Coumoxystrobin derivative containing triphenylphosphonium salt group as well as preparation method and application of coumoxystrobin derivative

Abstract

The invention belongs to the technical field of pesticide compounds, and particularly relates to coumoxystrobin derivatives containing triphenylphosphonium salt groups and a preparation method and application of the coumoxystrobin derivatives. The coumoxystrobin derivative has broad-spectrum and excellent bactericidal activity, and particularly has an excellent effect on plant diseases caused by ascomycetes, basidiomycetes, deuteromycetes and oomycetes. The inhibition rate of the preferable compound Ic-37 on various pathogenic bacteria at the low concentration of 0.05 mM is remarkably superior to that of maternal coumoxystrobin, and the synergistic interaction effect of the structural design is proved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pesticide compounds, and particularly relates to a coumoxystrobin derivative containing a triphenylphosphonium salt group, a preparation method and application thereof. BACKGROUND

[0002] Mitochondria, as the core organelle of fungal energy metabolism, not only serves as the site of cellular respiration and ATP synthesis, but also is the key node of regulating cell apoptosis. The inner membrane of mitochondria maintains a membrane potential of about-180 mV, which provides a natural targeting enrichment condition for lipophilic cationic compounds. As a typical mitochondrial targeting carrier, triphenylphosphonium salt (TPP) can achieve 10-100 times concentration enrichment in the mitochondrial matrix of fungi through the active transport mechanism driven by the membrane potential, thereby significantly increasing the local concentration of the drug at the target site, enhancing the drug efficacy and reducing the toxicity to non-target organisms.

[0003] Coumoxystrobin is the first self-invented strobilurin fungicide in China, which has broad-spectrum and high-efficiency fungicidal properties. Its molecular structure combines coumarin and methoxy acrylate active groups, forming a unique “coumarin-methoxy acrylate” bifunctional pharmacophore. The coumarin structure not only endows the molecule with good light stability and systemicity, but also enhances the binding ability to biological membranes through its conjugated system; while the methoxy acrylate fragment is responsible for specific binding to the Qo site of cytochrome bc1 complex in the fungal mitochondrial respiratory chain, blocking the electron transfer from cytochrome b to c1, thereby inhibiting the oxidative phosphorylation process, leading to the interruption of ATP synthesis, and ultimately triggering fungal cell apoptosis. However, as a representative of traditional strobilurin fungicides, coumoxystrobin mainly relies on passive diffusion to enter fungal cells, lacking an active targeting mechanism, resulting in low enrichment efficiency in mitochondria. In practical application, in order to maintain an effective concentration at the target site, it is often necessary to increase the dosage of the drug, which not only increases the cost of drug use, but also accelerates the evolution of fungal drug resistance. In addition, traditional strobilurin fungicides may also have cross effects on the mitochondria of non-target organisms (such as mammals and beneficial insects), posing potential environmental and ecological risks. SUMMARY

[0004] Therefore, the coumarin methoxy acrylate active fragment of coumoxystrobin is covalently linked to the triphenylphosphonium salt (TPP) mitochondrial targeting carrier through reasonable linker design to construct a new type of mitochondrial respiratory chain complex-targeted fungicide compound. This design not only retains the original electron transport chain inhibition function of coumoxystrobin, but also realizes the precise enrichment of the drug in the mitochondria of fungi through the active targeting action of TPP, thereby significantly improving the fungicidal efficiency.

[0005] In order to achieve the above object, the technical scheme of the present application is as follows:

[0006] In the first aspect, the present application discloses a coumeran derivative containing a triphenylphosphonium salt group, which is composed of the following three parts in sequence:

[0007] (1) a coumeran active fragment, which contains a coumarin ring and a methoxy acrylate structure;

[0008] (2) a flexible connecting unit, which has the structure of wherein n is an integer from 1 to 16, and X is selected from O or NH;

[0009] (3) a triphenylphosphonium salt targeting group, which has the structure of wherein Y - is a pharmaceutically acceptable negative anion.

[0010] Specifically, the coumeran derivative includes three types of structures of I-a, I-b and I-c in formula I, and the specific structures are as follows:

[0011]

[0012] In formula I, X is selected from O or NH;

[0013] Y is selected from Cl, Br, I, CH3SO3, CF3CO2, CH3CO2, CF3SO3 or PhCO2; and n is an integer from 1 to 16.

[0014] M is selected from CH or N.

[0015] When X is selected from O, formula I-a is named as IaO; and when X is selected from NH, formula I-a is named as IaN.

[0016] Formula I-b is abbreviated as Ib; and formula I-c is abbreviated as Ic; the structural formulas of IaO, IaN, Ib and Ic are as follows:

[0017] .

[0018] In order to more clearly illustrate the present application, the following table specifically lists the structures of substituent M, connecting unit length n and anion Y in representative compounds (IaO, IaN, Ib and Ic series).

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] In some embodiments of the present application, the coumeran derivative is a compound represented by I-c (Ic) :

[0034]

[0035] wherein M is preferably CH; n is preferably an integer from 3 to 12; and Y is selected from Cl, Br or I.

[0036] Specifically, the coumeran derivative includes a Z-type isomer, an E-type isomer, or a mixture of both in any ratio.

