CN104530013B - Pyrazol acid amide compounds based on indole ring as disinfectant use in agriculture purposes - Google Patents

Pyrazol acid amide compounds based on indole ring as disinfectant use in agriculture purposes Download PDF

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CN104530013B
CN104530013B CN201410728192.8A CN201410728192A CN104530013B CN 104530013 B CN104530013 B CN 104530013B CN 201410728192 A CN201410728192 A CN 201410728192A CN 104530013 B CN104530013 B CN 104530013B
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hydrogen
methyl
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acid amide
bromine
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CN104530013A (en
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黄家兴
解晓平
周君仪
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China Agricultural University
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China Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles

Abstract

The invention discloses a kind of pyrazol acid amide compounds with below formula and the purposes as disinfectant use in agriculture.

Description

Pyrazol acid amide compounds based on indole ring as disinfectant use in agriculture purposes
Technical field
The present invention relates to a kind of pyrazol acid amide compounds, more particularly to a kind of pyrazol acid amide compounds based on indole ring and the purposes as disinfectant use in agriculture.Belong to disinfectant use in agriculture field.
Background technology
Chemical prevention is the technical way of control of crop disease.Organic synthesis bactericide is the main part in current disinfectant use in agriculture, is also the important component of modern industry.But a large amount of with organic synthesis bactericide use, crop pathogenses show different degrees of drug resistance or the resistance to the action of a drug.To solve this problem, it is the continuing problem that pesticide industry faces constantly to develop various new type bactericides.
After finding the good characteristic that benomyl has preventing and treating fungal disease from nineteen sixty-eight, the sterilization idiocratic of benzimidazoles compound causes the close attention of major agricultural chemicals companies, and successfully develops the disinfectant use in agriculture such as carbendazim, probenazole successively.Benzimidazole germicide has good uptake and translocation as a kind of bactericide of broad spectrum activity in crop body, therefore available for a variety of occasions such as Seed Treatment, soil treatment and cauline leaf sprayings.But the maximum defect of the series bactericidal agent is to use shortly to generate the more serious resistance to the action of a drug.
Patent US4950668A, which discloses the pyrazole amide analog derivatives such as tebufenpyrad (tebufenpyrad), has pesticide and miticide actility.The N- benzyl pyrazole acidamide derivatives that patent US5039693A discloses the substitution of the phenoxy groups such as Tolfenpyrad (tolfenpyrad) have pesticide and miticide actility, are reported without bactericidal activity.Patent WO02083647A1, which discloses the pyrazole amide containing xenyl, has Insecticiding-miticiding and bactericidal activity.The pyrazole amide analog derivative that patent CN1927860A discloses benzene biaryl of grinning has pesticide and miticide actility, is reported without bactericidal activity.
Patent US5039693 discloses the compound with formula (B), with pesticide and miticide actility, but the patent does not disclose it has bactericidal activity.
Patent EP0365925A1 discloses the compound with formula (B) structure, with pesticide and miticide actility, without any bactericidal activity report.
Patent CN103081916A discloses the bactericidal activity with formula (B) structural compounds, to cucumber downy mildew, and the disease such as corn rust has excellent prevention effect.
Indole structure in the present invention introduces pyrazol acid amide compounds and has no document report as the application of disinfectant use in agriculture.
The content of the invention
In order to obtain the new type bactericide of the unique various crop diseases of preventing and treating of mechanism of action, indole structure is introduced pyrazol acid amide compounds by the present invention, bactericidal activity research has been carried out to the pyrazol acid amide compounds with formula (A), as a result find that the row compound has broad spectrum antibacterial activity, there is certain prevention effect to grey mold pathogen, rice blast pathogen, Asparagus Stem Blight opportunistic pathogen, early blight of eggplant opportunistic pathogen, Phytophthora capsici, it is particularly preferable to ash arrhizus bacteria and Pyricularia oryzae effect.
