CN114685398B - Cyclohexanothiadiazine compound and preparation method and application thereof - Google Patents
Cyclohexanothiadiazine compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of agricultural chemicals, and discloses a cyclohexane-thiadiazine compound, and a preparation method and application thereof. The invention synthesizes new cyclohexane thiadiazine series compounds, and the results of biological activity measurement show that the synthesized compounds have good bactericidal activity, and the cyclohexane thiadiazine series compounds have good application effect in inhibiting sclerotinia rot of colza, botrytis cinerea, rice sheath blight, rice blast and fusarium graminearum, and are suitable for wide popularization and application.
Description
Technical Field
The invention relates to the technical field of agricultural chemicals, in particular to a cyclohexane-thiadiazine compound and a preparation method and application thereof.
Background
Sulfonamide compounds are the first agents found by humans to have a selective effect on bacteria, and can be systemically applied to various problems caused by bacterial infection. Sulfonamides have a wide range of biological activities in medicine and pesticides, such as: sterilizing, weeding, killing parasite, resisting cancer, resisting diabetes, etc. In recent years, many studies have been made on sulfonamide compounds, and high-efficiency and low-toxicity bactericides such as flusulfamide (flusulfamide) and tolsulfamide (tolnifamide) have been developed in succession. The most developed contemporary sulfonamide herbicides are acetolactate synthase (ALS) inhibitors, and since the advent of sulfonamide herbicides, pesticides have entered the ultra-high-efficiency era. In the field of bactericides, sulfonamide products are rare, and only cyazofamid (cyazofamid) is widely applied to the market at present. Still other sulfonamides are in the final stage of development and development, i.e., are becoming commercially available. 2-oxo-cyclododecyl sulfonamide has better inhibitory activity on various plant pathogenic bacteria, and by taking the 2-oxo-cyclododecyl sulfonamide as a precursor, the 2-oxo-cyclododecyl sulfonamide compound is intensively researched, and a candidate bactericide variety, namely cyclamate (chesulfamide), is developed and is used for preventing and treating tomato gray mold (Botrytis cinerea) and cucumber leaf spot disease (corynesporacasicicola).
The thiadiazine compounds are also prominent in sterilization. In 2015, zhengyuguo and the like synthesized a series of pyrazole-containing 1,2, 4-triazole thiadiazine derivatives, and biological activity determination showed that the inhibition rate of cucumber anthracnose reached 90%. In 2019, a series of triazolothiadiazine compounds are synthesized by girls and the like, the growth regulating effect of the triazolothiadiazine compounds on plants is determined, and the series of compounds are found to have a remarkable inhibiting effect on the growth of dicotyledonous radish stems and monocotyledonous wheat stems. However, thiadiazine compounds are not commercialized, and the existing thiadiazine compounds only have bacteriostatic activity on specific bacteria. Therefore, there is a need in the art to develop thiadiazine compounds having excellent fungicidal properties and commercialize the same.
Disclosure of Invention
In view of the above, the invention provides a cyclohexane-thiadiazine compound and a preparation method and application thereof, and the synthesized compound has good bactericidal activity and bacteriostatic activity for various bacteria, thereby solving the problem that the existing thiadiazine compound is not commercialized.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a cyclohexane-thiadiazine compound, which has a structural formula as follows:
wherein R is alkyl, phenyl, benzyl or phenethyl.
The invention also provides a preparation method of the cyclohexane-thiadiazine compound, which comprises the following steps:
(1) Mixing cyclohexanone, sulfur trioxide-dioxane adduct and 1, 2-dichloroethane, reacting, and performing post-treatment with potassium carbonate to obtain potassium 2-oxocyclohexylsulfonate;
(2) Mixing 2-oxo-cyclohexane potassium sulfonate, anhydrous dichloromethane, N-dimethylformamide and oxalyl chloride, and dropwise adding the obtained mixed solution into a substituted amine solution for reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide;
(3) Mixing N-substituted-2-aminocyclohexyl sulfonamide, absolute ethyl alcohol, titanium tetraisopropoxide and sodium borohydride for reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide;
(4) Mixing N-substituted-2-aminocyclohexyl sulfonamide, ethyl acetate, triethylamine and triphosgene, and reacting to obtain the cyclohexanediazine compound.
Preferably, the reactions in step (2), step (3) and step (4) are independently carried out under a protective gas; the protective gas is nitrogen, helium or ammonia.
Preferably, in the step (1), the reaction temperature is-4 ℃, and the reaction time is 0.75-1.5 h; the mass volume ratio of the cyclohexanone to the sulfur trioxide-dioxane adduct to the 1, 2-dichloroethane is 58mL:90g:100mL. After the potassium carbonate treatment, the pH value of the solution is 8-9.
Preferably, in the step (2), the mass volume ratio of the potassium 2-oxocyclohexylalkylsulfonate to the anhydrous dichloromethane is 20 to 30g: 190-210 mL; the volume ratio of the anhydrous dichloromethane to the N, N-dimethylformamide to the oxalyl chloride is 200:0.5 to 1:10 to 12.
Preferably, in the step (2), the substituted amine solution comprises aniline, triethylamine and dichloromethane; the aniline is 2-bromoaniline, 2,4, 5-trifluoroaniline or 2-fluoro-5-trifluoromethyl aniline; the volume ratio of the aniline to the triethylamine to the dichloromethane is 8-10: 20 to 25:110; the adding amount of the substituted amine solution is 68-70% of the volume of the anhydrous dichloromethane.
Preferably, in the step (2), the dropping temperature of the mixed solution is-4 to 4 ℃, and the dropping time of the mixed solution is 20 to 40min; the reaction temperature is 20-30 ℃, and the reaction time is 3-5 h.
Preferably, in the step (3), the specific steps of the mixed reaction of the N-substituted-2-aminocyclohexyl alkyl sulfonamide, the anhydrous ethanol, the titanium tetraisopropoxide and the sodium borohydride are as follows: mixing N-substituted-2-aminocyclohexyl sulfonamide, absolute ethyl alcohol and tetraisopropoxytitanium for a first reaction, mixing a reaction product with sodium borohydride for a second reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide; the temperature of the first reaction and the second reaction is independently 20-30 ℃, the time of the first reaction is 2-3.5 h, and the time of the second reaction is 4-6 h; the mass volume ratio of the N-substituted-2-amino cyclohexane sulfonamide to the sodium borohydride to the ethanol is 3-4 g: 0.5-2 g:50mL; the volume ratio of the anhydrous ethanol to the titanium tetraisopropoxide is 50:8 to 10.
