Diflunisal derivative, preparation method and application thereof
By synthesizing diflunisal derivatives, the problems of simple structure and complex synthesis of existing SDHI fungicides have been solved, providing a novel fungicide with a novel structure and high-efficiency fungicidal activity, suitable for the prevention and control of plant diseases and providing a solution for drug resistance.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG ACADEMY OF PESTICIDE SCI
- Filing Date
- 2026-04-29
- Publication Date
- 2026-05-29
AI Technical Summary
Existing SDHI-type fungicides suffer from problems such as simple structure, complex synthesis, and high cost in agricultural applications, lacking compounds with novel structures and highly efficient fungicidal activity.
A class of diflunisal derivatives was designed and synthesized. By linking diflunisal with various aromatic or heterocyclic amines through amide bonds, a novel compound with a biphenyl skeleton was prepared using a simple one-pot condensation reaction, which can be used to prepare bactericides.
This study provides novel, simple to synthesize, and low-cost diflunisal derivatives that significantly inhibit various plant pathogenic fungi, solve the problem of drug resistance, and broaden the application potential of SDHI fungicides.
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Figure CN122102939A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of sterilization technology, specifically relating to a diflunisal derivative, its preparation method, and its application. Background Technology
[0002] The information disclosed in this background section is intended only to enhance some understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art.
[0003] Over the past decade, the continuous launch of new succinate dehydrogenase inhibitor (SDHI) fungicides has led to a year-on-year increase in sales. Currently, there are over 20 SDHI fungicides on the market, seven of which achieved sales exceeding $100 million in 2019: fluopyram, benzalkonium chloride, boscalid, bifenthrin, fluopyram, pyraclostrobin, and fluoxastrobin. New SDHI fungicides continue to emerge, with products like Syngenta's recently launched fluopyram, Sumitomo Chemical's inpyrfluxam, Bayer Crop Science's isoflucypram, and FMC's fluinbazin all showing significant market growth potential, further driving market growth for this class of fungicides. According to FRAC's list of SDHI fungicides, this class of fungicides is primarily explored from the perspectives of the carboxylic acid moiety, amine moiety, and amide bond moiety. The carboxylic acid moiety mainly consists of oxothiocyclohexadiene, pyridine, phenyl, furan, thiophene, thiazole, pyrazole, pyrazine, etc.
[0004] Recent studies have revealed that diflunisal and its derivatives not only exhibit significant anti-inflammatory and analgesic activities, but also show increasing potential as novel fungicides in agriculture. However, to promote the practical application of these promising compounds in agriculture, it is urgent to develop novel diflunisal derivatives with novel structures, excellent activity, and simple, efficient, and cost-effective synthetic routes. Summary of the Invention
[0005] To address the shortcomings of existing methods, this invention designs and synthesizes a diflunisal derivative. The target compound exhibits good bactericidal activity and has a low synthesis cost. No related reports have been found, indicating its potential for further research.
[0006] The technical solution adopted in this invention is as follows: In a first aspect of the invention, a diflunisal derivative is provided, the structure of which is shown in general formula I: I In the formula, R is selected from 4-fluorophenylethyl, 4-trifluoromethylphenylethyl, 4-methylphenylethyl, 2-bromophenyl, 2-fluorophenyl, 2,6-difluoroaniline, 2-fluoro-4-chloroaniline, 4-chloroaniline, phenylpropyl, (6-chloropyridin-3-yl)methyl, and 2-(pyridin-2-yl)ethyl.
[0007] Preferably, the compound is any of the following compounds: 2′,4′-Difluoro-N-(4-fluorophenylethyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-71); 2′,4′-Difluoro-N-(4-trifluoromethylphenylethyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-72); 2′,4′-Difluoro-N-(4-methylphenylethyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-73); 2′,4′-Difluoro-N-(2-bromophenyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-74); 2′,4′-Difluoro-N-(2-fluorophenyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-75); 2′,4′-Difluoro-N-(2,6-difluoroaniline)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-76); 2′,4′-Difluoro-N-(2-fluoro-4-chloroaniline)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-77); 2′,4′-Difluoro-N-(4-chloroaniline)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-78); 2′,4′-Difluoro-N-(phenylpropyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-79); 2′,4′-Difluoro-N-((6-chloropyridin-3-yl)methyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-80); 2′,4′-Difluoro-N-(2-(pyridin-2-yl)ethyl)-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (code name HA-81).