[0037] In a second aspect, the present application discloses a method for preparing the coumeran derivative as described above, comprising the following steps:

[0038] reacting a compound of formula II with triphenylphosphine in an organic solvent to undergo a nucleophilic substitution reaction, and obtaining the compound of formula I after the reaction and post-treatment;

[0039]

[0040] wherein the compound of formula II is selected from II-a, II-b or II-c;

[0041] The molar ratio of the compound of formula II to triphenylphosphine is 1:1 to 1:3.

[0042] The temperature of the nucleophilic substitution reaction is 30°C to 200°C, and the reaction time is 3 to 36 hours.

[0043] The definitions of X, Y, M and n in formula II are the same as those in formula I.

[0044] Specifically, the molar ratio of the compound of formula II to triphenylphosphine is 1:1.5 to 1:2.5, preferably 1:2.

[0045] Specifically, the temperature of the nucleophilic substitution reaction is 50°C to 100°C, preferably 80°C to 90°C.

[0046] Specifically, the time of the nucleophilic substitution reaction is 12 to 30 hours, preferably 20 to 26 hours.

[0047] In the preferred embodiment, the temperature of the nucleophilic substitution reaction is 80°C, and the time of the nucleophilic substitution reaction is 24 hours.

[0048] In some embodiments, the preparation of the compound of formula II-c comprises the following steps:

[0049] (1) under inert gas protection, reacting the compound of formula XIII with sodium hydride in an organic solvent at 50°C to 60°C for 0.5 to 2 hours;

[0050] (2) then cooling the reaction system to 0°C, adding the compound of formula XII, and performing ester exchange reaction at 0°C to 50°C for 2 to 10 hours, and obtaining the compound of formula XI after post-treatment;

[0051] (3) under inert gas protection and ice bath conditions, dissolving the compound of formula XI obtained in step (2) in an organic solvent with triphenylphosphine; adding carbon tetrabromide to the system, and reacting at 0°C to 50°C for 2 to 10 hours, and obtaining the compound of formula II-c after post-treatment;

[0052] wherein the molar ratio of the compound of formula XIII, sodium hydride and the compound of formula XII is 1:1.5-2.5:1.5-2.5; and the molar ratio of the compound of formula XI, triphenylphosphine and carbon tetrabromide is 1:1.0-1.5:1.0-1.5;

[0053] In the preferred embodiment, the material ratio of each step is as follows: in the step of preparing the compound of formula XI from the compound of formula XIII, the optimal molar ratio of the compound of formula XIII, sodium hydride and the compound of formula XII is 1:2:2; and in the bromination step of preparing the compound of formula II-c from the compound of formula XI, the optimal molar ratio of the compound of formula XI, triphenylphosphine and carbon tetrabromide is 1:1.2:1.2.

[0054] The structural formula of the compound of formula XII and the compound of formula XIII is as follows:

[0055] ;

[0056] The structural formula of the compound of formula XI is as follows:

[0057] .

[0058] The preparation route of the specific compound of formula II-c is shown below:

[0059] .

[0060] In some embodiments, the preparation of the compound of formula II-a comprises the following steps:

[0061] (1) condensing a compound of formula III with a compound of formula IV in an organic solvent in the presence of a condensing agent and a catalyst to obtain a compound of formula II-a;

[0062] The condensing agent is selected from DCC, EDC or HATU;

[0063] The catalyst is selected from DMAP or HOBt.

[0064] The molar ratio of the compound of formula III, the compound of formula IV, the condensing agent and the catalyst is 1:1:1.0-1.5:0.01-0.1; and the condensation reaction is carried out at -20°C to 35°C for 2 to 24 hours.

[0065] The preparation method of the compound of formula III comprises: deprotecting a compound of formula V with trifluoroacetic acid in an organic solvent to obtain a compound of formula III. The molar ratio of the compound of formula V to trifluoroacetic acid is 1:1.5-3.0; and the deprotection reaction is carried out at 0°C to 40°C for 1 to 8 hours.

[0066] The preparation method of the compound of formula V comprises: etherifying a compound of formula VI with a compound of formula VII in the presence of an inorganic base in an organic solvent to obtain a compound of formula V.

[0067] Specifically, the inorganic base is selected from potassium carbonate or cesium carbonate; the molar ratio of the compound of formula VI, the compound of formula VII and the inorganic base is 1:1:1.0-3.0; and the etherification reaction is carried out at 40°C to 100°C for 4 to 24 hours.

[0068] The structural formula of the compound of formula III and the compound of formula IV is shown below:

[0069] ;

[0070] The structural formula of the compound of formula V is shown below:

[0071] ;

[0072] The structural formula of the compound of formula VI and the compound of formula VII are as follows:

[0073] .

[0074] The preparation route of the specific compound of formula II-a is as follows:

[0075] .

[0076] In some embodiments, the preparation of the compound of formula II-b comprises the following steps:

[0077] The compound of formula VIII is subjected to bromination reaction with triphenylphosphine and carbon tetrabromide in inert gas protection and organic solvent to obtain the compound of formula II-b.

[0078] The molar ratio of the compound of formula VIII, triphenylphosphine and carbon tetrabromide is 1:1.0-1.5:1.0-1.5, preferably 1:1.2:1.2; the bromination reaction is carried out at 0°C to 50°C, and the reaction time is 2 to 10 hours.

