CN104530013A - Application of indole ring-based pyrazole amide compound used as agricultural fungicide - Google Patents

Application of indole ring-based pyrazole amide compound used as agricultural fungicide Download PDF

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CN104530013A
CN104530013A CN201410728192.8A CN201410728192A CN104530013A CN 104530013 A CN104530013 A CN 104530013A CN 201410728192 A CN201410728192 A CN 201410728192A CN 104530013 A CN104530013 A CN 104530013A
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hydrogen
methyl
general formula
bromine
chlorine
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CN104530013B (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 an application of a pyrazole amide compound as shown in the general formula in the specification that is used as an agricultural fungicide. The compound provided by the invention has a broad-spectrum bactericidal activity, has a certain control effect on Botrytis pathogen, rice blast pathogen, phomopasis asparagi pathogen, eggplant phytophthora fruit rot pathogen and phytophthora capsici, especially has a good effect on Botrytis cinerea, and has good practical application value. The invention belongs to the field of agricultural fungicides.

Description

Based on the pyrazol acid amide compounds of indole ring as the purposes of disinfectant use in agriculture
Technical field
The present invention relates to a kind of pyrazol acid amide compounds, relate to a kind of pyrazol acid amide compounds based on indole ring and the purposes as disinfectant use in agriculture particularly.Belong to disinfectant use in agriculture field.
Background technology
Chemical prevention is the technical way of control of crop disease.Organic synthesis sterilant is the main part in current disinfectant use in agriculture, is also the important component part of modern industry.But along with a large amount of uses of organic synthesis sterilant, crop pathogens shows resistance in various degree or resistance.For addressing this problem, constantly developing various new type bactericide is the continuing problem that pesticide industry faces.
After nineteen sixty-eight finds that F-1991 has the good characteristic of control fungal disease, the sterilization idiocratic of benzimidazoles compound causes the close attention of Ge great agricultural chemicals company, and successfully develops the disinfectant use in agriculture such as derosal, thiabendazole successively.Benzimidazole germicide, as a kind of sterilant of broad spectrum, doing to have good Uptake and translocation in object, therefore can be used for the multiple occasions such as seed treatment, soil treatment and cauline leaf spraying.But the maximum defect of this series bactericidal agent is to use and shortly creates comparatively serious resistance.
Patent US4950668A discloses the pyrazole amide analog derivatives such as tebufenpyrad (tebufenpyrad) and has pesticide and miticide actility.The N-benzyl pyrazole acidamide derivative that patent US5039693A discloses the phenoxy group replacements such as Tolfenpyrad (tolfenpyrad) has pesticide and miticide actility, all reports without fungicidal activity.The pyrazole amide that patent WO02083647A1 discloses containing xenyl has Insecticiding-miticiding and fungicidal activity.Openly the grin pyrazole amide analog derivative of benzene dibenzyl of patent CN1927860A has pesticide and miticide actility, all reports without fungicidal activity.
Patent US5039693 discloses the compound with general formula (B), has pesticide and miticide actility, but this patent does not disclose it has fungicidal activity.
Patent EP0365925A1 discloses the compound with general formula (B) structure, has pesticide and miticide actility, reports without any fungicidal activity.
Patent CN103081916A discloses the fungicidal activity with general formula (B) structural compounds, and to cucumber downy mildew, the diseases such as corn rust have excellent prevention effect.
Indole structure introducing pyrazol acid amide compounds in the present invention has no bibliographical information as the application of disinfectant use in agriculture.
Summary of the invention
In order to the new type bactericide of the various crop pest of the control obtaining mechanism of action uniqueness, indole structure is introduced pyrazol acid amide compounds by the present invention, fungicidal activity research has been carried out to the pyrazol acid amide compounds with general formula (A), found that this row compound has broad spectrum antibacterial activity, to grey mold pathogenic bacteria, rice blast pathogenic bacteria, the former bacterium of Asparagus Stem Blight, the former bacterium of early blight of eggplant, Phytophthora capsici, there is certain prevention effect, particularly to ash arrhizus bacteria and Pyricularia oryzae effect better.
