CN104829605A - 1-substituted-5-trifluoromethyl-4-pyrazol-1,3,4-oxadiazole thioether or sulfone derivatives and application of derivatives - Google Patents

1-substituted-5-trifluoromethyl-4-pyrazol-1,3,4-oxadiazole thioether or sulfone derivatives and application of derivatives Download PDF

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CN104829605A
CN104829605A CN201510257365.7A CN201510257365A CN104829605A CN 104829605 A CN104829605 A CN 104829605A CN 201510257365 A CN201510257365 A CN 201510257365A CN 104829605 A CN104829605 A CN 104829605A
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trifluoromethyl
pyrazoles
benzyl
replaces
oxadiazole
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CN104829605B (en
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杨松
张滕滕
叶意强
周翔
薛伟
吴志兵
陈玉婷
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention discloses a kind of 1-substituted-5-trifluoromethyl-4-pyrazol-1,3,4-oxadiazole thioether or sulfone derivatives and application of the derivatives. The derivatives have the structures represented by general formulae A and B shown in the specification. 1-substituted-5-trifluoromethyl-4-pyrazol-1,3,4-oxadiazole compounds are synthesized from ethyl trifluoroacetoacetate by the following five reactions: esterification, ring closure, hydrazinolysis, ring closure and substitution. The compounds have certain inhibition effects to plant bacterial diseases or plant fungous diseases and can be used as pesticides and pesticide additives for preventing and controlling the plant bacterial diseases or the plant fungous diseases.

Description

1-replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives and application thereof
Technical field
The present invention relates to antiseptic-germicide field, disclose and replace-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or the application of sulfone derivatives in agricultural plants pathogenic bacteria prevents and treats containing 1-.
Background technology
For the bacillary and fungal disease that current China agricultural is great, green candidate's agricultural chemicals that the discovery of scientific and efficient has potential market vitality is the vital task faced in China's New pesticides discovery fundamental research.In the development course of sterilant, synthetic chemistry sterilant plays an important role in antibacterial, sterilization and guarantee farm-forestry crop stable yields etc.But due to shortcoming and long-term irrational use of synthetic chemistry sterilant itself, and gradually expose some serious problems: as drug-fast generation, to problems such as the threats of human health.Therefore the initiative of green novel pesticide becomes the problem in science of focus technology tackling key problem in current agricultural industry and real problem.
1,3,4-oxadiazole thioether or sulfone compound are that its cyclic skeleton has obvious conjugacy and aromaticity containing the heteroatomic five member ring heterocyclic compound of S, O, N, thus have biological activity widely.Substituting group on 1,3,4-oxadiazole and derivative thereof 2,5 can participate in numerous chemical reactions, is usually introduced in pesticide molecule as active group, is the hot subject of modernization agronomy discipline research.
Pyrazole derivatives has an extensively bioactive compounds, plays important role and be widely used in sterilization, weeding, plant-growth regulator, Insecticiding-miticiding etc. in heterocyclic pesticide.And on pyrazole ring, the change of substituent replacement type and the position of substitution can bring abundant structure diversity, has vast potential for future development.
In order to obtain the anti-pathogenic microbial inoculum of high-efficiency low-toxicity of novel structure, mechanism of action uniqueness,-5-amino-4-pyrazoles connection 1 is replaced to the 1-synthesized by this seminar early stage, 3,4-oxadiazole compounds carries out further structure of modification, on " 1-substituted pyrazolecarboxylic ring " architecture basics, pyrazole ring " 5-position " introducing " trifluoromethyl ", a series of pyrazoles connection 1 of design and synthesis, 3,4-oxadiazole thioether and sulfone derivatives.
Summary of the invention
The object of the invention is:
-5-amino-4-pyrazoles connection 1 is replaced to the 1-synthesized by this seminar early stage, 3,4 oxadiazole compounds carry out further structure of modification, prepare a series of 1-and replace-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, and for preventing and treating the bacillary or fungal disease of crop plants; Prove that compound provided by the invention is to bacterial blight of rice, wheat scab, capsicum wilt, canker of apple fruit, sclerotinia rot of colza, the late blight of potato and rice sheath blight disease pathogenic bacteria, shows good inhibit activities by experiment.