[0079] The preparation method of the compound of formula VIII comprises: subjecting the compound of formula VIIII to etherification reaction with the compound of formula VII in the presence of organic solvent and inorganic base to obtain the compound of formula VIII.

[0080] The inorganic base is selected from potassium carbonate or cesium carbonate; the molar ratio of the compound of formula VIIII, the compound of formula VII and the inorganic base is (1-1.5):1:(1-3); the etherification reaction is carried out at 40°C to 100°C, and the reaction time is 4 to 24 hours.

[0081] The preparation method of the compound of formula VIIII is: subjecting the compound of formula X to cyclization condensation reaction with resorcinol in a mixed solution of concentrated sulfuric acid and ethanol to obtain the compound of formula VIIII.

[0082] The volume ratio of the concentrated sulfuric acid and ethanol is 5:5 to 8:2, preferably 7:3; the molar ratio of the compound of formula X and resorcinol is 1:1.0-2.0, preferably 1:1.5; the cyclization condensation reaction is carried out at 0°C to 30°C, and the reaction time is 2 to 8 hours.

[0083] The structural formula of the compound of formula VIII is as follows:

[0084] ;

[0085] The structural formula of the compound of formula VIIII and the compound of formula VII are as follows:

[0086] ;

[0087] The structural formula of the compound of formula X is shown as follows:

[0088]

[0089] The preparation route of the specific compound of formula II-b is shown as follows:

[0090]

[0091] In the method for preparing the coumethoxystrobins, the compounds can be obtained by commercial route or one-step reaction of raw materials.

[0092] In the method for preparing the coumethoxystrobins, the organic solvent is selected from acetonitrile, ethylene glycol dimethyl ether, benzene, toluene, 1,2-dichloroethane, or a mixed solvent of any proportion of the above-mentioned solvents, and is preferably acetonitrile.

[0093] The reaction is carried out under the protection of inert gas, which is nitrogen or argon, and is preferably nitrogen.

[0094] The post-treatment includes: after the reaction is completed, the reaction solution is cooled, the solvent is removed by concentration under reduced pressure, and the obtained crude product is purified by column chromatography or recrystallization to obtain the compound.

[0095] In a third aspect, the present application discloses a composition, which comprises 0.1-99% of the aforementioned coumethoxystrobins and an agriculturally acceptable carrier in percentage by weight.

[0096] The agriculturally acceptable carrier refers to a conventional carrier suitable for formulating agricultural fungicides, which can be compatible with the active ingredient and meet the requirements of application, storage, transportation and operation; the carrier includes a solid carrier, a liquid carrier and a compressed liquefied gas carrier.

[0097] The solid carrier is selected from at least one of natural or synthetic silicates, ammonium sulfate, calcium sulfate, aluminum silicate oxide, natural or synthetic resins, polychlorophenol, starch, bentonite and wax, wherein the natural or synthetic silicates are specifically at least one of attapulgite, talc, aluminum silicate, diatomite, mica, montmorillonite and calcium silicate, the natural or synthetic resins are specifically at least one of benzofuran resin, styrene polymer (molecular weight of 5-200,000) and styrene copolymer (such as styrene-butadiene copolymer), and the wax is specifically beeswax and / or paraffin wax.

[0098] The liquid carrier is selected from water, C1-C4 alcohol, C3-C8 ketone, aromatic hydrocarbon, petroleum distillate and C6-C 12 ​​at least one of the alcohols can be ethanol and / or ethylene glycol, at least one of the ketones can be acetophenone, acetone, methyl ethyl ketone and cyclohexanone, at least one of the aromatic hydrocarbons can be benzene, toluene and xylene, at least one of the petroleum fractions can be kerosene and / or mineral oil, and at least one of the chlorinated hydrocarbons can be carbon tetrachloride, dichloromethane and trichloroethane.

[0099] The composition provided by the present application can comprise a surfactant in an amount of a conventional amount of agricultural fungicides. The surfactant is selected from at least one of emulsifiers, dispersants, wetting agents and penetrants.

[0100] The emulsifier is selected from at least one of Farm Emulsifier 500#, Farm Emulsifier 600#, Farm Emulsifier 700#, Farm Emulsifier 1600#, polyoxyalkylene alkyl aryl ether and ethylene oxide-propylene oxide block copolymer; the dispersant is selected from at least one of polycarboxylate, lignin sulfonate, alkyl phenol polyoxyethylene formaldehyde condensate sulfate, calcium alkyl benzene sulfonate; the wetting agent is selected from at least one of sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and Laka Powder BX; and the penetrant is selected from at least one of siloxane polyoxyethylene ether, sulfonic acid alkyl aryl ester and alcohol ether succinate.

[0101] The composition can further comprise at least one of other agriculturally acceptable adjuvants, including disintegrants, antifoaming agents, antifreezing agents and thickening agents.

[0102] The composition can be formulated into at least one of wettable powder, emulsifiable concentrate, suspension concentrate and granules, and applied by foliar spraying, seed treatment or soil treatment.

[0103] In a fourth aspect, the present application discloses the use of the above-mentioned coumethoxystrobins or compositions in the preparation of fungicides for controlling plant pathogenic fungi.