Technical solution of the present invention is as follows:
A kind of pyrazol acid amide compounds, described compound structure is as shown in general formula (A):
In general formula (A):
X is selected from hydrogen, chlorine, bromine, iodine;
R 1be selected from hydrogen, methyl, ethyl, n-propyl, phenyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group;
R 3be selected from hydrogen, methyl, benzyl.
Preferred technical scheme, in general formula (A):
X is selected from chlorine, bromine;
R 1be selected from hydrogen, methyl, phenyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group;
R 3be selected from hydrogen, methyl.
Be preferred technical scheme again, in general formula (A):
X is selected from chlorine, bromine;
R 1be selected from hydrogen, methyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, methoxyl group;
R 3be selected from hydrogen, methyl.
Highly preferred technical scheme is:
In general formula (A):
X is selected from chlorine, bromine;
R 1be selected from hydrogen, methyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, methoxyl group;
R 3be selected from hydrogen.
Compou nd synthesis method shown in general formula of the present invention (A) is as follows:
Based on the pyrazol acid amide compounds of indole ring, i.e. target product A, is obtained through condensation reaction by pyrazoles fragment and indoles fragment.Described pyrazoles fragment 4 is 1-methyl-3-ethyl-4-chlorine (hydrogen or bromine) pyrazoles-5-formyl chloride; Described indoles fragment is substituted indole-3-methylamine.
Wherein, the preparation of pyrazoles fragment can reference: " study on the synthesis of 3-ethyl-5-pyrazoles acetoacetic ester, Zhejiang Polytechnical University's journal, Tan Chengxia, Shen Delong, Weng Jianquan, Fan Defang, 2005,32 (2): 204-206 "; " study on the synthesis of 1-methyl-3-ethyl-5-pyrazoles acetoacetic ester, Zhejiang Polytechnical University's journal, Tan Chengxia, Shen Delong, Weng Jianquan, Sun Nabo, 2005,33 (3): 331-335 "; " synthesis of Tolfenpyrad. modern, model essay political affairs, Gu Baoquan, Zhu Weiqing 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 general formula (1) substituted indole-3-carboxaldehyde, see document " organic chemistry, 2006,26 (4): 563-567 ", reaction is carried out usually between-10 DEG C to solvent boiling point, and comparatively suitable temperature is-10 ~ 100 DEG C; Reaction times is 30 minutes to 20 hours, is generally 1 ~ 10 hour; Suitable solvent is DMF.
General formula (2) replaces the preparation of 3-cyanoindole, with general formula (1) for raw material, according to document " Yang Yanmei. the synthesis of substituted indole-3-carbonitrile compounds: [Master's thesis]. Southeast China University; 2008. " carry out.Reaction is carried out usually between room temperature to solvent boiling point, and comparatively suitable temperature is 20 ~ 100 DEG C; Be 30 minutes to 8 hours between seasonable, be generally 1 ~ 6 hour; Suitable solvent can be selected from methyl alcohol, ethanol, butanols, water and methyl alcohol, ethanol, the mixture etc. of fourth alcohol and water.
General formula (6) utilizes methylcarbonate to carry out methylating and obtain general formula (7) in suitable solvent.Concrete preparation can the method that describes of reference literature " Organic Process Research & Development, 2001,5,604-608 " be carried out; Reaction is carried out usually between room temperature to solvent boiling point, and comparatively suitable temperature is 20 ~ 160 DEG C; Be 30 minutes to 20 hours between seasonable, be generally 1 ~ 10 hour; Suitable solvent can be selected from dimethylbenzene, acetone, acetonitrile, DMF, methyl-sulphoxide etc.; Reaction generally needs to add alkali and carries out catalysis, and conventional alkali has sodium carbonate, salt of wormwood etc.