Technical solution of the present invention is as follows：
A kind of pyrazol acid amide compounds, shown in the compound structure such as formula (A)：
In formula (A)：
X is selected from hydrogen, chlorine, bromine, iodine；
R1Selected from hydrogen, methyl, ethyl, n-propyl, phenyl；
R2Selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group；
R3Selected from hydrogen, methyl, benzyl.
It is preferred that technical scheme, in formula (A)：
X is selected from chlorine, bromine；
R1Selected from hydrogen, methyl, phenyl；
R2Selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group；
R3Selected from hydrogen, methyl.
It is again preferred technical scheme, in formula (A)：
X is selected from chlorine, bromine；
R1Selected from hydrogen, methyl；
R2Selected from hydrogen, chlorine, bromine, iodine, methoxyl group；
R3Selected from hydrogen, methyl.
Highly preferred technical scheme is：
In formula (A)：
X is selected from chlorine, bromine；
R1Selected from hydrogen, methyl；
R2Selected from hydrogen, chlorine, bromine, iodine, alkyl, methoxyl group；
R3Selected from hydrogen.
Compound synthesis method shown in formula (A) of the present invention is as follows：
Pyrazol acid amide compounds based on indole ring, i.e. target product A, are obtained by pyrazoles fragment and indoles fragment through condensation reaction.The pyrazoles fragment 4 is 1- methyl -3- ethyl -4- chlorine (hydrogen or bromine) pyrazoles -5- formyl chlorides；The indoles fragment is substituted indole -3- methylamines.
Wherein, the preparation of pyrazoles fragment may be referred to document：《The study on the synthesis of 3- ethyl -5- pyrazoles acetoacetic esters, Zhejiang Polytechnical University's journal, Tan Chengxia, Shen Delong, Weng Jianquan, Fan Defang, 2005,32 (2):204-206》；《The study on the synthesis of 1- methyl -3- ethyl -5- pyrazoles acetoacetic esters, Zhejiang Polytechnical University's journal, Tan Chengxia, Shen Delong, Weng Jianquan, Sun Nabo, 2005,33 (3)：331-335》；《The synthesis moderns of Tolfenpyrad, model essay political affairs, Gu Baoquan, Zhu Wei is clear etc., 2005,4 (2):9-11》；《Chemistry In China bulletin, magnifies strong etc., 2012,236 (6), 669-672》；《Modern, horse naval etc., 2011,10 (5), 16-20,23》.
The synthetic route of pyrazoles fragment is as follows：
The synthetic route of indoles fragment is as follows：
The synthesis of formula (1) substituted indole-3-carboxaldehyde, referring to document《Organic chemistry, 2006,26 (4):563-567》, reaction is generally at -10 DEG C to progress between solvent boiling point, and convenient temperature is -10~100 DEG C；Reaction time is 30 minutes to 20 hours, usually 1~10 hour；Suitable solvent is N,N-dimethylformamide.
Formula (2) replaces the preparation of 3- cyanoindoles, with formula (1) for raw material, according to document《The synthesis of Yang Yan U.S. substituted indole-3-carbonitrile class compounds:[Master's thesis] Southeast China University；2008.》Carry out.Reaction is generally carried out in room temperature between solvent boiling point, and convenient temperature is 20~100 DEG C；It is 30 minutes to 8 hours, usually 1~6 hour between seasonable；Suitable solvent may be selected from methanol, ethanol, butanol, water and methanol, ethanol, mixture of fourth alcohol and water etc..
Formula (6) using dimethyl carbonate methylate obtaining formula (7) in appropriate solvent.Specific prepare is referred to document《OrganicProcessResearch&Development,2001,5,604-608》The method of description is carried out；Reaction is generally carried out in room temperature between solvent boiling point, and convenient temperature is 20~160 DEG C；It is 30 minutes to 20 hours, usually 1~10 hour between seasonable；Suitable solvent may be selected from dimethylbenzene, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide etc.；Reaction generally needed to be added alkali and is catalyzed, and conventional alkali has sodium carbonate, potassium carbonate etc..
