A kind of bis-dihalogenphenol and its derivatives and preparation method and application

Abstract

The present invention belongs to the technical field of organic compounds, and specifically relates to a bis-dihalogenated phenol and its derivatives, and a preparation method and application thereof. The bis-dihalogenated phenol provided by the present invention has a structure as shown in Formula I, and the derivatives of the bis-dihalogenated phenol have structures as shown in Formula II and Formula III; wherein R1 and R2 are independently halogen atoms, nitro groups, alkyl groups, olefin groups or trifluoromethyl groups; R3 and R4 are independently metal ions, alkyl groups, olefin groups, methylaminoformyl groups or dialkoxyphosphoryl groups; R5 is ‑O‑, ‑S‑, ‑SO2‑, ‑NH‑, ‑CH2‑, ‑CO‑ or ‑SO‑; R6 and R7 are independently halogen atoms; and R8 is an alkyl group or an olefin group. The bis-dihalogenated phenol and its derivatives provided by the present invention have good inhibitory effects on plant pathogenic pathogens.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compounds, and specifically relates to a bis-dihalogen phenol and its derivatives, and a preparation method and application thereof. Background Art

[0002] Plant diseases refer to the phenomenon that plants undergo a series of morphological, physiological and biochemical pathological changes under the influence of biological or non-biological factors, which hinder the normal growth and development process and thus affect human economic benefits. Plant diseases include non-biological diseases and biological diseases. Among them, biological diseases of plants can be transmitted to each other and are more harmful to plants. Among biological diseases of plants, bacterial diseases of plants are the most common. With the change of crop planting system, plant bacterial diseases are becoming more and more serious. For example, wheat bud blight, rice sheath blight, gray mold, cotton verticillium wilt, fusarium wilt, watermelon wilt, etc. When the disease is serious, it will cause a significant reduction in production or even destroy the shed, which is a great threat to the production of protected vegetables. The existing plant antibacterial agents are not very ideal for the prevention and control of pathogens that cause plant diseases. For example, concentrated use of Streptomyces is prone to drug resistance, and the antibacterial performance will be reduced after repeated use; for example, although cypermethrin has certain antibacterial properties, it will also cause certain damage to the plants themselves. Summary of the invention

[0003] In view of this, the present invention provides a bis-dihalogen phenol and its derivatives, and a preparation method and application thereof. The bis-dihalogen phenol and its derivatives provided by the present invention have good control effects on plant pathogens.

[0004] In order to solve the above technical problems, the present invention provides a bis-dihalogen phenol and its derivatives, wherein the bis-dihalogen phenol has a structure as shown in Formula I, and the derivatives of the bis-dihalogen phenol have structures as shown in Formula II and Formula III:

[0005]

[0006] Wherein, R1 and R2 are independently halogen atoms, nitro groups, alkyl groups, olefin groups or trifluoromethyl groups;

[0007] R3 and R4 are independently metal ions, alkyl groups, olefin groups, methylcarbamoyl groups or dialkoxyphosphoryl groups;

[0008] R5 is -O-, -S-, -SO2-, -NH-, -CH2-, -CO- or -SO-;

[0009] R6 and R7 are independently halogen atoms;

[0010] R8 is an alkyl group or an alkene group.

[0011] Preferably, R1 and R2 are independently -F, -Br, nitro or alkyl;

[0012] R3 and R4 are independently metal ions, methylcarbamoyl or dialkoxyphosphoryl;

[0013] R5 is -S-, -SO- or -CH2-;

[0014] R6 and R7 are independently -Cl;

[0015] R8 is methyl.

[0016] Preferably, the bis-dihalogen phenol has a structure shown in Formula 1a or Formula 1h:

[0017]

[0018] Wherein, R1 and R2 are independently -F, -Cl, -Br or nitro.

[0019] Preferably, the derivative of the bis-dihalogen phenol has a structure as shown in Formula 1b, Formula 1c, Formula 1d, Formula 1e, Formula 1f, Formula 1g, Formula 1i, Formula 1j, Formula 1k, Formula 1m, Formula 1n or Formula 1p:

[0020]

[0021] Wherein, R1 and R2 are independently -F, -Cl, -Br or nitro.

[0022] The present invention also provides a method for preparing the bis-dihalogenated phenol and its derivatives described in the above technical solution, comprising the following steps:

[0023] The bis-dihalogen phenol is prepared according to method 1:

[0024] When R5 is -CH2-, the bis-dihalogen phenol is prepared according to method 1-1, which comprises the following steps:

[0025] Will and a first catalyst to obtain a first mixed solution;

[0026] The first mixed solution and formaldehyde are mixed to perform Friedel-Crafts alkylation reaction to obtain

[0027] When R5 is -NH- or -O-, the bis-dihalogen phenol is prepared according to method 1-2, which comprises the following steps:

[0028] Will The second raw material, the second catalyst and the second solvent are mixed and subjected to a substitution reaction to obtain The second raw material is

[0029] When R5 is -SO- or -SO2-, the bis-dihalogen phenol is prepared according to method 1-3, which comprises the following steps:

