CN114835696B - Phthalide hydrazide compound and preparation method and application thereof - Google Patents

Phthalide hydrazide compound and preparation method and application thereof Download PDF

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CN114835696B
CN114835696B CN202210570150.0A CN202210570150A CN114835696B CN 114835696 B CN114835696 B CN 114835696B CN 202210570150 A CN202210570150 A CN 202210570150A CN 114835696 B CN114835696 B CN 114835696B
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phthalide
hydrazide compound
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CN114835696A (en
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樊玲玲
李永
罗忠福
汤磊
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Guizhou Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention belongs to the technical field of pesticides, and particularly relates to a phthalide hydrazide compound, and a preparation method and application thereof. The phthalide hydrazide compound prepared by the invention has good antibacterial activity, and the application of the phthalide hydrazide compound serving as an active ingredient in the preparation of bactericides can be used for preventing and controlling plant diseases caused by plant pathogenic fungi, and is used for preventing and controlling plant diseases caused by brown spot of tobacco, rice blast, phytophthora capsici, watermelon fusarium wilt, potato dry rot, rape sclerotinia rot, apple rot, tomato gray mold, cabbage black spot and wheat scab.

Description

Phthalide hydrazide compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pesticides, and particularly relates to a phthalide hydrazide compound, and a preparation method and application thereof.
Background
Plant diseases are natural disasters which seriously damage agricultural production and are difficult to control, not only can lead to crop yield reduction and quality reduction, but also can lead part of pathogenic fungi to generate various secondary metabolites (such as aflatoxin, zearalenone and the like) with carcinogenicity, neurotoxicity or teratogenicity in the process of growing and metabolism in a host body, thereby seriously threatening the health and safety of human beings and animals. Therefore, various pesticides have been developed and developed in recent years, and these chemical fungicides have played a very important role in protecting agricultural production and human life, but plant resistance, environmental pollution, ecological imbalance, food safety and the like have been increasingly serious due to long-term dependence and large-scale use. Therefore, research and development of more novel, green and efficient bactericides with excellent antibacterial activity has important significance in ensuring agricultural production.
The phthalide skeleton being one kindThe important oxygen-containing heterocyclic skeleton widely existing in traditional Chinese medicines and natural plants is a compound with great development value, and molecules containing the skeleton have various pharmacological activities, such as: dilating blood vessel, inhibiting platelet aggregation, resisting atherosclerosis, reducing uric acid, resisting bacteria, and treating Alzheimer disease. Le Lo nA., del-M.,/>J.L.,Delgado G.Phthalides:distribution in nature,chemical reactivity,synthesis,and biological activity[J]The documents Progress in the Chemistry ofOrganic Natural Products,2017,104:127-246 and the like report that the natural phthalide compound, namely butylphthalide, extracted from plants has the effect of treating cardiovascular and cerebrovascular diseases and has a certain activity of inhibiting plant pathogenic fungi, but the antibacterial activity of the natural phthalide compound is obviously different from that of a commercial bactericide. Based on the above, in order to obtain the efficient green agricultural bactericide, the invention takes butylphthalide as a lead compound, introduces a hydrazide pharmacophore on the benzene ring of the butylphthalide, designs and synthesizes a series of phenylphthalide hydrazide compounds, and simultaneously determines the activity of the compounds for inhibiting plant pathogenic fungi, thereby laying a foundation for developing novel phenylphthalide high-activity bactericides.
Disclosure of Invention
In order to solve the problems, the invention provides a phthalide hydrazide compound, a preparation method and application thereof.
The invention solves the technical problems through the following technical proposal.
The invention provides a phthalide hydrazide compound which has a chemical structural general formula shown in a formula I:
wherein R is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted aryl.
Preferably, when R is a substituted alkyl, substituted aryl or substituted heteroaryl, it may be substituted or unsubstituted by one or more halogen, hydroxy, amino, nitro, oxo, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Substituted with alkoxy;
the R is 1 Substituted alkyl, substituted cycloalkyl, substituted alkoxy, substituted amino or substituted aryl, which may be substituted or unsubstituted by one or more halogen, hydroxy, amino, nitro, oxo, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 The substituent of the alkoxy group is substituted.