1-of the present invention replace-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives general structure as awith bshown in:
In formula:
R is selected from methyl, phenyl;
R1 is selected from alkyl, thiazolinyl, benzyl, substituted benzyl, substituted heterocycle methylene radical;
In general formula A, B:
R1 is selected from alkyl, the branched-chain alkyl of C1-C3, the thiazolinyl of C1-C3, benzyl, substituted benzyl, the substituted heterocycle methylene radical of C1-C3;
In general formula A, B:
In R1, the alkyl of the C1-C3 of indication is methyl, ethyl, n-propyl; The branched-chain alkyl of the C1-C3 of indication is sec.-propyl; The thiazolinyl of the C1-C3 of indication is allyl group; The substituted benzyl of indication is xylyl, halogen benzyl, methoxybenzyl, halogenated methyl benzyl; The substituted heterocycle methylene radical of indication is haloperidid ring methylene radical, halo thiazole ring methylene radical;
Wherein halogen atom is F, Cl.
1-of the present invention replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, and it is that the particular compound of having synthesized is as follows:
Derivative provided by the invention can be used as the application in the agricultural chemicals and pesticides additive agent of preparation control crop plants pathogenic bacteria; Described crop plants pathogenic bacteria be preferably rice leaf spot bacteria ( x. oryzae), fusarium graminearum ( g. zeae), capsicum wilt bacterium ( f. oxysporum), Valsa mali ( c. mandshurica), phytophthora infestans ( p.infestans), Sclerotinia sclerotiorum ( s.sclerotiorum) and Rhizoctonia solani Kuhn ( t.cucumeris).
The compounds of this invention awith bfollowing method can be adopted to be prepared:
Adopt 1 to obtain intermediate 2 with various hydrazine reaction closed loop, generate intermediate 3 through hydrazinolysis reaction, except desolventizing after reacting completely in suitable solvent with dithiocarbonic anhydride, add alkali reaction and obtain intermediate 4, react obtained target compound with various halogenated compound a, oxidation obtains target compound further b; Alkali can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, salt of wormwood, sodium carbonate, DMAP, triethylamine, pyridine, DMF etc.; Solvent can be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, DMF, acetonitrile, chloroform, methylene dichloride, tetrahydrofuran (THF), toluene, benzene, Isosorbide-5-Nitrae-dioxane, acetone etc.
In process of the present invention, the intermediate 1 adopted can be prepared in the following ways:
Adopt trifluoromethyl methyl aceto acetate 5 and triethyl orthoformate in acetic anhydride, 50 ~ 150 oreact 3 ~ 24 hours under the condition of C, obtain intermediate 1.Solvent can be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, DMF, acetonitrile, chloroform, methylene dichloride, tetrahydrofuran (THF), toluene, benzene, Isosorbide-5-Nitrae-dioxane, acetone etc.
In process of the present invention, the intermediate 2 adopted can be prepared in the following ways:
1 is adopted to be dissolved in suitable solvent, 50 ~ 200 with various hydrazine oreact 5 ~ 24 hours under the condition of C, obtain intermediate 2.Solvent can be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, DMF, acetonitrile, chloroform, methylene dichloride, tetrahydrofuran (THF), toluene, benzene, Isosorbide-5-Nitrae-dioxane, acetone etc.
In process of the present invention, can being prepared in the following ways of the intermediate 3 adopted:
2 are adopted to be dissolved in suitable solvent, 50 ~ 200 with hydrazine hydrate oreact 5 ~ 48 hours under the condition of C, obtain intermediate 3.Solvent can be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, DMF, acetonitrile, chloroform, methylene dichloride, tetrahydrofuran (THF), toluene, benzene, Isosorbide-5-Nitrae-dioxane, acetone etc.