Preferably, in the step (4), the triphosgene is an ethyl acetate solution of triphosgene, and the concentration of the ethyl acetate solution of triphosgene is 0.5-1 g/mL; the mass volume ratio of the N-substituted-2-aminocyclohexyl sulfonamide to the ethyl acetate is 1-1.9 g:30mL; the addition amount of the triphosgene is 15-20% of the volume of the ethyl acetate; the volume ratio of the ethyl acetate to the triethylamine is 30:0.3 to 0.9; the reaction temperature is 20-30 ℃, and the reaction time is 6-8 h.
The invention also provides application of the cyclohexanothiadiazine compound in inhibiting sclerotinia rot of colza, botrytis cinerea, rice sheath blight, rice blast and fusarium graminearum.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the inventive compound has good bactericidal activity, while it can restrain sclerotium of colza, gray mould of tomato, rice sheath blight, rice blast and fusarium graminearum, to be applied widely.
Detailed Description
The invention provides a cyclohexane-thiadiazine compound, which has a structural formula as follows:
wherein R is alkyl, phenyl, benzyl or phenethyl.
The invention also provides a preparation method of the cyclohexane-thiadiazine compound, which comprises the following steps:
(1) Mixing cyclohexanone, sulfur trioxide-dioxane adduct, potassium carbonate and 1, 2-dichloroethane, and reacting to obtain potassium 2-oxocyclohexylsulfonate;
(2) Mixing 2-oxo-cyclohexane potassium sulfonate, anhydrous dichloromethane, N-dimethylformamide and oxalyl chloride, and dropwise adding the obtained mixed solution into a substituted amine solution for reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide;
(3) Mixing and reacting N-substituted-2-aminocyclohexyl sulfonamide, absolute ethyl alcohol, titanium tetraisopropoxide and sodium borohydride to obtain N-substituted-2-aminocyclohexyl sulfonamide;
(4) Mixing N-substituted-2-aminocyclohexyl sulfonamide, ethyl acetate, triethylamine and triphosgene, and reacting to obtain the cyclohexanediazine compound.
In the invention, the reactions in the step (2), the step (3) and the step (4) are independently carried out under protective gas; the protective gas is preferably nitrogen, helium or ammonia, and more preferably nitrogen or ammonia.
In the present invention, in the step (1), the reaction temperature is preferably-4 to 4 ℃, and more preferably-2 to 0 ℃; the reaction time is preferably 0.75 to 1.5 hours, and more preferably 1 to 1.2 hours; the mass-to-volume ratio of the cyclohexanone, the sulfur trioxide-dioxane adduct and the 1, 2-dichloroethane is preferably 58mL:90g:100mL; the pH after the treatment with potassium carbonate is preferably 8 to 9, more preferably 9 to 10.
In the present invention, in the step (2), the mixing manner of the potassium 2-oxocyclohexylsulfonate, the anhydrous dichloromethane, the N, N-dimethylformamide and the oxalyl chloride is: firstly, mixing 2-oxo-cyclohexane potassium sulfonate, anhydrous dichloromethane and N, N-dimethylformamide, and then adding oxalyl chloride; the mixing temperature is preferably 20-30 ℃, and more preferably 22-28 ℃; the mixing time is preferably 1.5 to 3 hours, and more preferably 2 to 2.5 hours.
In the present invention, in the step (2), the mass-to-volume ratio of the potassium 2-oxocyclohexylsulfonate to the anhydrous dichloromethane is preferably 20 to 30g:190 to 210mL, more preferably 23 to 25g: 200-205 mL; the volume ratio of the anhydrous dichloromethane, the N, N-dimethylformamide and the oxalyl chloride is preferably 200:0.5 to 1:10 to 12, more preferably 200:0.8 to 0.9:11.
in the present invention, in the step (2), the substituted amine solution comprises aniline, triethylamine and dichloromethane; the aniline is 2-bromoaniline, 2,4, 5-trifluoroaniline or 2-fluoro-5-trifluoromethylaniline; the volume ratio of the aniline to the triethylamine to the dichloromethane is preferably 8-10: 20 to 25:110, more preferably 9 to 9.5:23 to 24:110; the amount of the substituted amine solution added is preferably 68 to 70% by volume of anhydrous dichloromethane, and more preferably 69% by volume of anhydrous dichloromethane.
In the invention, in the step (2), the dropping temperature of the mixed solution is preferably-4 to 4 ℃, and more preferably 2 to 4 ℃; the dropping time of the mixed solution is preferably 20 to 40min, and more preferably 30 to 35min; the reaction temperature is preferably 20 to 30 ℃, and more preferably 23 to 27 ℃; the reaction time is preferably 3 to 5 hours, more preferably 4 to 4.5 hours.
In the present invention, in the step (2), the progress of the reaction is monitored by TLC (V) Petroleum ether ：V Acetic acid ethyl ester =3: 1) The results showed that the reaction was stopped when no starting material was present in the reaction mixture.
In the present invention, in the step (2), after the reaction is completed, post-treatment is performed, and the post-treatment specifically includes: and (2) washing the reacted mixed solution with hydrochloric acid, saturated sodium bicarbonate and distilled water in sequence for 3 times, then drying the mixed solution for 2 to 4 hours by using anhydrous sodium sulfate, and then recrystallizing the dried mixed solution by using acetone and petroleum ether to obtain the N-substituted-2-aminocyclohexyl sulfonamide.
In the present invention, the molar concentration of the hydrochloric acid is preferably 2 to 4mol/L, and more preferably 2.5 to 3.5mol/L; the volume ratio of the hydrochloric acid to the saturated sodium bicarbonate to the distilled water is preferably 2.5-3.5: 1.5-2: 2, more preferably 3:2:2.
in the invention, in the step (3), the mixing reaction of the N-substituted-2-aminocyclohexyl sulfonamide, the anhydrous ethanol, the titanium tetraisopropoxide and the sodium borohydride comprises the following specific steps: mixing N-substituted-2-aminocyclohexyl sulfonamide, absolute ethyl alcohol and tetraisopropoxy titanium for a first reaction, and mixing a reaction product with sodium borohydride for a second reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide; the temperature of the first reaction and the second reaction is independently preferably 20-30 ℃, and more preferably 25-28 ℃; the time of the first reaction is preferably 2 to 3.5 hours, and more preferably 3 hours; the time of the second reaction is preferably 4 to 6 hours, and more preferably 4.5 to 5.5 hours; the mass volume ratio of the N-substituted-2-aminocyclohexyl sulfonamide to the sodium borohydride to the ethanol is preferably 3-4 g: 0.5-2 g:50mL, more preferably 3.5g: 1.5-1.8 g:50mL; the volume ratio of the anhydrous ethanol to the titanium tetraisopropoxide is preferably 50:8 to 10, more preferably 50:8.5 to 9.
