CN118851955A - A 2-arylmethoxyiminocyclohexanesulfonamide compound and its preparation method and application - Google Patents

Abstract

The invention discloses a 2-arylmethoxyiminocyclohexane sulfonamide compound, a preparation method and application thereof, and belongs to the technical field of agricultural chemicals. The invention takes the cycloheximide as a guide, combines the oxime ether structure with the sulfonamide compound, synthesizes the novel 2-arylmethoxyimino cyclohexane sulfonamide compound to inhibit pathogenic bacteria such as sclerotinia rot of colza, alternaria corn, downy mildew of cucumber and the like, and can be used for preventing and treating diseases.

Description

A 2-arylmethoxyiminocyclohexanesulfonamide compound and its preparation method and application

Technical Field

The present invention relates to the technical field of agricultural chemicals, and more specifically to a 2-arylmethoxyiminocyclohexane sulfonamide compound and a preparation method and application thereof.

Background Art

Sulfonamide compounds have good biological activity, and several fungicides have been developed in the pesticide field. Sulfonamide, developed by Mitsui Toa Co., Ltd. in Japan in 1986, is a soil fungicide that has a significant inhibitory effect on cabbage clubroot. Indazolesulfonamide is a triazolesulfonamide fungicide developed by Nissan Chemical Co., Ltd. in Japan in 2003 that has excellent control effects on oomycetes. In 2004, China Agricultural University independently developed a novel fungicide, cyclamamide, which has a broad fungicide spectrum and can be used to prevent and control tomato gray mold and rapeseed sclerotinia.

The agent acts on the mycelial cell membrane, causing damage to the cell membrane and thus causing cell death.

Oxime ether structure has been widely studied in the field of fungicide. The oxime ether structure developed by BASF combines the oxime ether structure with the methoxyacrylate structure. It is a strobilurins fungicide with a broad-spectrum fungicidal activity, mainly used to control grape powdery mildew, etc. Later, oxime oxime was developed for the control of rice blast and rice sheath blight. Enoxime and enoxime are fungicides independently developed by Shenyang Institute of Chemical Industry in my country. They have a wide fungicidal spectrum and have good control effects on diseases on crops such as cucumbers, wheat and rice. Pyribencarb, developed by Kumihiro Chemical Company of Japan in 2018, has a structure similar to methoxyacrylate fungicides and has excellent fungicidal activity against gray mold and rapeseed sclerotinia. Tetrazolylpyramine ester developed by Japan Soda Company in 2021 is a tetrazole fungicide that has good control effects on oomycetes, especially downy mildew and phytophthora. The above research provides guidance for the synthesis of the compounds in the present invention.

Summary of the invention

The purpose of the present invention is to overcome the above-mentioned defects of the prior art, provide a 2-arylmethoxyiminocyclohexane sulfonamide compound and its preparation method and application, take cyclamoxadine as the precursor, combine the oxime ether structure with the sulfonamide compound, synthesize the new 2-arylmethoxyiminocyclohexane sulfonamide compound, which has the inhibitory effect on the pathogens such as rapeseed sclerotinia, corn leaf blight and cucumber downy mildew, and can be used for the prevention and treatment of their diseases.

To achieve the above object, the technical solution of the present invention is as follows:

A 2-arylmethoxyiminocyclohexane sulfonamide compound, the general structural formula of the 2-arylmethoxyiminocyclohexane sulfonamide compound is as follows:

in, Selected from One of the for When R is selected from one of H, Cl, Br, F, NO ₂ , CF ₃ , CH _{3 , O—CH 3 ,} O—CF ₃ , CN, C(CH ₃ ) ₃ , O—Ph, and CN—Ph.

Optionally, the 2-arylmethoxyiminocyclohexanesulfonamide compound is preferably one of the following structures:

The present invention also discloses a method for preparing the above-mentioned 2-arylmethoxyiminocyclohexanesulfonamide compound, comprising the following steps:

(1) mixing acetohydroxamic acid, sodium hydroxide and methanol, adding chloro- or bromo-substituted benzyl to the obtained mixture dropwise for reaction, adding concentrated hydrochloric acid to the reaction product for further reaction to obtain oxygen-substituted hydroxylamine hydrochloride as shown in formula B;

(2) under nitrogen protection, adding anhydrous ethanol, tetraisopropyl titanate, the oxygen-substituted hydroxylamine hydrochloride and triethylamine to the cyclamic acid sulfonamide shown in formula A and mixing and reacting at room temperature to obtain the 2-arylmethoxyiminocyclohexane sulfonamide compound;

in, Selected from One of the for When R is selected from one of H, Cl, Br, F, NO ₂ , CF ₃ , CH _{3 , O—CH 3 ,} O—CF ₃ , CN, C(CH ₃ ) ₃ , O—Ph, and CN—Ph.

