Preparation and bactericidal application of aryl hydrazide compound containing biphenyl fragment

Abstract

The invention belongs to the field of bactericides. Relates to preparation and bactericidal application of an aryl hydrazide compound containing a biphenyl fragment. Wherein the structure of the aryl hydrazide compound containing the biphenyl fragment is shown as a general formula I: # imgabs0 # general formula I, and the definition of each substituent in the general formula I is shown in the specification. According to the design thought, amide groups in the bactericide fluxapyroxad are replaced with hydrazide groups, and terminal phenyl groups are migrated from ortho-position to meta-position, so that the fluxapyroxad is obtained. The obtained compound has a remarkably better inhibition effect on pathogenic bacteria such as colletotrichum gloeosporioides than fluxapyroxad.

Description

Technical Field

[0001] The invention belongs to the field of bactericides and relates to the preparation of an aromatic hydrazide compound containing a biphenyl fragment and its bactericidal use. Background Art

[0002] Literature reports (J. Agric. Food Chem. 2023, 71, 6803-6817) show that the biological activity of hydrazide derivatives is always higher than that of amide compounds; therefore, they are considered to be ideal and fully qualified substitutes for amides. Hydrazide derivatives have been found to be ubiquitous components in fungicides. WO2006087343 discloses a fungicide of the following general formula, in which a commercial fungicide fluopyrabamide is developed. The present invention replaces the amide bond with a hydrazide bond based on the structure of fluopyrabamide and optimizes the structure.

[0003]

[0004] In the prior art, there is no report on aromatic hydrazide compounds containing biphenyl fragments having a structure as shown in the general formula I of the present invention. Summary of the invention

[0005] The purpose of the present invention is to provide a preparation method of an aromatic hydrazide compound containing a biphenyl fragment and its sterilization use.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] An aromatic hydrazide compound containing a biphenyl fragment, as shown in the general formula I:

[0008]

[0009] Where:

[0010] R is optionally substituted mono- or poly-substituted by the following substituents: hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl, methoxy, cyano, nitro, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy;

[0011] Ar is selected from any substituted or unsubstituted aryl or heteroaryl.

[0012] The preferred technical solution of the present invention is that in the general formula I:

[0013] R is optionally substituted mono- or poly-substituted by the following substituents: hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy;

[0014] Ar is selected from Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q 10 , Q11 , Q 12 , Q 13 , Q 14 , Q 15 and Q 16 :

[0015]

[0016] A use of the compound of general formula I according to claim 1 for preparing fungicides in the agricultural field.

[0017] A fungicide composition, characterized in that the weight content of the compound of formula I as an active ingredient in the composition is 0.1-99%.

[0018] The aromatic hydrazide compounds containing biphenyl fragments of the present invention have a good inhibitory effect on Colletotrichum gloeosporioides and the like, while conventional succinate dehydrogenase inhibitor fungicides such as fluopyram are not ideal for Colletotrichum gloeosporioides. Therefore, the compounds of the present invention can be used as an effective supplement to conventional succinate dehydrogenase inhibitor fungicides in terms of the fungicidal spectrum.

[0019] The above contents of the present invention are further described in detail below through specific implementation modes, but this should not be construed as limiting the present invention. DETAILED DESCRIPTION

[0020] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0021] Example 1 Compound I-1 Preparation

[0022]

[0023] Under ice bath conditions, 0.96g (14.0mmol) of sodium nitrite was dissolved in 5mL of distilled water, and slowly dripped into 10mL of concentrated hydrochloric acid solution containing 2.0g (11.6mmol) of m-bromoaniline, and stirred for 1.5 to 2h. Under ice bath conditions, the above reaction solution was slowly dripped into 15mL of concentrated hydrochloric acid solution containing 7.87g (34.9mmol) of stannous chloride dihydrate, and stirred for 1.5 to 2h. A large amount of solid precipitated, which was filtered, and the filter cake was washed with a small amount of cold distilled water. The resulting solid was added to 20mL of concentrated hydrochloric acid solution. 石油醚 :V 乙酸乙酯 =3:1 mixed solvent, filtered, and the obtained solid was naturally dried to obtain m-bromophenylhydrazine hydrochloride.