[0008] In a second aspect of the invention, a method for preparing the diflunisal derivative is provided, the method comprising the following steps: Diflunisal (2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxylic acid) was mixed with a condensing agent and an organic base in an ice bath and an inert organic solvent, and activated for 10-30 minutes. Then, an amine compound (R-NH2) corresponding to the target compound was added, and the reaction was stirred at room temperature for 20-28 hours. After the reaction was complete, the target diflunisal derivative was obtained by extraction, washing, drying, concentration, and column chromatography purification.
[0009] The condensing agent is preferably (7-azabenzotriazol-1-yloxy)tripyrrolidinyl hexafluorophosphate (PyAOP); the organic base is preferably N,N-diisopropylethylamine (DIPEA); and the inert organic solvent is preferably dichloromethane.
[0010] The reaction formula is:
[0011] In a third aspect of the invention, the use of the diflunisal derivative in the preparation of a bactericide is provided.
[0012] Furthermore, the fungicide is used to control diseases caused by plant pathogenic fungi, which preferably include, but are not limited to, *Gyromyces cucumeris* (the causal agent of gray mold in cucumbers). Botrytis cinerea Rice sheath blight pathogen ( Rhizoctonia solani ), rapeseed sclerotinia pathogen ( Sclerotinia sclerotiorum ), wheat scab ( Fusarium graminearum ), tomato early blight pathogen ( Alternaria solani Rice blast fungus ( Magnaporthe oryzae ).
[0013] In a fourth aspect of the invention, a fungicide composition is provided, comprising a diflunisal derivative of the above-described general formula I as an active ingredient, and an agriculturally acceptable carrier and / or adjuvant.
[0014] Furthermore, the composition can be formulated into any dosage form known in the art, such as wettable powder, water-dispersible granules, suspension concentrate, emulsifiable concentrate, water emulsion, etc. The active ingredient constitutes 0.1% to 99% of the composition by mass.
[0015] Compared with the related technologies known to the inventors, one of the technical solutions of the present invention has the following beneficial effects: (1) Novel structure, broadening the lead structure of SDHI-type fungicides: This invention is the first to use diflunisal, which has a biphenyl skeleton, as the carboxylic acid moiety and connect it with various aromatic or heterocyclic amines through amide bonds to construct a new class of compounds. This type of structure has not been reported in commercially available SDHI-type fungicides, providing a new library of candidate compounds for the development of fungicides with novel mechanisms of action.
[0016] (2) The synthesis method is simple, efficient and low cost: The preparation method provided by the present invention adopts a "one-pot" condensation reaction, which is simple in steps and easy to operate. It does not require complex functional group protection and deprotection, the reaction conditions are mild, and the raw materials and reagents used are all conventional and readily available, which significantly reduces the synthesis cost and is conducive to industrial production.
[0017] (3) Excellent broad-spectrum bactericidal activity: Activity tests show that multiple compounds of the present invention exhibit significant inhibitory effects against various important agricultural pathogens at a concentration of 50 mg / L. For example, compound HA-79 showed an inhibitory activity of 50% against cucumber gray mold, while HA-72 and HA-75 showed inhibition rates of over 40%. Compounds HA-77 and HA-81 showed inhibitory activities of over 60% against rapeseed sclerotinia sclerotinia. Compounds HA-80 and HA-81 showed inhibitory activities of over 70% against rice sheath blight. Compound HA-75 showed an inhibitory activity of 60% against wheat scab. Compound HA-78 showed an inhibitory activity of over 50% against tomato early blight. Compound HA-80 showed an inhibitory activity of over 50% against wheat scab.
[0018] (4) Provides a new option for solving the problem of drug resistance: Given its novel core structure, the compound of the present invention may have different binding modes or mechanisms of action with existing SDHI fungicides, which can help to deal with the increasingly serious problem of pathogen resistance in current agricultural production and provide a new solution for disease control.
[0019] In summary, this invention provides a novel, easy-to-prepare, and highly active diflunisal derivative, which has promising applications in the field of agricultural sterilization. Attached Figure Description
[0020] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.