Optionally, in step (1), the molar ratio of acetohydroxamic acid and chloro- or bromo-substituted benzyl is 1:(0.5-3.0).

Optionally, in step (2), the molar ratio of cyclamic acid sulfamate to oxygen-substituted hydroxylamine hydrochloride is 1:(0.5-3.0).

Optionally, the preparation method of cyclamic acid comprises the following steps:

S1, mixing cyclohexanone, sulfur trioxide·dioxane complex, calcium carbonate, potassium carbonate, and 1,2-dichloroethane to react to obtain 2-oxocyclohexane sulfonic acid potassium salt;

S2. At room temperature, potassium 2-oxocyclohexanesulfonate, anhydrous dichloromethane, N,N-dimethylformamide, and oxalyl chloride are sequentially added dropwise to 2-trifluoromethyl-4-chloroaniline to react to obtain cyclamic acid sulfonamide as shown in formula A;

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

Optionally, in step S2, the molar ratio of the potassium salt of 2-oxocyclohexanesulfonate, N,N-dimethylformamide, oxalyl chloride, and 2-trifluoromethyl-4-chloroaniline is 1:(0.1-0.2):(1.0-2.0):(0.3-0.8).

The present invention also discloses the use of the 2-arylmethoxyiminocyclohexane sulfonamide compound as described above, or the 2-arylmethoxyiminocyclohexane sulfonamide compound prepared by the preparation method as described above, as an agricultural fungicide.

Optionally, it is used to inhibit one or more of rapeseed sclerotinia, corn leaf blight and cucumber downy mildew.

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

The invention uses cyclohexanesulfonamide as a precursor, combines an oxime ether structure with a sulfonamide compound, and synthesizes a new 2-arylmethoxyiminocyclohexane sulfonamide compound. The biological activity test results show that the synthesized compound has good bactericidal activity.

The 2-arylmethoxyiminocyclohexane sulfonamide compounds provided by the invention have an inhibitory effect on pathogenic bacteria such as rape sclerotinia, corn leaf blight and cucumber downy mildew, and are used for preventing and controlling the diseases.

DETAILED DESCRIPTION

The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials involved are all commercially available unless otherwise specified.

Example 1

The preparation of cyclamic acid sulfamethoxazole (compound A) and the specific preparation process are as follows:

Preparation of sulfur trioxide: Add broken porcelain pieces to a 500mL four-necked round-bottom flask, quickly weigh 100g of phosphorus pentoxide and 220mL of 98% concentrated sulfuric acid and add them to the round-bottom flask, and connect the tail pipe to a conical flask with built-in dry 1,2-dichloroethane. Adjust the transformer to always control the sulfur trioxide dripping rate to 1 drop per 2 seconds, and quickly remove the conical flask and weigh it when sulfur trioxide stops dripping.

Preparation of sulfur trioxide-1,4-dioxane adduct: Add dry 1,2-dichloroethane to a 1000mL four-necked round-bottom flask under ice bath conditions, and add dry 1,4-dioxane in an amount equimolar to sulfur trioxide, introduce nitrogen, and after the system is cooled, add sulfur trioxide in 1,2-dichloroethane solution dropwise with a dropping funnel, controlling the flow rate to 2 drops per second. After the addition is completed, continue the reaction for 1-2 hours. After the reaction is completed, filter and the resulting white solid is sulfur trioxide-1,4-dioxane adduct.

Preparation of potassium salt of 2-oxocyclohexane sulfonate: add dry cyclohexanone and dry 1,2-dichloroethane to a 1000mL four-necked bottom flask under ice bath conditions, and after stirring evenly, slowly add the adduct obtained in the previous step in batches, and use nitrogen protection throughout the process. Then react at -15℃, -5℃, and 0℃ for 1h each. After reacting for 3h, add the reaction solution to a 1000mL plastic cup, add water of equal volume to the reaction solution, add calcium carbonate to the system under slow stirring, adjust the pH to 6-7, filter, add _K2CO3 to the filtrate and continue stirring, adjust the pH to 8-9, _filter , retain the filtrate, separate the liquid, retain the water layer, spin dry, and dry the collected potassium salt of 2-oxocyclohexane sulfonate in a vacuum drying oven at 110℃ for 4 hours to obtain completely dried potassium salt of 2-oxocyclohexane sulfonate.