In the invention, the specific steps of mixing the N-substituted-2-aminocyclohexyl sulfonamide, the absolute ethyl alcohol and the titanium tetraisopropoxide for carrying out the first reaction are as follows: under the protection of nitrogen, mixing N-substituted-2-aminocyclohexyl sulfonamide with absolute ethyl alcohol, then adding titanium tetraisopropoxide, stirring for 1-3 min by using a magnetic stirrer, and then carrying out a first reaction; the reaction end time of the first reaction was according to TLC (V) Petroleum ether ：V Ethyl acetate =3: 1) And (5) monitoring.
In the invention, before the reaction product and sodium borohydride are mixed for the second reaction, the nitrogen gas is introduced instead of ammonia gas, and the ammonia gas is introduced to ensure that the pressure of the reaction system is 30-40 mm of mercury.
In the present invention, the reaction completion time of the second reaction is according to TLC (V petroleum ether: V) Ethyl acetate ：V Methanol =10:10: 1) And (5) monitoring.
In the invention, in the step (4), the triphosgene is an ethyl acetate solution of triphosgene, and the concentration of the ethyl acetate solution of triphosgene is preferably 0.5 to 1g/mL, and more preferably 0.6 to 0.8g/mL; the mass volume ratio of the N-substituted-2-aminocyclohexyl sulfonamide to the ethyl acetate is preferably 1-1.9 g:30mL, more preferably 1.2 to 1.6g:30mL; the addition amount of the triphosgene is preferably 15-20% of the volume of the ethyl acetate, and is further preferably 16-18% of the volume of the ethyl acetate; the volume ratio of ethyl acetate to triethylamine is preferably 30:0.3 to 0.9, more preferably 30:0.5 to 0.7; the reaction temperature is preferably 20-30 ℃, and more preferably 24-26 ℃; the reaction time is preferably 6 to 8 hours, more preferably 6.5 to 7.5 hours.
In the present invention, the reaction completion time in the step (4) is according to TLC (V) Petroleum ether ：V Ethyl acetate =2: 1) And (5) monitoring.
In the present invention, after the reaction in the step (4) is completed, the reaction product is subjected to a purification treatment, which comprises the following steps: the reaction product was washed with saturated sodium chloride solution, and the organic layer was collected, evaporated and dried. By (V) Ethyl acetate ：V Petroleum ether =1: 5) The chromatographic solution is processed by silica gel column chromatography to obtain the cyclohexane-thiadiazine compound.
The invention also provides application of the cyclohexanothiadiazine compound in inhibition of sclerotium rolfsii, botrytis cinerea, rice sheath blight, rice blast and fusarium graminearum.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The specific preparation process flow of the WY-1 compound is as follows:
the preparation process comprises the following steps: connecting a synthesis reaction experimental device, introducing nitrogen at the early stage to drive off the air in a reaction bottle, keeping the nitrogen introduction, introducing the nitrogen into the reaction device for 5min, adding 200mL of dry dichloromethane, 25g of potassium 2-oxocyclohexylalkylsulfonate and 0.6mL of DMF into a 1000mL round-bottom flask at room temperature, stirring uniformly to fully mix the raw materials, slowly dropwise adding 10.6mL of oxalyl chloride, and stirring at room temperature for reaction for 2h. Suction filtration is carried out, the filtrate is slowly dropped into a substituted amine solution which consists of 6.37mL of trifluoroethylamine, 20.8mL of triethylamine and 110mL of dichloromethane and is cooled by an ice water bath, and the reaction temperature is controlled to be 0 ℃ in the dropping process. After the dropwise addition, the temperature is naturally raised, the reaction is carried out for 4 hours, the reaction solution is an orange transparent solution, and the TLC monitoring is carried out (V) Petroleum ether ：V Ethyl acetate =3: 1) And (4) stopping the reaction when the reaction liquid has no raw materials according to the reaction progress and results show that the post-treatment operation is carried out. The reaction mixture was washed with 75mL of 3mol/L hydrochloric acid, 50mL of saturated sodium bicarbonate, and 50mL of distilled water, three times in total. And drying the washed reaction solution for 3 hours by using anhydrous sodium sulfate, carrying out suction filtration, and evaporating the filtrate by using a rotary evaporator to obtain a crude product. Recrystallizing with mixture of acetone and petroleum ether to obtain white solid 1;
stirring with a magnetic stirrer at room temperature under nitrogen protection, adding solvent anhydrous ethanol 50mL and the white solid 1 recrystallized from 2.59g into a sealed three-neck flask, adding titanium tetraisopropoxide 8,88mL into the reaction solution, and stirring for 2min. Then stopping introducing nitrogen into the system, changing into introducing ammonia gas, sealing each interface of the reaction instrument with a sealing film to prevent air leakage, connecting the tail end of the reaction with a U-shaped hydraulic gauge, and keeping the pressure of the ammonia gas introduced into the reaction bottle at 40mm Hg. Reaction for 3h, TLC (V) Petroleum ether ：V Ethyl acetate =3: 1) Monitoring, closing the ammonia valve and removing the U-shaped hydraulic gauge after the complete reaction is shown. Then, nitrogen is introduced into the reaction liquid, and after stirring for 5min, 1.13g of reducing agent sodium borohydride is slowly added for 5 times, 0.20-0.25 g each time, and after the sodium borohydride is added, the reaction is carried out for 5h. TLC (V) Petroleum ether ：V Ethyl acetate ：V Methanol =10:10: 1) After the reaction was monitored to be complete, ammonia was added to the reaction system to quench, and a large amount of white solid was seen to precipitate, and the reaction was stopped by stirring for 10 min. And carrying out vacuum filtration on the product under reduced pressure, leaving filtrate, carrying out vacuum concentration on ethanol and the aqueous solution in the filtrate, extracting the residual solution with ethyl acetate for three times, and leaving an organic layer. Washing the organic layer with saturated brine for 2 times, drying with a large amount of anhydrous sodium sulfate overnight, and concentrating under reduced pressure to obtain white solid 2;
adding 1.79g of white solid 2 and 30mL of dry ethyl acetate into a 100mL three-neck round-bottom flask under the protection of nitrogen and magnetic stirring, stirring for 10min, adding 0.63mL of dry triethylamine, dissolving 3g of triphosgene in 5mL of ethyl acetate, adding the solution into the reaction system in 2 times of 2.5mL each time, and performing TLC (V) Petroleum ether ：V Ethyl acetate =2: 1) Monitoring the reaction process, washing with saturated sodium chloride solution after the reaction is finished, collecting an organic layer, and evaporating and spin-drying. By (V) Ethyl acetate ：V Petroleum ether And = 1) performing silica gel column chromatography to obtain the WY-1 compound.
Example 2
The specific preparation process flow of the WY-2 compound is as follows:
the preparation process of WY-2 compound is different from that of WY-1 compound in that: the substituted amine solution consists of 7.82ml 2-fluoroaniline, 20.8mL triethylamine and 110mL dichloromethane; the amount of the obtained white solid 1 added was 2.71g; the amount of white solid 2 added was 1.36g.
