2-arylmethoxyimino cyclohexyl sulfonamide compounds, and preparation method and application thereof

Abstract

The application discloses a 2-arylmethoxy imino cyclohexane sulfonylamide compound and a preparation method and application thereof, and belongs to the technical field of agricultural chemicals. The 2-arylmethoxy imino cyclohexane sulfonylamide compound is synthesized by combining an oxime ether structure and a sulfonamide compound with cyclohexanecarbothioamide as a lead, and has inhibitory effects on pathogenic bacteria such as Sclerotinia sclerotiorum, Exserohilum turcicum and Pseudoperonospora cubensis, and can be used for the prevention and treatment of diseases.

Description

Technical Field

[0001] This invention relates to the field of agricultural chemicals, and more specifically, to a 2-arylmethoxyiminocyclohexylsulfonamide compound, its preparation method, and its application. Background Technology

[0002] Sulfonamide compounds possess good biological activity, and several fungicides have been developed in the pesticide field. Sulfonamide, developed by Mitsui Toa Chemical Co., Ltd. of Japan in 1986, is a soil fungicide with a significant inhibitory effect on clubroot disease in Chinese cabbage. Indazole sulfonamide, developed by Nissan Chemical Co., Ltd. of Japan in 2003, is a triazole sulfonamide fungicide with excellent control efficacy against oomycetes. In 2004, China Agricultural University independently developed a novel fungicide, cyclohexylsulfonamide, with a broad fungicidal spectrum, which can be used to control gray mold in tomatoes and sclerotinia rot in rapeseed.

[0003] This agent acts on the cell membrane of mycelium, damaging the cell membrane and causing cell death.

[0004]

[0005] Oxime ether structures have been extensively studied for their fungicidal properties. BASF's strobilurins, combining an oxime ether structure with a methoxyacrylate structure, are broad-spectrum fungicides primarily used to control grape powdery mildew. Later, oxime acetamiprid was developed for controlling rice blast and rice sheath blight. Enoxime acetamiprid and enoxime acetamiprid are fungicides independently developed by the Shenyang Chemical Research Institute in my country, exhibiting broad-spectrum fungicidal activity and good control effects against diseases in crops such as cucumber, wheat, and rice. In 2018, Pyribencarb, developed by Japan's Combinatorial Chemicals Co., Ltd., has a structure similar to methoxyacrylate fungicides and shows excellent fungicidal activity against gray mold and rapeseed sclerotinia. In 2021, Nippon Soda Co., Ltd. developed tetrazolium, a tetraazole fungicide with good control effects against oomycetes, especially downy mildew and Phytophthora blight. The above research provides guidance for the synthesis of the compounds in this invention.

[0006] Summary of the Invention

[0007] The purpose of this invention is to overcome the above-mentioned defects in the prior art and provide a 2-arylmethoxyiminocyclohexylsulfonamide compound, its preparation method and application. Using cyclohexylsulfonamide as a lead compound, the oxime ether structure is combined with the sulfonamide compound to synthesize a new 2-arylmethoxyiminocyclohexylsulfonamide compound that inhibits the growth of pathogens such as Sclerotinia sclerotiorum, corn leaf blight, and cucumber downy mildew, and can be used for the prevention and control of their diseases.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] A 2-arylmethoxyiminocyclohexylsulfonamide compound, the general structural formula of which is shown below:

[0010]

[0011] in, Selected from One of them; when for In this case, R is selected from one of H, Cl, Br, F, NO2, CF3, CH3, O-CH3, O-CF3, CN, C(CH3)3, O-Ph, and CN-Ph.

[0012] Optionally, the 2-arylmethoxyiminocyclohexylsulfonamide compound preferably has one of the following structures:

[0013]

[0014] This invention also discloses a method for preparing the 2-arylmethoxyiminocyclohexylsulfonamide compound as described above, comprising the following steps:

[0015] (1) Mix acetoxyoxime acid, sodium hydroxide and methanol, add chlorinated or brominated benzyl groups dropwise to the mixture to react, add concentrated hydrochloric acid to the reaction product and continue the reaction to obtain oxygen-substituted hydroxylamine hydrochloride as shown in formula B.