[0030] Will The third catalyst and the third solvent are mixed to obtain a third mixed solution; the third mixed solution is mixed with the third raw material for acylation reaction to obtain The third raw material is thionyl chloride or sulfonyl chloride;

[0031] When R5 is -S-, the bis-dihalogen phenol is prepared according to method 1-4, which comprises the following steps:

[0032] Prepared according to method 1-3

[0033] The The first reducing agent and the fourth solvent are mixed to perform a reduction reaction to obtain

[0034] When R5 is -CO-, the bis-dihalogen phenol is prepared according to method 1-5, which comprises the following steps:

[0035] Will The fifth catalyst and the fifth solvent are mixed to carry out Friedel-Crafts acylation reaction to obtain

[0036] The bis-linked dihalogenphenol derivatives shown in formula II are prepared according to method 2:

[0037] When R3 and R4 are independently metal ions, the bis-dihalogenphenol derivative represented by formula II is prepared according to method 2-1, which comprises the following steps:

[0038] Prepared according to method 1

[0039] The The hydroxide containing R3 and R4 and the sixth solvent are mixed to undergo an acid-base reaction to obtain

[0040] When R3 and R4 are independently alkyl and olefin groups, the bis-linked dihalogenphenol derivative represented by formula II is prepared according to method 2-2, which comprises the following steps:

[0041] Prepared according to method 1

[0042] The A halide containing R3 and R4, a seventh catalyst, and a seventh solvent are mixed to undergo a nucleophilic substitution reaction to obtain

[0043] When R3 and R4 are independently methylcarbamoyl or dialkoxyphosphoryl, the bis-linked dihalogenphenol derivative represented by formula II is prepared according to method 2-3, which comprises the following steps:

[0044] Prepared according to method 1

[0045] The The acyl halide containing R3 and R4, the eighth catalyst, and the eighth solvent are mixed to carry out acylation reaction to obtain

[0046] The cyclic derivative of the bis-linked dihalogen phenol represented by formula III is prepared according to method 3, which comprises the following steps:

[0047] Prepared according to method 1

[0048] The A phosphoryl halide, a ninth catalyst, and a ninth solvent are mixed to carry out an acylation cyclization reaction to obtain

[0049] Preferably, the temperature of the Friedel-Crafts alkylation reaction is 90-120° C., and the time of the Friedel-Crafts acylation reaction is 2-5 h.

[0050] Preferably, the temperature of the substitution reaction is 100-150° C., and the time of the substitution reaction is 5-12 hours.

[0051] Preferably, the temperature of the acylation reaction is 0 to 50° C., and the time of the acylation reaction is 5 to 12 hours.

[0052] Preferably, the temperature of the reduction reaction is 50-110° C., and the time of the reduction reaction is 0.5-5 h.

[0053] Preferably, the temperature of the acid-base reaction is 0-50° C., and the time of the reduction reaction is 0.5-2 h.

[0054] Preferably, the temperature of the nucleophilic substitution reaction is 50-100° C., and the time of the nucleophilic substitution reaction is 5-12 h.

[0055] The present invention also provides the use of the bis-dihalogen phenols and their derivatives described in the above technical solution or the bis-dihalogen phenols and their derivatives prepared by the preparation method described in the above technical solution as plant antibacterial agents.

[0056] The present invention provides a bis-dihalogen phenol and its derivatives. The bis-dihalogen phenol has a structure as shown in Formula I, and the derivatives of the bis-dihalogen phenol have structures as shown in Formula II and Formula III:

[0057]

[0058] Wherein, R1 and R2 are independently halogen atoms, nitro groups, alkyl groups, olefin groups or trifluoromethyl groups; R3 and R4 are independently metal ions, alkyl groups, olefin groups, methylcarbamoyl groups or dialkoxyphosphoryl groups; R5 is -O-, -S-, -SO2-, -NH-, -CH2-, -CO- or -SO-; R6 and R7 are independently halogen atoms; R8 is an alkyl group or an olefin group. The bis-dihalogenated phenols and their derivatives provided by the present invention are based on the bis-dihalogenated phenol structure, have good inhibitory effects on plant pathogenic bacteria (bacteria and fungi), and can effectively prevent and treat plant diseases caused by plant pathogens. The bis-dihalogenated phenols and their derivatives provided by the present invention can effectively prevent and treat wheat bud blight, rice sheath blight, gray mold, cotton verticillium wilt, fusarium head blight and watermelon wilt. DETAILED DESCRIPTION

[0059] The present invention provides a bis-dihalogen phenol and its derivatives. The bis-dihalogen phenol has a structure as shown in Formula I, and the derivatives of the bis-dihalogen phenol have structures as shown in Formula II and Formula III:

[0060]

[0061] In the present invention, R1 and R2 are independently halogen atoms, nitro groups, alkyl groups, olefin groups or trifluoromethyl groups, and are independently preferably halogen atoms or alkyl groups, and are more preferably halogen atoms. In the present invention, the halogen atoms are preferably -F, -Cl or -Br, and are more preferably -F or -Br. In the present invention, the alkyl group is preferably butyl, and is more preferably tert-butyl. In the present invention, the olefin group is preferably allyl.

