Sulfonyl fluoride coumarin compounds, preparation method and application thereof

Abstract

The application discloses a class of sulfonyl fluoride coumarin compounds, a preparation method and application thereof. The sulfonyl fluoride coumarin compound has broad-spectrum and high-efficiency bactericidal activity, especially has better antibacterial activity on plant pathogenic bacteria, and has better prevention and treatment effect on diseases caused by the plant pathogenic bacteria.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of agricultural bactericides. More particularly, it relates to a sulfonyl fluoride coumarin compound, a preparation method and application thereof. BACKGROUND

[0002] Plant bacterial diseases are diseases caused by plant infection by pathogenic bacteria. The global rice yield loss caused by the difficult-to-cure plant bacterial diseases has seriously restricted the development of agricultural products and has seriously endangered food security. At present, although a variety of molecular structures can be obtained through chemical means, developing new pesticides based on natural products is still an important method. Many natural products have complex structures and excellent biological activities and show good application prospects in the development of pharmaceuticals / agricultural chemicals. In addition, natural products have different antibacterial mechanisms from existing antibacterial drugs. Therefore, developing novel structures and new action mechanisms of pesticides through the modification or modification of the structure of natural products is still one of the most effective ways for the development of new pesticides.

[0003] The activity of sulfonyl fluoride derivatives has not been studied for a long time. Recently, Ravindar et al. utilized the relative chemical stability of sulfonyl fluoride derivatives and made some unique modifications to retain the sulfonyl fluoride functional group to study the antibacterial activity, synthesized a series of sulfonyl fluoride derivatives, and conducted in vitro antibacterial activity determination, and found that they showed strong antibacterial activity against Staphylococcus aureus. Subsequently, Zhang Jiong et al. successfully synthesized a series of sulfonyl fluoride derivatives using the SuFEx reaction, most of which showed rapid bactericidal efficacy and selectively killed gram-positive bacterial strains. It has become a technical problem to be solved to explore more compounds with bactericidal activity against plant pathogenic bacteria based on sulfonyl fluoride derivatives. SUMMARY

[0004] Based on the above existing technical problems, the primary object of the present application is to provide a class of sulfonyl fluoride coumarin compounds. The sulfonyl fluoride coumarin compound has broad-spectrum and high-efficiency bactericidal activity, especially good antibacterial activity against plant pathogenic bacteria, and good control effect on diseases caused by them.

[0005] The second object of the present application is to provide a preparation method of the sulfonyl fluoride coumarin compound.

[0006] The third object of the present application is to provide an agricultural composition.

[0007] The fourth object of the present application is to provide the application of the above-mentioned sulfonyl fluoride coumarin compound or the agricultural composition in the preparation of a drug or bactericide for preventing and treating plant pathogenic bacteria.

[0008] The above object of the present application is achieved by the following technical solutions.

[0009] The present application claims a sulfilimine coumarin compound, the structure of which is shown in formula (I):

[0010]

[0011] In the formula, R1 is mono- or polysubstituted, and each R1 is independently selected from hydrogen, C 1-8 alkyl, halogen or C 1-8 alkoxy.

[0012] R2 is selected from hydrogen, halogen, C 1-8 alkyl.

[0013] In some embodiments, R1 is mono- or polysubstituted, and each R1 is independently selected from hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine, iodine or C 1-6 alkoxy; R2 is selected from hydrogen, fluorine, chlorine, bromine, C 1-6 alkyl.

[0014] In some embodiments, the structure of the sulfilimine coumarin compound is shown in formula (II):

[0015]

[0016] In the formula,

[0017] R2 is selected from hydrogen, C 1-4 alkyl.

[0018] R3 is selected from hydrogen, C 1-4 alkyl.

[0019] R4 is selected from chlorine, methyl, butyl, t-butyl;

[0020] R5 is selected from hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy.

[0021] R6 is selected from hydrogen, fluorine, chlorine, bromine.

[0022] In some embodiments, the structure of the sulfilimine coumarin compound is selected from any one of the following structures:

[0023]

[0024] In some embodiments, the structure of the sulfilimine coumarin compound is selected from any one of the following structures:

[0025]

[0026] Further, the present application claims a method for preparing the sulfonyl fluoride coumarin compound, comprising the following steps:

[0027] The hydroxyl coumarin compound represented by formula (I-1) and the fluorosulfonylimidazole salt represented by formula (I-2) are reacted by SuFEx reaction to prepare the sulfonyl fluoride coumarin compound represented by formula (I).