Example 3
The specific preparation process flow of the WY-3 compound is as follows:
the specific preparation process of WY-3 is different from that of WY-1 in that: the amine content in the substituted amine solution was 7.82ml 3-fluoroaniline, and the amount of the obtained white solid 1 added was 2.71g, and the amount of the obtained white solid 2 added was 1.36g.
Example 4
The specific preparation process flow of the WY-4 compound is as follows:
the specific preparation process of WY-4 is different from that of WY-1 in that: the amine content in the substituted amine solution was 7.68mL4-fluoroaniline, and the amount of the obtained white solid 1 added was 2.71g and the amount of the obtained white solid 2 added was 1.36g.
Example 5
The specific preparation process of WY-5 is different from that of WY-1 in that: the amine in the substituted amine solution was 8.52mL2-chloroaniline, and the amount of the obtained white solid 1 was 2.87g and the amount of the obtained white solid 2 was 1.44g.
Example 6
The specific preparation process of WY-6 is different from that of WY-1 in that: the amine content in the substituted amine solution was 8.57ml 3-chloroaniline, and the amount of the obtained white solid 1 was 2.87g and the amount of the obtained white solid 2 was 1.44g.
The specific preparation process flow of the WY-7 compound is as follows:
example 7
The specific preparation process of WY-7 is different from that of WY-1 in that: the amine in the substituted amine solution was 8.40mL4-chloroaniline, and the amount of white solid 1 added was 2.87g, and the amount of white solid 2 added was 1.44g.
Example 8
The specific preparation process flow of the WY-8 compound is as follows:
the preparation method comprises the following specific steps: connecting a synthesis reaction experimental device, introducing nitrogen at the early stage to drive off the air in a reaction bottle, keeping the nitrogen introduction, introducing the nitrogen into the reaction device for 5min, adding 200mL of dry dichloromethane, 25g of potassium 2-oxocyclohexylalkylsulfonate and 0.6mL of DMF into a 1000mL round-bottom flask at room temperature, stirring uniformly to fully mix the raw materials, slowly dropwise adding 10.6mL of oxalyl chloride, and stirring at room temperature for reaction for 2h. Suction filtration, filtrate slowly added to the ice water bath temperature reduction of 8.9mL2-bromoaniline, 20.8mL triethylamine, and 110mL dichloromethane composed of substituted amine solution, the dropping process of the reaction temperature is controlled at 0 ℃. After the dropwise addition, the temperature is naturally raised, the reaction is carried out for 4 hours, the reaction solution is an orange transparent solution, and the TLC monitoring is carried out (V) Petroleum ether ：V Ethyl acetate =3: 1) And (4) stopping the reaction when the reaction liquid has no raw materials according to the reaction progress and results show that the post-treatment operation is carried out. The reaction mixture was washed with 75mL of 3mol/L hydrochloric acid, 50mL of saturated sodium bicarbonate, and 50mL of distilled water, three times in total. And drying the washed reaction solution for 3 hours by using anhydrous sodium sulfate, carrying out suction filtration, and evaporating the filtrate by using a rotary evaporator to obtain a crude product. Recrystallizing with mixture of acetone and petroleum ether to obtain white solid 1;
stirring with a magnetic stirrer at room temperature under nitrogen protection, adding solvent anhydrous ethanol 50mL and 3.32g of the recrystallized white solid 1 into a sealed three-neck flask, adding titanium tetraisopropoxide 8.88mL into the reaction solution, and stirring for 2min. Then stopping introducing nitrogen into the system, changing into introducing ammonia gas, sealing each interface of the reaction instrument with a sealing film to prevent air leakage, connecting the tail end of the reaction with a U-shaped hydraulic gauge, and keeping the pressure of the ammonia gas introduced into the reaction bottle at 40mm Hg. Reaction for 3h, TLC (V) Petroleum ether ：V Acetic acid ethyl ester =3: 1) Monitoring, after showing complete reaction, closing the ammonia gas valve and removing the U-shaped hydraulic gauge. Then, nitrogen is introduced into the reaction liquid, and after stirring for 5min, 1.13g of reducing agent sodium borohydride is slowly added for 5 times, 0.20-0.25 g each time, and after the sodium borohydride is added, the reaction is carried out for 5h. TLC (V) Petroleum ether ：V Acetic acid ethyl ester ：V Methanol =10:10: 1) After the reaction was monitored to be complete, ammonia was added to the reaction system to quench, and a large amount of white solid was seen to precipitate, and the reaction was stopped by stirring for 10 min. And carrying out vacuum filtration on the product under reduced pressure, leaving filtrate, carrying out vacuum concentration on ethanol and the aqueous solution in the filtrate, extracting the residual solution with ethyl acetate for three times, and leaving an organic layer. Washing the organic layer with saturated brine for 2 times, drying with a large amount of anhydrous sodium sulfate overnight, and concentrating under reduced pressure to obtain white solid 2;
adding 1.67g of white solid 2 and 30mL of dry ethyl acetate into a 100mL three-neck round-bottom flask under the protection of nitrogen and magnetic stirring, stirring for 10min, adding 0.63mL of dry triethylamine, dissolving 3g of triphosgene in 5mL of ethyl acetate, adding the solution into the reaction system in 2 times of 2.5mL each time, and performing TLC (V) Petroleum ether ：V Ethyl acetate =2: 1) Monitoring the progress of the reaction, reactionAfter the reaction, the mixture was washed with a saturated sodium chloride solution, and the organic layer was collected, evaporated and spin-dried. With (V) Ethyl acetate ：V Petroleum ether And (4) = 1).
Example 9
The specific preparation process flow of the WY-9 compound is as follows:
the specific preparation process of WY-9 is different from that of WY-1 in that: the amine content in the substituted amine solution was 8.90ml 3-bromoaniline, and the amount of the obtained white solid 1 added was 3.32g, and the amount of the obtained white solid 2 added was 1.67.
Example 10
The specific preparation process of WY-10 is different from that of WY-1 in that: the amine content in the substituted amine solution was 9.31ml of 4-bromoaniline, and the amount of the obtained white solid 1 added was 3.32g and the amount of the obtained white solid 2 added was 1.67g.
Example 11
The specific preparation process of WY-11 is different from that of WY-1 in that: the amine content in the substituted amine solution was 8.25mL2, 4-difluoroaniline, and the amount of the obtained white solid 1 added was 2.90g, and the amount of the obtained white solid 2 added was 1.45g.
Example 12
The specific preparation process of WY-12 is different from that of WY-1 in that: the amine content in the substituted amine solution was 8.05ml3, 4-difluoroaniline, and the amount of white solid 1 added was 2.90g and the amount of white solid 2 added was 1.45g.