[0104] The fungicides provided by the present application are particularly suitable for controlling plant diseases caused by four major classes of pathogenic fungi, i.e. Ascomycetes, Basidiomycetes, Deuteromycetes and Oomycetes, and exhibit excellent broad-spectrum fungicidal activity.

[0105] In specific applications, the coumethoxystrobins are applied in the fungicides at a dosage of 0.05 mM to 0.5 mM. Within this concentration range, the derivatives exhibit significantly superior fungicidal activity and a broader spectrum of fungicidal activity than the parent coumethoxystrobins.

[0106] Furthermore, the aforementioned fungicide can be used in combination with other fungicides of similar mechanisms of action, such as triazoles, methoxyacrylates, or succinate dehydrogenase inhibitors, to further broaden the control spectrum, improve control efficacy, and delay the development of resistance. This combination can significantly enhance the overall control effect against multiple plant diseases without increasing the application concentration.

[0107] Compared with the prior art, the present invention has the following beneficial effects:

[0108] (1) This invention covalently bonds the active fragment of eugenol to triphenylphosphonium salt via a reasonable linker, resulting in a significant synergistic effect. The representative compound Ic-37, at the same molar concentration, significantly outperforms the parent compound eugenol and some other compounds with different structural types in its inhibitory activity against various pathogenic fungi. Especially in the test against *Botrytis cinerea*, the causal agent of tomato fungus, where eugenol itself has low activity, Ic-37 exhibited an excellent inhibition rate of nearly 90%, demonstrating the great potential of the Ic-type structure in broadening the fungicidal spectrum and overcoming potential resistance.

[0109] (2) This invention successfully expands the antibacterial spectrum from the main targets of traditional fungicides to the four major pathogenic fungi (Ascomycetes, Basidiomycetes, Deuteromycetes and Oomycetes), especially achieving a key breakthrough in Oomycete diseases and solving the technical problem of limited spectrum of single agent control.

[0110] (3) This invention clarifies the intrinsic relationship between linker length and bactericidal activity, and finds that the 5-6 carbon chain length is the "golden range" for achieving the best activity, providing a clear direction for subsequent structural optimization. Detailed Implementation

[0111] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0112] The present invention will be further illustrated below with examples. It should be noted that the following examples are only for illustrating the present invention and are not intended to limit the present invention. Any non-essential improvements and adjustments made on the basis of the present invention shall fall within the scope of protection claimed by the present invention.

[0113] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0114] Example 1: Eugenol ester derivative IaO-35 and its preparation method

[0115] (1) Preparation of tert-butyl (E)-7-((2-(l,3-dimethoxy-3-oxoprop-l-en-2- yl)benzyl)oxy)-2-oxo-2H-chromene-3-carboxylate (Compound of Formula V)

[0116] tert-Butyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate (10.0 g, 38.1 mmol) and (E)-2-(2-(chloromethyl)phenyl)-3-methoxyacrylate (11.0 g, 42.8 mmol) were dissolved in 100 mL of N,N-dimethylformamide (DMF). To the solution was added 10.5 g (76.3 mmol) of anhydrous potassium carbonate and the reaction was stirred at 80 °C for 12 hours. After the reaction was completed as monitored by TLC, the reaction was allowed to cool to room temperature and poured into ice water. The organic phase was extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 3: 1, v / v) to give the title compound as a white solid in 63% yield.

[0117] (2) Preparation of (E)-7-((2-(l,3-dimethoxy-3-oxoprop-l-en-2-yl)benzyl)oxy)-2- oxo-2H-chromene-3-carboxylic acid (Compound of Formula III)

[0118] The ester obtained in Step (1) (10.0 g, 21.4 mmol) was dissolved in 100 mL of dichloromethane (DCM). To the solution was slowly added 4.89 g (42.9 mmol) of trifluoroacetic acid dropwise at 0 °C in an ice bath. After the addition was completed, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. After the disappearance of the starting material was confirmed by TLC, the reaction was concentrated to dryness under reduced pressure to give the crude carboxylic acid. The crude product was slurried with diethyl ether, suction filtered and dried to be used directly in the next step in 91% yield.

[0119] (3) Preparation of 3-bromopropyl (E)-7-((2-(l,3-dimethoxy-3-oxoprop-l-en-2- yl)benzyl)oxy)-2-oxo-2H-chromene-3-carboxylate (Compound of Formula II-a)

[0120] The carboxylic acid from step (2) (8.0 g, 19.5 mmol) was dissolved in 80 mL of dry dichloromethane and cooled to 0 °C in an ice bath. With stirring, 4.8 g (23.4 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) and 119 mg (0.97 mmol) of 4-dimethylaminopyridine (DMAP) were added sequentially. After stirring at this temperature for 30 min, 2.7 g (19.5 mmol) of 3-bromo-1-propanol was added dropwise. After the addition was complete, the reaction was allowed to warm to room temperature and stirred overnight (ca. 12 h). After the reaction was complete, the white precipitate (urea) was removed by filtration, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 4:1, v / v) to give the title bromide as a colorless oil in 74% yield.

[0121] (4) Preparation of Compound IaO-35

[0122] The bromide from step (3) (2.0 g, 3.8 mmol) was dissolved in 20 mL of dry acetonitrile under nitrogen protection. To this solution was added dropwise a solution of 1.9 g (7.6 mmol) of triphenylphosphine in 5 mL of acetonitrile. After the addition was complete, the reaction system was heated to reflux (ca. 85 °C) and stirred at this temperature for 24 h. After the reaction was complete, the reaction was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 10:1, v / v) to give the title compound IaO-35 as a white solid in 51% yield.