Preferably, said R 1 Is unsubstituted alkyl, R is substituted or unsubstituted aryl or heteroaryl, and when R is substituted aryl or heteroaryl, R may be substituted with one or more fluoro, chloro, bromo, methyl or trifluoromethyl groups.
Preferably, when said R 1 When the alkyl group is unsubstituted, the alkyl group is an alkyl group having 10 or less carbon atoms.
Preferably, said R 1 Is butyl.
Preferably, R is the following substituent:
the preparation method of the phthalide hydrazide compound, when R is 1 When the compound is butyl, 6-bromobutylphthalide as a raw material is added with cuprous cyanide to obtain a compound of a formula III through cyano substitution, the compound of a formula IV is obtained through reflux hydrolysis under an acidic condition, and then an aryl hydrazine hydrochloride compound is added to carry out acylation reaction on a phthalide hydrazide compound of a formula V, wherein the specific synthetic route is as follows:
wherein R is:
the invention also provides application of the phthalide hydrazide compound as an active ingredient in preparation of bactericides.
Preferably, the bactericide can prevent and treat plant diseases caused by plant pathogenic fungi, wherein the plant pathogenic fungi comprise Alternaria tabaci, pyricularia oryzae, phytophthora capsici, fusarium oxysporum, rhizoctonia solani, sclerotinia cinerea, botrytis cinerea, alternaria brassicae and Alternaria wheat.
The invention also provides a bactericidal composition, which comprises the phthalide hydrazide compound of claim 1, wherein the bactericidal composition is in the form of emulsifiable concentrate, suspending agent, aqueous emulsion, wettable powder, microemulsion or water dispersible granule.
Compared with the prior art, the invention has the following beneficial effects:
(1) The phthalide hydrazide compound prepared by the invention has good antibacterial activity, and the application of the phthalide hydrazide compound serving as an active ingredient in the preparation of bactericides can be used for preventing and controlling plant diseases caused by plant pathogenic fungi, and is used for preventing and controlling plant diseases caused by brown spot of tobacco, rice blast, phytophthora capsici, watermelon fusarium wilt, potato dry rot, rape sclerotinia rot, apple rot, tomato gray mold, cabbage black spot and wheat scab.
(2) The compounds designed and synthesized by the invention belong to derivatives of natural product butylphthalide (medicine for treating ischemic cerebral apoplexy clinically) and are novel compounds. Meanwhile, compared with the existing common chemical pesticides (chlorothalonil, hymexazol and carbendazim), the inhibiting activity of part of compounds on plant pathogenic fungi has the characteristics of potential low toxicity, high efficiency and broad spectrum. The invention can provide candidate compounds and theoretical basis for the development of plant-source bacteriostat based on natural phthalide skeleton.
Drawings
FIG. 1 shows the compound a in example 3 of the present invention 1 H NMR chart;
FIG. 2 shows the compound a in example 3 of the present invention 13 C NMR chart;
FIG. 3 shows the compound b of example 3 of the present invention 1 H NMR chart;
FIG. 4 shows the compound b in example 3 of the present invention 13 C NMR chart;
FIG. 5 is a graph showing the inhibitory activity of Compound b of example 4 of the present invention against five pathogenic fungi at various concentrations;
FIG. 6 is a graph showing the inhibitory activity of Compound e of example 4 of the present invention against five pathogenic fungi at various concentrations.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that the technical terms used in the present invention are only for describing specific embodiments, and are not intended to limit the scope of the present invention, and various raw materials, reagents, instruments and equipment used in the following embodiments of the present invention may be purchased commercially or prepared by existing methods unless otherwise specifically described.
A phthalide hydrazide compound has a chemical structural general formula shown in a formula I:
wherein R is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted aryl.
Where R is substituted alkyl, substituted aryl or substituted heteroaryl, each may be substituted with one or more halogen, hydroxy, amino, nitro, oxo, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Substituted with alkoxy;
the R is 1 Substituted alkyl, substituted cycloalkyl, substituted alkoxy, substituted amino or substituted aryl, which may be substituted or unsubstituted by one or more halogen, hydroxy, amino, nitro, oxo, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 The substituent of the alkoxy group is substituted.
The R is 1 Is unsubstituted alkyl, R is substituted or unsubstituted aryl or heteroaryl, and when R is substituted aryl or heteroaryl, R may be substituted with one or more fluoro, chloro, bromo, methyl or trifluoromethyl groups.