In suitable solvent, general formula (6) and general formula (7) obtain general formula (8) through hydrogenating reduction under suitable catalyzer and ammoniacal liquor exist.Concrete preparation can the method that describes of reference literature " J.Am.Chem.Soc, 1963,85 (22): 3683-3685 " be carried out.Reaction is carried out usually between room temperature to solvent boiling point, and comparatively suitable temperature is 20 ~ 100 DEG C; Reaction times is 30 minutes to 20 hours, is generally 1 ~ 10 hour; Suitable solvent can be selected from benzene,toluene,xylene, acetone, methylethylketone, tetrahydrofuran (THF), acetonitrile, dioxan, DMF, methyl-sulphoxide, pyridine, methylene dichloride, ethylene dichloride, ethyl acetate and methyl acetate etc.; Suitable catalyzer can be selected from Raney's nickel, palladium carbon or platinum oxide etc.
Target product A can by the pyrazol formyl chloride shown in the amine shown in general formula (8) and indoles fragment and general formula (4) and pyrazoles fragment in suitable solvent, and suitable alkali exists or alkali does not exist lower condensation and obtains.Concrete preparation method is with reference to EP0365925A1, US5264448A.Suitable solvent can be selected from benzene,toluene,xylene, acetone, methylethylketone, tetrahydrofuran (THF), acetonitrile, dioxan, DMF, methyl-sulphoxide, pyridine, methylene dichloride, ethylene dichloride, ethyl acetate and methyl acetate etc.; Suitable alkali can be selected from potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, pyridine etc.; Temperature of reaction between room temperature to solvent boiling point temperature, can be generally 0 ~ 100 DEG C; Reaction times is 30 minutes to 20 hours, is generally 1 ~ 10 hour.Reaction process is as follows:
With the compound that table one the following is listed, the present invention can be described, but not limit the present invention.
The part of compounds of table one general formula (A)
Numbering X R1 R2 R3
1 Cl H H H
2 Cl CH 3 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-OCH 3 H
8 Cl H 6-Cl H
9 Cl H 6-Br H
10 Cl H H CH 3
11 Cl CH 3 H CH 3
12 Cl Ph H CH 3
13 Cl H 4-Cl CH 3
14 Cl H 4-Br CH 3
15 Cl H 5-Br CH 3
16 Cl H 5-OCH 3 CH 3
17 Cl H 6-Cl CH 3
18 Cl H 6-Br CH 3
19 H CH 3 H H
20 H Ph H H
21 H H H CH 3
[0051]
22 H Ph H CH 3
23 H H 4-Br CH 3
24 Br H H H
25 Br H 4-Br H
26 Br H 4-Cl CH 3
27 Br H 6-Cl CH 3
28 Br H 4-Cl H
29 Br H 5-OCH 3 H
30 Br H 6-Cl H
31 Br Ph H H
32 Br H 4-Br CH 3
33 Br H H CH 3
34 Br H 5-Br H
35 Br H 5-Br CH 3
36 Br H 5-OCH 3 CH 3
Based on the pyrazol acid amide compounds of indole ring as the disinfectant use in agriculture of various Plant diseases.This compound has broad spectrum antibacterial activity.The disinfectant use in agriculture of Plant diseases is using the pyrazol acid amide compounds shown in general formula (A) as activeconstituents.
Described Plant diseases comprises: grey mold pathogenic bacteria, rice blast pathogenic bacteria, the former bacterium of Asparagus Stem Blight, the former bacterium of early blight of eggplant and Phytophthora capsici.Particularly ash arrhizus bacteria and Pyricularia oryzae.
Target compound for contrast is according to People's Republic of China's agricultural industry criteria (NY/T1156.2-2006), adopts mycelial growth rate method to carry out fungicidal activity mensuration with m-tetrachlorophthalodinitrile and derosal.Wherein to Pyricularia oryzae preventive effect: when liquor strength is 400ppm, in table one, compound 1,2,6,32, the preventive effect of 33 grades is 100%; When liquor strength is 50ppm, compound 2,32, the preventive effect of 33 grades is 100%.To ash arrhizus bacteria preventive effect: when liquor strength is 400ppm, compound 6,21,23, the preventive effect of 35 grades is 100%; When liquor strength is 50ppm, compound 6,21, the preventive effect of 23 grades is more than 80%.