In appropriate solvent, the hydrogenated reduction in the presence of appropriate catalyst and ammoniacal liquor of formula (6) and formula (7) obtains formula (8).Specific prepare is referred to document《J.Am.Chem.Soc,1963,85(22):3683-3685》The method of description is carried out.Reaction is generally carried out in room temperature between solvent boiling point, and convenient temperature is 20~100 DEG C；Reaction time is 30 minutes to 20 hours, usually 1~10 hour；Suitable solvent may be selected from benzene,toluene,xylene, acetone, MEK, tetrahydrofuran, acetonitrile, dioxanes, DMF, dimethyl sulfoxide, pyridine, dichloromethane, dichloroethanes, ethyl acetate and methyl acetate etc.；Suitable catalyst may be selected from Raney's nickel, palladium carbon or platinum oxide etc..
Target product A can be indoles fragment as the amine shown in formula (8) with the pyrazol formyl chloride i.e. pyrazoles fragment shown in formula (4) in suitable solvent, appropriate alkali exist or alkali in the absence of be condensed and be made.Specific preparation method is with reference to EP0365925A1, US5264448A.Suitable solvent may be selected from benzene,toluene,xylene, acetone, MEK, tetrahydrofuran, acetonitrile, dioxanes, DMF, dimethyl sulfoxide, pyridine, dichloromethane, dichloroethanes, ethyl acetate and methyl acetate etc.；Appropriate alkali may be selected from potassium hydroxide, NaOH, sodium carbonate, sodium acid carbonate, triethylamine, pyridine etc.；Reaction temperature can be in room temperature between solvent boiling point temperature, usually 0~100 DEG C；Reaction time is 30 minutes to 20 hours, usually 1~10 hour.Course of reaction is as follows：
The compound that can be listed with table one the following illustrates the present invention, but does not limit the present invention.
The part of compounds of the formula of table one (A)
Numbering X R1 R2 R3
1 Cl H H H
2 Cl CH3 H H
3 Cl Ph H H
4 Cl H 4-Cl H
5 Cl H 4-Br H
6 Cl H 5-Br H
7 Cl H 5-OCH3 H
8 Cl H 6-Cl H
9 Cl H 6-Br H
10 Cl H H CH3
11 Cl CH3 H CH3
12 Cl Ph H CH3
13 Cl H 4-Cl CH3
14 Cl H 4-Br CH3
15 Cl H 5-Br CH3
16 Cl H 5-OCH3 CH3
17 Cl H 6-Cl CH3
18 Cl H 6-Br CH3 4 -->
19 H CH3 H H
20 H Ph H H
21 H H H CH3
22 H Ph H CH3
23 H H 4-Br CH3
24 Br H H H
25 Br H 4-Br H
26 Br H 4-Cl CH3
27 Br H 6-Cl CH3
28 Br H 4-Cl H
29 Br H 5-OCH3 H
30 Br H 6-Cl H
31 Br Ph H H
32 Br H 4-Br CH3
33 Br H H CH3
34 Br H 5-Br H
35 Br H 5-Br CH3
36 Br H 5-OCH3 CH3
Pyrazol acid amide compounds based on indole ring as various plant diseases disinfectant use in agriculture.The compound has broad spectrum antibacterial activity.Pyrazol acid amide compounds shown in the disinfectant use in agriculture of plant disease using formula (A) are used as active component.
The plant disease includes：Grey mold pathogen, rice blast pathogen, Asparagus Stem Blight opportunistic pathogen, early blight of eggplant opportunistic pathogen and Phytophthora capsici.Particularly ash arrhizus bacteria and Pyricularia oryzae.
Target compound is to compare according to People's Republic of China's agricultural industry criteria (NY/T1156.2-2006) using Bravo and carbendazim, and bactericidal activity measure has been carried out using mycelial growth rate method.Wherein to Pyricularia oryzae preventive effect：When liquor strength is 400ppm, in table one, the preventive effect of the grade of compound 1,2,6,32,33 is 100%；When liquor strength is 50ppm, the preventive effect of the grade of compound 2,32,33 is 100%.To ash arrhizus bacteria preventive effect：When liquor strength is 400ppm, the preventive effect of the grade of compound 6,21,23,35 is 100%；When liquor strength is 50ppm, the preventive effect of the grade of compound 6,21,23 is more than 80%.