Preparation of cyclamoxadiazole: 200 mL of dry dichloromethane, 20 g of potassium salt of 2-oxocyclohexanesulfonic acid, and 3 mL of N,N-dimethylformamide were added to a 500 mL three-necked round-bottom flask under nitrogen protection, and stirred under an ice bath. After the raw materials were evenly mixed, 8.5 mL of oxalyl chloride was slowly added dropwise, and then stirred under an ice bath for 2 h. After the reaction was completed, the filtrate was collected by suction. 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 evenly, and the above filtrate was added dropwise to the system at 0-5 ° C. After the addition was completed, the ice bath was removed, the reaction was continued for 4 h, and TLC was used to monitor until the reaction was completed. After the reaction was completed, a small amount of water was added to the reaction system to quench. Then, the mixture was washed three times with 150 mL 3 mol/L hydrochloric acid, 150 mL saturated NaHCO ₃ solution, and 150 mL distilled water, dried over anhydrous sodium sulfate, filtered, and spin-dried. Cyclamate (Compound A) was obtained by recrystallization using an acetone-petroleum ether system.

Example 2

The preparation of oxygen-substituted hydroxylamine hydrochloride (compound B), the specific preparation process is as follows:

Add 2g of acetohydroxamic acid and 25mL of methanol into a 50mL three-necked flask, dissolve 1.27g of NaOH in 5mL of water and add to the reaction solution, drop 3.80mL (taking AN-2 as an example), and after the dropwise addition is complete, heat to 60°C, stir and reflux for 3-4h. Cool to room temperature, wash with water, wash with ethyl acetate, collect the upper organic phase, and remove the solvent under reduced pressure.

The above product was dissolved with an appropriate amount of ethanol, put into a 50 mL round-bottom flask, and then 6.47 mL of concentrated hydrochloric acid was added, stirred at 50°C, and the reaction end point was monitored by TLC. After the reaction, two treatment methods were used: adding petroleum ether to the reaction solution, treating at low temperature, and precipitating the oxygen-substituted hydroxylamine in the form of hydrochloride, or removing the solvent ethanol under reduced pressure, adding NaOH aqueous solution to the reaction system to make its pH value 9.0, extracting with ethyl acetate 3 times, collecting the upper organic phase, drying over _{anhydrous Na2SO4} , and desolventizing under reduced pressure to obtain oxygen-substituted hydroxylamine hydrochloride (compound B).

Example 3

The preparation process of 2-arylmethoxyiminocyclohexanesulfonamide compounds is as follows:

At room temperature, under nitrogen protection, add 1g of cyclamic acid sulfamate and 30mL of anhydrous ethanol to a 250mL three-necked round-bottom flask, add 1mL of tetraisopropoxytitanium to the round-bottom flask with a pipette, and stir for 15min to mix thoroughly. Then weigh 0.99g of oxygen-substituted hydroxylamine hydrochloride and dissolve it in 10mL of anhydrous ethanol, and add 0.78mL of triethylamine to release the oxygen-substituted hydroxylamine (if the oxygen-substituted hydroxylamine neutralized in the previous step can be directly put into the reaction), then add this mixed solution to the reaction system, stir for 3-4h, and monitor the reaction by TLC. After the reaction is complete, add 40mL of 2mol/L ammonia water or distilled water to the reaction system and stir for 10min to quench the reaction, filter the system under reduced pressure, rinse the filter residue with ethyl acetate several times, collect the filtrate, then remove the anhydrous ethanol under reduced pressure, extract the remaining reaction solution, and combine the organic phases. Dry with anhydrous Na ₂ SO ₄ , filter, and distill under reduced pressure to obtain the target crude product. Purify by column chromatography to obtain a pure product.

The physicochemical data of compounds AN-1 to AN-28 prepared in Example 2 and Example 3 are shown in Table 1 below, and the ¹ HNMR and HRMS data are shown in Table 2 below.