[0024] In a round-bottom flask, 0.50 g (1.00 mmol) of m-bromophenylhydrazine hydrochloride, 20 mL of tetrahydrofuran, and 0.60 g (2.50 mmol) of N, N-diisopropylethylamine were slowly added in sequence, and stirred in an ice-water bath for 5 min. Then, 0.43 g (1.20 mmol) of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.02 g (0.10 mmol) of 1-hydroxybenzotriazole, and 0.47 g (1.00 mmol) of difluoropyrazole acid were slowly added to the above reaction solution in sequence. The reaction was continued for 5 to 6 hours under ice bath conditions, and the reaction was detected by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic layer was dried with anhydrous sodium sulfate. Column chromatography [v (ethyl acetate): v (petroleum ether) = 1:2] was performed to obtain N-(3-bromophenyl) 3-difluoromethyl 1-methyl-1H-pyrazole-4-carboxylic acid hydrazide (hydrazide intermediate 1).

[0025] In a round-bottom flask, 0.50 g (1.00 mmol) of hydrazide intermediate 1, 0.35 g (2.00 mmol) of 3,4,5-trifluorophenylboric acid, a catalytic amount of tetrakis (triphenylphosphine) palladium, 0.42 g (2.50 mmol) of potassium carbonate, 20 mL of tetrahydrofuran and 10 mL of water were slowly added in sequence. The mixture was stirred at 70 ° C for 16 h, and the reaction was detected by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, and the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The crude product was subjected to column chromatography [v (ethyl acetate): v (petroleum ether) = 3:2] to obtain the target compound I-1.

[0026] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.40(s,1H),8.06(s,1H),7.50(t,J=8.0Hz,2H),7 .42–7.11(m,2H),7.04(d,J=8.0Hz,1H),7.00(s,1H),6.81(d,J=8.1Hz,1H),3.96(s,3H). 13 C NMR (101MHz, DMSO-d6) δ161.41,151.77(d,J=11.9Hz),150.19(d,J=8.28Hz),149.25,145.14,144.91,139.24,137.65( d,J=17.6Hz),132.55,129.65,117.45,113.97,112.53,111.16,110.95,110.35,109.70(t,J=234.2Hz),39.52.ESI-MS m / z395.22[MH] - .

[0027] Example 2 Compound I-2 Preparation

[0028] The preparation method of compound I-2 is the same as the synthesis method of compound I-1.

[0029] 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.41(s,1H),8.04(s,1H),7.55(d,J=7.6Hz,2H),7.44( t,J=7.3Hz,2H),7.38–7.13(m,3H),7.01(d,J=7.2Hz,2H),6.78(d,J=8.1Hz,1H),3.96(s,3H). 13 C NMR(101MHz,DMSO-d6)δ161.41,150.08,144.95(t,J=23.4Hz),140.97,140.74,132.46,129.44, 128.90,127.36,126.56,117.42,114.02,111.54,110.48,109.69(t,J=234.6Hz),39.46.ESI-MS m / z 341.22[MH] - .

[0030] Example 3 Compound I-3 Preparation

[0031] The preparation method of compound I-3 is the same as the synthesis method of compound I-1.

[0032] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.41(s,1H),8.12(s,1H),7.83–7.74(m,3H),7.30(d, J=7.8Hz,1H),7.28(t,J=54.0Hz,1H),7.07(d,J=7.8Hz,2H),6.93–6.67(m,2H),3.96(s,3H). 13C NMR (101MHz, DMSO-d6) δ161.41,151.24,150.25,144.94(t,J=21.9Hz),139.38,132.49,130.80,129.69,127.34,125.79(d,J=3.8 Hz),124.47(q,J=231.6Hz),122.13,117.62,114.14(d,J=34.6Hz),112.43,111.27,110.58,109.68(t,J=234.5Hz),39.46.ESI-MS m / z 409.23[MH] - .

[0033] Example 4 Compound I-4 Preparation

[0034] The preparation method of compound I-4 is the same as the synthesis method of compound I-1.

[0035] 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.47(dd,J=8.5,5.3Hz,2H),7.29(t,J =7.9Hz,1H),7.14–6.98(m,4H),6.84(d,J=8.2Hz,1H),6.47(s,1H),2.74(s,3H). 13 CNMR(101MHz,Chloroform-d)δ169.32,164.88,163.88,161.25,159.63,147.61,141.64,137.09,132.29,1 29.95,128.76(d,J=8.1Hz),120.82,120.25(q,J=278.2Hz),115.82,115.60,112.75,112.43,19.38.ESI-MS m / z 394.07[MH] - .