Because this invention is found that the pyrazol acid amide compounds shown in formula (A) have bactericidal activity first, the compound has broad spectrum antibacterial activity, therefore such compound can be applied to the disease on the various crops of the agricultural uses such as preventing and treating agricultural, gardening and flower culture, be particularly suitable for preventing and treating following plants disease：Grey mold pathogen, rice blast pathogen, Asparagus Stem Blight opportunistic pathogen, early blight of eggplant opportunistic pathogen, particularly Phytophthora capsici, ash arrhizus bacteria and Pyricularia oryzae.The phytopathogen that the compound of the present invention can be prevented and treated is not limited to the above.Therefore, technical scheme includes purposes of the pyrazol acid amide compounds shown in formula (A) as disinfectant use in agriculture, with good actual application value.
Embodiment
Below, the present invention is further illustrated with reference to specific example.All raw materials unless otherwise specified are commercially available.
Synthetic example
First, the preparation method of intermediate 4
1) preparation of ethyl propionylpyruvate
50mL absolute ethyl alcohols are added into 250mL there-necked flasks, metallic sodium 6.25g (270mmol) is added portionwise, it is heated to backflow, after sodium reaction completely, steam ethanol, obtain caustic alcohol, add 40mL dry toluenes thereto again, be cooled to 0 DEG C, diethy-aceto oxalate 34mL (250mmol) and butanone 22.5mL (250mmol) mixture is then added dropwise, temperature control is at 0 DEG C or so, 1h or so is dripped off, and continues stirring reaction after dripping off 0.5 hour, TLC monitorings, after diethy-aceto oxalate reaction completely, stop reaction.Obtained brown liquid is slowly poured into the 7.5mL concentrated sulfuric acids and the mixture of ice carries out pickling, and ether extraction, anhydrous sodium sulfate drying carries out vacuum distillation, collects 94~96 DEG C of (150pa) cuts and obtains light yellow product 30.9g, yield 72.1%.
2) preparation of 3- ethyls -5- pyrazoles acetoacetic esters
The hydrazine hydrate 16mL (300mmol) and water 40mL that 85% is added into 250mL there-necked flasks are placed in ice-water bath, 5 DEG C of stirrings are lower to be added dropwise the chloroformic solution that 50mL contains ethyl propionylpyruvate 47.4g (300mmol), drop continues to react 2h after finishing, divide liquid, 3 × 50mL of chloroform extracts organic phase, and solvent is evaporated off in anhydrous sodium sulfate drying, obtain thick dark product 34.0g, yield：80.1%.
3) synthesis of the chloro- 5- pyrazoles acetoacetic esters (4) of 3- ethyls -4-
3- ethyl -5- pyrazoles acetoacetic ester 10g (60mmol) are taken to be dissolved in 50mL dichloroethanes, 11.4g dimethyl suflfates (80mmol) are added dropwise at 40-50 DEG C of control, it is added dropwise within 3 hours complete, flow back 4h again, TLC detects that reaction is complete, removes solvent, light brown liquid 9.0g is obtained, yield is about：74%.Product is obtained without purifying, is reacted directly down.
4) synthesis of the chloro- 5- pyrazoles acetoacetic esters (5) of 1- methyl -3- ethyls -4-
3- ethyl -5- pyrazole carboxylic acid ethyl ester 6.92g (40.6mmol) are mixed with sulfonic acid chloride 4.57mL (48mmol), 3h is stirred at 90 DEG C.TLC is monitored, and after reaction completely, is neutralized with saturated aqueous sodium carbonate, branch vibration layer, low-boiling-point substance is removed under reduced pressure in organic layer anhydrous sodium sulfate drying, obtains crude product 6.5g, can be directly used for next step reaction.