[0028] The reaction formula of the preparation method is shown as follows:

[0029]

[0030] Preferably, a base is added to form an alkaline condition in the SuFEx reaction, and the base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and pyridine.

[0031] Preferably, the solvent is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide.

[0032] In some embodiments, the temperature of the reaction is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent. More specifically, the temperature of the reaction is 20-110°C. For example, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e. under reflux.

[0033] In some embodiments, the time of the reaction is 0.1-48h, for example, 0.5h, 1h, 3h, 5h, 8h, 10h, 12h, 15h, 18h, 20h, 23h, 25h, 28h, 30h, 33h, 35h, 38h, 40h, 44h or 48h.

[0034] Further, the present application claims an agricultural composition comprising:

[0035] (a) 0.001-99.99% by weight of the sulfonyl fluoride coumarin compound, an optical isomer thereof, a cis-trans isomer thereof or a pesticidally acceptable salt thereof, or a combination thereof; and

[0036] (b) a pesticidally acceptable carrier and / or excipient.

[0037] Further, the present application claims the use of the sulfonyl fluoride coumarin compound or the agricultural composition in the preparation of a medicament or bactericide for controlling plant pathogenic bacteria.

[0038] Preferably, the medicament or bactericide is directly applied to the plant pathogenic bacteria or the locus contacted by the plant pathogenic bacteria.

[0039] Preferably, the plant pathogenic bacteria are selected from the group consisting of:

[0040] Gram-negative bacteria: Erwinia (causing pear fire blight, etc.); Pectobacterium (causing soft rot of cruciferous vegetables, potato black leg, etc.); Dickeya (causing sweet potato stem rot, corn bacterial stalk rot, rice bacterial basal rot, potato black leg, pear rust water disease, etc.); Pantoea (causing corn bacterial wilt, corn Pantoea leaf spot, azuki bean bacterial leaf blight, stone fruit canker, etc.); Pseudomonas (causing peach canker, pea bacterial blight, cruciferous bacterial black spot, tomato bacterial leaf spot, tomato bacterial mottle, rape bacterial black spot, sesame bacterial angular spot, cucumber bacterial angular spot, tobacco wildfire, corn bacterial brown spot, corn bacterial brown spot, broad bean bacterial stem blight, soybean bacterial mottle, beet bacterial mottle, tomato bacterial heart rot, ginseng Pseudomonas soft rot, etc.); Ralstonia (causing various bacterial wilt diseases, such as tobacco bacterial wilt); Burkholderia (causing carnation bacterial wilt, onion bacterial rot, rice bacterial panicle rot, etc.); Acidovorax (causing melon fruit spot, orchid brown spot, oat brown stripe, konjac bacterial leaf spot, etc.); Xanthomonas (causing rice bacterial leaf blight, rice bacterial stripe, pepper and tomato mottle, pepper and tomato scab, mango bacterial black spot, poinsettia bacterial blight, cotton angular spot, soybean bacterial mottle, cruciferous black rot, cassava bacterial wilt, sugarcane ratoon stunting, anthurium bacterial blight, citrus canker, hyacinth yellow rot, peach bacterial perforation, strawberry angular spot, poplar bacterial canker, etc.); Agrobacterium (causing root cancer of Rosaceae, etc.); Liberibacter (causing grape Pierce's disease and citrus variegated chlorosis, etc.); Lonsdalea (causing citrus Huanglongbing, etc.); Enterobacter (causing poplar wilt, etc.); Ligniivorus (causing bacterial blight of grape, etc.).

[0041] Gram-positive bacteria: Clavibacter (causing potato ring rot, tomato canker, alfalfa bacterial wilt, corn northern wilt, wheat bacterial leaf blight, etc.); Streptomyces (causing potato scab, etc.); Curtobacterium (causing bean bacterial wilt, tulip yellow blister spot, bean wilt, etc.); Arthrobacter (causing American holly leaf blight, etc.); Rhodococcus (causing pea streak disease, etc.); Bacillus (causing corn bacterial leaf spot, wheat white leaf stripe, etc.); Laceyella (causing fescue honeyhead disease, etc.).

[0042] Further preferably, the plant pathogenic bacteria are selected from one or more of the group consisting of Xanthomonas, Clavibacter, and Pseudomonas. Further preferably, the plant pathogenic bacteria are selected from one or more of the group consisting of Xanthomonas campestris, Clavibacter michiganensis, and Pseudomonas syringae. Further, the sulfuryl fluoride coumarin compounds of the present application have good control effects on various plant diseases caused by the above-mentioned plant pathogenic bacteria, such as citrus canker, tomato canker, and cucumber bacterial angular spot.