[0062] In the present invention, R3 and R4 are independently metal ions, alkyl groups, olefin groups, methylcarbamoyl groups or dialkoxyphosphoryl groups, and are independently preferably methylcarbamoyl groups. or dialkoxyphosphoryl In the present invention, the metal ion is preferably a potassium ion. In the present invention, the alkyl group is preferably a methyl group. In the present invention, the olefin group is preferably an allyl group.

[0063] In the present invention, R5 is -O-, -S-, -SO2-, -NH-, -CH2-, -CO- or -SO-, preferably -S-, -SO- or -CH2-, more preferably -S- or -CH2-.

[0064] In the present invention, R6 and R7 are independently halogen atoms, and are preferably independently -F, -Cl or -Br, and more preferably -Cl.

[0065] In the present invention, R8 is an alkyl group or an alkene group, preferably an alkyl group. In the present invention, the alkyl group is preferably a methyl group; the alkene group is preferably an allyl group.

[0066] In the present invention, the bis-dihalogen phenol preferably has a structure shown in Formula 1a or Formula 1h:

[0067]

[0068] Among them, R1 and R2 are independently preferably -F, -Cl, -Br or nitro, more preferably -F.

[0069] The derivatives of the bis-dihalogen phenols have structures as shown in Formulas 1b to 1p:

[0070]

[0071] Among them, R1 and R2 are preferably independently -F, -Cl, -Br or nitro.

[0072] The bis-dihalogen phenols and their derivatives provided by the present invention can effectively inhibit the activity of plant pathogens, and at the same time, the bis-dihalogen phenols and their derivatives provided by the present invention have the advantages of low toxicity, low residue and environmental friendliness. The bis-dihalogen phenols and their derivatives provided by the present invention can be used as plant antibacterial agents to solve the problem of pathogen resistance.

[0073] The present invention also provides a method for preparing the bis-dihalogenated phenol and its derivatives described in the above technical solution, comprising the following steps:

[0074] The bis-linked dihalogen phenol is prepared according to method 1: when R5 is -CH2-, the bis-linked dihalogen phenol is prepared according to method 1-1; when R5 is -NH- or -O-, the bis-linked dihalogen phenol is prepared according to method 1-2; when R5 is -SO- or -SO2-, the bis-linked dihalogen phenol is prepared according to method 1-3; when R5 is -S-, the bis-linked dihalogen phenol is prepared according to method 1-4; when R5 is -CO-, the bis-linked dihalogen phenol is prepared according to method 1-5; the bis-linked dihalogen phenol having formula II The derivatives are prepared according to method 2: when R3 and R4 are independently metal ions, the bis-dihalophenol derivatives shown in formula II are prepared according to method 2-1; when R3 and R4 are independently alkyl and olefin groups, the bis-dihalophenol derivatives shown in formula II are prepared according to method 2-2; when R3 and R4 are independently methylaminoformyl or dialkoxyphosphoryl, the bis-dihalophenol derivatives shown in formula II are prepared according to method 2-3; the cyclic derivatives of the bis-dihalophenols shown in formula III are prepared according to method 3.

[0075] In the present invention, the method 1-1 comprises the following steps:

[0076] Will and a first catalyst to obtain a first mixed solution;

[0077] The first mixed solution and formaldehyde are mixed to perform Friedel-Crafts alkylation reaction to obtain

[0078] The present invention will and a first catalyst to obtain a first mixed solution. The molar ratio of is preferably 0.8 to 1.2:1, more preferably 1:1. In the present invention, the first catalyst preferably comprises sulfuric acid or phosphoric acid, more preferably sulfuric acid. In the present invention, when When both are solid, it is preferred to first Dissolved in a first solvent, the first solvent is preferably sulfuric acid. The present invention has no special requirements for the mass concentration of the sulfuric acid, as long as it can be completely dissolved. The present invention has no special restrictions on the amount of the first solvent as long as it can completely dissolve the reactants. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0079] After obtaining the first mixed solution, the present invention mixes the first mixed solution with formaldehyde to perform Friedel-Crafts alkylation reaction to obtain In the present invention, the formaldehyde preferably comprises a formaldehyde aqueous solution or paraformaldehyde, more preferably a formaldehyde aqueous solution. The molar ratio is preferably 0.8 to 1.2:2, more preferably 1:2.

[0080] In the present invention, the temperature of the Friedel-Crafts alkylation reaction is preferably 90-120° C., more preferably 110° C.; the time of the Friedel-Crafts alkylation reaction is preferably 2-5 h, more preferably 3 h. The present invention preferably uses a thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction and determine the reaction end point.