In process of the present invention, can being prepared in the following ways of the intermediate 4 adopted:
3 are adopted to be dissolved in suitable solvent in the basic conditions, 20 ~ 120 with dithiocarbonic anhydride oreact under the condition of C after 2 ~ 48 hours and remove desolventizing, add alkali, 0 ~ 120 oreact 1 ~ 10 hour under the condition of C, obtained intermediate 4.Alkali can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, salt of wormwood, sodium carbonate, DMAP, triethylamine, pyridine, DMF etc.; Solvent can be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, DMF, acetonitrile, chloroform, methylene dichloride, tetrahydrofuran (THF), toluene, benzene, Isosorbide-5-Nitrae-dioxane, acetone etc.
beneficial effect
The 1-that contains synthesized by the present invention replaces-5-trifluoromethyl-4-pyrazoles connection 1,3, the biological activity test result of 4-oxadiazole class thioether and sulfone compound shows, compound has good biological activity to the water prevention bacterial blight of rice, wheat scab, capsicum wilt, canker of apple fruit, sclerotinia rot of colza, the late blight of potato and rice sheath blight disease.
Embodiment
embodiment 1:1-phenyl-4-((5-methylthio group)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 H-pyrazoles ( a1) preparation
1) 1-phenyl-5-Trifluoromethyl-1 hthe preparation of-4-pyrazoles hydrazides
In the 250 mL there-necked flasks with prolong, thermometer, add oxyethyl group methene trifluoroacetic ethyl acetoacetate (66.05 mmol), phenylhydrazine (69.35 mmol) successively, ethanol (50 mL), is heated to 80 oc, reacts 24 h, and TLC detection reaction terminates, be down to normal temperature, underpressure distillation goes out solvent, and oily liquids is not purified is directly dissolved in 80% hydrazine hydrate solution (100 mmol) for residue, reflux 2 hours, TLC detection reaction terminates, and system is down to normal temperature, suction filtration, product is obtained after solids washed with water, drying, white solid, yield 81.8%, fusing point 146 – 148 oc; 1h-NMR (500 MHz, DMSO-D 6): δ: 9.73 (s, 1H, NH), 8.05 (s, 1H, pyrazole H), 7.73-7.41 (m, 5H, benzene H), 4.50 (s, 2H, NH 2); 13cNMR (125 MHz, DMSO- d 6 ) δ: 160.35,139.94,139.37,130.51,129.90,126.50,120.92,120.35,118.77; IR (KBr) ν: 3324,3256,3107,3037,1678,1622,1569,1532,1500,1465,1400,1284,1174,1138,973,859,768,678 cm -1; MS (ESI): m/z 271 [M+H] +.
2) preparation of 5-(5-Trifluoromethyl-1-phenyl-1H-pyrazoles-4-base)-1,3,4-oxadiazole-2-mercaptan
In the 250 mL there-necked flasks with prolong, thermometer, add 1-phenyl-5-Trifluoromethyl-1 respectively h-4-pyrazoles hydrazides (13.1 mmol), potassium hydroxide (13.1mol), dithiocarbonic anhydride (26.1mmol) and ethanol (100 mL), stirring at room temperature 24 hours, TCL detection reaction terminates, and is not further purified, continue to add potassium hydroxide (13.1mol), 70 oafter C stirs 24 hours, TLC detects and terminates reaction, revolves and desolventizes, rare HCl(1 mol/L) washing, suction filtration, filter cake washes with water, obtains white solid, yield 76.4%, fusing point 169-170 after drying oc; 1h-NMR (500 MHz, DMSO-D 6) δ: 9.43 (s, 1H, SH), 8.43 (s, 1H, pyrazole H), 7.72 – 7.46 (m, 5H, Ar H); 13c NMR (125 MHz, DMSO- d 6 ) δ: 177.96,154.21,141.15,138.89,130.96,129.95,126.65,120.45,118.30,108.04; IR (KBr) ν: 3101,2925,2775,1640,1596,1540,1500,1419,1408,1299,1184,1088,980,950,767,691 cm -1; MS (ESI): m/z 311 [M+H] +.