[0123] IaO-35: 1 H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 7.92 – 7.84 (m, 6H),7.80 – 7.65 (m, 10H), 7.61 (s, 1H), 7.47 (dd, J = 5.6, 3.5 Hz, 1H), 7.33 (dd,J = 5.8, 3.4 Hz, 2H), 7.18 (dd, J = 5.6, 3.4 Hz, 1H), 6.90 (dd, J = 8.7, 2.4Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 5.05 (s, 2H), 4.63 – 4.49 (m, 2H), 4.18 –4.11 (m, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 2.21 – 2.09 (m, 2H). 13C NMR (126 MHz, CDC13) δ 167.70, 164.46, 163.41, 160.37, 157.50, 157.45, 150.50, 135.11, 135.09, 134.50, 133.84, 133.75, 131.62, 131.47, 131.32, 130.59, 130.49, 128.24, 128.09, 127.41, 118.33, 117.65, 114.28, 113.04, 111.92, 109.74, 101.29, 68.83, 64.36, 64.23, 62.28, 51.83, 22.42, 22.39, 19.88, 19.46.

[0124] Example 2: Coumermycin derivative Ib-35 and a method for preparing the same

[0125] This example demonstrates a preparation route of the compound of type I-b.

[0126] (1) Preparation of 7-hydroxy-3-(3-hydroxypropyl)-4-methyl-2H-chromen-2-one (compound of formula VIIII)

[0127] Dissolve 10.0 g (53.1 mmol) of ethyl 2-acetyl-5-hydroxypentanoate in a mixed solution of concentrated sulfuric acid and ethanol (V:V = 7:3) of 30 mL. Under ice-bath cooling and stirring, add 8.6 g (80.0 mmol) of resorcinol in batches. After the addition, remove the ice bath and react at room temperature for 8 hours. Slowly pour the reaction solution into crushed ice and extract with ethyl acetate three times. Wash the combined organic phase with saturated sodium bicarbonate solution and brine successively, and dry over anhydrous sodium sulfate. After filtration and concentration, the obtained crude product is recrystallized from ethanol to obtain the title coumarin derivative as white needle-like crystals with a yield of 43%.

[0128] (2) Preparation of methyl (E)-2-(2-(((3-(3-hydroxypropyl)-4-methyl-2-oxo-2H-chromen-7- yl)oxy)methyl)phenyl)-3-methoxyacrylate (compound of formula VIII)

[0129] The alcohol obtained in step (1) (6.0 g, 25.6 mmol), 8.8 g, (30.1 mmol) (E)-2-(2-(chloromethyl)phenyl)-3-methoxyacrylate and 7.1 g (51.2 mmol) of anhydrous potassium carbonate were suspended in 80 mL of anhydrous DMF. The mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1, v / v) to obtain the title enoate compound in a yield of 64%.

[0130] (3) Preparation of methyl (E)-2-(2-(((3-(3-bromopropyl)-4-methyl-2-oxo-2H-chromen-7- yl)oxy)methyl)phenyl)-3-methoxyacrylate (compound of formula II-b)

[0131] The enoate compound obtained in step (2) (6.0 g, 13.7 mmol) and 3.6 g (13.7 mmol) of triphenylphosphine were dissolved in 50 mL of anhydrous dichloromethane under nitrogen protection and ice bath cooling. A solution of 6.8 g (20.5 mmol) of carbon tetrabromide in 20 mL of dichloromethane was slowly added dropwise with stirring. After the addition was completed, the reaction was continued at room temperature for 10 hours. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1, v / v) to obtain the title bromide in a yield of 86%.

[0132] (4) Preparation of compound Ib-35

[0133] Referring to the method of step (4) of Example 1, the bromide obtained in step (3) (5.0 g, 10.0 mmol) was used as a raw material and reacted with 5.2 g (20.0 mmol) of triphenylphosphine in 20 mL of acetonitrile. After work-up and column chromatography purification, the title compound Ib-35 was obtained in a yield of 54%.

[0134] Ib-35: 1H NMR (500 MHz, CDCl3) δ 7.90 - 7.71 (m, 9H), 7.65 (td, J = 7.8, 3.3 Hz, 6H), 7.59 (s, 1H), 7.52 - 7.42 (m, 2H), 7.33 - 7.27 (m, 2H), 7.16 (dd, J = 5.7, 3.4 Hz, 1H), 6.83 (dd, J = 8.9, 2.5 Hz, 1H), 6.68 (dd, J = 2.5, 1.2 Hz, 1H), 4.99 (s, 2H), 3.96 - 3.88 (m, 2H), 3.83 (s, 3H), 3.69 (d, J = 1.1 Hz, 3H), 3.04 (t, J = 7.8 Hz, 2H), 2.60 - 2.43 (m, 3H), 1.91 (h, J = 9.0 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 167.78, 162.17, 160.96, 160.26, 153.57, 149.15, 149.12, 135.04, 135.01, 134.98, 133.76, 133.69, 131.38, 131.20, 130.50, 130.41, 128.14, 127.85, 127.34, 126.04, 121.10, 118.65, 118.63, 117.96, 117.95, 114.23, 112.88, 109.84, 101.52, 68.39, 62.21, 51.80, 28.43, 28.29, 22.71, 22.31, 21.61, 21.58, 15.93.