The R is 1 When the alkyl group is unsubstituted, the alkyl group is an alkyl group having 10 or less carbon atoms.
The R is 1 Is butyl.
The R is the following substituent:
when R is 1 When the compound is butyl, 6-bromobutylphthalide as a raw material is added with cuprous cyanide to obtain a compound of a formula III through cyano substitution, the compound of the formula IV is obtained through reflux hydrolysis under an acidic condition, and then an aryl hydrazine hydrochloride compound is added to carry out acylation reaction on phthalide hydrazide compounds, wherein the specific synthetic route is as follows:
wherein R is:
example 1
Preparation of 1-butyl-3-oxo-1, 3-dihydroisobenzofuran-5-carbonitrile (formula III)
The compound 6-bromo-3-butylisobenzofuran-1 (3H) -one of formula II (2.5 g,9.3 mmol) and cuprous cyanide (2.0 g,14 mmol) were dissolved in N-methylpyrrolidine (NMP, 10 mL) under nitrogen protection and reacted at 180℃for 3H, after the reaction was complete the reaction was cooled to room temperature, 50mL of water was added, extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure and recrystallized from ethyl acetate to give 1.0g of the compound of formula III as a white solid in 50.0% yield, m.p.82-83 ℃. 1 HNMR(600MHz,CDCl 3 )δ8.19(d,J＝1.2Hz,1H),7.95(dd,J＝8.4,1.2Hz,1H),7.61(d,J＝7.8Hz,1H),5.56-5.54(m,1H),2.11-2.05(m,1H),1.82-1.76(m,1H),1.52-1.36(m,4H),0.93(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ168.2,153.8,137.0,129.9,127.5,123.1,117.3,113.7,81.5,34.1,26.8,22.3,13.8；HRMS(ESI)calcd for C 13 H 14 NO 2 [M+H] + m/z:216.1023,found 216.1035.
Example 2
Preparation of 1-butyl-3-oxo-1, 3-dihydroisobenzofuran-5-carboxylic acid (formula IV)
Under nitrogen, compound III (1.0 g,4.65 mmol) was dissolved in 98% H 2 SO 4 (2.5 mL) of H was added at 0deg.C 2 O (2.5 mL), stirring at room temperature for 0.5h, transferring to 100 ℃ for oil bath reflux reaction for 24h, pouring the reaction solution into 20mL of water after the reaction is completed, extracting by ethyl acetate (50 mL multiplied by 3), drying by anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing by ethyl acetate to obtain 0.71g of white solid compound formula IV, wherein the yield is 65.1%, m.p.145-147 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.10(d,J＝7.8Hz,1H),9.04(s,1H),8.62(d,J＝7.8Hz,1H),6.53-6.51(m,1H),2.96-2.86(m,1H),2.54-2.49(m,1H),2.14-2.03(m,4H),1.66(t,J＝6.6Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.5,166.6,154.6,135.3,132.5,126.4,126.0,123.6,81.8,33.6,26.9,22.3,14.2；HRMS(ESI)calcd for C 13 H 15 O 4 [M+H] + m/z:235.0970,found 235.0968.
Example 3
Preparation of arylhydrazobenzphthalides (formula V):
under the protection of nitrogen, dissolving a compound (80 mg,0.34 mmol) in thionyl chloride (2 mL), carrying out reflux reaction for 8h, concentrating the reaction solution after TLC detection reaction is finished, and dissolving the reaction solution in dry tetrahydrofuran for later use; a10 mL two-necked flask was further prepared, and an arylhydrazine hydrochloride compound (0.2 mmol) was dissolved in dry pyridine (2 mL), and the above tetrahydrofuran solution was slowly dropped at 0℃to react at room temperature for 1h, after completion of TLC detection, the reaction solution was poured into 20mL of water, extracted with methylene chloride (20 mL. Times.3), dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate to give Compound formula V. Specific compounds are shown in table 1.