[0036] Example 5 Compound I-5 Preparation

[0037] The preparation method of compound I-5 is the same as the synthesis method of compound I-1.

[0038] 1H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.31(t,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H ),7.02(m,3H),6.89(d,J=8.0Hz,1H),6.78(t,J=7.2Hz,1H),6.52(s,1H),2.75(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.42,164.57(d,J=12.9Hz),162.11(d,J=13.2Hz),159.72,147.78,144.33,141.95,140.26,132.18,13 0.16,120.69,120.27(q,J=275.2Hz),113.82,112.30,110.03(d,J=11.5Hz),110.03(d,J=25.7Hz),102.79(t,J=25.3Hz),19.41.ESI-MS m / z 412.17[MH] - .

[0039] Example 6 Determination of fungicidal activity of aromatic hydrazide compounds containing biphenyl fragments against plant pathogenic fungi

[0040] 1. Plant pathogenic fungi

[0041] The plant fungi used were strains preserved at 4°C in the laboratory, including rice sheath blight (Rhizoctonia solani), gloeosporioides anthracnose (Colletotrichum gloeosporioides), apple black rot (Valsamali), rapeseed sclerotinia (Sclerotonia sclerotiorum), tomato early blight (Alternaria solani) and grape cavity disease (Botryosphaeria dothidea).

[0042] 2. Experimental Methods

[0043] The mycelium growth rate method was used. Dissolve the sample to be tested with dimethyl sulfoxide (DMSO), dilute it to 1000 mg / L with a sterile aqueous solution of 0.1% Tween-80, add 1 mL of the above solution to a conical flask and dilute it to 50 mL with PDA culture medium, oscillate and mix evenly, pour it into a culture dish to make a 20 mg / L drug-containing plate, use DMSO as a blank control, use a 5 mm diameter puncher to cut the bacterial cake along the outer edge of the mycelium, and move it to the center of the drug-containing plate. Repeat each treatment 3 times. Place the culture dish in a constant temperature incubator at 25°C and culture it. When the mycelium growth of the blank control group reaches 2 / 3 of the diameter of the culture dish, use a vernier caliper to measure the diameter of the bacterial cake (mm) using the cross method, calculate the average value, and calculate the relative inhibition rate by comparing it with the blank control group. The calculation formula is as follows:

[0044]

[0045] 3. Experimental results

[0046] The results of the inhibitory activity of aromatic hydrazide compounds containing biphenyl fragments on plant pathogenic fungi are shown in Table 1. As shown in Table 1, this type of compound also has a good inhibitory effect on plant pathogenic fungi.

[0047] Table 1 Relative inhibition rate of compounds I-1 to I-5 on plant pathogenic fungi (%)

[0048]

[0049] The results of the antibacterial activity test showed that the compounds of the examples were superior to the positive control fluopyram against Colletotrichum gloeosporioides, black rot of apples and Botrytis cinerea. In addition, the inhibitory effect of compound I-3 on rice sheath blight was also superior to fluopyram. Although fluopyram has a good inhibitory effect on pathogens such as rapeseed sclerotinia and tomato early blight, the compounds of the present invention can be used for fluopyram to prevent and control undesirable crop diseases. Therefore, these compounds can be used as alternative drugs for plant fungicides.

Claims

1. Aromatic hydrazide compound containing biphenyl fragment, characterized in that: The compound is shown in general formula I, Where: R is optionally substituted mono- or poly-substituted by the following substituents: hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl, methoxy, cyano, nitro, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy; Ar is selected from any substituted or unsubstituted aryl or heteroaryl.

2. The compound according to claim 1, characterized in that In the general formula I: R is optionally substituted mono- or poly-substituted by the following substituents: hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy; Ar is selected from Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q 10 , Q 11 , Q 12 , Q 13 , Q 14 , Q 15 and Q 16 :

3. Use of the compound of general formula I according to claim 1 for preparing fungicides in the agricultural field.

4. A fungicide composition, characterized in that: The weight content of the compound of formula I as an active ingredient in the composition is 0.1-99%.

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