 drops of glacial acetic acid were added dropwise as a catalyst, and the reaction was stirred at room temperature. It could be observed that the solution gradually became turbid and a solid was produced; after monitoring by TLC plate until the reaction was complete, ethanol was removed by rotary evaporation, and the obtained solid was recrystallized with ethyl acetate to obtain 0.44 g of a yellow solid IA-05, with a yield of 51.6% and a melting point of 216.2 - 217.1 °C. 1 H NMR(500MHz,DMSO-d 6 )δ:11.57(s,1H),8.52(2s,1H),8.01(2d,J=7.5Hz,1H),7.71~7.59(m,2H),7.53~6.97(m,5H),3.99(s,3H).

[0045] Example 3: Preparation of Compound IA-06

[0046]

[0047] In a 250 mL single-necked flask, (0.53 g, 2.50 mmol) of the intermediate (E)-3-(4-bromophenyl)acrolein was dissolved in 10 mL of anhydrous ethanol and stirred at room temperature (25 °C); (0.48 g, 2.50 mmol) of the intermediate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide (1) was dissolved in 15 mL of anhydrous ethanol and added to the reaction system of the single-necked flask at one time. 3 drops of glacial acetic acid were added dropwise as a catalyst, and the reaction was stirred at room temperature. It could be observed that the solution gradually became turbid and a solid was produced; after monitoring by TLC plate until the reaction was complete, ethanol was removed by rotary evaporation, and the obtained solid was recrystallized with ethyl acetate to obtain 0.75 g of a yellow solid IA-06, with a yield of 78.3% and a melting point of 208.3 - 209.1 °C. 1 H NMR(500MHz,DMSO-d 6 )δ:11.57(s,1H),8.51(2s,1H),8.00(2d,J=8.7Hz,1H),7.59(s,4H),7.51~7.25(m,1H),7.22~6.96(m,2H),3.98(s,3H).

[0048] According to the same method as that for preparing compounds IA-02, IA-05, and IA-06 above, only by replacing R 1 , R 2 , R 3 in formula I with the corresponding substituents, products IA-01 to IA-18 can be obtained.

[0049] Example 4: Preparation of Compound IB-10

[0050]

[0051] In a 250 mL single-necked flask, dissolve (0.48 g, 1.98 mmol) of the above intermediate (Z)-3-(4-chlorophenyl)-3-phenylacrolein in 10 mL of anhydrous ethanol and stir at room temperature (25 °C); dissolve (0.41 g, 2.18 mmol) of intermediate 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide (1) in 15 mL of anhydrous ethanol, and add it to the reaction system in the single-necked flask at one time. Add 3 drops of glacial acetic acid as a catalyst and stir the reaction at room temperature (25 °C). It can be observed that the solution gradually becomes turbid and a solid is produced; after monitoring by TLC plate until the reaction is complete, rotate the evaporator to remove ethanol, and the obtained solid is recrystallized with ethyl acetate to obtain 0.66 g of yellow solid IB-10, with a yield of 80.5% and a melting point of 230.7 - 231.1 °C. 1 H NMR (500 MHz, DMSO-d 6 ) δ: 11.50~11.27 (m, 1H), 8.48 (2s, 1H), 7.80 (2d, J = 9.5 Hz, 1H), 7.60~7.20 (m, 10H), 7.01 (2d, J = 9.6 Hz, 1H), 3.94 (2s, 3H).

[0052] According to the same method as that for preparing compound IB-10 above, only by replacing R 1 , R 2 , R 3 in formula I with the corresponding substituents, products IB-01 to IB-15 can be obtained.