3) 1-phenyl-4-((5-methylthio group)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 H-pyrazoles ( a1) preparation
In the reaction flask of 25 mL, add 5-(5-Trifluoromethyl-1-phenyl-1 respectively h-pyrazoles-4-base)-1,3,4-oxadiazole-2-mercaptan (1.6 mmol), methyl iodide (3.2 mmol) and 50% potassium hydroxide aqueous solution (20 mL), stirring at room temperature, reacts 12 hours, and TLC detects and terminates reaction, filter, obtain thick product, through column chromatography (petrol ether/ethyl acetate=20:1) purifying, obtain target compound a1, white solid, yield 98.0%, fusing point 88 ~ 89 oc; 1h NMR (500 MHz, DMSO- d 6 ) δ: 8.42 (s, 1H, pyrazole H), 7.99-7.24 (m, 5H, Ar H), 2.72 (s, 3H, CH 3); 13c NMR (125 MHz, DMSO- d 6 ) δ: 165.87,158.47,141.10,138.97,130.85,129.90,126.60,120.56,118.41,108.46,14.77; IR (KBr) ν: 3121,3054,2933,1635,1597,1507,1498,1472,1410,1292,1186,1137,979,941,767,693 cm -1; MS (ESI): m/z 327 [M+H] +.
embodiment 2:1-methyl-4-((5-methylthio group)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 H-pyrazoles ( a14) preparation
1) preparation of 1-methyl-5-Trifluoromethyl-1 H-4-pyrazoles hydrazides
In the 250 mL there-necked flasks with prolong, thermometer, add oxyethyl group methene trifluoroacetic ethyl acetoacetate (66.05 mmol), methyl hydrazine (40%) (69.35 mmol) successively, ethanol (50 mL), is heated to 80 oc, reacts 24 h, and TLC detection reaction terminates, be down to normal temperature, underpressure distillation goes out solvent, and oily liquids is not purified is directly dissolved in 80% hydrazine hydrate solution (100 mmol) for residue, reflux 2 hours, TLC detection reaction terminates, and system is down to normal temperature, suction filtration, product is obtained after solids washed with water, drying, white solid, yield 64.6%, fusing point 115 – 116 oc; 1h-NMR (500 MHz, DMSO-D 6): δ: 9.42 (s, 1H, NH), 8.20 (s, 1H, pyrazole H), 4.37 (s, 2H, NH 2), 3.89 (s, 3H, CH 3); 13cNMR (125 MHz, DMSO- d 6 ) δ: 160.51,139.47,133.82,121.47,115.42,40.44; MS (ESI): m/z 209 [M+H] +.
2) preparation of 5-(5-Trifluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-base)-1,3,4-oxadiazole-2-mercaptan
In the 250 mL there-necked flasks with prolong, thermometer, add 1-methyl-5-Trifluoromethyl-1 H-4-pyrazoles hydrazides (13.1 mmol) respectively, potassium hydroxide (13.1mol), dithiocarbonic anhydride (26.1mmol) and ethanol (100 mL), stirring at room temperature 24 hours, TCL detection reaction terminates, and is not further purified, continue to add potassium hydroxide (13.1mol), 70 oafter C stirs 24 hours, TLC detects and terminates reaction, revolves and desolventizes, rare HCl(1 mol/L) washing, suction filtration, filter cake washes with water, obtains white solid, yield 70.8%, fusing point 140-141 after drying oc; 1h-NMR (500 MHz, DMSO-D 6) δ: 14.81 (s, 1H, SH), 8.16 (s, 1H, pyrazole H), 4.06 (s, 3H, CH 3); 13c NMR (125 MHz, DMSO- d 6 ) δ: 177.78,154.40,139.74,129.19,119.75,106.98,40.46; MS (ESI): m/z 251 [M+H] +.