[0016]

[0017] (2) Under nitrogen protection, anhydrous ethanol, tetraisopropyl titanate, the oxygen-substituted hydroxylamine hydrochloride and triethylamine were added to cyclohexylsulfonamide as shown in Formula A and reacted at room temperature to obtain the 2-arylmethoxyiminocyclohexylsulfonamide compound.

[0018]

[0019] in, Selected from One of them; when for In this case, R is selected from one of H, Cl, Br, F, NO2, CF3, CH3, O-CH3, O-CF3, CN, C(CH3)3, O-Ph, and CN-Ph.

[0020] Optionally, in step (1), the molar ratio of the acetoxyoxime acid, chloro- or bromo-substituted benzyl group is 1:(0.5 to 3.0).

[0021] Optionally, in step (2), the molar ratio of cyclohexylsulfamethoxam and oxy-substituted hydroxylamine hydrochloride is 1:(0.5-3.0).

[0022] Optionally, the preparation method of the cyclohexylsulfamethoxam includes the following steps;

[0023] S1. Cyclohexanone, sulfur trioxide-dioxane complex, calcium carbonate, potassium carbonate and 1,2-dichloroethane are mixed and reacted to obtain potassium 2-oxocyclohexyl sulfonate.

[0024] S2. At room temperature, potassium 2-oxocyclohexyl sulfonate, anhydrous dichloromethane, N,N-dimethylformamide, and oxalyl chloride are added dropwise to 2-trifluoromethyl-4-chloroaniline to react and obtain cyclohexyl sulfonamide as shown in Formula A.

[0025]

[0026] Optionally, in step S1, the molar ratio of cyclohexanone to sulfur trioxide-dioxane complex is 1:(0.5-1.2).

[0027] Optionally, in step S2, the molar ratio of potassium 2-oxocyclohexyl sulfonate, N,N-dimethylformamide, oxaloyl chloride, and 2-trifluoromethyl-4-chloroaniline is 1:(0.1-0.2):(1.0-2.0):(0.3-0.8).

[0028] The present invention also discloses the application of the 2-arylmethoxyiminocyclohexylsulfonamide compound as described above, or the 2-arylmethoxyiminocyclohexylsulfonamide compound prepared by the preparation method described above, as an agricultural fungicide.

[0029] Optionally, it can be used to inhibit one or more of the following: Sclerotinia sclerotiniae, corn leaf blight pathogens, and cucumber downy mildew pathogens.

[0030] Implementing the embodiments of the present invention will have the following beneficial effects:

[0031] This invention uses cyclohexylsulfonamide as a lead compound, combining the oxime ether structure with a sulfonamide compound to synthesize a new 2-arylmethoxyiminocyclohexylsulfonamide compound. Bioactivity assays show that the synthesized compound has good bactericidal activity.

[0032] The 2-arylmethoxyiminocyclohexylsulfonamide compounds provided by this invention have inhibitory effects on pathogens such as Sclerotinia sclerotiorum var. sclerotiorum, Corn leaf spot fungus, and Cucumber downy mildew fungus, and can be used for the prevention and control of their diseases. Detailed Implementation

[0033] The present invention will be further described below with reference to specific embodiments, but this does not limit the present invention in any way.

[0034] Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials involved are commercially available unless otherwise specified.

[0035] Example 1

[0036] The specific preparation process of cyclohexylsulfamethoxam (compound A) is shown below:

[0037]

[0038] Preparation of sulfur trioxide: Add broken porcelain pieces to a 500mL four-necked round-bottom flask. Quickly weigh 100g of phosphorus pentoxide and add 220mL of 98% concentrated sulfuric acid to the round-bottom flask. Connect the tail tube to an Erlenmeyer flask containing dried 1,2-dichloroethane. Adjust the transformer to maintain a sulfur trioxide dripping rate of 1 drop every 2 seconds until no more sulfur trioxide drips. Quickly remove the Erlenmeyer flask and weigh it.