[0053] Example 5: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide (1)

[0054]

[0055] In a 250 mL single-necked flask, dissolve (3.52 g, 20.00 mmol) of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in 60 mL of anhydrous CH 2 Cl 2In it, stir at room temperature (25 °C); weigh (3.24 g, 24.00 mmol) HOBt and (4.60 g, 24.00 mmol) EDCI, add them to a single-necked flask all at once, and continue stirring for 1 h to form an activated ester; ice-bath (0 °C) and stir the reaction solution, dissolve (2.50 g, 40.00 mmol) hydrazine hydrate in 50 mL of CH 2 Cl 2 in a conical flask, pour it into the above single-necked flask, and the reaction system continues to react at 0 °C for 8 h until the activated ester reacts completely. Rotate and evaporate to remove the solvent, add about 100 mL of deionized water to dissolve all the residues, extract the aqueous phase with ethyl acetate (200 mL × 3), combine the organic phases, dry over anhydrous magnesium sulfate, remove part of the ethyl acetate under reduced pressure, and perform recrystallization of the crude product with ethyl acetate to obtain 2.50 g of white crystalline acylhydrazide solid intermediate 1, with a yield of 65.79%. 1 H NMR (300 MHz, DMSO-d 6 ) δ: 9.47 (s, 1H), 8.18 (s, 1H), 7.33 (t, J = 54.2 Hz, 1H), 4.45 (s, 2H), 3.91 (s, 3H).

[0056] The appearance, melting point and yield of some compounds of general formula I in the present invention are listed in Table 1, 1 and the H NMR data are listed in Table 2.

[0057] Table 1: Melting point, appearance and yield of some compounds of formula I

[0058]

[0059] Table 2: 1H NMR data of some compounds of formula I

[0060]

[0061]

[0062] Example 6: Inhibitory activity of the compound of formula I against phytopathogenic fungi (oomycetes)

[0063] The in vitro antibacterial activities of some compounds of the present invention against various phytopathogenic fungi and oomycetes were tested. The tested strains were Alternaria solani, Rhizoctonia solani, Gibberella zeae, Valsa mali, Fusarium moniliforme, Magnaporthe oryzae, Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, Phytophthora nicotianae, Peronophythora litchi, Pythium aphanidermatum, Pythium ultimum, etc.

[0064] Dissolve 10 mg of some compounds of the present invention in 1 mL of dimethyl sulfoxide to prepare a stock solution of 10000 μg / ml, and store it at low temperature for later use. Continue to prepare a potato dextrose agar medium (PDA) plate containing the drug at a concentration of 50 μg / mL for experiments. Pour it into a petri dish with a diameter of 9 cm, and each drug corresponds to 3 replicates for each pathogen. After the agar solidifies, inoculate the pre-activated test pathogen cake and place it in an incubator at (25±2)°C for dark cultivation. Use DMSO as the negative control and sterile water as the blank control. All the above operations are strictly aseptic operations carried out on a laminar flow bench. After the blank control colonies grow sufficiently, measure the diameter of each colony by the cross method and take the average value. And calculate the mycelial growth inhibition rate according to the following formula:

[0065] Inhibition rate (%) = (Diameter of DMSO control colony - Diameter of treated colony) / (Diameter of DMSO control colony - 5 mm of the diameter of the pathogen cake) × 100%

[0066] The in vitro antibacterial activity data of some compounds (IA-01 to IA-18) of the present invention against Alternaria solani, Rhizoctonia solani, Phytophthora capsici, and Pythium aphanidermatum are shown in Table 3. The in vitro antibacterial activity data of some compounds (IB-01 to IB-18) against Fusarium graminearum, Valsa mali, Gibberella fujikuroi, and Magnaporthe oryzae are shown in Table 4. The median effective concentration (EC 50 ) test results are shown in Table 5. The present invention shows good inhibitory activity against a variety of plant pathogenic fungi and oomycetes, and can be used as a potential fungicide for the prevention and control of the above plant pathogenic fungi and oomycetes.

[0067] Table 3: Mycelial growth inhibition rate (%) of some compounds of formula I against test pathogens in vitro (IA-01 to IA-18, 50 μg / mL)

[0068]

[0069] As can be seen from Table 3, some compounds of formula I (IA-01 to IA-18) provided by the present invention have certain inhibitory activities against the 4 tested plant pathogens. At a concentration of 50 μg / mL, the inhibition rates of multiple compounds against Alternaria solani and Rhizoctonia solani exceed 50%. The inhibition rates of compounds IA-02, IA-05, and IA-06 against Phytophthora capsici are 100%.