5) synthesis of the chloro- 5- pyrazoles acid of 1- methyl -3- ethyls -4-
The chloro- 5- pyrazoles acetoacetic ester 2.2g (10mmol) of 1- methyl 3- ethyls -4- are taken to be dissolved in the mixed solution of 10mL methanol and 10mL water, stirring is lower to add NaOH0.58g (15mmol), it is being warming up to backflow, react 1h, cooling, it is 3 or so that concentrated hydrochloric acid, which is acidified to PH, and white solid 1.72g is dried to obtain in filtering.Yield：95%.
6) synthesis of the chloro- 5- pyrazole acyl chlorides (8) of 1- methyl -3- ethyls -4-
In the there-necked flask equipped with device for absorbing tail gas, the chloro- 5- pyrazole carboxylic acids 8.3g (44mmol) of 1- methyl -3- ethyls -4-, 50mL dichloroethanes are added, thionyl chloride 7.2mL (88mmol), is heated to reflux 4h, solvent is evaporated off, obtain colourless liquid about 8.5g, yield 96%.
2nd, the preparation method of intermediate 8
1) synthesis of substituted indole-3-carboxaldehyde (1), so that indole -3-formaldehyde is synthesized as an example.
To equipped with mechanical agitation, DMF14.4mL is added in the 500mL of thermometer there-necked flask, 0-5 DEG C is cooled to, is slowly dropped into POCl34.3mL (47mmol), control temperature is at 0 DEG C or so, and about 0.5h is dripped off, and continues to stir 15 minutes after dripping off.5g containing indoles (42.5mmol) and 5mLDMF solution are added dropwise below 10 DEG C, about 1h is dripped off.35 DEG C are heated to after dripping off, keep 1h, cooling is lower to add 30g mixture of ice and water, and it is to be added dropwise to add before the solution containing NaOH18.8g (470mmol) and water 50mL, discoloration, it can be directly added into after discoloration, 20min, cooling, suction filtration, washing are heated to reflux after adding, drying, obtains pale yellow crystals 5.5g.M.p.184-186 DEG C, yield 97%.
2) preparation of substitution 3- cyanoindoles (2), by taking the synthesis of 3- cyanoindoles as an example.
Indole -3-formaldehyde 3.6g (25mmol) is added into the 500mL there-necked flasks equipped with agitator, thermometer and reflux condensing tube, hydroxylamine hydrochloride 2.6g (37mmol), pyridine 3mL and ethanol 40mL, it is heated to reflux two hours, acetic anhydride 35.5mL, heated overnight at reflux are added dropwise after cooling.About 2/3 solvent is evaporated off after cooling, 30mL water is added, suction filtration, water washing, drying obtains light red solid 3.1g, yield 88%.m.p.70-72℃.
3) synthesis of N- methyl substitution -3- cyanoindoles, by taking the synthesis of N- methyl -3- cyano group as an example.
3- cyanoindoles 7g (49mmol) is added into 250mL there-necked flasks, potassium carbonate 3.54g (0.52mmol), dimethyl carbonate 12.67mL (150mmol), DMF50mL are heated to reflux 2h, TLC is monitored, if reaction cannot be reacted completely completely, a small amount of dimethyl carbonate can be added and stop heating, extracted after cooling with 200mL water and 100mL+50mL+30mL ethyl acetate, salt water washing, anhydrous sodium sulfate drying.Concentration, obtains white-yellowish solid 7.2g, yield 94.2%.
4) preparation of substituted indole -3- methylamines (4), by taking indoles -3- methylamines as an example.
3- cyanoindoles (21mmol) will be replaced to add in the saturation ammonia solution of 150mL methanol, 1gW-2 type Raney's nickels are added and make catalyst, the reduction reaction 5h under 0.4MPa Hydrogen Vapor Pressures, until hydrogen is completely absorbed in theory.Filtering, removal of solvent under reduced pressure, obtained grease.The product need not be purified to react directly down.