Due to this invention Late Cambrian, pyrazol acid amide compounds shown in general formula (A) has fungicidal activity, this compound has broad spectrum antibacterial activity, therefore this compounds can be applied to the disease on the various crops of the agricultural use such as control agricultural, gardening and flower culture, be particularly suitable for preventing and treating following plants disease: grey mold pathogenic bacteria, rice blast pathogenic bacteria, the former bacterium of Asparagus Stem Blight, the former bacterium of early blight of eggplant, Phytophthora capsici, particularly ash arrhizus bacteria and Pyricularia oryzae.The phytopathogen that compound of the present invention can be prevented and treated is not limited to foregoing.Therefore, technical scheme of the present invention includes the purposes of the pyrazol acid amide compounds shown in general formula (A) as disinfectant use in agriculture, has good actual application value.
 
Embodiment
Below, the present invention is further illustrated in conjunction with concrete example.All raw materials except specified otherwise all have commercially available.
Synthetic example
One, the preparation method of intermediate 4
1) preparation of ethyl propionylpyruvate
50mL dehydrated alcohol is added in 250mL there-necked flask, add sodium Metal 99.5 6.25g (270mmol) in batches, be heated to backflow, after sodium complete reaction, steam ethanol, obtain sodium ethylate, add 40mL dry toluene wherein again, be cooled to 0 DEG C, drip the mixture of oxalic acid diethyl ester 34mL (250mmol) and butanone 22.5mL (250mmol) subsequently, temperature controls at about 0 DEG C, about 1h drips off, and drips off rear continuation stirring reaction 0.5 hour, and TLC monitors, after oxalic acid diethyl ester reacts completely, stopped reaction.The mixture that the brown liquid obtained slowly is poured into the 7.5mL vitriol oil and ice carries out pickling, extracted with diethyl ether, anhydrous sodium sulfate drying, carries out underpressure distillation, collects 94 ~ 96 DEG C of (150pa) cuts and obtains light yellow product 30.9g, yield 72.1%.
2) preparation of 3-ethyl-5-pyrazoles acetoacetic ester
Hydrazine hydrate 16mL (300mmol) and the water 40mL be placed in ice-water bath of 85% is added in 250mL there-necked flask, 5 DEG C are stirred the lower chloroformic solution dripping 50mL and contain ethyl propionylpyruvate 47.4g (300mmol), drip after finishing and continue reaction 2h, separatory, chloroform 3 × 50mL extracted organic phase, anhydrous sodium sulfate drying, steaming desolventizes, obtain thick dark product 34.0g, yield: 80.1%.
3) synthesis of 3-ethyl-4-chloro-5-pyrazoles acetoacetic ester (4)
Getting 3-ethyl-5-pyrazoles acetoacetic ester 10g (60mmol) is dissolved in 50mL ethylene dichloride, 11.4g methyl-sulfate (80mmol) is dripped at control 40-50 DEG C, within 3 hours, drip completely, reflux 4h again, TLC detects, and reacts completely, except desolventizing, obtain light brown liquid 9.0g, yield about: 74%.Obtain product without the need to purifying, directly to lower reaction.
4) synthesis of 1-methyl-3-ethyl-4-chloro-5-pyrazoles acetoacetic ester (5)
3-ethyl-5-pyrazole carboxylic acid ethyl ester 6.92g (40.6mmol) is mixed with SULPHURYL CHLORIDE 4.57mL (48mmol), at 90 DEG C, stirs 3h.TLC monitors, and after reacting completely, by saturated aqueous sodium carbonate neutralization, branch vibration layer, organic over anhydrous dried over sodium sulfate, decompression removing low-boiling-point substance, obtains crude product 6.5g, can be directly used in next step reaction.
5) synthesis of 1-methyl-3-ethyl-4-chloro-5-pyrazoles acid
Getting 1-methyl 3-ethyl-4-chloro-5-pyrazoles acetoacetic ester 2.2g (10mmol) is dissolved in the mixing solutions of 10mL methyl alcohol and 10mL water, NaOH 0.58g (15mmol) is added under stirring, be warming up to backflow, reaction 1h, cooling, it is about 3 that concentrated hydrochloric acid is acidified to PH, filters, dries to obtain white solid 1.72g.Yield: 95%.