Example 13
The specific preparation process of WY-13 is different from that of WY-1 in that: the amine content in the substituted amine solution was 9.22ml 2-fluoro-4-bromoaniline, and the amount of the obtained white solid 1 added was 3.51g, and the amount of the obtained white solid 2 added was 1.76g.
Example 14
The specific preparation process of WY-14 is different from that of WY-1 in that: the amine content in the substituted amine solution was 15.71ml of 3-fluoro-4-bromoaniline, and the amount of the obtained white solid 1 added was 3.51g, and the amount of the obtained white solid 2 added was 1.76g.
Example 15
The specific preparation process of WY-15 is different from that of WY-1 in that: the amine content in the substituted amine solution was 9.00mL4-fluoro-3-bromoaniline, and the amount of the obtained white solid 1 added was 3.51g, and the amount of the obtained white solid 2 added was 1.76g.
Example 16
The specific preparation process flow of the WY-16 compound is as follows:
the preparation method comprises the following specific steps: connecting a synthesis reaction experimental device, introducing nitrogen at the early stage to drive off air in a reaction bottle, keeping nitrogen introduction, introducing nitrogen into the reaction device for 5min, adding 200mL of dry dichloromethane, 25g of potassium 2-oxocyclohexylsulfonate and 0.6mL of DMF into a 1000mL round-bottom flask at room temperature, stirring uniformly to mix the raw materials uniformly, slowly dropwise adding 10.6mL of oxalyl chloride, and stirring at room temperature for reaction for 2h. Suction filtration is carried out, the filtrate is slowly dripped into a substituted amine solution consisting of 8.34mL2,4, 5-trifluoroaniline, 20.8mL triethylamine and 110mL dichloromethane which are cooled by an ice water bath, and the reaction temperature is controlled at 4 ℃ in the dripping process. After the dropwise addition, the temperature is naturally raised, the reaction is carried out for 4h, the reaction solution is an orange transparent solution at the moment, and the TLC monitoring is carried out (V) Petroleum ether ：V Acetic acid ethyl ester =3: 1) And (4) stopping the reaction when the reaction liquid has no raw materials according to the reaction progress and results show that the post-treatment operation is carried out. The reaction mixture was washed with 75mL of 3mol/L hydrochloric acid, 50mL of saturated sodium bicarbonate, and 50mL of distilled water, three times in total. And drying the washed reaction solution for 3 hours by using anhydrous sodium sulfate, carrying out suction filtration, and evaporating the filtrate by using a rotary evaporator to obtain a crude product. Recrystallizing with a mixed solution of acetone and petroleum ether to obtain a white solid 1;
stirring with a magnetic stirrer at room temperature under nitrogen protection, adding solvent anhydrous ethanol 50mL and 3.07g of the recrystallized white solid 1 into a sealed three-neck flask, adding titanium tetraisopropoxide 8.88mL into the reaction solution, and stirring for 2min. Immediately stopping introducing nitrogen into the system, changing into introducing ammonia, sealing each interface of the reaction instrument with a sealing film to prevent air leakage, connecting the tail end of the reaction with a U-shaped hydraulic gauge, and keeping ammonia introduced into the reaction flaskThe pressure was maintained at 30mm Hg. Reacting for 3h, and performing TLC (V) Petroleum ether ：V Ethyl acetate =3: 1) Monitoring, closing the ammonia valve and removing the U-shaped hydraulic gauge after the complete reaction is shown. Then, nitrogen is introduced into the reaction liquid, and after stirring for 5min, the reducing agent sodium borohydride 1.13g is added for 5 times, 0.2-0.25 g each time, and the reaction is carried out for 5h after the sodium borohydride is added. TLC (V) Petroleum ether ：V Ethyl acetate ：V Methanol =10:10: 1) After the reaction was monitored to be complete, ammonia was added to the reaction system to quench, and a large amount of white solid was seen to precipitate, and the reaction was stopped by stirring for 10 min. And carrying out vacuum filtration on the product under reduced pressure, leaving filtrate, carrying out vacuum concentration on ethanol and the aqueous solution in the filtrate, extracting the residual solution with ethyl acetate for three times, and leaving an organic layer. Washing the organic layer with saturated saline solution for 2 times, drying with a large amount of anhydrous sodium sulfate overnight, and concentrating under reduced pressure to obtain white solid 2;
adding 1.54g of white solid 2 and 30mL of dry ethyl acetate into a 100mL three-neck round-bottom flask under the protection of nitrogen and magnetic stirring, stirring for 10min, adding 0.63mL of dry triethylamine, dissolving 3g of triphosgene in 5mL of ethyl acetate, adding the solution into the reaction system in 2 times of 2.5mL each time, and performing TLC (V) Petroleum ether ：V Acetic acid ethyl ester =2: 1) Monitoring the reaction process, washing with saturated sodium chloride solution after the reaction is finished, collecting an organic layer, and evaporating and spin-drying. With (V) Ethyl acetate ：V Petroleum ether =1: 5) Performing silica gel column chromatography on the chromatographic solution to obtain the WY-16 compound.
Example 17
The specific preparation process of WY-17 is different from that of WY-1 in that: the amine content in the substituted amine solution was 10.34mL2,4, 5-trichloroaniline, and the amount of the white solid 1 added was 3.58g and the amount of the white solid 2 added was 1.79g.
Example 18
The specific preparation process of WY-18 is different from that of WY-1 in that: the amine content in the substituted amine solution was 9.41ml2, 6-difluoro-4-bromoaniline, and the amount of the obtained white solid 1 added was 3.69g, and the amount of the obtained white solid 2 added was 1.85g.
Example 19
The specific preparation process of WY-19 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.19g4-nitroaniline, and the amount of the white solid 1 added was 2.62g, and the amount of the white solid 2 added was 1.31g.
Example 20
The specific preparation process of WY-20 is different from that of WY-1 in that: the amine content in the substituted amine solution was 13.98g of 2-chloro-4-nitroaniline, and the amount of the obtained white solid 1 was 3.33g and the amount of the obtained white solid 2 was 1.67g.
Example 21
The specific preparation process of WY-21 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.46ml 2-trifluoromethylaniline, and the amount of the white solid 1 added was 3.17g, and the amount of the white solid 2 added was 1.59g.