[0043] Compared with the prior art, the present application has the following beneficial effects:

[0044] The present application provides a class of sulfuryl fluoride coumarin compounds, which have broad-spectrum and high-efficiency bactericidal activity, especially excellent bactericidal activity against plant pathogenic bacteria, and have good control effects on various plant diseases caused by plant pathogenic bacteria, and have great application potential and value in the field of plant disease control. DETAILED DESCRIPTION

[0045] The present application will be further described below in conjunction with specific examples, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods, and equipment used in the present application are conventional reagents, methods, and equipment in the technical field. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0046] In the present application, unless otherwise specified in the context, the meanings of the words, phrases, and symbols to be used below are as follows. The meanings of the following abbreviations and terms are consistent throughout the text:

[0047] Example 1

[0048] The preparation of the sulfuryl fluoride coumarin compound is as follows:

[0049]

[0050] In a 100 mL round-bottom flask, 4-hydroxycoumarin compound (compound of formula (I-1), 0.5 mmol), triethylamine (0.75 mmol), and acetonitrile (3.0 mL) were sequentially added and stirred for 5 min. At 0°C, fluorosulfonylimidazole salt (compound of formula (I-2), 0.6 mmol) was dissolved in acetonitrile solvent and slowly added dropwise to the above solution. The mixture was reacted at room temperature for 0.5 h, which was monitored by TLC. After the reaction was completed, it was cooled to room temperature, then extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered through a Buchner funnel to remove anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1; v / v) to obtain the sulfuryl fluoride coumarin compound (compound of formula (I)).

[0051] The compounds D1 to D38 were prepared according to the above method. The compound structural formula, yield and characterization data of the compounds D1 to D38 are shown in Table 1 below.

[0052] Table 1 Structure and data characterization of the sulfonyl fluoride coumarin compounds

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] Test Example 1 Bacteriostatic activity and EC of the sulfonyl fluoride coumarin compounds on three plant pathogenic bacteria 50 Values

[0062] The reference turbidity method was tested and improved by changing the NA liquid medium to NA solid medium. The bacterial liquid was uniformly coated on the NA solid plate medium with or without drugs, and after incubation at a suitable temperature of 26-28°C for 24-48h, the bacteria on the plate were washed to form a bacterial suspension, and the turbidity of the bacterial suspension was tested, and the absorbance (OD 600 ) was used as an indicator to calculate the inhibition rate. The plant diseases and corresponding test bacteria were citrus canker (Xanthomonas campestris), tomato canker (Erwinia stewartii) and cucumber bacterial angular spot (Pseudomonas syringae).

[0063] The above NA solid medium was prepared: proteose peptone 5.0g, beef extract powder 3.0g, yeast extract powder 1.0g, sucrose 10.0g, agar powder 20g, add water to 1L, mix well, adjust the pH to about 7.0, and then seal the triangular bottle and sterilize with high-pressure steam. The NA liquid medium was prepared by removing the agar powder from the NA solid medium.

[0064] The drug was configured as a mother liquor, 20 mg of the target compound, 20 mg of the original drug of folpet and thiabendazole were weighed respectively, and then the samples were dissolved in dimethyl sulfoxide to prepare a drug solution with a concentration of 10000 μg / mL for standby. A single colony of pathogenic bacteria was picked into 50 mL of NA liquid medium, and cultured at 28°C with 180 r / min shaking for 24 h to obtain a bacterial seed solution. The seed solution was diluted to 1×10 8 bacterial suspension for standby.

[0065] 0.25 mL and 0.125 mL of the drug solution with a concentration of 10000 μg / mL were mixed with 49.5 mL and 49.775 mL of melted NA medium to prepare 50 mL of toxic medium with a concentration of 50 μg / mL and 25 μg / mL. The toxic medium was evenly divided into 4 portions and poured into 4 culture dishes with a diameter of 9 cm to prepare toxic NA plates. When the toxic medium in the dishes was condensed. 0.1 mL of bacterial suspension was evenly coated on the drug-containing plates and placed in a 25°C incubator for culture. The same concentration of folpet and thiabendazole was used as a control drug, dimethyl sulfoxide as a solvent control, and sterile water as a blank control. Each sample was repeated 4 times, and all the above operations were sterile operations. 0.1 mL of bacterial suspension was evenly coated on the drug-containing plates and placed in a 28°C constant temperature incubator for 24 h. 10 mL of sterile water was used to wash the bacterial colonies on the lesions and mix evenly. The absorbance value (OD 600 ) was measured by ultraviolet spectrophotometer. Gradient drug plates were prepared according to the test design, and blank controls without drugs were added with an equal amount of sterile water, and each treatment was repeated 3 times. After inoculation of pathogenic bacteria, the absorbance value was measured after culture and washing.