6) synthesis of the chloro-5-pyrazole acyl chloride (8) of 1-methyl-3-ethyl-4-
In the there-necked flask that device for absorbing tail gas is housed, add 1-methyl-3-ethyl-4-chloro-5-pyrazole carboxylic acid 8.3g (44mmol), 50mL ethylene dichloride, thionyl chloride 7.2mL (88mmol), reflux 4h, steaming desolventizes, obtain colourless liquid and be about 8.5g, yield 96%.
Two, the preparation method of intermediate 8
1) synthesis of substituted indole-3-carboxaldehyde (1), synthesizes example with indole-3-formaldehyde.
To being furnished with mechanical stirring, adding DMF 14.4mL in the there-necked flask of the 500mL of thermometer, being cooled to 0-5 DEG C, slowly instilling POCl 34.3mL (47mmol), control temperature is at about 0 DEG C, and about 0.5h drips off, and drips off rear continuation stirring 15 minutes.Below 10 DEG C, drip the solution containing indoles 5g (42.5mmol) and 5mL DMF, about 1h drips off.Drip off post-heating to 35 DEG C, keep 1h, adding 30g mixture of ice and water under cooling, then add the solution containing NaOH 18.8g (470mmol) and water 50mL, is drip before variable color, can directly add after variable color, add post-heating backflow 20min, cooling, suction filtration, washing, dry, obtain pale yellow crystals 5.5g.M.p.184-186 DEG C, yield 97%.
2) replace the preparation of 3-cyanoindole (2), synthesize example with 3-cyanoindole.
Indole-3-formaldehyde 3.6g (25mmol) is added in the 500mL there-necked flask being furnished with agitator, thermometer and reflux condensing tube, oxammonium hydrochloride 2.6g (37mmol), pyridine 3mL and ethanol 40mL, reflux two hours, acetic anhydride 35.5mL is dripped, heated overnight at reflux after cooling.Steam except about 2/3 solvent after cooling, add 30mL water, suction filtration, water washing, dry, obtain light red solid 3.1g, yield 88%.m.p.70-72℃。
3) synthesis of N-methyl substituted-3-cyanoindole, synthesizes example with N-methyl-3-cyano group.
3-cyanoindole 7g (49mmol) is added in 250mL there-necked flask, salt of wormwood 3.54g (0.52mmol), methylcarbonate 12.67mL (150mmol), DMF 50mL, reflux 2h, TLC monitors, cannot react completely if react completely, a small amount of methylcarbonate can be added and stop heating, with 200mL water and 100mL+50mL+30mL extraction into ethyl acetate after cooling, salt water washing, anhydrous sodium sulfate drying.Concentrated, obtain white-yellowish solid 7.2g, productive rate 94.2%.
4) preparation of substituted indole-3-methylamine (4), for indoles-3-methylamine.
3-cyanoindole (21mmol) will be replaced add in the saturated ammonia solution of 150mL methyl alcohol, and add 1g W-2 type Raney's nickel and make catalyzer, reduction reaction 5h under 0.4MPa hydrogen pressure, until hydrogen is completely absorbed in theory.Filter, removal of solvent under reduced pressure, the oily matter obtained.This product need not purifying directly to lower reaction.
Three, the preparation method of target product A
1) preparation of N-((1H-indol-3-yl) methyl) the chloro-3-ethyl of-4--1-methyl isophthalic acid H-pyrazoles-5-methane amide:
2 methyl indole-3-methylamine crude product (4) is dissolved in 30mL tetrahydrofuran (THF), is transferred in the there-necked flask of a 250mL, adds triethylamine 2.31g (22.7mmol) and do acid binding agent.Drip the 10mL tetrahydrofuran solution containing 1-methyl-3-ethyl-4-chloro-5-pyrazole acyl chloride 3.92g (18.9mmol) under stirring at room temperature, within 0.5 hour, drip completely.At room temperature react 0.5 hour afterwards, thin layer detection reaction raw material disappears, and sherwood oil: ethyl acetate 2:1 launches, Rf value 0.32.Cross and filter triethylamine hydrochloride, after concentrating under reduced pressure desolvation, add 30mL acetic acid ethyl dissolution, 10mL water washing, the water washing of 10mL saturated common salt, anhydrous sodium sulfate drying, decompression desolventizing.Pillar layer separation, 2:1 sherwood oil: eluent ethyl acetate, obtains white solid 4.79g, yield 77%, m.p.174 ~ 176 DEG C.