[0039] Preparation of sulfur trioxide-1,4-dioxane adduct: Dry 1,2-dichloroethane was added to a 1000 mL four-necked round-bottom flask under ice bath conditions, followed by an equimolar amount of dry 1,4-dioxane containing sulfur trioxide. Nitrogen gas was introduced, and after the system cooled, a 1,2-dichloroethane solution of sulfur trioxide was added dropwise using a dropping funnel at a flow rate of 2 drops per second. The reaction was continued for 1-2 hours after the addition was complete. After the reaction was complete, the mixture was filtered, and the resulting white solid was the sulfur trioxide-1,4-dioxane adduct.

[0040] Preparation of potassium 2-oxocyclohexylsulfonate: Dry cyclohexanone and dry 1,2-dichloroethane were added to a 1000 mL four-necked bottom flask under ice bath conditions. After stirring until homogeneous, the adduct obtained in the previous step was slowly added in batches, under nitrogen protection throughout the process. The reaction was then carried out at -15℃, -5℃, and 0℃ for 1 h each. After 3 h of reaction, the reaction solution was added to a 1000 mL plastic cup, and an equal volume of water was added. Calcium carbonate was added to the system while stirring slowly to adjust the pH to 6-7. The mixture was filtered, and K₂CO₃ was added to the filtrate with continuous stirring to adjust the pH to 8-9. The mixture was then filtered again, and the filtrate was retained. The aqueous layer was separated and evaporated to dryness. The collected potassium 2-oxocyclohexylsulfonate was dried in a vacuum drying oven at 110℃ for 4 hours to obtain completely dry potassium 2-oxocyclohexylsulfonate.

[0041] Preparation of cyclohexylsulfonamide: Under nitrogen protection, 200 mL of dry dichloromethane, 20 g of potassium 2-oxocyclohexylsulfonate, and 3 mL of N,N-dimethylformamide were added to a 500 mL three-necked round-bottom flask. The mixture was stirred in an ice bath until homogeneous. Then, 8.5 mL of oxalyl chloride was slowly added dropwise, followed by stirring in an ice bath for 2 hours. After the reaction was complete, the mixture was filtered and the filtrate was collected. Under ice bath and nitrogen protection, 6.5 mL of 2-trifluoromethyl-4-chloroaniline, 16.7 mL of triethylamine, and 100 mL of dichloromethane were added to a 500 mL three-necked round-bottom flask and stirred until homogeneous. The filtrate was added dropwise to the system within the range of 0-5 °C. After the addition was complete, the ice bath was removed, and the reaction was continued for 4 hours. The reaction was monitored by TLC until completion. After the reaction was complete, a small amount of water was added to the reaction system to quench the reaction. The sample was then washed three times with 150 mL of 3 mol / L hydrochloric acid, 150 mL of saturated NaHCO3 solution, and 150 mL of distilled water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Recrystallization from an acetone-petroleum ether system yielded cyclohexylsulfamethoxam (compound A).

[0042] Example 2

[0043] The specific preparation process of oxygen-substituted hydroxylamine hydrochloride (compound B) is shown below:

[0044]

[0045] Add 2g of acetyloxyoxime acid and 25mL of methanol to a 50mL three-necked flask. Dissolve 1.27g of NaOH in 5mL of water and add it to the reaction mixture. Add 3.80mL dropwise (using AN-2 as an example). After the addition is complete, heat to 60℃ and stir under reflux for 3-4 hours. Cool to room temperature, wash with water, wash with ethyl acetate, collect the upper organic phase, and remove the solvent under reduced pressure.