[0081] In the present invention, the method 1-2 comprises the following steps:

[0082] Will The second raw material, the second catalyst and the second solvent are mixed and subjected to a substitution reaction to obtain The second raw material is

[0083] In the present invention, the The molar ratio of the second raw material is preferably 0.8 to 1.2:1, more preferably 1:1. In the present invention, the second catalyst preferably includes cuprous bromide or cuprous iodide, more preferably cuprous iodide. In the present invention, the second solvent preferably includes dimethyl sulfoxide or N,N-dimethylformamide, more preferably dimethyl sulfoxide. The present invention has no special restrictions on the amount of the second solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0084] In the present invention, the temperature of the substitution reaction is preferably 100-150°C, more preferably 120-140°C; the time of the substitution reaction is preferably 5-12h, more preferably 8-10h. The present invention preferably uses thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction to determine the reaction end node.

[0085] In the present invention, the method 1-3 comprises the following steps:

[0086] Will The third catalyst and the third solvent are mixed to obtain a third mixed solution; the third mixed solution is mixed with the third raw material for acylation reaction to obtain The third raw material is thionyl chloride or sulfonyl chloride.

[0087] The present invention will The third catalyst and the third solvent are mixed to obtain a third mixed solution. The molar ratio is preferably 0.8 to 1.2:1, more preferably 1:1. In the present invention, the third catalyst preferably includes aluminum chloride or zinc chloride, more preferably aluminum chloride. In the present invention, the third solvent preferably includes dichloromethane or tetrahydrofuran, more preferably dichloromethane. The present invention has no special restrictions on the amount of the third solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0088] After obtaining the third mixed solution, the present invention mixes the third mixed solution with the third raw material to perform an acylation reaction to obtain In the present invention, the third raw material and The molar ratio is preferably 0.8 to 1.2:1, more preferably 1:1.

[0089] In the present invention, the temperature of the acylation reaction is preferably 0 to 50°C, more preferably 0 to 25°C; the time of the substitution reaction is preferably 5 to 12 hours, more preferably 8 to 10 hours. The present invention preferably uses a thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction and determine the reaction end point.

[0090] In the present invention, the method 1-4 comprises the following steps:

[0091] Prepared according to method 1-3

[0092] The The first reducing agent and the fourth solvent are mixed to perform a reduction reaction to obtain

[0093] In the present invention, the The molar ratio of the first reducing agent to the first reducing agent is preferably 1:0.8 to 3, more preferably 1:1.3. In the present invention, the first reducing agent preferably includes zinc powder or iron powder, more preferably zinc powder. In the present invention, the fourth solvent preferably includes acetic acid or ethanol, more preferably acetic acid. The present invention has no special restrictions on the amount of the fourth solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0094] In the present invention, the temperature of the reduction reaction is preferably 50-110°C, more preferably 75-100°C; the time of the substitution reaction is preferably 0.5-5h, more preferably 2-3h. The present invention preferably uses thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction and determine the reaction end node.

[0095] In the present invention, the method 1-5 comprises the following steps:

[0096] Will The fifth catalyst and the fifth solvent are mixed to carry out Friedel-Crafts acylation reaction to obtain

[0097] In the present invention, the The molar ratio is preferably 0.8 to 1.2:1, more preferably 1:1. In the present invention, the fifth catalyst preferably includes aluminum chloride or zinc chloride, more preferably aluminum chloride. In the present invention, the fifth solvent preferably includes dichloromethane or tetrahydrofuran, more preferably dichloromethane. The present invention has no special restrictions on the amount of the third solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0098] In the present invention, the temperature of the Friedel-Crafts acylation reaction is preferably 0-50°C, more preferably 0-25°C; the time of the substitution reaction is preferably 5-12h, more preferably 8-10h. The present invention preferably uses a thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction and determine the reaction end point.

[0099] In the present invention, the method 2-1 comprises the following steps:

[0100] Prepared according to method 1

[0101] The The hydroxide containing R3 and R4 and the sixth solvent are mixed to undergo an acid-base reaction to obtain

[0102] In the present invention, the The molar ratio of the hydroxide containing R3 and R4 is preferably 1:1.5 to 2.5, more preferably 1:2. In the present invention, the hydroxide preferably includes sodium hydroxide or potassium hydroxide, more preferably potassium hydroxide. In the present invention, the sixth solvent preferably includes water or methanol, more preferably water. The present invention has no special restrictions on the amount of the sixth solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0103] In the present invention, the temperature of the acid-base reaction is preferably 0-50°C, more preferably 15-25°C; the time of the acid-base reaction is preferably 0.5-2h, more preferably 0.5-1h.

[0104] In the present invention, the method 2-2 comprises the following steps:

[0105] Prepared according to method 1

[0106] The A halide containing R3 and R4, a seventh catalyst, and a seventh solvent are mixed to undergo a nucleophilic substitution reaction to obtain

[0107] In the present invention, the The molar ratio of the seventh solvent to the halide is preferably 1:1.5 to 2.5, more preferably 1:2. In the present invention, the halide preferably includes chloride, bromide and iodide, more preferably iodide. In the present invention, the seventh solvent preferably includes acetonitrile or N,N-dimethylformamide, more preferably acetonitrile. The present invention has no special restrictions on the amount of the seventh solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0108] In the present invention, the temperature of the nucleophilic substitution reaction is preferably 50 to 100° C., more preferably 60 to 75° C.; the time of the nucleophilic substitution reaction is preferably 5 to 12 h, more preferably 6 to 8 h.