TABLE 1 when R 1 In the case of butyl, the specific compound is of formula V
Table 1 physical properties and spectroscopic data for specific compounds a-m in formula V are as follows:
1-butyl-3-oxo-N' -phenyl-1, 3-dihydroisobenzofuran-5-carboxylic acid hydrazide (a): yield 74.8%, white solid, m.p.188-191 ℃; as shown in figure 1 of the drawings, 1 H NMR(600MHz,CDCl 3 )δ10.60(d,J＝2.4Hz,1H),8.37(s,1H),8.29(d,J＝7.8Hz,1H),7.98(d,J＝2.4Hz,1H),7.83(d,J＝7.8Hz,1H),7.17(t,J＝7.8Hz,2H),6.81(d,J＝7.8Hz,2H),6.74(t,J＝7.2Hz,1H),5.74-5.72 (m, 1H), 2.13-2.09 (m, 1H), 1.77-1.72 (m, 1H), 1.39-1.27 (m, 4H), 0.88 (t, j=6.8 hz, 3H); as shown in the figure 2 of the drawings, 13 C NMR(150MHz,DMSO-d 6 )δ169.8,165.5,153.5,149.7,134.5,133.9,129.2,126.2,124.1,123.5,119.2,112.8,81.7,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 21 N 2 O 3 [M+H] + m/z:325.1552,found325.1555.
1-butyl-N' - (2-fluorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (b): yield 85.6%, white solid, m.p.136-142 ℃; as shown in the figure 3 of the drawings, 1 H NMR(600MHz,DMSO-d 6 ) δ10.67 (s, 1H), 8.38 (s, 1H), 8.29 (d, j=8.4 hz, 1H), 7.89 (s, 1H), 7.84 (d, j=8.4 hz, 1H), 7.12-7.09 (m, 1H), 7.00 (t, j=8.4 hz, 1H), 6.88 (t, j=8.4 hz, 1H), 6.77-6.73 (m, 1H), 5.75-5.73 (m, 1H), 2.14-2.08 (m, 1H), 1.78-1.72 (m, 1H), 1.40-1.25 (m, 4H), 0.88 (t, j=7.2 hz, 3H); as shown in figure 4 of the drawings, 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.6,153.6,151.5,149.9,137.3,133.9,126.2,124.1,123.5,119.4,115.4,115.3,114.2,81.8,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 F[M+H] + m/z:343.1458,found 343.1455.
1-butyl-N' - (3-fluorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (c): yield 39.2%, white solid, m.p.213-217 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.64(d,J＝2.4Hz,1H),8.37(s,1H),8.30(d,J＝7.8Hz,1H),8.28(s,1H),7.84(d,J＝7.8Hz,1H),7.19-7.16(m,1H),6.65-6.63(m,1H),6.56-6.50(m,2H),5.74-5.73(m,1H),2.13-2.09(m,1H),1.78-1.73(m,1H),1.39-1.26(m,4H),0.89(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.6,164.4,162.8,153.6,152.0,134.3,130.8,126.2,124.2,123.5,108.8,105.3,99.4,81.7,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 F[M+H] + m/z:343.1458,found 343.1459.
1-butyl-N' - (4-fluorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (d): yield 60.1%, white solid, m.p.186-190 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.63(s,1H),8.37(s,1H),8.29(d,J＝7.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.02(t,J＝8.0Hz,2H),6.83-6.81(m,2H),5.74-5.72(m,1H),2.14-2.08(m,1H),1.78-1.72(m,1H),1.40-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.8,165.6,157.2,155.7,153.6,146.3,134.5,133.9,126.2,124.1,123.5,115.7,114.1,81.7,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 F[M+H] + m/z:343.1458,found 343.1459.
1-butyl-N' - (2, 4-difluorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (e): yield 83.3%, white solid, m.p.177-180 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.68(s,1H,NH),8.37(s,1H),8.28(d,J＝8.4Hz,1H),7.90(s,1H,NH),7.84(d,J＝7.8Hz,1H),7.19-7.15(m,1H),6.89-6.88(m,2H),5.75-5.73(m,1H),2.13-2.08(m,1H),1.77-1.72(m,1H),1.39-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.7,156.2,154.5,153.6,151.0,149.4,134.3,126.2,124.2,123.5,114.9,111.2,104.2,81.7,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 19 N 2 O 3 F 2 [M+H] + m/z:361.1364,found 361.1363.