[0135] Example 3: Coumermycin derivative Ic-37 and a method for preparing the same

[0136] This example illustrates in detail the preparation route of the I-c type compound which is the focus of the present application.

[0137] (1) Preparation of 5-hydroxypentyl (E)-3-methoxy-2-(2-(((4-methyl-2-oxo-3- propyl-2H-chromen-7-yl)oxy)methyl)phenyl)acrylate (compound of formula XI)

[0138] Under nitrogen protection and at room temperature, 10.0 g (22.2 mmol) of coumarin was dissolved in 50 mL of anhydrous tetrahydrofuran (THF). Under stirring, 1.3 g (32.2 mmol, 60% dispersion in mineral oil) of sodium hydride (NaH) was added carefully in small portions. After the addition was completed, the reaction mixture was warmed to 50°C and stirred for 1 hour to ensure the complete formation of phenoxide anion. Subsequently, the reaction solution was re-cooled to 0°C (ice bath). At 0°C, a solution of 2.3 g (22.2 mmol) of 1,5-pentanediol in 10 mL of THF was added dropwise slowly. After the addition was completed, the reaction was continued to stir at 0°C for 3 hours. TLC monitoring showed that the coumarin starting material was almost completely consumed. The reaction solution was carefully poured into ice water and the pH was adjusted to neutral with 1M dilute hydrochloric acid. It was extracted with ethyl acetate for three times, and the organic phase was combined and washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1 gradient elution to 1:1, v / v) to give the title hydroxy ester compound as a colorless viscous liquid in a yield of 36%.

[0139] (2) Preparation of 5-bromopentyl (E)-2-(2-(((3-butyl-4-methyl-2-oxo-2H-chromen-7- yl)oxy)methyl)phenyl)-3-methoxyacrylate (compound of formula II-c)

[0140] Under nitrogen protection and at 0°C ice bath, the hydroxy ester compound obtained from step (1) (4.0 g, 7.6 mmol) and 2.0 g (7.6 mmol) of triphenylphosphine were dissolved in 40 mL of anhydrous dichloromethane. Under light shielding condition, a solution of 3.1 g (9.2 mmol) of carbon tetrabromide in 15 mL of dichloromethane was added dropwise slowly. White precipitate was generated during the addition. After the addition was completed, the reaction was continued to react at room temperature for 10 hours under light shielding. After the reaction was completed as monitored by TLC, the reaction solution was directly concentrated under reduced pressure. The residue was quickly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8:1, v / v) to give the title bromo intermediate II-c as a light yellow oil in a yield of 79%. The product was unstable and should be used as soon as possible for the next step reaction.

[0141] (3) Preparation of compound Ic-37

[0142] The bromide II-c (2.0 g, 3.4 mmol) obtained in Step (2) was dissolved in 15 mL of dry acetonitrile under nitrogen protection. To this solution was added slowly and dropwise a solution of 1.8 g (6.8 mmol) of triphenylphosphine in 5 mL of acetonitrile. After the addition was completed, the reaction mixture was heated to reflux (about 85 °C) and stirred at this temperature for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature and a solid was precipitated. After the partial solvent was removed by evaporation under reduced pressure, the solid was filtered, washed with a small amount of cold acetonitrile, and further purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15:1, v / v) to obtain the title compound Ic-37 as a white solid in a yield of 56%.

[0143] Ic-37: 1 H NMR (500 MHz, CDCl3) δ 7.85 – 7.69 (m, 9H), 7.69 – 7.59 (m,7H), 7.46 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 6.9, 2.0 Hz, 1H), 7.25 – 7.17(m, 2H), 6.85 (dd, J = 8.9, 2.6 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 4.99 (s,2H), 4.03 (d, J = 6.3 Hz, 2H), 3.77 – 3.70 (m, 2H), 3.69 (s, 3H), 2.51 (t, J= 8.0 Hz, 2H), 2.32 (s, 3H), 1.70 (d, J = 4.8 Hz, 4H), 1.64 (q, J = 7.9 Hz,2H), 1.45 – 1.30 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ167.8, 162.0, 160.6, 159.3, 153.4, 146.2, 135.2, 135.0, 135.0, 133.7, 133.6,131.4, 131.3, 130.5, 130.4, 127.9, 127.6, 126.8, 125.5, 123.5, 118.6, 117.9,114.3, 112.9, 109.4, 101.5, 75.0, 68.3, 51.7, 30.9, 29.0, 27.2, 26.3, 26.2,22.8, 22.4, 22.1, 22.1, 14.9, 14.0.

[0144] Example 4 Wettable powder containing 50% of compound Ic-37

[0145] Formulation: Compound Ic-37 50.0%, polycarboxylate (dispersant) 5.0%, sodium dodecyl sulfate (wetting agent) 3.0%, bentonite (filler / disintegrant) to 100%;

[0146] Preparation method: The above components are mixed uniformly in proportion in advance, and then sent to an air jet mill for micronization to ensure that the particle size reaches D95 < 10 μm. The crushed material is mixed uniformly again to obtain the wettable powder containing 50% of compound Ic-37.