2) preparation of N-((1H-indol-3-yl) methyl) the chloro-3-ethyl of-4--1-methyl isophthalic acid H-pyrazoles-5-methane amide:
Indoles-3-methylamine crude product (4) is dissolved in 30mL tetrahydrofuran (THF), is transferred in the there-necked flask of a 250mL, adds triethylamine 2.31g (22.7mmol) and do acid binding agent.Drip the 10mL tetrahydrofuran solution containing 1-methyl-3-ethyl-4-chloro-5-pyrazole acyl chloride 3.92g (18.9mmol) under stirring at room temperature, within 0.5 hour, drip completely.At room temperature react 0.5 hour afterwards, thin layer detection reaction raw material disappears, and sherwood oil: ethyl acetate 2:1 launches, Rf value 0.32.Cross and filter triethylamine hydrochloride, after concentrating under reduced pressure desolvation, add 30mL acetic acid ethyl dissolution, 10mL water washing, the water washing of 10mL saturated common salt, anhydrous sodium sulfate drying, decompression desolventizing.Pillar layer separation, 2:1 sherwood oil: eluent ethyl acetate, obtains white solid 6.6g, yield 87%, m.p.108 ~ 110 DEG C.
3) preparation of N-((1H-indol-3-yl) methyl) the chloro-3-ethyl of-4--1-methyl isophthalic acid H-pyrazoles-5-methane amide:
Indoles-3-methylamine crude product (4) is dissolved in 30mL tetrahydrofuran (THF), is transferred in the there-necked flask of a 250mL, adds triethylamine 2.31g (22.7mmol) and do acid binding agent.Drip the 10mL tetrahydrofuran solution containing 1-methyl-3-ethyl-4-chloro-5-pyrazole acyl chloride 3.92g (18.9mmol) under stirring at room temperature, within 0.5 hour, drip completely.At room temperature react 0.5 hour afterwards, thin layer detection reaction raw material disappears, and sherwood oil: ethyl acetate 2:1 launches, Rf value 0.32.Cross and filter triethylamine hydrochloride, after concentrating under reduced pressure desolvation, add 30mL acetic acid ethyl dissolution, 10mL water washing, the water washing of 10mL saturated common salt, anhydrous sodium sulfate drying, decompression desolventizing.Pillar layer separation, 2:1 sherwood oil: eluent ethyl acetate, obtains white solid 6.1g, yield 91%, m.p.147 ~ 149 DEG C.
4) preparation of N-((1H-indol-3-yl) methyl) the chloro-3-ethyl of-4--1-methyl isophthalic acid H-pyrazoles-5-methane amide:
Indoles-3-methylamine crude product (4) is dissolved in 30mL tetrahydrofuran (THF), is transferred in the there-necked flask of a 250mL, adds triethylamine 2.31g (22.7mmol) and do acid binding agent.Drip the 10mL tetrahydrofuran solution containing 1-methyl-3-ethyl-4-chloro-5-pyrazole acyl chloride 3.92g (18.9mmol) under stirring at room temperature, within 0.5 hour, drip completely.At room temperature react 0.5 hour afterwards, thin layer detection reaction raw material disappears, and sherwood oil: ethyl acetate 2:1 launches, Rf value 0.32.Cross and filter triethylamine hydrochloride, after concentrating under reduced pressure desolvation, add 30mL acetic acid ethyl dissolution, 10mL water washing, the water washing of 10mL saturated common salt, anhydrous sodium sulfate drying, decompression desolventizing.Pillar layer separation, 2:1 sherwood oil: eluent ethyl acetate, obtains white solid 6.56g, yield 89%, m.p.125 ~ 127 DEG C.