1-butyl-N' - (4-trifluoromethylphenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (f): yield 62.5%, white solid, m.p.223-226 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.73(s,1H),8.63(s,1H),8.39(s,1H),8.30(dd,J＝8.4,1.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.50(d,J＝9.0Hz,2H),6.92(d,J＝8.4Hz,2H),5.75-5.73(m,1H),2.14-2.09(m,1H),1.78-1.73(m,1H),1.38-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.6,153.7,152.9,134.2,134.0,126.7,126.3,124.6,123.6,119.0,118.8,112.1,81.8,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 20 H 20 N 2 O 3 F 3 [M+H] + m/z:393.1426,found 393.1428.
1-butyl-N' - (2-chlorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxylic acid hydrazide (g): yield 19.2%, white solid, m.p.145-147 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ10.75(s,1H),8.39(s,1H),8.30(d,J＝7.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.68(d,J＝2.4Hz,1H),7.33(d,J＝7.2Hz,1H),7.17(t,J＝7.2Hz,1H),6.89(d,J＝7.8Hz,1H),6.79(t,J＝7.8Hz,1H),5.75-5.73(m,1H),2.14-2.08(m,1H),1.78-1.72(m,1H),1.38-1.27(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.5,153.7,145.1,134.2,134.0,129.6,128.3,126.27124.2,123.6,120.2,117.8,113.6,81.8,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 Cl[M+H] + m/z:359.1162,found 359.1165.
1-butyl-N' - (3-chlorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (h): yield 68.1%, white solid, m.p.215-218 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ10.66(s,1H),8.38(s,1H),8.30(dd,J＝7.8,1.2Hz,1H),7.84(d,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),6.80-6.74(m,3H),5.75-5.73(m,1H),2.13-2.08(m,1H),1.78-1.72(m,1H),1.39-1.27(m,4H),0.89(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.5,153.6,151.3,134.2,134.0,133.9,130.9,126.2,124.1,123.6,118.6,112.1,111.4,81.8,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 F[M+H] + m/z:343.1458,found 343.1459.
1-butyl-N' - (4-chlorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxylic acid hydrazide (i): yield 86.1%, white solid, m.p.208-210 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ10.64(s,1H),8.37(s,1H),8.29(dd,J＝8.4,1.8Hz,1H),7.84(d,J＝7.8Hz,1H),7.20(d,J＝8.4Hz,2H),6.82(d,J＝8.4Hz,2H),5.74-5.72(m,1H),2.13-2.08(m,1H),1.77-1.72(m,1H),1.39-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.5,153.6,148.7,134.3,134.0,129.0,126.2,124.1,123.58,122.53,114.3,81.7,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 Cl[M+H] + m/z:359.1162,found 359.1163.
1-butyl-N' - (2, 4-dichlorophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (j): yield 51.6%, white solid, m.p.173-176 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ10.77(d,J＝1.8Hz,1H),8.38(s,1H),8.29(dd,J＝7.8,1.2Hz,1H),7.89(d,J＝1.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.46(d,J＝2.4Hz,1H),7.22(dd,J＝8.4,2.4Hz,1H),6.89(d,J＝9.0Hz,1H),5.75-5.73(m,1H),2.14-2.08(m,1H),1.78-1.74(m,1H),1.39-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.6,153.7,144.3,134.1,134.0,128.9,128.2,126.2,124.2,123.6,122.6,118.2,114.6,81.8,33.6,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 19 N 2 O 3 C l2 [M+H] + m/z:393.0773,found 393.0771.
1-butyl-N' - (4-bromophenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxylic acid hydrazide (k): yield 29.5%, white solid, m.p.211-216 ℃; 1 HNMR(600MHz,DMSO-d 6 )δ10.64(s,1H),8.36(s,1H),8.28(dd,J＝7.8,1.2Hz,1H),8.19(d,J＝2.4Hz,1H),7.84(d,J＝7.8Hz,1H),7.31(d,J＝9.0Hz,2H),6.78(d,J＝9.0Hz,2H),5.74-5.72(m,1H),2.13-2.08(m,1H),1.77-1.73(m,1H),1.38-1.25(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.5,153.6,149.1,134.3,133.9,131.8,126.2,124.17123.5,114.8,110.0,81.8,81.7,33.6,26.8,26.8,22.3,14.2；HRMS(ESI)calcd for C 19 H 20 N 2 O 3 Br[M+H] + m/z:403.0657,found403.0649.