[0109] In the present invention, the method 2-3 comprises the following steps:

[0110] Prepared according to method 1

[0111] The The acyl halide containing R3 and R4, the eighth catalyst, and the eighth solvent are mixed to carry out acylation reaction to obtain

[0112] In the present invention, the The molar ratio of the acyl halide to the acyl halide is preferably 1:0.8 to 2.5, more preferably 1:2. In the present invention, the acyl halide preferably includes acyl chlorides and acyl bromides, more preferably acyl chlorides. In the present invention, the eighth solvent preferably includes dichloromethane or tetrahydrofuran, more preferably dichloromethane. The present invention has no special restrictions on the amount of the eighth solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0113] In the present invention, the temperature of the acylation reaction is preferably 0 to 50°C, more preferably 0 to 25°C; the time of the substitution reaction is preferably 5 to 12 hours, more preferably 6 to 8 hours. The present invention preferably uses a thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction and determine the reaction end point.

[0114] In the present invention, the method 3 comprises the following steps:

[0115] Prepared according to method 1

[0116] The A phosphoryl halide, a ninth catalyst, and a ninth solvent are mixed to carry out an acylation cyclization reaction to obtain

[0117] In the present invention, the The molar ratio of the acyl halide to the phosphoryl halide is preferably 1:0.8 to 2.5, more preferably 1:1. In the present invention, the acyl halide preferably includes phosphoryl chloride and phosphoryl bromide, more preferably phosphoryl chloride. In the present invention, the ninth solvent preferably includes dichloromethane or tetrahydrofuran, more preferably dichloromethane. The present invention has no special restrictions on the amount of the eighth solvent as long as the reactants can be completely dissolved. The present invention has no special requirements for the mixing, as long as it can be mixed evenly.

[0118] In the present invention, the temperature of the acylation cyclization reaction is preferably 0 to 50°C, more preferably 0 to 25°C; the time of the acylation cyclization reaction is preferably 5 to 12 hours, more preferably 8 hours. The present invention preferably uses a thin layer chromatography silica gel plate to monitor the Friedel-Crafts alkylation reaction to determine the reaction end node.

[0119] In the present invention, after the chemical reaction is completed, the post-reaction system is preferably post-treated, and the post-treatment can improve the purity of the product. The present invention has no special requirements for the post-treatment, and conventional methods in the art can be used.

[0120] The present invention also provides the use of the bis-dihalogen phenols and their derivatives described in the above technical solution or the bis-dihalogen phenols and their derivatives prepared by the preparation method described in the above technical solution as plant antibacterial agents. The present invention has no special requirements for the method of the application, and the conventional method in the art can be used. In the present invention, the bis-dihalogen phenols and their derivatives are preferably used as plant antibacterial agents for pathogens in crops or cash crops. In the present invention, the crops preferably include wheat or rice, and the cash crops preferably include tobacco, cotton or watermelon. In the present invention, the pathogens preferably include wheat bud blight, rice sheath blight, gray mold, cotton Verticillium wilt, Gibberellic acid or watermelon wilt.

[0121] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0122] Example 1

[0123]

[0124] 4-Chloro-3-fluorophenol (1.47 g, 10.0 mmol, 1 equiv.) and aluminum chloride (4.0 g, 30.0 mmol, 3 equiv.) were placed in a reaction vessel; 15 mL of anhydrous dichloromethane was injected into the reactor with a syringe under anhydrous and oxygen-free conditions, and stirred at 25° C. for 1 h to obtain a first mixed solution;

[0125] Dissolve thionyl chloride (731.4 L, 10.0 mmol, 1 equiv.) in 15 mL of anhydrous dichloromethane to obtain a thionyl chloride solution; inject the thionyl chloride solution into the first mixed solution with a syringe under stirring, and perform Friedel-Crafts acylation reaction (with stirring) at 110° C. for 12 h; monitor the reaction by thin layer chromatography silica gel plate (TLC) until the raw material almost completely disappears, indicating that the reaction is complete. After the reaction is complete, slowly add the reaction solution dropwise into ice water and stir for 10 min, extract with 50 mL of dichloromethane 3 times, combine the organic phases, and finally dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product; purify the crude product by silica gel column chromatography to obtain 675 mg of a bis-dihalogen phenol having a structure shown in Formula 2.

[0126] The yield of the bis-dihalogen phenol having the structure shown in Formula 2 is 40%. 1 HNMR(400MHz, DMSO-d6)δ11.26(s,2H),7.56–7.30(d,J=8.2Hz,2H),6.81–6.68(d,J=

[0127] 10.5 Hz, 2H).