[0066] The inhibition rate of each drug at different concentrations on the growth of pathogenic bacteria was calculated according to the following formula. The data was statistically processed by Excel data processing software, and the virulence regression equation (Y=b+aX) of the drug, the correlation coefficient (R) and the inhibition medium concentration (EC 50 ) of the drug on the bacteria were calculated.

[0067]

[0068] The in vitro antibacterial activity results of the thiofluoroflavone compounds D1 to D38 are shown in Table 1.

[0069] Table 1

[0070]

[0071]

[0072]

[0073] As can be seen from Table 1, most of the compounds show good primary screening activity against Xanthomonas campestris (Xac), Pseudomonas syringae pv. Lachrymans (CBALS) and Xanthomonas vesicatoria (TBC). Among these compounds, the fungistatic activity of halogen substituent is better. In which, the fungistatic activity of halogen substituent at position 6 is generally greater than that at positions 5, 7 and 8. The compounds with inhibition rate > 70% at a concentration of 50 mg / L are subjected to secondary screening, and the EC 50 values are calculated.

[0074] Table 2 EC 50 values of the sulfuryl fluoride coumarin compounds against three plant pathogenic bacteria

[0075]

[0076]

[0077]

[0078] As can be seen from Table 2, the fungistatic activity of Cl at position 6 of the sulfuryl fluoride coumarin compound is the best, and the EC 50 values of the sulfuryl fluoride coumarin compound against Xanthomonas campestris, Pseudomonas syringae pv. Lachrymans and Xanthomonas vesicatoria are between 1.15-32.5 mg / L, 3.25-40.5 mg / L and 2.10-25.5 mg / L, respectively, showing excellent fungicidal activity.

[0079] Among them, the EC 50 value of compound D21 against Xanthomonas campestris reaches 1.15 mg / L, which is much higher than that of benthiazole (30.1 mg / L) and thiodiazole (48.00 mg / L); the EC 50 value of compound D21 against Pseudomonas syringae pv. Lachrymans reaches 3.40 mg / L, which is much higher than that of benthiazole (59.40 mg / L) and thiodiazole (27.60 mg / L); the EC 50 value of compound D21 against Xanthomonas vesicatoria reaches 2.10 mg / L, which is much higher than that of benthiazole (28.20 mg / L) and thiodiazole (24.50 mg / L). In summary, the sulfuryl fluoride coumarin compound has great development value and significance in the prevention and control of plant agricultural pathogenic fungi.

[0080] Test Example 2 Pot experiment of fungicidal activity of compound D21 against Xanthomonas campestris

[0081] Compound D21 is used to determine the protective and therapeutic effects of citrus canker.

[0082] The experiment with thiabendazole and bithionol as control drugs, DMSO as blank control and water, the high activity of compound D21 was carried out against citrus canker bacteria in vivo pot experiment. Two years old citrus plants were selected for treatment and protection activity test.

[0083] For treatment effect: use a disposable sterile syringe on both sides of the new citrus leaf two 3x3 rectangular wounds, the Xac bacteria liquid (OD 595 = 0.01) soaked through the filter paper close to the wound, 24 hours later, throw away the bacteria filter paper, re-paste the filter paper containing 200ug / mL of drug solution on the leaf for 24h, put into the incubator, the culture conditions are: light 16h, temperature 28℃, dark 25℃, 8h, humidity 95%.

[0084] For protection effect: use a disposable sterile syringe on both sides of the new citrus leaf two 3x3 rectangular wounds, the Xac bacteria liquid (OD 595 = 0.01) soaked through the filter paper close to the wound, 24 hours later, throw away the bacteria filter paper, re-paste the filter paper containing 200ug / mL of drug solution on the leaf for 24h, put into the incubator, the culture conditions are: light 16h, temperature 28℃, dark 25℃, 8h, humidity 95%. 14 days later, observe the incidence.