[0046] The above product was dissolved in an appropriate amount of ethanol and placed in a 50 mL round-bottom flask. Then, 6.47 mL of concentrated hydrochloric acid was added, and the mixture was stirred at 50 °C. The reaction endpoint was monitored by TLC. After the reaction was completed, two treatment methods were used: petroleum ether was added to the reaction solution and the mixture was subjected to low-temperature treatment to precipitate the oxygen-substituted hydroxylamine as hydrochloride. Alternatively, the solvent ethanol was removed under reduced pressure, and an aqueous solution of NaOH was added to the reaction system to make the pH value 9.0. The mixture was then extracted three times with ethyl acetate, and the upper organic phase was collected, dried over anhydrous Na2SO4, and dissolved under reduced pressure to obtain oxygen-substituted hydroxylamine hydrochloride (compound B).

[0047] Example 3

[0048] The specific preparation process of 2-arylmethoxyiminocyclohexylsulfonamide compounds is shown below:

[0049]

[0050] At room temperature, under nitrogen protection, 1 g of cyclohexylsulfamethoxam and 30 mL of anhydrous ethanol were added to a 250 mL three-necked round-bottom flask. 1 mL of tetraisopropoxytitanium was added to the flask using a pipette, and the mixture was stirred for 15 min to ensure thorough mixing. Then, 0.99 g of oxygen-substituted hydroxylamine hydrochloride was weighed and dissolved in 10 mL of anhydrous ethanol, and 0.78 mL of triethylamine was added to release the oxygen-substituted hydroxylamine (if the oxygen-substituted hydroxylamine from the previous step has been neutralized, it can be directly added to the reaction). This mixture was then added to the reaction system, and the mixture was stirred for 3-4 h. The reaction was monitored by TLC. After complete reaction, 40 mL of 2 mol / L ammonia or distilled water was added to the reaction system, and the reaction was quenched by stirring for 10 min. The system was then filtered under reduced pressure, and the residue was washed several times with ethyl acetate. The filtrate was collected, and then dehydrogenated under reduced pressure. The remaining reaction solution was extracted, and the organic phases were combined. The mixture was dried over anhydrous Na₂SO₄, filtered, and distilled under reduced pressure to obtain the target crude product. The product was purified by column chromatography to obtain a pure product.

[0051] The physicochemical data of compounds AN-1 to AN-28 prepared in Examples 2 and 3 are shown in Table 1 below. 1 HNMR and HRMS data are shown in Table 2.

[0052] Table 1 Physicochemical data of compounds AN-1 to AN-28

[0053]

[0054]

[0055] Table 2. Compounds AN-1 to AN-28 1 H NMR and HRMS data

[0056]

[0057]

[0058]

[0059] The following section uses the compounds provided by this invention as examples to specifically verify the bactericidal activity of these compounds.

[0060] (I) Determination of the bactericidal activity of compounds AN-1 to AN-28 against maize large spot blight.

[0061] The fungicidal activity of the compound against *Hymenococcus faecium*, the pathogen of maize leaf spot, was determined using the mycelial growth rate method. The specific method is as follows: Preparation of the reagent: Weigh 10 mg of both the test reagent and the control reagent into 5 mL centrifuge tubes. Add 2 mL of acetone as a solvent to prepare a 5000 μg / mL stock solution. Dissolve the reagent completely before use. Sterilize the pipette tips in an autoclave beforehand. Sterilize the petri dishes, pipettes, etc., under UV light for 30 min in a sterile operating table. In the operating table, add 300 μL of the 5000 μg / mL stock solution to 30 mL of culture medium to prepare a 50 μg / mL drug-containing medium (the blank control is prepared similarly). Pour the prepared drug-containing medium into petri dishes, with three replicates. After the culture medium cools, use a punch to create uniform 0.5cm mycelial discs from the edges of the activated inoculum. Place each disc in the center of a petri dish, cover and seal the dish, and incubate at 25℃. When the mycelial diameter is greater than 5cm but less than 7cm, measure the mycelial diameter using the cross-sectional method. Mycelial inhibition rate formula:

[0062]

[0063] Table 3. Fungicidal activity of compounds AN-1 to AN-28 against *Heterophyte macrocarpa*.