5) preparation of N-((1H-indol-3-yl) methyl) the chloro-3-ethyl of-4--1-methyl isophthalic acid H-pyrazoles-5-methane amide:
Indoles-3-methylamine crude product (4) is dissolved in 30mL tetrahydrofuran (THF), is transferred in the there-necked flask of a 250mL, adds triethylamine 2.31g (22.7mmol) and do acid binding agent.Drip the 10mL tetrahydrofuran solution containing 1-methyl-3-ethyl-4-chloro-5-pyrazole acyl chloride 3.92g (18.9mmol) under stirring at room temperature, within 0.5 hour, drip completely.At room temperature react 0.5 hour afterwards, thin layer detection reaction raw material disappears, and sherwood oil: ethyl acetate 2:1 launches, Rf value 0.32.Cross and filter triethylamine hydrochloride, after concentrating under reduced pressure desolvation, add 30mL acetic acid ethyl dissolution, 10mL water washing, the water washing of 10mL saturated common salt, anhydrous sodium sulfate drying, decompression desolventizing.Pillar layer separation, 2:1 sherwood oil: eluent ethyl acetate, obtains white solid 7.05g, yield 93%, m.p.150 ~ 152 DEG C.
Other compounds of general formula (A) can be prepared by method provided by the invention.
Part of compounds fusing point and nuclear magnetic data ( 1hNMR, 300MHz, interior mark TMS, solvent C DCl 3) as table 2 and 3:
The physico data of table 2 compound
Table 3 target compound 1h NMR data
Application Example biological activity
All target compound sterilization biological activity tests with m-tetrachlorophthalodinitrile and carbendazim active compound for contrast medicament, determine target compound former to capsicum epidemic disease, rice blast cause of disease, Asparagus Stem Blight is former, the inhibit activities of the various plants pathogenic bacteria mycelial growth rates such as gray mold of cucumber is former, and early blight of eggplant is former.According to People's Republic of China's agricultural industry criteria (NY/T1156.2-2006), mycelial growth rate method is adopted to measure.
The former medicine of 98% m-tetrachlorophthalodinitrile, 98% carbendazim active compound.
Bacterial classification used is the Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide and is separated preservation bacterial classification with utilisation technology emphasis open laboratory.
The former bacterium of Asparagus Stem Blight [Phomopsis asparagi (Sacc.) Bubas], belongs to fungi Deuteromycotina, Sphaeropsidales, Phomopsis, Radix Asparagi Phomopsis.
Rice blast cause of disease [Pyriculariaoryzae Cav]: Deuteromycotina, hyphomycetales, pears born of the same parents belong to, rice pears born of the same parents.
Early blight of eggplant former [Phytophtora parasitica Dast]: belong to fungi Mastigomycotina, phytophthora, eggplant epidemic disease is mould, fungi oomycetes disease.
Gray mold of cucumber former [Botrytis cinerea Pers]: belong to fungi Deuteromycotina, hyphomycetales, Staphlosporonites, Botrytis cinerea.
Phytophthora capsici cause of disease [Phytophtnora capsicia]: belong to fungi Mastigomycotina, phytophthora, Phytophthora capsici.
Testing method: measure with growth rate method
Drug solution preparing is become finite concentration, in the middle of the substratum adding thawing, shakes up, make the malicious culture medium flat plate of band, inoculate pathogenic bacteria in the plane, judge the virulence size of medicament according to the growth velocity size of germ.Pathogen growth speed can with two kinds of method representations: the size of colony growth diameter in (1) certain hour; (2) colony growth is to certain diameter required time.Take first method herein.
Investigation and calculating
Mycelial growth condition survey: by observing the colony growth situation in blank culture dish, investigate cause of disease mycelia growing state.Observe the bacterium colony in blank, when it grows to close to culture dish edge, adopt right-angled intersection method to measure the colony diameter of each process, calculate bacterium colony and increase diameter (see following formula), get its mean value.
Bacterium colony increases diameter=colony diameter-bacterium cake diameter
The calculating of measurement result: adopt following method calculated activity data: the bacterium colony increasing diameter and chemicals treatment with blank bacterium colony increases diameter and calculates the mycelial growth inhibition rate of each chemicals treatment to various pathogenic bacteria, and formula is as follows:
Mycelial growth inhibition rate (%)=(contrast bacterium colony increases diameter-chemicals treatment bacterium colony and increases diameter)/contrast bacterium colony increases diameter × 100%.