1-butyl-N' - (4-methylphenyl) -3-oxo-1, 3-dihydroisobenzofuran-5-carboxamide (l): white solid; yield 41.2%, m.p.198-201 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.59(s,1H),8.36(s,1H),8.29(dd,J＝8.4,1.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.80(s,1H),6.98(d,J＝8.4Hz,2H),6.73(d,J＝8.4Hz,2H),5.74-5.72(m,1H),2.18(s,3H),2.13-2.08(m,1H),1.78-1.72(m,1H),1.38-1.27(m,4H),0.89(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.8,165.5,153.5,147.4,134.6,133.9,129.6,127.9,126.2,124.1,123.5,113.1,81.7,33.6,26.8,22.3,20.6,14.2；HRMS(ESI)calcd for C 20 H 23 N 2 O 3 [M+H] + m/z:339.1709,found 339.1711.
1-butyl-N' - (3-chloropyridin-4-yl) -3-oxo-o-1, 3-dihydroisobenzofuran-5-carboxylic acid hydrazide (m): white solid; yield 37.5%; m.p.191-195 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ10.79(s,1H),9.13(s,1H),8.39(s,1H),8.30(dd,J＝7.8,1.2Hz,1H),7.97(d,J＝5.4Hz,1H),7.86(d,J＝8.4Hz,1H),6.73-6.70(m,2H),5.76-5.74(m,1H),2.13-2.09(m,1H),1.78-1.72(m,1H),1.38-1.27(m,4H),0.88(t,J＝7.2Hz,3H)； 13 C NMR(150MHz,DMSO-d 6 )δ169.7,165.4,159.4,157.5,153.8,151.4,149.9,134.1,133.8,126.2,124.4,123.6,81.8,33.6,26.8,22.3,14.5,14.2.HRMS(ESI)calcd for C 18 H 19 N 3 O 3 Cl[M+H] + m/z:360.1115,found 360.1117.
example 4
The inhibitory activity of the compounds against eight plant pathogenic fungi of Alternaria tabaci (Altenaria alternariae, AA), pyricularia oryzae (Pyricularia oryzae, PO), solanum tuberosum (Fusarium sulphureum, FS), sclerotinia Sclerotiorum (SS), mallotus canker (Valsa mali, VM), botrytis Cinerea (BC), alternaria brassicae (Alternaria brassicae, AB) and Alternaria wheat (FG) was determined by the growth rate method. Acetone (AR grade) solution served as blank solvent control; hymexazol (Hymexazol), carbendazim (Carbendazim) and Chlorothalonil (chlorthalil) as positive agent controls.
The test drug was dissolved with acetone, and the quantitative drug solution was accurately removed and poured into Potato Dextrose Agar (PDA) to prepare 50. Mu.g/mL of drug-containing medium, which was then poured into a sterilized petri dish and cooled. Then respectively inoculating different bacterial cakes to be tested (with the diameter of 4 mm), setting 3 repeats for each group, setting a blank control group and a hymexazol control group at the same time, culturing (T=26+/-1 ℃, RH=70-80%, L/D=12 h/12 h) for 96h under proper conditions, measuring the diameters of bacterial colonies by a crisscross method, and determining the inhibition rate of each medicament on hypha growth according to the following formula.
The activity test results are shown in table 2:
inhibitory Activity against nine plant pathogenic fungi under the Compounds of Table 2
As can be seen from table 2, the compounds have a certain inhibition effect at the concentration of 50 mug/mL, wherein the compounds d, e, i and k have remarkable inhibition effect on the AA and PO strains, and the inhibition rate is superior to that of the positive drugs hymexazol and chlorothalonil; the compounds b and m have higher inhibition activity on PC strains, and the inhibition rates are respectively 60.8% and 99.6%; the antibacterial rate of the compound a, d, e, i, l on FS and FG strains is 56.0-98.0%, and the antibacterial effect is obviously better than that of two positive control medicines of hymexazol (21.2-84.5%) and chlorothalonil (33.0-69.1%); compounds d (89.7%), e (88.3%), i (79.6%) and l (60.0%) have higher inhibitory activity on VM than hymexazol (28.2%) and chlorothalonil (58.5%); for BC strains, compounds b (81.1%) and e (86.8%) had comparable inhibitory effects to hymexazol (84.5%).