3) 1-methyl-4-((5-methylthio group)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 H-pyrazoles ( a14) preparation
In the reaction flask of 25 mL, add 5-(5-Trifluoromethyl-1-methyl isophthalic acid H-pyrazoles-4-base)-1 respectively, 3,4-oxadiazole-2-mercaptan (1.6 mmol), methyl iodide (3.2 mmol) and 50% potassium hydroxide aqueous solution (20 mL), stirring at room temperature, react 12 hours, TLC detects and terminates reaction, filters, obtains thick product, through column chromatography (petrol ether/ethyl acetate=20:1) purifying, obtain target compound a14, white solid, yield 96.8%, fusing point 54 ~ 55 oc; 1h NMR (500 MHz, DMSO- d 6 ) δ: 8.17 (s, 1H, pyrazole H), 4.07 (s, 3H, N-CH 3), 2.71 (s, 3H, S-CH 3); 13c NMR (125 MHz, DMSO- d 6 ) δ: 165.50,158.64,139.71,129.09,119.89,107.42,40.44,14.81; MS (ESI): m/z 265 [M+H] +.
embodiment 3:1-phenyl-4-((5-ethylsulfonyl)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 h-pyrazoles ( b1) preparation
In the 25 mL there-necked flasks with prolong, thermometer, add 1-phenyl-4-((5-ethylmercapto group)-1,3,4-oxadiazolyls)-5-Trifluoromethyl-1 successively h-pyrazoles (615.8 μmol), acetic acid (3 mL) and KMnO 4(615.8 μmol), normal-temperature reaction 24 hours, TLC detect terminate reaction, adjust ph to 7 ~ 8, suction filtration, thick product through column chromatography (methylene dichloride: ethyl acetate=10:1) purifying, target compound b1.White solid, yield 64.6%, fusing point 72 ~ 73 oc; 1h NMR (500 MHz, DMSO- d 6 ) δ: 8.58 (s, 1H, pyrazole H), 7.64-7.58 (m, 5H, benzene H), 3.78 (q, j=7.3 Hz, 2H, S-CH 2), 1.31 (t, j=7.4 Hz, 3H, CH 3); 13c NMR (125 MHz, DMSO- d 6 ) δ: 161.83,159.90,141.92,138.81,131.12,130.02,126.75,120.40,118.24,107.54,50.07,7.15; IR (KBr): ν3089,2981,2936,1627,1595,1506,1489,1457,1418,1354,1186,1155,978,944,767,730,690,621 cm -1; MS (ESI): m/z 373 [M+H] +.
Utilize similar synthetic method, synthesize other compound of the present invention, the proton nmr spectra of part of compounds ( 1h NMR) data, physico-chemical property and analytical data of mass spectrum be as shown 1shown in:
biological activity test example
embodiment 4:part of compounds indoor suppression bacterial blight of rice pathogenic bacteria ( x. oryzae) biological activity test
By bacterial blight of rice pathogenic bacteria at NA(extractum carnis: 3 g, peptone: 5 g, yeast extract: 1 g, glucose: 10 g, agar: 15 g, intermediate water: 1 L; About pH=7.0 is adjusted, 121 with 5 mol/L NaOH solution oc sterilizing 20 min) rule, 28 above solid medium ocultivate until grow single bacterium colony under C.On picking NA solid medium, the single bacterium colony of bacterial blight of rice pathogenic bacteria is to NB liquid nutrient medium (extractum carnis: 3 g, peptone: 5 g, yeast extract: 1 g, glucose: 10 g, intermediate water: 1 L; About pH=7.0 is adjusted, 121 with 5 mol/L NaOH solution oc sterilizing 20 min) in, 28 oc, 180 rpm constant-temperature table shaking culture are for subsequent use to growth logarithmic phase.
It is 200,100 that synthesized compound and contrast medicament are mixed with concentration respectively μthe toxic NB liquid nutrient medium of g/mL, adds 40 μthe NB liquid nutrient medium containing bacterial blight of rice pathogenic bacteria of the above-mentioned preparation of L, 28 oc, 180 rpm constant-temperature table shaking culture 24 ~ 48 h, measure OD value (OD by the bacterium liquid of each concentration in microplate reader 595).And measuring concentration is in addition 200,100 μthe NB liquid nutrient medium OD value of g/mL medicament and contrast medicament, corrects the OD value that medicament itself causes.The calculation formula correcting OD value and inhibiting rate is as follows:
Correction OD value=containing bacterium culture medium OD value-aseptic culture medium OD value
Inhibiting rate=(control medium bacterium liquid OD value after correcting-correct toxic substratum OD value)/correct rear control medium bacterium liquid OD value × 100%
Measure according to above method, the inhibit activities of partial target compound is in table 2.