[0128] Example 2

[0129]

[0130] 6,6'-sulfinylbis(4-chloro-3-fluorophenol) (339.2 mg, 1.0 mmol, 1 equiv.) having the structure shown in Formula 2 was dissolved in 10 mL of acetic acid and mixed with zinc powder (325.0 g, 5.0 mmol, 5 equiv.), and the reduction reaction was carried out for 3 h under reflux at 50°C with stirring. The reaction was monitored by thin layer chromatography silica gel plate (TLC) until the raw material almost completely disappeared, indicating that the reaction was complete. After the reaction was complete, it was cooled to room temperature, the reaction solution was filtered with diatomaceous earth, and then extracted with 50 mL of ethyl acetate for 3 times, and the organic phases were combined; the combined organic phases were mixed with anhydrous sodium sulfate and dried, and then filtered, and the filtrate obtained by filtration was concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 257 mg of a bis-dihalogen phenol having the structure shown in Formula 1a-1.

[0131] The yield of the bis-dihalogen phenol having the structure shown in Formula 1a-1 is 76%. 1 H NMR (400MHz, DMSO-d6) δ 10.78 (s, 2H), 7.03–6.93 (d, J = 8.4Hz, 2H), 6.83–6.76 (d, J = 10.8Hz, 2H).

[0132] Example 3

[0133]

[0134] 4-Chloro-2-fluorophenol (1.48 mL, 14.0 mmol, 2 equiv.) with a purity of more than 98% and a formaldehyde aqueous solution (0.52 mL, 7.0 mmol, 1 equiv.) with a mass concentration of 37% are mixed and placed in a reaction container. 6 mL of phosphoric acid (mass concentration of 75%) is added dropwise to the reaction container under stirring, and a Friedel-Crafts alkylation reaction is carried out (with stirring) at 120° C. under reflux conditions for 5 h. The reaction is monitored by thin layer chromatography silica gel plate (TLC) until the raw material almost completely disappears, indicating that the reaction is complete. After the reaction is complete, the mixture is cooled to room temperature, diluted with 150 mL of water, and then extracted with 50 mL of ethyl acetate for 3 times, and the organic phases are combined. The combined organic phases are mixed with anhydrous sodium sulfate, dried, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain 1.12 g of a bis-dihalogen phenol having a structure shown in formula 1h-1.

[0135] The yield of the bis-dihalogen phenol having the structure shown in Formula 1h-1 is 26%. 1HNMR (400MHz, DMSO-d6) δ9.94 (s, 2H), 7.30–7.22 (dd, J = 10.5, 2.6Hz, 2H), 6.85 (s, 2H), 3.89 (s, 2H).

[0136] Example 4

[0137]

[0138] Sodium hydride solid (672.0 mg, 16.0 mmol, 4 equiv.) with a purity of 60% and 6,6'-methylenebis(4-chloro-2-fluorophenol) (1220.4 mg, 4.0 mmol, 1 equiv.) having a structure as shown in Formula 1h-1 are mixed and placed in a Shrek tube, 15 mL of anhydrous tetrahydrofuran solution is drawn with a syringe and added to the Shrek tube to dissolve 6,6'-methylenebis(4-chloro-2-fluorophenol) to obtain a solution to be reacted; the solution in the Shrek tube is drawn with a syringe into a reactor under anhydrous and oxygen-free conditions, and stirred at room temperature for 1 hour;

[0139] Solid methylaminoformyl chloride (1664.0 mg, 16.0 mmol, 4 equiv.) was dissolved in 15 mL of anhydrous tetrahydrofuran to obtain a methylaminoformyl chloride solution. The methylaminoformyl chloride solution was slowly injected into the reaction solution with a syringe under stirring, and the acylation reaction was carried out at 30° C. (accompanied by stirring) for 12 hours; the reaction was monitored by thin layer chromatography silica gel plate (TLC) until the raw material almost completely disappeared, indicating that the reaction was complete. After the reaction was complete, the post-reaction system was placed in an ice-water bath and 10 mL of water was added dropwise to the post-reaction system; then, it was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate for 3 times, the organic phases were combined, the combined organic phases and anhydrous sodium sulfate were mixed, dried, filtered and concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 445 mg of a bis-dihalogen phenol as shown in formula 1k-1.

[0140] The yield of the bis-dihalogen phenol shown in formula 1k-1 is 37%. 1 H NMR (400MHz, DMSO-d6) δ7.82 (q, J = 4.5Hz, 1H), 7.47 (dd, J = 9.9, 2.5Hz, 1H), 7.14–7.02 (m, 1H), 3.81 (s, 1H), 2.65 (d, J = 4.6Hz, 3H).

[0141] Example 5

[0142]

[0143] Sodium hydride solid (480.0 mg, 12.0 mmol, 4 equiv.) with a purity of 60% and 6,6'-methylenebis(4-chloro-2-fluorophenol) (915.3 mg, 3.0 mmol, 1 equiv.) having a structure as shown in Formula 1h-1 are placed in a Shrek tube, 15 mL of anhydrous tetrahydrofuran solution is drawn with a syringe and added to the Shrek tube to dissolve 6,6'-methylenebis(4-chloro-3-fluorophenol) to obtain a solution to be reacted; the solution in the Shrek tube is drawn with a syringe and injected into a reactor under anhydrous and oxygen-free conditions, and stirred at room temperature for 1 hour;