Table 1 Physical and chemical data of compounds AN-1 to AN-28

Table 2 ¹ H NMR and HRMS data of compounds AN-1 to AN-28

The following is an example of the compounds provided by the present invention to specifically verify the fungicidal activity of these compounds.

(I) Determination of fungicidal activity of compounds AN-1 to AN-28 against Pseudomonas aeruginosa

The mycelium growth rate method was used to determine the fungicidal activity of the compound against the corn leaf blight pathogen. The specific method is as follows: Preparation of the agent: weigh 10 mg of the test agent and the control agent in a 5 mL centrifuge tube, add 2 mL of acetone as a solvent, and prepare a 5000 μg/mL mother solution. After the drug is completely dissolved, it is ready for use. Sterilize the gun tip in a high pressure sterilizer in advance. Sterilize the culture dish, pipette, etc. under ultraviolet light on the sterile operating table for 30 minutes. On the operating table, take 300 μL of the 5000 μg/mL mother solution and add it to 30 mL of culture medium to make a 50 μg/mL drug-containing culture medium (the same as the blank control). Pour the prepared drug-containing culture medium into the culture dish, and repeat 3 times. After the culture medium cools down, use a puncher to punch the edge of the activated mycelium into a uniform 0.5 cm cake, place the cake in the center of the culture dish, cover the culture dish, seal it, and culture it in a 25°C incubator. When the diameter is greater than 5 cm and less than 7 cm, use the cross method to measure the mycelium diameter. Mycelium inhibition rate formula:

Table 3 Bactericidal activity of compounds AN-1 to AN-28 against Pseudomonas maydis

AN series compounds have good inhibitory effects on Setospora turcica. When the compound is a thiazole ring, the inhibitory effect is the best. When it is benzyl substituted, when R is substituted with 4-Cl, 4-F, NO ₂ , C(CH ₃ ) ₃ and O-Ph, the inhibitory effect is better.

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

It was carried out according to the guidelines for indoor bioassay tests of pesticides. The preparation of the agent was the same as above, and 400μg/mL, 100μg/mL and 50μg/mL of the agent were prepared. Three cucumber seedlings were used as one treatment. Use a vacuum compressor to evenly spray the liquid medicine onto the three cucumber seedlings. Filter the cucumber downy mildew spores with gauze and sterile water to obtain a cucumber downy mildew spore suspension. Use a hemocytometer to check whether the number of spores reaches 1×10 ⁵ /mL. 24 hours after spraying the agent, spray the spore suspension evenly on the cucumber seedlings. After that, seal the shelf with a cooked bag to keep the humidity >90%, the temperature at 20-23℃, and the light-dark ratio at 12Lh:12Dh. Investigate the disease situation after CK is fully developed.

Records are graded as follows:

Level 0: No lesions.

Level 1: Leaf spot area ≤5%.

Level 3: 6% ≤ The lesion area on the leaves ≤ 10%.

Level 5: 11% ≤ The lesion area on the leaves ≤ 25%.

Level 7: 26% ≤ The lesion area on the leaves ≤ 50%.

Level 9: The lesion area on the leaves is > 50%.

(III) Determination of the in vivo fungicidal activity of compounds AN-1 to AN-28 against Sclerotinia sclerotiorum

The preparation of the agent is the same as above. Use a 0.5 cm hole puncher to punch out uniform-sized fungus cakes on the edges of the two-week-old sclerotinia. Three rapeseeds are used as one treatment. Spray 200 μg/mL of the agent onto evenly growing rapeseed seedlings using a vacuum compressor. After 24 hours, wait for the agent to dry and then spray it on even-sized rapeseed leaves, avoiding the veins and using a toothpick to cut the wound (avoid cutting through). Place the fungus cake with the mycelium side facing down on the wound. Seal the shelf with plastic and spray water every day to maintain humidity. Keep the room temperature at 25°C. After the blank control is fully diseased, investigate and record. Measure the diameter of the lesions using the cross method and calculate the inhibition rate according to the following calculation formula.

The test used the previously synthesized 2-alkoxyiminocyclohexanesulfonamide compound 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 rapeseed pot test results of the target compound are shown in Table 7.

Table 4 Structure of 2-alkoxyiminocyclohexanesulfonamide compounds

Table 5 Control effect of target compounds on cucumber downy mildew

Table 6 Control effect of compounds on cucumber downy mildew after gradient treatment

Table 7 Results of in vivo pot test of target compounds against Sclerotinia sclerotiorum of rapeseed

Compared with 2-alkoxyiminocyclohexane sulfonamide compounds, the series of compounds in the present invention have better control effects on 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 of cucumber downy mildew is higher; when the aromatic group is a pyridine ring and a thiazole ring, the inhibition rate of the compound on cucumber downy mildew is higher, and the compound containing substituted thiazole has the highest activity.