Example 22
The specific preparation process flow of the WY-22 compound is as follows:
the preparation process comprises the following steps: connecting a synthesis reaction experimental device, introducing nitrogen at the early stage to drive off air in a reaction bottle, keeping nitrogen introduction, introducing nitrogen into the reaction device for 5min, adding 200mL of dry dichloromethane, 25g of potassium 2-oxocyclohexylsulfonate and 0.6mL of DMF into a 1000mL round-bottom flask at room temperature, stirring uniformly to mix the raw materials uniformly, slowly dropwise adding 10.6mL of oxalyl chloride, and stirring at room temperature for reaction for 2h. Filtering, slowly dripping the filtrate into a reaction solution consisting of 9.81mL2-fluoro-5-trifluoromethylaniline, 20.8mL of triethylamine and 110mL of dichloromethane which are cooled by an ice water bath, and controlling the reaction temperature to be 5 ℃ in the dripping process. After the dropwise addition, the temperature is naturally raised, the reaction is carried out for 4h, the reaction solution is an orange transparent solution at the moment, and the TLC monitoring is carried out (V) Petroleum ether ：V Acetic acid ethyl ester =3: 1) And (4) stopping the reaction when the reaction liquid has no raw materials according to the reaction progress and results show that the post-treatment operation is carried out. The reaction mixture was washed 3 times with 75mL of 3mol/L hydrochloric acid, 50mL of saturated sodium bicarbonate, and 50mL of distilled water. Anhydrous sulfuric acid for washed reaction solutionDrying sodium for 3h, filtering, evaporating filtrate by using a rotary evaporator to obtain a crude product. Recrystallizing with mixture of acetone and petroleum ether to obtain white solid 1;
stirring the mixture with a magnetic stirrer at room temperature under the protection of nitrogen, adding 50mL of absolute ethanol serving as a solvent and 3.39g of the white solid 1 recrystallized from the above into a sealed three-neck flask, adding 8.88mL of titanium tetraisopropoxide into the reaction solution, and stirring for 2min. Then stopping introducing nitrogen into the system, changing the introduction of ammonia into the system, sealing each interface of the reaction instrument by using a sealing film to prevent air leakage, connecting the tail end of the reaction with a U-shaped hydraulic gauge, and keeping the pressure of introducing ammonia into the reaction bottle at 35mm mercury. Reaction for 3h, TLC (V) Petroleum ether ：V Ethyl acetate =3: 1) Monitoring, closing the ammonia valve and removing the U-shaped hydraulic gauge after the complete reaction is shown. Then, nitrogen is introduced into the reaction liquid, and after stirring for 5min, 0.2-0.25 g of reducing agent sodium borohydride is slowly added for 5 times, 1.13g of reducing agent sodium borohydride is added, and the reaction is carried out for 5h after the sodium borohydride is added. TLC (V) Petroleum ether ：V Ethyl acetate ：V Methanol =10:10: 1) After the reaction was monitored to be complete, ammonia was added to the reaction system to quench, and a large amount of white solid was seen to precipitate, and the reaction was stopped by stirring for 10 min. And carrying out vacuum filtration on the product under reduced pressure, leaving filtrate, carrying out vacuum concentration on ethanol and the aqueous solution in the filtrate, extracting the residual solution with ethyl acetate for three times, and leaving an organic layer. Washing the organic layer with saturated saline solution for 2 times, drying with a large amount of anhydrous sodium sulfate overnight, and concentrating under reduced pressure to obtain white solid 2;
adding 1.7g of white solid 2 and 30mL of dried ethyl acetate into a 100mL three-neck round-bottom flask under the protection of nitrogen and magnetic stirring, stirring for 10min, adding 0.63mL of dried triethylamine, dissolving 3g of triphosgene in 5mL of ethyl acetate, adding the solution into the reaction system in 2 times of 2.5mL each time, and performing TLC (V) Petroleum ether ：V Ethyl acetate =2: 1) Monitoring the reaction process, washing with saturated sodium chloride solution after the reaction is finished, collecting an organic layer, and evaporating and spin-drying. With (V) Ethyl acetate ：V Petroleum ether =1: 5) The chromatographic solution is processed by silica gel column chromatography to obtain the WY-22 compound.
Example 23
The specific preparation process of WY-23 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.23mL2-chloro-5-trifluoromethylaniline, and the amount of the obtained white solid 1 was 3.56g and the amount of the obtained white solid 2 was 1.78g.
Example 24
The specific preparation process of WY-24 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.40mL2-trifluoromethyl-4-chloroaniline, and the amount of the obtained white solid 1 was 3.57g and the amount of the obtained white solid 2 was 1.79g.
Example 25
The specific preparation process of WY-25 is different from that of WY-1 in that: the amine content in the substituted amine solution was 11.44mL of 2-trifluoromethyl-4-bromoaniline, and the amount of the obtained white solid 1 added was 4.01g, and the amount of the obtained white solid 2 added was 2.00g.
Example 26
The specific preparation process of WY-26 is different from that of WY-1 in that: the amine content in the substituted amine solution was 9.15mL of 2-methoxyaniline, and the amount of the obtained white solid 1 added was 2.84g and the amount of the obtained white solid 2 added was 1.42g.
Example 27
The specific preparation process of WY-27 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.04ml of 2-trifluoromethoxyaniline, and the amount of the obtained white solid 1 was 3.38g and the amount of the obtained white solid 2 was 1.69g.
Example 28
The specific preparation process of WY-28 is different from that of WY-1 in that: the amine in the substituted amine solution was 11.04ml of 4-trifluoromethoxyaniline, and the amount of the obtained white solid 1 was 3.38g and the amount of the obtained white solid 2 was 1.69g.
Example 29
The specific preparation process of WY-29 is different from that of WY-1 in that: the amine content in the substituted amine solution was 11.47g of 2-chlorobenzylamine, and the amount of the obtained white solid 1 added was 3.03g and the amount of the obtained white solid 2 added was 1.52g.
Example 30
The specific preparation process of WY-30 is different from that of WY-1 in that: the amine in the substituted amine solution was 10.54ml 3-fluorophenylethylamine, and the amount of the resulting white solid 1 added was 3.00g, and the amount of the resulting white solid 2 added was 1.5g.
The results of the tests on the physicochemical data of the WY-1 to WY-30 compounds obtained in the examples are shown in Table 1.
TABLE 1 physicochemical data for the compounds WY-1 to WY-30
For WY-1 to WY-30 compounds obtained in examples 1 H NMR、 13 C NMR and HRMS were measured, and the results are shown in Table 2.