3rd, target product A preparation method
1) preparation of the chloro- 3- ethyls -1- methyl isophthalic acids H- pyrazoles -5- formamides of N- ((1H- indol-3-yls) methyl) -4-：
2 methyl indole -3- methylamines crude product (4) is dissolved in 30mL tetrahydrofurans, in the there-necked flask for being transferred to a 250mL, triethylamine 2.31g (22.7mmol) is added and does acid binding agent.The lower 10mL tetrahydrofuran solutions for being added dropwise and containing the chloro- 5- pyrazole acyl chlorides 3.92g (18.9mmol) of 1- methyl -3- ethyls -4- are stirred at room temperature, are added dropwise within 0.5 hour complete.React 0.5 hour at room temperature afterwards, thin layer detection reaction raw materials disappear, petroleum ether：Ethyl acetate 2:1 expansion, Rf values 0.32.Triethylamine hydrochloride is filtered to remove, the dissolving of 30mL ethyl acetate is added after the desolvation that is concentrated under reduced pressure, 10mL water washings, 10mL saturated common salt water washings, anhydrous sodium sulfate drying depressurizes desolventizing.Pillar layer separation, 2:1 petroleum ether：Ethyl acetate is eluted, and obtains white solid 4.79g, yield 77%, m.p.174~176 DEG C.
2) preparation of the chloro- 3- ethyls -1- methyl isophthalic acids H- pyrazoles -5- formamides of N- ((1H- indol-3-yls) methyl) -4-：
Indoles -3- methylamines crude product (4) is dissolved in 30mL tetrahydrofurans, in the there-necked flask for being transferred to a 250mL, triethylamine 2.31g (22.7mmol) is added and does acid binding agent.The lower 10mL tetrahydrofuran solutions for being added dropwise and containing the chloro- 5- pyrazole acyl chlorides 3.92g (18.9mmol) of 1- methyl -3- ethyls -4- are stirred at room temperature, are added dropwise within 0.5 hour complete.React 0.5 hour at room temperature afterwards, thin layer detection reaction raw materials disappear, petroleum ether：Ethyl acetate 2:1 expansion, Rf values 0.32.Triethylamine hydrochloride is filtered to remove, the dissolving of 30mL ethyl acetate is added after the desolvation that is concentrated under reduced pressure, 10mL water washings, 10mL saturated common salt water washings, anhydrous sodium sulfate drying depressurizes desolventizing.Pillar layer separation, 2:1 petroleum ether：Ethyl acetate is eluted, and obtains white solid 6.6g, yield 87%, m.p.108~110 DEG C.
3) preparation of the chloro- 3- ethyls -1- methyl isophthalic acids H- pyrazoles -5- formamides of N- ((1H- indol-3-yls) methyl) -4-：
Indoles -3- methylamines crude product (4) is dissolved in 30mL tetrahydrofurans, in the there-necked flask for being transferred to a 250mL, triethylamine 2.31g (22.7mmol) is added and does acid binding agent.The lower 10mL tetrahydrofuran solutions for being added dropwise and containing the chloro- 5- pyrazole acyl chlorides 3.92g (18.9mmol) of 1- methyl -3- ethyls -4- are stirred at room temperature, are added dropwise within 0.5 hour complete.React 0.5 hour at room temperature afterwards, thin layer detection reaction raw materials disappear, petroleum ether：Ethyl acetate 2:1 expansion, Rf values 0.32.Triethylamine hydrochloride is filtered to remove, the dissolving of 30mL ethyl acetate is added after the desolvation that is concentrated under reduced pressure, 10mL water washings, 10mL saturated common salt water washings, anhydrous sodium sulfate drying depressurizes desolventizing.Pillar layer separation, 2:1 petroleum ether：Ethyl acetate is eluted, and obtains white solid 6.1g, yield 91%, m.p.147~149 DEG C.