From table 2can find out, such thioether and sulfone compound to rice leaf spot bacteria ( x. oryzae) there is certain inhibit activities.100 μ gunder/mL concentration, wherein compound a4, a6, b1, b2to the inhibiting rate of rice leaf spot bacteria all more than 60%, be better than contrast medicament bismerthiazol (54.2%); Target compound b1, b2100 μ gunder/mL concentration, to the inhibiting rate of rice leaf spot bacteria nearly 100%; Compound a1, a8, a9, a11, b4to the inhibiting rate of rice leaf spot bacteria with to contrast medicament bismerthiazol suitable.Can find by analysis, when in structure, on thioether and alkylsulfonyl, substituting group is branched paraffin, comparatively branched paraffin activity will be got well; When in structure, on alkylsulfonyl, substituting group is alkane, comparatively benzyl activity will be got well.
embodiment 5:high-activity compound is to bacterial blight of rice pathogen virulence regression equation and EC 50the mensuration of value
The compound of synthesis and commercial References medicament are configured to respectively the toxic NB liquid nutrient medium of 5 respective concentration, get 5 mL in test tube, measure toxic aseptic liquid nutrient medium OD value (OD by microplate reader 595), add 40 μl contains the NB liquid nutrient medium of bacterial blight of rice pathogenic bacteria, then 28 oc, 180 rpm constant-temperature table shaking culture 24 h, measure the OD value (OD of each concentration bacterium liquid by microplate reader 595).And the OD value of each concentration bacterium liquid, corrects the OD value caused due to medicament itself after measuring the OD value contrasting the toxic aseptic NB liquid nutrient medium of medicament and 24 h in addition.Inhibiting rate data-switching is become probability value (y), drug concentration ( μg/mL) convert logarithmic value to (x), in Excel data processing software, carry out regression analysis, obtain virulence regression equation (y=ax+b) and relation conefficient (R), calculate medicament to concentration (EC in pathogenic bacteria suppression 50), and with corresponding commodity medicament in contrast.For bacterial blight of rice pathogenic bacteria, choose high-activity compound in target compound b1, b2carry out virulence regression equation and concentration (EC in suppressing 50) mensuration, the results are shown in Table 3.
From table 3can find out, target compound b1, b2to the EC of rice leaf spot bacteria 50value is respectively 31.64 and 16.56 μg/mL, is all better than commodity medicament bismerthiazol (92.61 μg/mL), efficient biological activity is shown.
embodiment 6:part of compounds is to the biological activity test of phytopathogen (fusarium graminearum, capsicum wilt bacterium and Valsa mali)
Adopt isolated growth rate method (Tarum, K. C. et al.; j. Agric. Food Chem., 2006,54,2129-2133.) measure the bacteriostatic activity of compound.Heating potato dextrose agar (PDA substratum: potato 800 g, agar 80 g, glucose 80 g, distilled water 4000 mL) is to molten state, 10 mL liquids (liquids of 10 times of final concentrations) are imported in 90 mL PDA substratum, fully shake up, evenly pour in the culture dish of diameter 9 cm, horizontal positioned, to be cooledly solidifies.Play at the edge punch tool of the fresh pathogenic bacteria bacterium colony cultivating 4 d the bacterium dish that cut-off footpath is 4 mm, bacterium dish is inverted in containing the dull and stereotyped central authorities of medicament PDA, is then placed in 27 obe inverted in C fixed temperature and humidity incubator and cultivate, observe to close to starting during plate 2/3rds place until blank colony growth, right-angled intersection method measures colony diameter, averages.Blank is adding medicine not, but contains solvent and 0.5% Tween 20 of same concentration, and each process in triplicate.
By following formulae discovery medicament to the inhibiting rate of mycelial growth:
I(%)=(C-T)/（C-0.4）×100%
Wherein I is inhibiting rate, and C is blank diameter (cm), T is process diameter (cm)
Part of compounds is 100 μunder g/mL concentration to the inhibiting rate of fusarium graminearum, capsicum wilt bacterium and Valsa mali in table 4.