[0064]

[0065]

[0066] The AN series compounds have a good inhibitory effect on maize leaf spot pathogen. The inhibitory effect is best when the compound has a thiazole ring. When the compound is benzyl substituted, the inhibitory effect is better when R is substituted with 4-Cl, 4-F, NO2, C(CH3)3 and O-Ph.

[0067] (II) Determination of the in vivo fungicidal activity of compounds AN-1 to AN-28 against cucumber downy mildew

[0068] The pesticide bioassay test was conducted according to the guidelines. The pesticide preparation procedure was the same as above, preparing 400 μg / mL, 100 μg / mL, and 50 μg / mL solutions. Three cucumber seedlings constituted one treatment. The pesticide solution was evenly sprayed onto the three cucumber seedlings using a vacuum compressor. The cucumber downy mildew spores were filtered through gauze with sterile water to obtain a cucumber downy mildew spore suspension. The spore count was checked using a hemocytometer to determine if the spore count reached 1 × 10⁻⁶. 5 spores / mL. 24 hours after spraying the agent, evenly spray the spore suspension onto the cucumber seedlings. Then seal the rack with a plastic bag to maintain humidity >90%, keep the temperature at 20-23℃, and the light-dark ratio at 12Lh:12Dh. After the control group (CK) has fully developed disease, investigate the disease situation.

[0069] Recorded according to the following hierarchical structure:

[0070] Grade 0: No lesions.

[0071] Grade 1: Leaf lesion area ≤ 5%.

[0072] Grade 3: 6% ≤ leaf spot area ≤ 10%.

[0073] Level 5: 11% ≤ leaf spot area ≤ 25%.

[0074] Level 7: 26% ≤ leaf spot area ≤ 50%.

[0075] Grade 9: The area of ​​lesions on the leaves is greater than 50%.

[0076]

[0077] (III) Determination of the in vivo bactericidal activity of compounds AN-1 to AN-28 against Sclerotinia sclerotiorum var. sclerotiorum, the causal agent of rapeseed rot.

[0078] The preparation of the fungicide is the same as above. Using a 0.5cm punch, create uniformly sized mycelial cakes at the edges of the two-week-old *Sclerotium sclerotiorum* cultured for 24 hours. Three rapeseed plants constitute one treatment. Apply 200 μg / mL of the fungicide to the uniformly growing rapeseed seedlings using a vacuum compressor. After 24 hours, once the fungicide has dried, spray it onto uniformly sized rapeseed leaves, avoiding the veins, and make small incisions with a toothpick (avoid cutting through the veins). Place the mycelial cakes, mycelial side down, onto the incisions. Seal the rack with plastic and spray with water daily to maintain humidity. Maintain a room temperature of 25℃. After the blank control has fully developed disease, investigate and record the results. Measure the diameter of the lesions using the cross-sectional method and calculate the inhibition rate according to the formula below.

[0079]

[0080] The previously synthesized 2-alkoxyiminocyclohexylsulfonamide compound was used as a control. The compound structure is shown in Table 4. The control effect of the target compound on cucumber downy mildew is shown in Table 5. The control effect of the compound after gradient treatment on cucumber downy mildew is shown in Table 6. The results of the rapeseed pot experiment of the target compound are shown in Table 7.

[0081] Table 4. Structures of 2-alkoxyiminocyclohexylsulfonamide compounds

[0082]

[0083] Table 5. Control efficacy of the target compound against cucumber downy mildew.

[0084]

[0085] Table 6. Control effects of compounds after gradient treatment on cucumber downy mildew.

[0086]

[0087] Table 7. Results of in vivo pot experiments on the target compound against Sclerotinia sclerotiorum var. sclerotiorum.