4) preparation of the chloro- 3- ethyls -1- methyl isophthalic acids H- pyrazoles -5- formamides of N- ((1H- indol-3-yls) methyl) -4-：
Indoles -3- methylamines crude product (4) is dissolved in 30mL tetrahydrofurans, in the there-necked flask for being transferred to a 250mL, triethylamine 2.31g (22.7mmol) is added and does acid binding agent.The lower 10mL tetrahydrofuran solutions for being added dropwise and containing the chloro- 5- pyrazole acyl chlorides 3.92g (18.9mmol) of 1- methyl -3- ethyls -4- are stirred at room temperature, are added dropwise within 0.5 hour complete.React 0.5 hour at room temperature afterwards, thin layer detection reaction raw materials disappear, petroleum ether：Ethyl acetate 2:1 expansion, Rf values 0.32.Triethylamine hydrochloride is filtered to remove, the dissolving of 30mL ethyl acetate is added after the desolvation that is concentrated under reduced pressure, 10mL water washings, 10mL saturated common salt water washings, anhydrous sodium sulfate drying depressurizes desolventizing.Pillar layer separation, 2:1 petroleum ether：Ethyl acetate is eluted, and obtains white solid 6.56g, yield 89%, m.p.125~127 DEG C.
5) preparation of the chloro- 3- ethyls -1- methyl isophthalic acids H- pyrazoles -5- formamides of N- ((1H- indol-3-yls) methyl) -4-：
Indoles -3- methylamines crude product (4) is dissolved in 30mL tetrahydrofurans, in the there-necked flask for being transferred to a 250mL, triethylamine 2.31g (22.7mmol) is added and does acid binding agent.The lower 10mL tetrahydrofuran solutions for being added dropwise and containing the chloro- 5- pyrazole acyl chlorides 3.92g (18.9mmol) of 1- methyl -3- ethyls -4- are stirred at room temperature, are added dropwise within 0.5 hour complete.React 0.5 hour at room temperature afterwards, thin layer detection reaction raw materials disappear, petroleum ether：Ethyl acetate 2:1 expansion, Rf values 0.32.Triethylamine hydrochloride is filtered to remove, the dissolving of 30mL ethyl acetate is added after the desolvation that is concentrated under reduced pressure, 10mL water washings, 10mL saturated common salt water washings, anhydrous sodium sulfate drying depressurizes desolventizing.Pillar layer separation, 2:1 petroleum ether：Ethyl acetate is eluted, and obtains white solid 7.05g, yield 93%, m.p.150~152 DEG C.
It is prepared by the method that other compounds of formula (A) can be provided by the present invention.
Part of compounds fusing point and nuclear magnetic data (1HNMR, 300MHz, internal standard TMS, solvent C DCl3) such as table 2 and 3：
The physico data of the compound of table 2
The target compound of table 31HNMR data
Application Example bioactivity
The sterilized biological activity test of all target compounds is using Bravo and carbendazim active compound as comparison medicament, determine target compound former to capsicum epidemic disease, rice blast cause of disease, Asparagus Stem Blight is former, gray mold of cucumber is former, the inhibitory activity of the various plants pathogen mycelial growth rate such as early blight of eggplant original.According to People's Republic of China's agricultural industry criteria (NY/T1156.2-2006), it is measured using mycelial growth rate method.
98% Bravo active compound, 98% carbendazim active compound.
Strain used is the Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide and separates preservation strain with application technology emphasis open laboratory.
Asparagus Stem Blight opportunistic pathogen [Phomopsisasparagi (Sacc.) Bubas], belongs to fungi Deuteromycotina, Sphaeropsidales, Phomopsis, lucid asparagus Phomopsis.
Rice blast cause of disease [PyriculariaoryzaeCav]:Deuteromycotina, hyphomycetales, pears born of the same parents category, rice pears born of the same parents.
Early blight of eggplant original [PhytophtoraparasiticaDast]:Belong to fungi Mastigomycotina, Phytophthora, eggplant phytophthora, fungi oomycetes disease.
Gray mold of cucumber original [BotrytiscinereaPers]:Belong to fungi Deuteromycotina, hyphomycetales, Botrytis, Botrytis cinerea.
Phytophthora capsici cause of disease [Phytophtnoracapsicia]:Belong to fungi Mastigomycotina, Phytophthora, Phytophthora capsici.
Method of testing：Determined with growth rate method
By drug solution preparing into finite concentration, add among the culture medium melted, shake up, the malicious culture medium flat plate of band is made, pathogen is inoculated with the plane, the virulence size of medicament is judged according to the growth rate size of germ.Pathogen growth speed can be represented with two methods：(1) in certain time colony growth diameter size；(2) colony growth is to the time required to certain diameter.First method is taken herein.