From table 4can find out, be 100 in concentration μ gduring/mL, such thioether and sulfone compound to fusarium graminearum ( g. zeae), capsicum wilt bacterium ( f. oxysporum), Valsa mali ( c. mandshurica) there is certain inhibit activities.When substituting group be alkane or alkene time, target compound is 100 in concentration μ gduring/mL, to fusarium graminearum ( g. zeae) capsicum wilt bacterium ( f. oxysporum) Valsa mali ( c. mandshurica) there is good inhibit activities, wherein compound a1, a2, b1, b2to fusarium graminearum ( g. zeae) inhibiting rate all more than 50%; a1, b1, b2to capsicum wilt bacterium ( f. oxysporum) inhibiting rate all more than 50%; a1, b1, b2to Valsa mali ( c. mandshurica) inhibiting rate all more than 50%; Wherein compound b1, b2to capsicum wilt bacterium ( f. oxysporum) inhibiting rate be all better than Dui Zhao Yao hymexazo (63.1%); Target compound b1to Valsa mali ( c. mandshurica) inhibiting rate be better than Dui Zhao Yao hymexazo (66.1%), target compound b2to Valsa mali ( c. mandshurica) inhibiting rate suitable with Dui Zhao Yao hymexazo.Binding compounds structure, Structure-activity Relationship analysis discovery is carried out to measured compound anti-mycotic activity, in thioether and sulfone compound, when substituting group is alkane, the anti-microbial activity of compound declines along with the growth of chain length, when carbon atom number is identical, the bacteriostatic activity of the compound that the compound that branched paraffin replaces replaces compared with straight-chain paraffin wants high; When substituting group is benzyl, compound to fusarium graminearum ( g. zeae), capsicum wilt bacterium ( f. oxysporum), Valsa mali ( c. mandshurica) 3 kinds all do not show good inhibit activities for examination fungi, the position of substitution of substituted benzyl and little on the impact of its biological activity on electron attractivity, also do not make its biological activity make moderate progress, when being substituted with other heterocycles by phenyl ring on benzyl, its biological activity still fails to increase.Compared with thio-ether type compounds, the biological activity of sulfone compound that its alkane replaces increases, and to fusarium graminearum ( g. zeae), capsicum wilt bacterium ( f. oxysporum), Valsa mali ( c. mandshurica) 3 kinds for examination fungi, all there is certain inhibit activities, show certain broad spectrum.
embodiment 7:part of compounds is to the biological activity test of phytopathogen (Sclerotinia sclerotiorum, phytophthora infestans and Rhizoctonia solani Kuhn)
Testing method and embodiment 6identical, part of compounds to the inhibiting rate of Sclerotinia sclerotiorum, phytophthora infestans and Rhizoctonia solani Kuhn in Table 5.
From table 5can find out, be 100 in concentration μ gduring/mL, such thioether and sulfone compound Phytophthora infestans ( p. infestans), Sclerotinia sclerotiorum ( s. sclerotiorum), Rhizoctonia solani Kuhn ( t.cucumeris) there is certain inhibit activities.When substituting group be alkane or alkene time, target compound is 100 in concentration μ gduring/mL, to little phytophthora infestans ( p. infestans), Sclerotinia sclerotiorum ( s. sclerotiorum), Rhizoctonia solani Kuhn ( t.cucumeris) there is good inhibit activities, wherein compound a1, a4, b1, b2phytophthora infestans ( p. infestans) inhibiting rate all more than 50%; Target compound a1, a2, a4, a5, b1, b2to Sclerotinia sclerotiorum ( s. sclerotiorum) inhibiting rate all more than 50%; Target compound a1, a2, a5, b1, b2to Rhizoctonia solani Kuhn ( t.cucumeris) inhibiting rate all more than 50%.Binding compounds structure, Structure-activity Relationship analysis discovery is carried out to measured compound anti-mycotic activity, in thioether and sulfone compound, when substituting group is alkane, the anti-microbial activity of compound declines along with the growth of chain length, when carbon atom number is identical, the bacteriostatic activity of the compound that the compound that branched paraffin replaces replaces compared with straight-chain paraffin wants high; When substituting group is benzyl, compound Phytophthora infestans ( p. infestans), Sclerotinia sclerotiorum ( s. sclerotiorum), Rhizoctonia solani Kuhn ( t.cucumeris) 3 kinds all do not show good inhibit activities for examination fungi, the position of substitution of substituted benzyl and little on the impact of its biological activity on electron attractivity, when being substituted with other heterocycles by phenyl ring on benzyl, its biological activity fails to increase.Generally, compared with thio-ether type compounds, the biological activity of the sulfone compound that its alkane replaces increases, and Phytophthora infestans ( p. infestans), Sclerotinia sclerotiorum ( s. sclerotiorum), Rhizoctonia solani Kuhn ( t.cucumeris) 3 kinds for examination fungi, all there is certain inhibit activities, show certain broad spectrum.