[0147] Example 5 Emulsifiable concentrate containing 30% of compound Ic-37

[0148] Formulation: Compound Ic-37 30.0%, alkylphenol formaldehyde resin polyoxyethyl ether (emulsifier) 12.0%, alkyl aryl sulfonate (penetrant) 10%, liquid carrier cyclohexanone to 100%;

[0149] Preparation method: The above components are added in proportion to a mixing container in sequence, stirred at room temperature until completely dissolved to form a uniform transparent solution, and after quality inspection, the emulsifiable concentrate containing 30% of compound Ic-37 is obtained.

[0150] Example 6 Water dispersible granules containing 70% of compound Ic-37

[0151] Formulation: Compound Ic-37 70.0%, calcium alkylbenzenesulfonate (dispersant) 3.0%, lignosulfonate (dispersant) 3.0%, sodium dodecyl sulfate (wetting agent) 4.0%, starch (solid carrier / filler) to 100%;

[0152] Preparation method: The above components are mixed uniformly in proportion in advance, treated by a super-micro pulverizer to a particle size of D95 < 15 μm. The crushed material is granulated with water, dried in a fluidized bed at 50-60°C to a moisture content of < 3%, and finally sieved to obtain granules with a particle size range of 150-850 μm, thereby obtaining the water dispersible granules containing 70% of compound Ic-37.

[0153] Effect example: Determination of the fungicidal activity of the clofentezine derivative of the present application

[0154] The effect example aims to verify the fungicidal activity of the new compound constructed by covalently connecting the coumarin methoxyl acrylate active fragment in coumethoxystrobin with triphenyl phosphonium salt mitochondrial targeting carrier through reasonable linker design. The experiment not only takes the representative compounds prepared in Examples 1-3 as the core test object, but also investigates other series of compounds composed of the general formula. At the same time, coumethoxystrobin parent and triphenyl phosphine are set as parallel controls, and the inhibition rates of each sample on pathogenic fungal mycelial growth under the same conditions are compared.

[0155] Test method: Mycelial growth rate method (referring to the People's Republic of China Agricultural Industry Standard NY / T 1156.2-2006) was adopted. Under sterile conditions, the test pathogenic fungi (such as Sclerotinia sclerotiorum, Fusarium oxysporum f. sp. niveum, etc.) were inoculated in the center of the PDA plate containing the drug, and the plate without the drug was used as a blank control. Each treatment was set with 3 replicates. The culture dishes were placed in a 25°C constant temperature incubator for incubation, and when the colony diameter of the control group reached 6-8 cm, the cross method was used to measure the colony diameter of each treatment.

[0156] Colony growth diameter (mm) = measured colony diameter - petri dish diameter;

[0157] Mycelial growth inhibition rate (%) = [(control colony growth diameter - treatment colony growth diameter) / control colony growth diameter] x 100%.

[0158] Table 1 is the inhibition rate determination results of each test compound (0.05 mM) on representative pathogenic fungi.

[0159] Table 1 Fungicidal activity comparison test results Inhibition rate % (0.05 mM)

[0160]

[0161] Table 2 Number and chemical structure characteristics of each test compound

[0162]

[0163] As can be seen from Table 1 and Table 2, the length (n) of the linker is a key factor affecting the activity: when the length n of the linker is 5 or 6 (such as Ic-37, Ic-38), the compounds generally exhibit optimal and balanced broad-spectrum high activity; when n is shortened to 3 (such as IaO-35, Ib-35), the activity spectrum is narrowed, and the activity against some pathogenic fungi (such as wheat scab and cotton damping-off) is significantly reduced; when n is extended to 8 or more (such as Ic-40, Ic-41, Ic-44, Ic-47), the overall activity is sharply reduced, and there is almost no effect on key pathogenic fungi such as P. aphanidermatum and P. capsici. This indicates that too long a linker may destroy the effective interaction between the pharmacophore and the target. Under the same or similar length of the linker, the activity and broad spectrum of I-c type compounds (such as Ic-37, Ic-38) are generally superior to those of corresponding IaO type and Ib type compounds. The high-activity compound (such as Ic-37) has significantly higher inhibition rate than coumoxystrobin against most of the tested pathogenic fungi, especially for P. capsici (Ic-37: 73.26% vs coumoxystrobin: 8.71%) and wheat scab (Ic-37: 65.78% vs coumoxystrobin: 20.67%) for which coumoxystrobin has relatively weak activity, and the improvement is huge. This strongly proves that coupling the active fragment of coumoxystrobin with triphenylphosphonium salt through a linker of appropriate length produces a significant synergistic effect, rather than a simple additive effect. The synergistic mechanism is that the mitochondrial targeting of triphenylphosphonium salt (TPP) greatly increases the local concentration of the active fragment at the target site, and the linker of appropriate length ensures the optimal spatial combination of the fragment and the target, thereby achieving a doubling of the efficacy.

[0164] In summary, the present application uses I-c as the mother nucleus, and is combined with a linker of 5-6 carbon atoms in length (such as the lead compound Ic-37), which is the optimal structure combination for achieving broad-spectrum and high-efficiency fungicidal activity. This design cleverly uses linker length optimization to achieve the best spatial synergy of the two pharmacophores (the coumoxystrobin fragment and the triphenylphosphonium salt) within the molecule, and ultimately achieves a breakthrough improvement in fungicidal activity. Through synergistic effect, the present application successfully expands the prevention spectrum from the main target of traditional fungicides (such as ascomycetes) to four major pathogenic fungal classes including oomycetes and basidiomycetes, and provides a breakthrough solution for single molecules to solve the problem of multiple crop diseases.