Investigation and calculating
Mycelial growth condition survey：By observing the colony growth situation in blank control culture dish, to investigate cause of disease mycelia growing state.The bacterium colony in blank control is observed, when it is grown to close to culture dish edge, the colony diameter of each processing is measured using crossing method, bacterium colony is calculated and increases diameter (referring to equation below), take its average value.
Bacterium colony increases diameter=colony diameter-bacteria cake diameter
The calculating of measurement result：Activity data is calculated using following method：Mycelial growth inhibition rate of each chemicals treatment of diameter calculating to various pathogens is increased with the bacterium colony that blank control bacterium colony increases diameter and chemicals treatment, formula is as follows：
Mycelial growth inhibition rate (%)=(control bacterium colony increases diameter-chemicals treatment bacterium colony and increases diameter)/control bacterium colony increases diameter × 100%.
Partial test result is as follows：
Pyricularia oryzae preventive effect：
When liquor strength is 400ppm, the preventive effect of the grade of compound 1,2,6,32,33 is 100%.
When liquor strength is 50ppm, the preventive effect of the grade of compound 2,32,33 is 100%.
Ash arrhizus bacteria preventive effect：
When liquor strength is 400ppm, the preventive effect of the grade of compound 6,21,23,35 is 100%.
When liquor strength is 50ppm, the preventive effect of the grade of compound 6,21,23 is more than 80%.
The preferable possible embodiments of the present invention are the foregoing is only, not thereby limit to the scope of the claims of the present invention, therefore equivalence changes that every utilization present invention is made are both contained in protection scope of the present invention.

Claims (9)

1. a kind of pyrazol acid amide compounds, shown in the compound structure such as formula (A)：
In formula (A)：
X is selected from hydrogen, chlorine, bromine, iodine；
R1Selected from hydrogen, methyl, ethyl, n-propyl, phenyl；
R2Selected from hydrogen, chlorine, bromine, iodine, cyano group, methoxyl group；
R3Selected from hydrogen, methyl.
2. pyrazol acid amide compounds according to claim 1, it is characterised in that in formula (A)：
X is selected from chlorine, bromine；
R1Selected from hydrogen, methyl, phenyl；
R2Selected from hydrogen, chlorine, bromine, iodine, cyano group, methoxyl group；
R3Selected from hydrogen, methyl.
3. pyrazol acid amide compounds according to claim 2, it is characterised in that in formula (A)：
R1Selected from hydrogen, methyl；
R2Selected from hydrogen, chlorine, bromine, iodine, methoxyl group.
4. pyrazol acid amide compounds according to claim 3, it is characterised in that in formula (A)：
R2Selected from hydrogen, chlorine, bromine, iodine, methoxyl group；
R3Selected from hydrogen.
5. a kind of synthetic method of the compound as described in any one of Claims 1 to 4, the compound is obtained by pyrazoles fragment and indoles fragment through condensation reaction；
The pyrazoles fragment is 1- methyl -3- ethyl -4- chlorine pyrazoles -5- formyl chlorides, or is 1- methyl -3- ethyl -4- hydrogen pyrazoles -5- formyl chlorides, or is 1- methyl -3- ethyl -4- bromine pyrazoles -5- formyl chlorides；
The indoles fragment is substituted indole -3- methylamines.
6. as described in any one of Claims 1 to 4 compound as plant disease disinfectant use in agriculture purposes.
7. the purposes according to claim 6, it is characterised in that the active component of pyrazol acid amide compounds shown in the disinfectant use in agriculture using formula (A) as composition.
8. the purposes according to claim 6, it is characterised in that the plant disease includes：Grey mold pathogen, rice blast pathogen, Asparagus Stem Blight opportunistic pathogen, early blight of eggplant opportunistic pathogen and Phytophthora capsici.
9. the purposes according to claim 8, it is characterised in that the plant disease includes：Ash arrhizus bacteria and Pyricularia oryzae.
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