[0085] Control effect calculation: the chlorophyll content in the leaf is used to reflect the control effect of citrus canker. According to the method reported in the literature, about 0.1g of diseased leaves were accurately weighed, cut into pieces, 10.0mL of extraction solution (extraction solution was prepared by 85% acetone: 85% ethanol = 1:1) was added, 4℃ grinding into powder, transferred into 15mL test tube, covered with lid, 35℃, dark treatment for 2h, 200L of supernatant was taken and placed in 96 well plate, the absorbance at 663nm and 645nm was measured respectively.

[0086] The content of chlorophyll was calculated according to the following formula:

[0087] Ca(mg L -1 ) = 9.784 OD 663 - 0.990 OD 645

[0088] Cb(mg L -1 ) = 21.426 OD 645 - 4.650 OD 663

[0089] Ct(mg L -1 ) = Ca + Cb = 5.135 OD 663 + 20.643 OD 645

[0090] Chlorophyll content (mg g -1 ) = [concentration (mg L -1 ) x total volume of extract (mL)] / total weight of leaves (g). In the formula, Ca, Cb and Ct represent the concentration of chlorophyll a, the concentration of chlorophyll b and the concentration of total chlorophyll, respectively.

[0091] EC value of compound D21 against X. axonopodis pv. citri 50 The EC value of compound D21 against X. axonopodis pv. citri was 1.15 ug / mL. Therefore, we conducted a pot experiment in vivo at a concentration of 200 mg / L, with thiodicarb (TC) and bethoxazole (BT) as control drugs. The results of the activity test are shown in Table 3.

[0092] Table 3

[0093]

[0094] Note: TC-P is the control effect of thiodicarb; TC-C is the treatment effect of thiodicarb; other samples are equivalent.

[0095] As can be seen from Table 3, compound D21 has good protective and therapeutic effects against X. axonopodis pv. citri, and is better than thiodicarb and bethoxazole. Compound D21 shows good activity in vivo against X. axonopodis pv. citri. After 14 days of inoculation, at a concentration of 200 mg / L, compound D21 shows good protective and therapeutic effects, which are 91.20% and 61.59%, respectively, and the activity is better than that of thiodicarb (82.86% and 26.60%) and bethoxazole (79.70% and 41.54%).

[0096] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods and are included in the protection scope of the present application.

Claims

1. A sulfuryl fluorocoumarin compound, characterized in that, The structure of the sulfuryl fluorocoumarin compound is shown in formula (I): In the formula, R1 can be monosubstituted or polysubstituted, and each R1 is independently selected from hydrogen, C 1-4 Alkyl, halogen or C 1-4 Alkoxy; R2 is selected from hydrogen, halogens, and C. 1-4 alkyl.

2. The thioyl fluorocoumarin compound according to claim 1, characterized in that, The structure of the sulfuryl fluorocoumarin compound is shown in formula (II): In the formula, R2 is selected from hydrogen, C 1-4 alkyl; R3 is selected from hydrogen, C 1-4 alkyl; R4 is selected from chloro, methyl, butyl, and tert-butyl; R5 is selected from hydrogen, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 1-4 Alkoxy; R6 is selected from hydrogen, fluorine, chlorine, and bromine.

3. The thioyl fluorocoumarin compound according to claim 1, characterized in that, The structure of the sulfuryl fluorocoumarin compound is selected from any of the following structures: 。 4. The method for preparing the thioylfluorocoumarin compound according to any one of claims 1-3, characterized in that, Includes the following steps: The hydroxycoumarin compound shown in formula (I-1) and the fluorosulfonyl imidazole salt shown in formula (I-2) were reacted via SuFEx to prepare the thioyl fluorocoumarin compound shown in formula (I); The reaction formula for the preparation method is shown below: 。 5. The preparation method according to claim 4, characterized in that, In the SuFEx reaction, a base is added to form alkaline conditions, wherein the base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and pyridine.

6. The preparation method according to claim 4, characterized in that, The solvent used in the SuFEx reaction is selected from acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane, and... N,N One or more of dimethylformamide.

7. An agricultural composition, characterized in that, Include: (a) 0.001-99.99% by weight of any one of claims 1-3, a pesticide-acceptable salt thereof, or a combination thereof; and (b) Acceptable carriers and / or excipients for pesticides.

8. The use of the thioylfluorocoumarin compound according to any one of claims 1-3 or the agricultural composition according to claim 7 in the preparation of a medicament or bactericide for controlling diseases caused by plant pathogenic bacteria, characterized in that, The disease is one or more of the following: bacterial canker of citrus, bacterial angular leaf spot of cucumber, and bacterial canker of tomato.

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