2-Arylmethoxyiminocyclohexanesulfonamide compounds have higher fungicidal activity against rapeseed sclerotinia pathogen, and the prevention efficiency of several compounds exceeds 90%, which is much higher than that of 2-alkoxyiminocyclohexanesulfonamide compounds.

The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims (10)

1. A2-arylmethoxyiminocyclohexane sulfonamide compound is characterized in that, the structural general formula of the 2-arylmethoxyiminocyclohexane sulfonamide compound is shown as follows:

Wherein, Selected from the group consisting ofOne of the following;

When (when) Is thatWhen R is one of H、Cl、Br、F、NO₂、CF₃、CH₃、O-CH₃、O-CF₃、CN、C(CH₃)₃、O-Ph、CN-Ph.

2. 2-Arylmethoxyasia according to claim 1 an aminocyclohexane-based sulfonamide compound, it is characterized in that the method comprises the steps of, the 2-arylmethoxyiminocyclohexane sulfonamide compound is preferably one of the following structures:

3. A process for the preparation of 2-arylmethoxyiminocyclohexane sulfonamide compounds according to any of claims 1 to 2, comprising the steps of:

(1) Mixing acetohydroxamic acid, sodium hydroxide and methanol, dropwise adding chloro or bromo substituted benzyl into the obtained mixed solution for reaction, and adding concentrated hydrochloric acid into the reaction product for continuous reaction to obtain oxygen substituted hydroxylamine hydrochloride shown in a formula B;

(2) Under the protection of nitrogen, adding absolute ethyl alcohol, tetraisopropyl titanate, the oxygen-substituted hydroxylamine hydrochloride and triethylamine into the cyclohexenesulfonamide shown in the formula A, and carrying out mixed reaction at room temperature to obtain the 2-arylmethoxyimino cyclohexane sulfonamide compound;

Wherein, Selected from the group consisting ofOne of the following;

When (when) Is thatWhen R is one of H、Cl、Br、F、NO₂、CF₃、CH₃、O-CH₃、O-CF₃、CN、C(CH₃)₃、O-Ph、CN-Ph.

4. The process according to claim 3, wherein in the step (1), the molar ratio of the acetohydroxamic acid, the chloro-substituted benzyl group or the bromo-substituted benzyl group is 1 (0.5 to 3.0).

5. The process according to claim 3, wherein in the step (2), the molar ratio of the cyclohexylsulfamide to the oxygen-substituted hydroxylamine hydrochloride is 1 (0.5 to 3.0).

6. A method of preparation according to claim 3, wherein the method of preparation of cycloheximide comprises the steps of;

S1, mixing cyclohexanone, sulfur trioxide and dioxane compound, calcium carbonate, potassium carbonate and 1, 2-dichloroethane as raw materials for reaction to obtain 2-oxo-cyclohexane sulfonic acid potassium salt;

S2, under the condition of room temperature, dropwise adding 2-oxo-cyclohexane sulfonic acid potassium salt, anhydrous methylene dichloride, N-dimethylformamide and oxalyl chloride into 2-trifluoromethyl-4-chloroaniline in sequence to react to obtain the cyclohexenesulfonamide shown in the formula A;

7. the method according to claim 6, wherein in the step S1, the molar ratio of the cyclohexanone to the sulfur trioxide dioxane complex is 1 (0.5 to 1.2).

8. The method according to claim 6, wherein in the step S2, the molar ratio of the potassium salt of 2-oxocyclohexane sulfonate, N-dimethylformamide, oxalyl chloride, and 2-trifluoromethyl-4-chloroaniline is 1 (0.1-0.2): 1.0-2.0): 0.3-0.8.

9. Use of a 2-arylmethoxyiminocyclohexane sulfonamide compound according to any one of claims 1 to 2, or a 2-arylmethoxyiminocyclohexane sulfonamide compound prepared by a preparation method according to any one of claims 3 to 8, as an agricultural bactericide.

10. The use according to claim 9, for inhibiting one or more than two of sclerotinia sclerotiorum, phoma maydis and cucumber downy mildew.