[0088]

[0089]

[0090] Compared with 2-alkoxyiminocyclohexylsulfonamides, the series of compounds in this invention exhibit better control effects against cucumber downy mildew and rapeseed sclerotinia. When the compound is benzyl-substituted, especially when the R substituent on the benzene ring is Cl, the inhibition rate against cucumber downy mildew is higher; when the aryl group is a pyridine ring or a thiazole ring, the inhibition rate against cucumber downy mildew is high, with compounds containing substituted thiazoles showing the highest activity.

[0091] 2-Arylmethoxyiminocyclohexylsulfonamides exhibit higher bactericidal activity against Sclerotinia sclerotiorum var. sclerotiorum, with several compounds showing efficacy exceeding 90%, far surpassing the activity of 2-alkoxyiminocyclohexylsulfonamides.

[0092] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A 2-arylmethoxyiminocyclohexylsulfonamide compound, characterized in that, The general structural formula of the 2-arylmethoxyiminocyclohexylsulfonamide compounds is shown below: Formula I in, Selected from , , , , One of them; when for In this case, R is selected from one of Cl, Br, F, NO2, CF3, CH3, O-CH3, O-CF3, CN, and C(CH3)3.

2. The 2-arylmethoxyiminocyclohexylsulfonamide compound according to claim 1, characterized in that, The 2-arylmethoxyiminocyclohexylsulfonamide compound is preferably one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. A method for preparing a 2-arylmethoxyiminocyclohexylsulfonamide compound as described in any one of claims 1-2, characterized in that, Includes the following steps: (1) Mix acetyloxyoxime acid, sodium hydroxide and methanol, add chlorinated or brominated benzyl groups dropwise to the mixture to react, add concentrated hydrochloric acid to the reaction product and continue the reaction to obtain oxygen-substituted hydroxylamine hydrochloride as shown in formula B; (2) Under nitrogen protection, anhydrous ethanol, tetraisopropyl titanate, the oxygen-substituted hydroxylamine hydrochloride and triethylamine were added to cyclohexylsulfonamide as shown in Formula A and reacted at room temperature to obtain the 2-arylmethoxyiminocyclohexylsulfonamide compound. in, Selected from , , , , One of them; when for In this case, R is selected from one of Cl, Br, F, NO2, CF3, CH3, O-CH3, O-CF3, CN, and C(CH3)3.

4. The preparation method according to claim 3, characterized in that, In step (1), the molar ratio of the acetoxyoxime acid, chloro- or bromo-substituted benzyl group is 1: (0.5~3.0).

5. The preparation method according to claim 3, characterized in that, In step (2), the molar ratio of cyclohexylsulfamethoxam and oxygen-substituted hydroxylamine hydrochloride is 1: (0.5~3.0).

6. The preparation method according to claim 3, characterized in that, The preparation method of the cyclohexylsulfamethoxam includes the following steps: S1. A mixture of cyclohexanone, sulfur trioxide-dioxane complex, calcium carbonate, potassium carbonate, and 1,2-dichloroethane was reacted to obtain potassium 2-oxocyclohexyl sulfonate. S2. At room temperature, potassium 2-oxocyclohexylsulfonate, anhydrous dichloromethane, N,N-dimethylformamide, and oxalyl chloride were sequentially added to 2-trifluoromethyl-4-chloroaniline to react and obtain cyclohexylsulfonamide as shown in Formula A. 。 7. The preparation method according to claim 6, characterized in that, In step S1, the molar ratio of cyclohexanone and sulfur trioxide-dioxane complex is 1: (0.5~1.2).

8. The preparation method according to claim 6, characterized in that, In step S2, the potassium 2-oxocyclohexyl sulfonate, N,N The molar ratio of dimethylformamide, oxaloyl chloride, and 2-trifluoromethyl-4-chloroaniline is 1: (0.1~0.2): (1.0~2.0): (0.3~0.8).

9. The application of a 2-arylmethoxyiminocyclohexylsulfonamide compound as described in any one of claims 1-2, or a 2-arylmethoxyiminocyclohexylsulfonamide compound prepared by the preparation method described in any one of claims 3-8, as an agricultural fungicide, characterized in that, Used to suppress corn leaf blight.

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