[0144] O,O-dimethylphosphoryl chloride (1.3 mL, 12.0 mmol, 4 equiv.) was dissolved in 15 mL of anhydrous tetrahydrofuran to obtain an O,O-dimethylphosphoryl chloride solution; the O,O-dimethylphosphoryl chloride solution was slowly added to the reaction solution with a syringe under stirring, and the acylation reaction was carried out at 30° C. (accompanied by stirring) for 12 h; the reaction was monitored by thin layer chromatography silica gel plate (TLC) until the raw material almost completely disappeared, indicating that the reaction was complete. After the reaction was complete, the post-reaction system was placed in an ice water bath and 10 mL of water was added dropwise to the post-reaction system; then, it was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate for 3 times, the organic phases were combined, the combined organic phases were mixed with anhydrous sodium sulfate, dried, filtered and concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 718 mg of tetramethyl (methylene bis (4-chloro-5-fluoro-2,1-phenylene) bisphosphate as shown in formula 1n-1.

[0145] The yield of tetramethyl (methylene bis (4-chloro-5-fluoro-2,1-phenylene) bisphosphate was 34%, 1 H NMR (400MHz, DMSO-d6) δ7.46–7.23 (m, 4H), 4.08 (s, 2H), 3.79–3.73 (d, J = 11.5Hz, 12H).

[0146] Depend on 1 The H NMR results can prove that the product prepared in the example is the corresponding bis-dihalophenol.

[0147] Comparative Example 1

[0148] Take Sclerotinia as a comparative example.

[0149] The inhibitory performance of the substances in Examples 1 to 5 and Comparative Example 1 on plant pathogens was tested as follows: 10 mL of sterile water was used to wash the spores on the Gibberella FC plate, and 2 mL of the washed spores were mixed with 50 mL of PSA medium with an agar concentration of 0.3% to prepare a Gibberella-containing medium;

[0150] The wheat poplar blight SN PSA liquid medium was shaken and cultured for 120 hours, and 2 mL of the cultured bacteria was mixed with 50 mL of PSA medium with an agar concentration of 0.3% to prepare a culture medium containing wheat poplar blight pathogens;

[0151] The PSA liquid culture medium of Verticillium dahliae and Rhizoctonia solani was shaken and cultured for 30 hours respectively, and 0.3 mL of the cultured bacteria was mixed with 50 mL of PSA culture medium with an agar concentration of 0.3% to prepare a culture medium containing Verticillium dahliae and Rhizoctonia solani;

[0152] The compounds in Examples 1 to 5 and Comparative Example 1 were diluted to a concentration of 12.5 ppm and then added to the above pathogen culture medium. The antibacterial rates were measured after 96 hours. The results are listed in Table 1.

[0153] Table 1 Inhibitory properties of the compounds in Examples 1 to 5 and Comparative Example 1 against plant pathogens

[0154]

[0155]

[0156] It can be seen from the test results in Table 1 that the compounds provided by the present invention have a good inhibition rate on plant pathogens.

[0157] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. Application of bis-dihalogenphenols and their derivatives as plant antibacterial agents; The pathogenic bacteria of the antibacterial agent include wheat blast pathogen, rice sheath blight pathogen, cotton verticillium dahliae pathogen or wheat fusarium wilt pathogen; The bis-dihalogen phenol has the following structure: The derivative of the bis-dihalogen phenol has the following structure:

2. The application according to claim 1, characterized in that: The bis-dihalogen phenol and the derivatives of bis-dihalogen phenol are suitable for pathogenic bacteria in crops or economic crops when used as plant antibacterial agents.

3. The use according to claim 2, characterized in that: The agricultural crops include wheat or rice, and the cash crops include tobacco, cotton or watermelon.

4. The use according to claim 1, characterized in that: When the bis-dihalogen phenol and the derivatives of bis-dihalogen phenol are used as plant antibacterial agents, they are diluted to a concentration of 12.5 ppm.

5. The use according to claim 1, characterized in that: Said The preparation method is as follows: 1.47 g 4-chloro-3-fluorophenol and 4.0 g aluminum chloride are placed in a reaction vessel 15 mL of anhydrous dichloromethane was injected into the reactor by syringe under anhydrous and oxygen-free conditions, and stirred at 25° C. for 1 h to obtain a first mixed solution; 731.4 L of thionyl chloride was dissolved in 15 mL of anhydrous dichloromethane to obtain a thionyl chloride solution; the thionyl chloride solution was injected into the first mixed solution with a syringe under stirring, and Friedel-Crafts acylation reaction was carried out at 110° C. and stirred for 12 hours; the reaction was monitored by thin layer chromatography silica gel plate until the raw material almost completely disappeared, indicating that the reaction was complete. After the reaction was complete, the reaction solution was slowly added dropwise to ice water and stirred for 10 minutes, extracted with 50 mL of dichloromethane for 3 times, and the organic phases were combined. Finally, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 675 mg of a bis-dihalogen phenol having a structure shown in Formula 2.