Claims

1. A eugenol derivative containing a triphenylphosphonium salt group, characterized in that, The eugenol derivative is composed of the following three parts connected in sequence: (1) Eugenol active fragment, which contains a coumarin ring and a methoxyacrylate structure; (2) Flexible connecting unit, the structure of which is -(CH2) n -X-, where n is an integer from 1 to 16, and X is selected from 0 or NH; (3) Triphenylphosphonium salt targeting group, the structure of which is -P + (Ph)3·Y - , where Y - It is a pharmaceutically acceptable negatively charged anion.

2. The eugenol derivative according to claim 1, characterized in that, The eugenol derivatives include three types of structures, Ia, Ib, and Ic, as shown in Formula I, with the specific structures as follows: In Formula I, X is selected from O or NH; Y is selected from Cl, Br, I, CH3SO3, CF3CO2, CH3CO2, CF3SO3 or PhCO2; n is an integer from 1 to 16; M is selected from CH or N; The eugenol derivatives include Z-isomers, E-isomers, or a mixture of both in any proportion.

3. The eugenol derivative according to claim 2, characterized in that, The eugenol derivative is the compound shown in Ic: Wherein, M is preferably CH; n is preferably an integer between 3 and 12; Y is selected from Cl, Br or I.

4. A method for preparing the eugenol derivative as described in claim 1, characterized in that, The method includes the following steps: In an organic solvent, compound II is subjected to a nucleophilic substitution reaction with triphenylphosphine, and after the reaction is completed, compound I is obtained by post-treatment. The structural formula of compound II is shown below: Wherein, the compound of formula II is selected from II-a, II-b or II-c; The molar ratio of the compound of formula II to triphenylphosphine is 1:1 to 1:3; The nucleophilic substitution reaction is carried out at a temperature of 30°C to 200°C for a reaction time of 3 to 36 hours. The definitions of X, Y, M, and n in Equation II are the same as those in Equation I.

5. The method according to claim 4, characterized in that, The molar ratio of the compound of formula II to triphenylphosphine is from 1:1.5 to 1:2.5; The nucleophilic substitution reaction is performed at a temperature of 50°C to 100°C. The nucleophilic substitution reaction takes 12 to 30 hours.

6. The method according to claim 4, characterized in that, The preparation of the compound of formula II-c includes the following steps: (1) Under the protection of an inert gas, in an organic solvent, the compound of formula XIII is reacted with sodium hydride at 50°C to 60°C for 0.5 to 2 hours; (2) The reaction system was then cooled to 0°C, and compound XII was added. The transesterification reaction was carried out at 0°C to 50°C for 2 to 10 hours. After post-treatment, compound XI was obtained. (3) Under inert gas protection and ice bath conditions, the compound of formula XI obtained in step (2) and triphenylphosphine are dissolved in an organic solvent; carbon tetrabromide is added to the system and reacted at 0°C to 50°C for 2 to 10 hours, and after post-treatment, the compound of formula II-c is obtained. Wherein, the molar ratio of compound XIII, sodium hydride and compound XII is 1:1.5-2.5:1.5-2.5; the molar ratio of compound XI, triphenylphosphine and carbon tetrabromide is 1:1.0-1.5:1.0-1.5; The structural formulas of compounds XII and XIII are shown below: The structural formula of compound XI is shown below:

7. The method according to claim 6, characterized in that, The organic solvent is selected from acetonitrile, ethylene glycol dimethyl ether, benzene, toluene, 1,2-dichloroethane, or any mixture of the above solvents in any proportion, preferably acetonitrile.

8. A composition, characterized in that, The composition comprises, by weight percentage, 0.1-99% of the eugenol derivative of any one of claims 1-3, and an agriculturally acceptable carrier; Agriculturally acceptable carriers include solid carriers and / or liquid carriers; The solid carrier is selected from at least one of silicates, diatomaceous earth, kaolin, bentonite, talc, calcium carbonate, silica, starch, sucrose, urea, ammonium sulfate, or resin. The liquid carrier is selected from at least one of water, ethanol, ethylene glycol, acetone, methyl ethyl ketone, cyclohexanone, toluene, xylene, mesitylene, kerosene, mineral oil, N,N-dimethylformamide, dimethyl sulfoxide, or vegetable oil.

9. The composition according to claim 8, characterized in that, The composition also contains surfactants and / or other auxiliaries; The surfactant is selected from at least one of emulsifiers, dispersants, wetting agents, or penetrants; The other additives are selected from at least one of disintegrants, defoamers, antifreeze agents, or thickeners.

10. The use of the eugenol derivative according to any one of claims 1-3 or the composition according to claim 8 in the preparation of a fungicide for controlling plant pathogenic fungi, characterized in that, The fungicide is used to prevent and control plant diseases caused by ascomycetes, basidiomycetes, deuteromycetes, or oomycetes; the dosage of the eugenol derivative in the fungicide is 0.05 mM to 0.5 mM.

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