[0021] Figure 1 Compounds HA-75, HA-80 and HA-81 exhibit antibacterial activity against rice sheath blight pathogen.
[0022] Figure 2 The inhibitory activity of compounds HA-74, HA-77 and HA-81 against Sclerotinia sclerotiorum var. sclerotiorum in rapeseed.
[0023] Figure 3 The antibacterial activity of compound HA-75 against Fusarium graminearum, the causal agent of wheat blight. Detailed Implementation
[0024] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
[0025] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.
[0026] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0027] Example 1: Preparation of compound HA-71
[0028] Under ice bath conditions, 0.799 mmol (200 mg) diflunisal, 10 mL dichloromethane, 0.879 mmol (458 mg) PyAOP, and 1.60 mmol (207 mg) DIPEA were added sequentially to a 100 mL single-necked flask, and the reaction was allowed to proceed for 15 min. Then, 0.799 mmol (111 mg) 4-fluorophenylethylamine was added with stirring, and the reaction was allowed to proceed for 24 h at room temperature. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation, and the mixture was extracted with water and dichloromethane. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 2',4'-difluoro-N-(4-fluorophenylethyl)-4-hydroxy-[1,1'-biphenyl]-3-carboxamide (white solid, yield 51%).
[0029] Example 2: Preparation of compound HA-79
[0030] Under ice bath conditions, 0.799 mmol (200 mg) diflunisal, 10 mL dichloromethane, 0.879 mmol (458 mg) PyAOP, and 1.60 mmol (207 mg) DIPEA were added sequentially to a 100 mL single-necked flask, and the reaction was allowed to proceed for 15 min. Then, 0.799 mmol (108 mg) amphetamine was added with stirring, and the reaction was allowed to proceed at room temperature for 24 h. After the reaction was complete as determined by TLC, the solvent was removed by rotary evaporation, and the mixture was extracted with water and dichloromethane. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 2',4'-difluoro-N-(phenylpropyl)-4-hydroxy-[1,1'-biphenyl]-3-carboxamide (yellow oil, yield 71%).
[0031] Example 3: Preparation of compound HA-81
[0032] Under ice bath conditions, 0.799 mmol (200 mg) diflunisal, 10 mL dichloromethane, 0.879 mmol (458 mg) PyAOP, and 1.60 mmol (207 mg) DIPEA were added sequentially to a 100 mL single-necked flask, and the reaction was allowed to proceed for 15 min. Then, 0.799 mmol (98 mg) 2-(pyridin-2-yl)ethylamine was added with stirring, and the reaction was allowed to proceed at room temperature for 24 h. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation, and the mixture was extracted with water and dichloromethane. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 2',4'-difluoro-N-(2-(pyridin-2-yl)ethyl)-4-hydroxy-[1,1'-biphenyl]-3-carboxamide (white solid, yield 74%).
[0033] Example 4: Preparation of other diflunisal derivatives (HA-72 to HA-78, HA-80) Following the general procedure of Example 1, diflunisal (200 mg, 0.799 mmol) was reacted with the corresponding amine starting materials to prepare the target compounds HA-72, HA-73, HA-74, HA-75, HA-76, HA-77, HA-78, and HA-80. The specific amine starting materials were: 4-trifluoromethylphenethylamine (HA-72), 4-methylphenethylamine (HA-73), 2-bromoaniline (HA-74), 2-fluoroaniline (HA-75), 2,6-difluoroaniline (HA-76), 2-fluoro-4-chloroaniline (HA-77), 4-chloroaniline (HA-78), and (6-chloropyridin-3-yl)methylamine (HA-80). Wherein, 2-bromoaniline, 2-fluoroaniline, 2,6-difluoroaniline, 2-fluoro-4-chloroaniline and 4-chloroaniline are used to form 2-bromophenyl, 2-fluorophenyl, 2,6-difluoroaniline, 2-fluoro-4-chloroaniline and 4-chloroaniline substituents in the target compound, respectively.
[0034] The ¹H NMR data of all the prepared compounds are shown in Table 2.