Partial test result is as follows:
Pyricularia oryzae preventive effect:
When liquor strength is 400ppm, compound 1,2,6,32, the preventive effect of 33 grades is 100%.
When liquor strength is 50ppm, compound 2,32, the preventive effect of 33 grades is 100%.
Ash arrhizus bacteria preventive effect:
When liquor strength is 400ppm, compound 6,21,23, the preventive effect of 35 grades is 100%.
When liquor strength is 50ppm, compound 6,21, the preventive effect of 23 grades is more than 80%.
The foregoing is only better possible embodiments of the present invention, not thereby limit to the scope of the claims of the present invention, therefore the equivalence change that every utilization content of the present invention is done, be all contained in protection scope of the present invention.

Claims (10)

1. a pyrazol acid amide compounds, described compound structure is as shown in general formula (A):
In general formula (A):
X is selected from hydrogen, chlorine, bromine, iodine;
R 1be selected from hydrogen, methyl, ethyl, n-propyl, phenyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group;
R 3be selected from hydrogen, methyl, benzyl.
2. pyrazol acid amide compounds according to claim 1, is characterized in that, in general formula (A):
X is selected from chlorine, bromine;
R 1be selected from hydrogen, methyl, phenyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, cyano group, methoxyl group;
R 3be selected from hydrogen, methyl.
3. pyrazol acid amide compounds according to claim 2, is characterized in that, in general formula (A):
R 1be selected from hydrogen, methyl;
R 2be selected from hydrogen, chlorine, bromine, iodine, methoxyl group.
4. pyrazol acid amide compounds according to claim 3, is characterized in that, in general formula (A):
R 2be selected from hydrogen, chlorine, bromine, iodine, alkyl, methoxyl group;
R 3be selected from hydrogen.
5. the synthetic method of compound as described in any one of Claims 1 to 4, described compound is obtained through condensation reaction by pyrazoles fragment and indoles fragment.
6. synthetic method according to claim 5, it is characterized in that, described pyrazoles fragment is 1-methyl-3-ethyl-4-chlorine (hydrogen or bromine) pyrazoles-5-formyl chloride; Described indoles fragment is substituted indole-3-methylamine.
7. as described in any one of Claims 1 to 4 compound as the purposes of Plant diseases disinfectant use in agriculture.
8. according to the purposes described in claims 7, it is characterized in that, described disinfectant use in agriculture is using the pyrazol acid amide compounds shown in general formula (A) as the activeconstituents of composition.
9. according to the purposes described in claims 7, it is characterized in that, described Plant diseases comprises: grey mold pathogenic bacteria, rice blast pathogenic bacteria, the former bacterium of Asparagus Stem Blight, the former bacterium of early blight of eggplant and Phytophthora capsici.
10. according to the purposes described in claims 9, it is characterized in that, described Plant diseases comprises: ash arrhizus bacteria and Pyricularia oryzae.
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CN106187894A (en) * 2016-07-04 2016-12-07 潍坊鑫诺化工有限公司 The preparation method of 1 methyl 3 ethyl 4 chlorine 5 pyrazole carboxylic acid ethyl ester

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WO2021155264A1 (en) * 2020-01-29 2021-08-05 Foghorn Therapeutics Inc. Compounds and uses thereof

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WO2014188211A1 (en) * 2013-05-23 2014-11-27 Kalvista Pharmaceuticals Limited Heterocyclic derivates

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CN102725284A (en) * 2009-12-16 2012-10-10 神经孔医疗有限公司 Compound suitable for the treatment of synucleopathies
WO2014188211A1 (en) * 2013-05-23 2014-11-27 Kalvista Pharmaceuticals Limited Heterocyclic derivates

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106187894A (en) * 2016-07-04 2016-12-07 潍坊鑫诺化工有限公司 The preparation method of 1 methyl 3 ethyl 4 chlorine 5 pyrazole carboxylic acid ethyl ester

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