Next, to further determine the inhibitory effect of the compounds on some plant pathogenic fungi, the present invention tested EC of compound a, b, c, d, e, i, l, n, k with an inhibition ratio of greater than 80.0% at a concentration of 50. Mu.g/mL 50 The values and results are shown in Table 3. From Table 3, it can be seen that the compounds have good antibacterial activity and EC 50 The value range is between 0.61-25.79 mug/mL, which is superior to positive control hymexazol (EC) 50 =10.92-58.61). Of these, the compound e is the most active, and its EC against plant pathogenic fungi AA, PO, FS, VM and FG strains 50 The antibacterial effect is 11-58 times that of hymexazol, and the inhibition activity of the hymexazol on FG strains is better than that of carbendazim (0.89 mu g/mL). EC of Compound b against phytopathogenic fungi AA, PO, AB, FG and BC Strain 50 The antibacterial activity of the hymexazol is 2.65 mug/mL, 2.39 mug/mL, 6.04 mug/mL, 1.13 mug/mL and 5.62 mug/mL respectively, and is also superior to that of the positive control hymexazol.
Table 3 partial Compounds inhibit EC of phytopathogenic fungi 50 (μg·mL -1 ) Value of
/>
FIG. 5 is a graph showing the inhibitory activity of Compound b of the present invention against five plant pathogenic fungi (PO, AA, AB, FG, BC) at mass concentrations of 12.5. Mu.g/mL, 6.25. Mu.g/mL, 3.125. Mu.g/mL, 1.5625. Mu.g/mL and 0.78125. Mu.g/mL, with a significant decrease in colony diameter for each pathogenic fungus as the mass concentration of Compound b increases, as compared to the Control (Control). Compound b was completely inhibited from wheat scab at mass concentrations of 12.5 μg/mL and 6.25 μg/mL.
FIG. 6 is a graph showing the inhibitory activity of compound e of the present invention against five plant pathogenic fungi (AA, AB, FG, BC, FS) at mass concentrations of 3.125. Mu.g/mL, 1.5625. Mu.g/mL, 0.78125. Mu.g/mL, 0.3906. Mu.g/mL and 0.1953. Mu.g/mL, and compound e has excellent inhibitory activity against all five pathogenic fungi at lower mass concentrations compared to the Control (Control).
In conclusion, the phthalide hydrazide compound is prepared and applied to plant diseases caused by plant pathogenic fungi. The research result of the inhibition activity of the compound on plant pathogenic fungi shows that the phthalide hydrazide compound prepared by the invention has the activity of inhibiting plant pathogenic fungi, and among 13 prepared compounds, the compounds d, e and i have excellent inhibition activity on various plant pathogenic fungi, and are obviously better than commercial broad-spectrum antibacterial agent hymexazol. Therefore, the invention provides a candidate compound with novel skeleton, excellent activity and wide bacteriostasis spectrum for research and development of agricultural bactericides.
It should be noted that, when numerical ranges are referred to in the present invention, it should be understood that two endpoints of each numerical range and any numerical value between the two endpoints are optional, and because the adopted step method is the same as the embodiment, in order to prevent redundancy, the present invention describes a preferred embodiment. While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (5)

1. The phthalide hydrazide compound is characterized by having a chemical structural general formula shown in a formula I:
wherein said R is 1 Is butyl, and R is the following substituent:
2. the method for preparing phthalide hydrazide compound according to claim 1, wherein when R 1 When the compound is butyl, 6-bromobutylphthalide as a raw material is added with cuprous cyanide to obtain a compound of a formula III through cyano substitution, the compound of a formula IV is obtained through reflux hydrolysis under an acidic condition, then an aryl hydrazine hydrochloride compound is added to carry out acylation reaction to obtain a phthalide hydrazide compound of a formula V, and the specific synthetic route is as follows:
wherein R is:
3. use of the phthalide hydrazide compound of claim 1 as an active ingredient in the preparation of a bactericide.
4. The use according to claim 3, wherein the fungicide is capable of controlling plant diseases caused by plant pathogenic fungi including brown spot of tobacco, rice blast, phytophthora capsici, fusarium wilt of watermelon, potato, sclerotinia rot of apple, botrytis cinerea, black spot of cabbage and red rot of wheat.
5. A bactericidal composition characterized by comprising the phthalide hydrazide compound of claim 1, wherein the bactericidal composition is in the form of emulsifiable concentrate, suspending agent, aqueous emulsion, wettable powder, microemulsion or water dispersible granule.
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