[0035] Example 5: Bactericidal activity test (in vitro plate method) The inhibitory activity of the compounds of this invention against various plant pathogenic fungi was tested using the mycelial growth rate method. The test compounds were dissolved in an appropriate amount of acetone and added to water containing 0.1% Tween-80 to prepare drug-containing plates (PDA medium) with a concentration of 50 mg / L. Plates treated with an equal volume of acetone and 0.1% Tween-80 aqueous solution served as blank controls.
[0036] Using a 5 mm diameter punch, take activated bacterial pellets from each pathogenic fungus onto a PDA plate, inoculating them with the mycelial side down in the center of the drug-containing plate. Repeat each treatment three times. Incubate in the dark in a constant temperature incubator at the appropriate temperature for the corresponding pathogen. When the diameter of the blank control colonies grows to approximately 2 / 3 of the plate diameter, measure the colony diameter of each treatment using the cross-sectional method and calculate the mycelial growth inhibition rate.
[0037] Inhibition rate (%) = [(Control colony diameter - Treated colony diameter) / (Control colony diameter - 5)] × 100% The test results are shown in the table below: Table 1: Inhibition rate (%) of the compounds of this invention on the mycelial growth of various plant pathogenic fungi at a concentration of 50 mg / L. ,
[0038] Experimental results showed that the compounds of this invention exhibited varying degrees of inhibitory activity against the tested pathogens at a concentration of 50 mg / L. Among them, compounds HA-75, HA-80, and HA-81 showed excellent activity against *Rhizoctonia solani* (inhibition rate ≥65%). Figure 1 Compounds HA-74, HA-77, and HA-81 showed good activity against *Sclerotinia sclerotinia* causal agent of rapeseed infection (inhibition rate ≥56%), such as... Figure 2 Compound HA-75 exhibited a 60% inhibition rate against Fusarium graminearum, the causal agent of wheat blight, demonstrating outstanding selective activity. Figure 3 .
[0039] Table 2: ¹H NMR data of the compounds of this invention ,
[0040] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A diflunisal derivative, characterized in that, The structure is shown in general formula I: Ⅰ， In the formula, R is selected from 4-fluorophenylethyl, 4-trifluoromethylphenylethyl, 4-methylphenylethyl, 2-bromophenyl, 2-fluorophenyl, 2,6-difluoroaniline, 2-fluoro-4-chloroaniline, 4-chloroaniline, phenylpropyl, (6-chloropyridin-3-yl)methyl or 2-(pyridin-2-yl)ethyl.
2. A method for preparing the diflunisal derivative according to claim 1, characterized in that, Includes the following steps: In an ice bath and in an inert organic solvent, 2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxylic acid was mixed with a condensing agent and an organic base and activated for 10-30 minutes; then an amine compound with the general formula R-NH2 was added, and the reaction was stirred at room temperature for 20-28 hours; after the reaction was complete, the target diflunisal derivative was obtained by extraction, washing, drying, concentration, and column chromatography purification.
3. The preparation method according to claim 2, characterized in that, The condensing agent is (7-azabenzotriazole-1-yloxy)tripyrrolidinyl hexafluorophosphate.
4. The preparation method according to claim 2, characterized in that, The organic base is N,N-diisopropylethylamine.
5. The preparation method according to claim 2, characterized in that, The inert organic solvent is dichloromethane.
6. The application of the diflunisal derivative according to claim 1 in the preparation of a bactericide, characterized in that, The fungicide is used to prevent and control diseases caused by plant pathogenic fungi; the plant pathogenic fungi are selected from *Gray Mold of Cucumber*. (Botrytis cinerea Rice sheath blight pathogen ( Rhizoctonia solani ), rapeseed sclerotinia pathogen ( Sclerotinia sclerotiorum ), wheat scab ( Fusarium graminearum ), tomato early blight pathogen ( Alternaria solani ) or rice blast fungus ( Magnaporthe oryzae One or more of the following.
7. A bactericide composition, characterized in that, It comprises the diflunisal derivative of claim 1 as an active ingredient, and an agriculturally acceptable carrier and / or adjuvant.
8. The bactericide composition according to claim 7, characterized in that, The active ingredient comprises 0.1% to 99% by mass in the composition.
9. The bactericide composition according to claim 7, characterized in that, The composition is in the form of a wettable powder, a water-dispersible granule, a suspension, an emulsifiable concentrate, or a water-emulsion.