TABLE 2 preparation of WY-1 to WY-30 compounds 1 H NMR、 13 C NMR and HRMS data
The bactericidal activity of the WY-1 to WY-30 compounds obtained in the examples was verified:
1. and (3) determining the bactericidal activity of the WY-1-WY-30 compounds on various plant pathogenic bacteria:
a hypha growth rate method is adopted to measure the bactericidal activity of the compound to various plant pathogenic bacteria, and the specific method is as follows:
weighing WY-1-WY-30 compounds respectively, dissolving with acetone, diluting to constant volume to obtain test reagent with concentration of 5000mg/L, and placing in a low temperature refrigerator for activity measurement. 0.3mL of the test reagent with a concentration of 5000mg/L was aseptically mixed with 30mL of thawed (60. + -. 5 ℃) PDA medium to prepare 30mL of a 50mg/L cell culture medium, and then 30mL of the cell culture medium was poured into 3 dishes of 10mL each having a diameter of 9 cm. Boscalid and carbendazim are used as contrast agents of botrytis cinerea, rhizoctonia solani, fusarium graminearum and pyricularia oryzae, an acetone solvent is used as a blank contrast, the concentration of a common sieve is 50mg/L, and after a toxic culture medium in a culture dish is condensed, the culture medium is respectively inoculated to cultured pathogenic bacterium blocks with the diameter of 0.5 cm. Culturing in 28 deg.C incubator. After the colonies in the blank had grown sufficiently, the diameter of each treated colony was measured by a cross method, and the average value was taken. The inhibition was calculated from the corrected blank and the mean diameter of the treated colonies. The bactericidal activity of the compounds WY-1 to WY-30 on various phytopathogens is calculated and shown in the following table 3.
TABLE 3 fungicidal Activity of WY-1-WY-30 Compounds against various plant pathogenic fungi
As can be seen from Table 3, the obtained compound has a certain bactericidal effect on various plant pathogenic fungi, and shows a broad spectrum. Meanwhile, different compounds show different activity effects on the same phytopathogen.
2. And (3) determining the bactericidal activity of the WY-1-WY-30 compounds on sclerotinia sclerotiorum:
a hypha growth rate method is adopted to determine the bactericidal activity of the compound on sclerotinia sclerotiorum, and the specific method is as follows:
weighing WY-1-WY-30 compounds respectively, dissolving with acetone, diluting to a constant volume to prepare test reagents with a concentration of 5000mg/L, preparing test reagents with concentrations of 5000, 1250, 312.5, 78 and 19.5mg/L by adopting a multiple dilution method, and placing the test reagents in a low-temperature refrigerating box for activity measurement. Under aseptic condition, 0.3mL of the drug with concentration of 5000mg/L is uniformly mixed with 30mL of melted (60 +/-5 ℃) PDA culture medium to prepare 30mL of toxic culture medium with concentration of 50mg/L, and then 30mL of toxic culture medium is uniformly poured into 3 culture dishes with diameter of 9cm, wherein each dish is 10mL. By analogy, four gradients of toxic medium with concentrations of 50, 12.5, 3.125, 0.78 and 0.195mg/L are prepared.
Carbendazim and boscalid are adopted, an acetone solvent is set as a blank control, the concentration of a common sieve is 50mg/L, and the gradient concentration is 50, 12.5, 3.125, 0.78 and 0.195mg/L. After the toxic culture medium in the dish is condensed, the cultured pathogenic bacteria blocks with the diameter of 0.5cm are respectively inoculated. Culturing in 28 deg.C incubator. After the colonies in the blank had grown sufficiently, the diameter of each treated colony was measured by the cross method, and the average value was taken. And calculating the inhibition rate by using the corrected blank control and the average diameter of the treated colony, and determining the inhibitory activity of each compound on sclerotinia sclerotiorum by adopting a hypha growth rate method.
After the inoculation culture, the colony diameter was measured, the inhibition rate was calculated according to the following formula, and the EC50 value of the corresponding compound was calculated, 3 replicates for each compound and control agent.
The bactericidal activity of the compound is determined by adopting a rape living leaf method, and the specific method is as follows:
after 20mg of compound and 15mg of Tween-20 are mixed uniformly, 0.1mL of DMSO is used for dissolving, then the mixture is mixed with 7.5mg of agricultural milk 500 and 30mg of agricultural milk 600 and dissolved in 0.4mL of dimethyl sulfoxide, finally the dimethyl sulfoxide is used for complementing to 1mL to prepare missible oil containing the compound with the mass concentration of 2mg/L, and the missible oil is diluted into test solution of test solution with the mass concentration of 500mg/L by water. The carbendazim technical product is prepared into 2mg/L carbendazim, the boscalid technical product is prepared into 2mg/L boscalid emulsifiable solution, the boscalid emulsifiable solution is used as a control medicament, and the emulsifiable solution without a target compound is sprayed as a blank control. And uniformly spraying the liquid medicine when the rape seedlings grow to 4 cotyledons. After the liquid medicine is naturally dried, inoculating sclerotinia sclerotiorum fungus cakes with the diameter of 5mm in the middle of each piece of the cotyledon, placing the sclerotinia sclerotiorum fungus cakes in an intelligent artificial climate box, culturing the sclerotinia sclerotiorum fungus cakes in a dark environment at the temperature of 26 +/-1 ℃ and the relative humidity of more than 90 percent for 12 hours, culturing the sclerotinia sclerotiorum fungus cakes in an illumination environment for 12 hours, measuring the diameter of a disease spot after a blank control is fully developed, and inspecting the control effect by the inhibition rate. There were 5 replicates per treatment. The bactericidal activity of WY-1 to WY-30 compounds against Sclerotinia sclerotiorum is shown in Table 4, and the virulence of some compounds against Sclerotinia sclerotiorum is shown in Table 5.
TABLE 4 fungicidal Activity of WY-1 to WY-30 Compounds against Sclerotinia sclerotiorum
As can be seen from Table 4, the target compounds exhibited excellent in vivo control effects on Sclerotinia sclerotiorum. Of the 30 compounds, 10 compounds had a control effect of more than 70%, WY-1, WY-2, WY-3, WY-4, WY-7, WY-8, WY-9, WY-16, WY-22 and WY-23, respectively. The control effects of the 10 target compounds are better than those of a contrast medicament carbendazim, and in the rest compounds, the control effects of the inhibition rates of 69.32 percent and 64.55 percent of WY-10 and WY-13 are also better than those of the control medicament carbendazim of 63.86 percent. The obtained compounds have 3 compounds, and the inhibition rate of WY-8, WY-16 and WY-22 is more than 80 percent of the inhibition rate of procymidone.