6. The use according to claim 1, characterized in that: Said The preparation method is as follows: 339.2 mg of 6,6'-sulfinylbis(4-chloro-3-fluorophenol) having a structure shown in Formula 2 is dissolved in 10 mL of acetic acid and then mixed with 325.0 g of zinc powder, and a reduction reaction is carried out at 50°C under reflux conditions for 3 hours with stirring; the reaction is monitored by a thin layer chromatography silica gel plate; the reaction is monitored until the raw material almost completely disappears, indicating that the reaction is complete, and after the reaction is complete, the reaction solution is cooled to room temperature, and the reaction solution is filtered through diatomaceous earth, and then extracted three times with 50 mL of ethyl acetate, and the organic phases are combined; the combined organic phases and anhydrous sodium sulfate are mixed and dried, and then filtered, and the filtrate obtained by filtration is concentrated under reduced pressure to obtain a crude product; the crude product is purified by silica gel column chromatography to obtain 257 mg of a bis-dihalogen phenol having a structure shown in Formula 1a-1.

7. The use according to claim 1, characterized in that: Said The preparation method is as follows: 1.48 mL of 4-chloro-2-fluorophenol with a purity of more than 98% and 0.52 mL of a formaldehyde aqueous solution with a mass concentration of 37% are mixed and placed in a reaction container, 6 mL of phosphoric acid with a mass concentration of 75% is added dropwise to the reaction container under stirring, and Friedel-Crafts alkylation reaction is carried out under reflux conditions at 120° C. and stirred for 5 hours; the reaction is monitored by thin layer chromatography silica gel plate until the raw material almost completely disappears, indicating that the reaction is complete, after the reaction is complete, it is cooled to room temperature, 150 mL of water is added to dilute, and then extracted with 50 mL of ethyl acetate for 3 times, and the organic phases are combined; the combined organic phases are mixed with anhydrous sodium sulfate, dried, filtered, and concentrated under reduced pressure to obtain a crude product; the crude product is purified by silica gel column chromatography to obtain 1.12 g of a bis-dihalogen phenol having a structure shown in Formula 1h-1.

8. The use according to claim 1, characterized in that: Said The preparation method is as follows: 672.0 mg of sodium hydride solid with a purity of 60% and 1220.4 mg of 6,6'-methylenebis(4-chloro-2-fluorophenol) having a structure as shown in Formula 1h-1 are mixed and placed in a Shrek tube, 15 mL of anhydrous tetrahydrofuran solution is drawn with a syringe and added to the Shrek tube to dissolve 6,6'-methylenebis(4-chloro-2-fluorophenol) to obtain a solution to be reacted; the solution in the Shrek tube is drawn with a syringe and injected into a reactor under anhydrous and oxygen-free conditions, and stirred for 1 hour; 1664.0 mg of methylaminoformyl chloride solid was dissolved in 15 mL of anhydrous tetrahydrofuran to obtain a methylaminoformyl chloride solution, and the methylaminoformyl chloride solution was slowly added to the reaction solution under stirring, and the acylation reaction was carried out at 30° C. and stirred for 12 hours; the reaction was monitored by thin layer chromatography silica gel plate until the raw material almost completely disappeared, indicating that the reaction was complete, and after the reaction was complete, the post-reaction system was placed in an ice water bath and 10 mL of water was added dropwise to the post-reaction system; then it was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate for 3 times, the organic phases were combined, the combined organic phases and anhydrous sodium sulfate were mixed, dried, filtered and concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 445 mg of a bis-dihalogenphenol derivative as shown in formula 1k-1.

9. The use according to claim 1, characterized in that: Said The preparation method is as follows: 480.0 mg of sodium hydride solid with a purity of 60% and 915.3 mg of 6,6'-methylenebis(4-chloro-2-fluorophenol) having a structure as shown in Formula 1h-1 are placed in a Shrek tube, 15 mL of anhydrous tetrahydrofuran solution is drawn with a syringe and added to the Shrek tube to dissolve 6,6'-methylenebis(4-chloro-3-fluorophenol) to obtain a solution to be reacted; the solution in the Shrek tube is drawn with a syringe and injected into a reactor under anhydrous and oxygen-free conditions, and stirred for 1 hour; 1.3 mL of O,O-dimethylphosphoryl chloride was dissolved in 15 mL of anhydrous tetrahydrofuran to obtain an O,O-dimethylphosphoryl chloride solution; the O,O-dimethylphosphoryl chloride solution was slowly added to the reaction solution with a syringe under stirring, and the acylation reaction was carried out at 30° C. and stirred for 12 hours; the reaction was monitored by thin layer chromatography silica gel plate until the raw material almost completely disappeared, indicating that the reaction was complete. After the reaction was complete, the post-reaction system was placed in an ice water bath and 10 mL of water was added dropwise to the post-reaction system; then, it was concentrated under reduced pressure and extracted with 50 mL of ethyl acetate for 3 times, the organic phases were combined, the combined organic phases were mixed with anhydrous sodium sulfate, dried, filtered and concentrated under reduced pressure to obtain a crude product; the crude product was purified by silica gel column chromatography to obtain 718 mg of tetramethylmethylenebis(4-chloro-5-fluoro-2,1-phenylene)bisphosphate as shown in formula 1n-1.

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