[0070] Table 4: Mycelial growth inhibition rate (%) of some compounds of formula I against test pathogens in vitro (IB-01 to IB-15, 50 μg / mL)

[0071]

[0072]

[0073] As can be seen from Table 4, some of the type Ⅰ compounds (IB-01 to IB-15) provided by the present invention have certain inhibitory activities against the 4 plant pathogenic fungi tested. At a concentration of 50 μg / mL, the inhibition rates of multiple compounds against Magnaporthe oryzae exceed 50%.

[0074] Table 5: Toxicity test results of some type I compounds against some pathogenic oomycetes (EC 50 , μg / mL)

[0075]

[0076]

[0077] As can be seen from Table 5, compounds IA-02, IA-05, and IA-06 all showed obvious in vitro inhibitory effects against 6 pathogenic oomycetes, and their median effective concentration EC 50 values are all between 1.00 - 3.12 μg / mL. Among them, the inhibitory activities against Phytophthora capsici and Phytophthora nicotianae are better than those of the commercial agent cyazofamid. And cyazofamid is a highly effective agent for controlling pathogenic oomycetes of the genus Phytophthora in the current market.

[0078] Although the present invention has been described in detail with general descriptions and specific embodiments above, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection of the present invention.

Claims

1. A compound represented by Formula I: In Formula I: R 1 selected from any of the following groups: 4-CH 3 , 4-Cl, 4-Br; R 2 selected from H; R 3 selected from H; R 4 selected from 3-CHF 2 .

2. A method for preparing the compound according to Claim 1, comprising the following steps: subjecting the compound represented by Formula II to a condensation reaction with the compound represented by Formula III, thereby obtaining the compound represented by Formula I; Wherein, In the compound represented by Formula II, R 1 , R 2 , R 3 are as defined in Formula I; In the compound represented by Formula III, R 4 is as defined in Formula I.

3. According to the preparation method described in Claim 2, It is characterized in that: The condensation reaction is carried out under catalyst-free conditions or under the condition of adding an acid catalyst; The condensation reaction is carried out in a solvent, and the solvent is an alcohol solvent, including methanol, ethanol or n-propanol.

4. According to the preparation method described in Claim 3, It is characterized in that: The acid catalyst is glacial acetic acid.

5. According to the preparation method described in any one of Claims 2-4, It is characterized in that: The reaction temperature of the condensation reaction is 18-50 °C, and the reaction time is 0.5-24 hours; In the condensation reaction, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is 1: (1-2).

6. According to the preparation method described in Claim 5, It is characterized in that: The reaction temperature of the condensation reaction is 20-40 °C, and the reaction time is 1-3 hours.

7. Use of the compound according to Claim 1 in the following 1) and / or 2): 1) Use in preventing and controlling plant pathogenic bacteria that cause harm to agricultural production; 2) Use in preparing a fungicide for plant pathogenic bacteria.

8. According to the use described in Claim 7, It is characterized in that: The plant pathogenic bacteria include fungi and oomycetes.

9. According to the use described in Claim 7, It is characterized in that: The plant pathogenic bacteria are selected from at least one of the following: Alternaria solani, Rhizoctonia solani, Gibberella zeae, Valsa mali, Fusarium moniliforme, Magnaporthe oryzae, Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, Phytophthora nicotianae, Peronophythora litchi, Pythium aphanidermatum, Pythium ultimum.

10. A fungicide for plant pathogenic bacteria, It is characterized in that: The active ingredient of the fungicide is the compound according to Claim 1.

11. According to the fungicide for plant pathogenic bacteria described in Claim 10, It is characterized in that: The plant pathogenic bacteria include fungi and oomycetes; Or, when the fungicide is used, the concentration of the active ingredient is 0.1 μg / mL - 500 μg / mL.

12. According to the fungicide for plant pathogenic bacteria described in Claim 10, It is characterized in that: The plant pathogenic bacteria are selected from at least one of the following: Alternaria solani, Rhizoctonia solani, Gibberella zeae, Valsa mali, Fusarium moniliforme, Magnaporthe oryzae, Phytophthora capsici, Phytophthora sojae, Phytophthora infestans, Phytophthora nicotianae, Peronophythora litchi, Pythium aphanidermatum, Pythium ultimum.

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