TABLE 5 virulence of some compounds against Sclerotinia sclerotiorum
As can be seen from Table 5, the EC for 20 of the 21 rescreened compounds 50 Less than 10 μ g/mL, wherein the EC of WY-13, WY-17, WY-22, WY-25 50 Less than 1 μ g/mL, 0.9782 μ g/mL,0.3934 μ g/mL,0.0638 μ g/mL,0.1792 μ g/mL, WY-22 minimum, respectively. Therefore, the compound obtained by the invention has very good effect on sclerotinia sclerotiorumGood inhibition effect.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (8)
1. A cyclohexanothiadiazine compound, wherein the structural formula of the cyclohexanothiadiazine compound is as follows:
wherein R is-CH 2 CF 3 、-C 6 H 4 -2-F、-C 6 H 4 -3-F、-C 6 H 4 -4-F、-C 6 H 4 -2-Cl、-C 6 H 4 -3-Cl、-C 6 H 4 -4-Cl、-C 6 H 4 -2-Br、-C 6 H 4 -3-Br、-C 6 H 4 -4-Br、-C 6 H 3 -2,4-F 2 、-C 6 H 3 -3,4-F 2 、-C 6 H 3 -2-F-4-Br、-C 6 H 3 -3-F-4-Br、-C 6 H 3 -3-Br-4-F、-C 6 H 2 -2,4,5-F 3 、-C 6 H 2 -2,4,5-Cl 3 、-C 6 H 2 -4-Br-2,6-F 2 、-C 6 H 4 -4-NO 2 、-C 6 H 3 -2-Cl-4-NO 2 、-C 6 H 4 -2-CF 3 、-C 6 H 3 -2-F-5-CF 3 、-C 6 H 3 -2-Cl-5-CF 3 、-C 6 H 3 -2-CF 3 -4-Cl、-C 6 H 3 -2-CF 3 -4-Br、-C 6 H 4 -2-OCH 3 、-C 6 H 4 -2-OCF 3 、-C 6 H 4 -4-OCF 3 、-CH 2 C 6 H 4 -2-Cl or-CH 2 CH 2 C 6 H 4 -3-F。
2. A method for producing a cyclohexanothiadiazine compound according to claim 1, comprising the steps of:
(1) Mixing cyclohexanone, sulfur trioxide-dioxane adduct, potassium carbonate and 1, 2-dichloroethane, and reacting to obtain potassium 2-oxocyclohexylsulfonate;
(2) Mixing 2-oxo-cyclohexane potassium sulfonate, anhydrous dichloromethane, N-dimethylformamide and oxalyl chloride, and dropwise adding the obtained mixture into a substituted amine solution for reaction to obtain N-substituted-2-oxo-cyclohexane sulfonamide;
(3) Under the protection of nitrogen, mixing N-substituted-2-oxo-cyclohexane sulfonamide with absolute ethyl alcohol, then adding titanium tetraisopropoxide, and stirring for 1-3 min by using a magnetic stirrer; changing the introduction of nitrogen into the introduction of ammonia gas, introducing the ammonia gas to ensure that the pressure of the reaction system is 30-40 mm of mercury, and then mixing the obtained reaction product with sodium borohydride for reaction to obtain N-substituted-2-aminocyclohexyl sulfonamide;
(4) Mixing N-substituted-2-aminocyclohexyl sulfonamide, ethyl acetate, triethylamine and triphosgene, and reacting to obtain the cyclohexane-thiadiazine compound.
3. The method for producing a cyclohexanothiadiazine compound according to claim 2, wherein the reactions in the step (2) and the step (4) are independently carried out under a protective gas; the protective gas is nitrogen, helium or ammonia.
4. The method for preparing a cyclohexanothiadiazine compound according to claim 3, wherein in the step (1), the reaction temperature is-4 to 4 ℃ and the reaction time is 0.75 to 1.5 hours; the mass-volume ratio of the cyclohexanone to the sulfur trioxide-dioxane adduct to the 1, 2-dichloroethane is 58mL:90g:100mL, after potassium carbonate treatment, the pH of the solution is 8-9.
5. The process for producing a cyclohexanothiadiazine compound according to any one of claims 2 to 4, wherein in the step (2), the mass-to-volume ratio of potassium 2-oxocyclohexanesulfonate to anhydrous dichloromethane is 20 to 30g: 190-210 mL; the volume ratio of the anhydrous dichloromethane to the N, N-dimethylformamide to the oxalyl chloride is 200:0.5 to 1:10 to 12.
6. The method for preparing a cyclohexanediazine compound according to claim 5, wherein in the step (2), the temperature of the dropwise addition of the mixed solution is 0 to 5 ℃, and the time of the dropwise addition of the mixed solution is 20 to 40min; the reaction temperature is 20-30 ℃, and the reaction time is 3-5 h.
7. The method for preparing a cyclohexanothiadiazine compound according to claim 2, wherein in the step (4), the triphosgene is an ethyl acetate solution of triphosgene, and the concentration of the ethyl acetate solution of triphosgene is 0.5 to 1g/mL; the mass volume ratio of the N-substituted-2-aminocyclohexyl sulfonamide to the ethyl acetate is 1-1.9 g:30mL; the addition amount of the triphosgene is 15-20% of the volume of the ethyl acetate; the volume ratio of the ethyl acetate to the triethylamine is 30:0.3 to 0.9; the reaction temperature is 20-30 ℃, and the reaction time is 6-8 h.
8. The use of the cyclohexanothiadiazine compound according to claim 1 for inhibiting sclerotinia sclerotiorum, botrytis cinerea, rhizoctonia solani, pyricularia oryzae, fusarium graminearum.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107337620A (en) * | 2017-05-23 | 2017-11-10 | 沈阳农业大学 | 2 amide groups b-sulfonamide compounds, preparation method and the purposes as bactericide, herbicide |
| CN108440412A (en) * | 2018-05-18 | 2018-08-24 | 沈阳农业大学 | A kind of 2- pyrazole amides cyclohexyl sulfonamide compounds, preparation method and applications |
| CN113563237A (en) * | 2021-07-29 | 2021-10-29 | 沈阳农业大学 | 2-methoxy amino-4-substituted cyclohexyl sulfonamide compound and preparation method and application thereof |
| CN113563238A (en) * | 2021-07-29 | 2021-10-29 | 沈阳农业大学 | 2-phenoxyethylamino cyclohexane sulfonamide compound and preparation method and application thereof |
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| CN102633697A (en) * | 2012-04-01 | 2012-08-15 | 沈阳农业大学 | Naphthenic sulfonamide series compounds and preparation method thereof as well as application of compounds serving as bactericides and herbicides |
| CN107337620A (en) * | 2017-05-23 | 2017-11-10 | 沈阳农业大学 | 2 amide groups b-sulfonamide compounds, preparation method and the purposes as bactericide, herbicide |
| CN108440412A (en) * | 2018-05-18 | 2018-08-24 | 沈阳农业大学 | A kind of 2- pyrazole amides cyclohexyl sulfonamide compounds, preparation method and applications |
| CN113563237A (en) * | 2021-07-29 | 2021-10-29 | 沈阳农业大学 | 2-methoxy amino-4-substituted cyclohexyl sulfonamide compound and preparation method and application thereof |
| CN113563238A (en) * | 2021-07-29 | 2021-10-29 | 沈阳农业大学 | 2-phenoxyethylamino cyclohexane sulfonamide compound and preparation method and application thereof |
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