Claims (6)

1.1-replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, and structure is as general formula a, Bshown in:
In formula:
R is selected from methyl, phenyl;
R 1be selected from alkyl, thiazolinyl, benzyl, substituted benzyl, substituted heterocycle methylene radical.
2. 1-according to claim 1 replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, it is characterized in that, at general formula a, Bin:
R 1be selected from the alkyl of C1-C3, the branched-chain alkyl of C1-C3, the thiazolinyl of C1-C3, benzyl, substituted benzyl, substituted heterocycle methylene radical.
3. 1-according to claim 2 replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, it is characterized in that, at general formula a, Bin:
R 1the alkyl of the C1-C3 of middle indication is methyl, ethyl, n-propyl; The branched-chain alkyl of the C1-C3 of indication is sec.-propyl; The thiazolinyl of the C1-C3 of indication is allyl group; The substituted benzyl of indication is xylyl, halogen benzyl, methoxybenzyl, halogenated methyl benzyl; The substituted heterocycle methylene radical of indication is haloperidid ring methylene radical, halo thiazole ring methylene radical;
Wherein halogen atom is F, Cl.
4. the 1-according to any one of claim 1 ~ 3 replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or sulfone derivatives, it is characterized in that the particular compound of having synthesized is as follows:
。
5. the 1-according to any one of claim 1-4 replaces-5-trifluoromethyl-4-pyrazoles connection 1,3,4-oxadiazole thioether or the application of sulfone derivatives in the agricultural chemicals and pesticides additive agent of control crop plants pathogenic bacteria.
6. 1-according to claim 5 replaces-5-trifluoromethyl-4-pyrazoles connection 1,3, the application of 4-oxadiazole thioether or sulfone derivatives, is characterized in that preparing the application in water prevention rice bacterial leaf spot pathogenic bacteria, fusarium graminearum, capsicum wilt bacterium, Valsa mali, Sclerotinia sclerotiorum, the agricultural chemicals of phytophthora infestans and Rhizoctonia solani Kuhn and pesticides additive agent.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106167472A (en) * 2016-03-30 2016-11-30 贵州大学 A kind of 2,5 substituent group 1,3,4 diazole thioether analog derivatives, its preparation method and application
CN106243101A (en) * 2016-07-28 2016-12-21 浙江工业大学 A kind of 1,3,4 thiadiazoles sulfide derivatives and its preparation method and application
CN106234381A (en) * 2016-07-28 2016-12-21 浙江工业大学 A kind of thiadiazoles 2 thio-ether type compounds containing trifluoromethyl pyrazol is as the application of antibacterial
CN106336409A (en) * 2016-07-28 2017-01-18 浙江工业大学 Trifluoromethylpyrazole-containing thiadiazole-2-thioether compound, and preparation method and application thereof
CN107056773A (en) * 2017-04-24 2017-08-18 贵州大学 Pyrazoles Lian Evil containing pyridiniujm（Thiophene）Diazoles compound and preparation method and application
CN108218848A (en) * 2018-01-22 2018-06-29 贵州大学 A kind of trifluoromethyl pyridine oxadiazoles（Ether）Analog derivative and its application
CN112239464A (en) * 2019-07-19 2021-01-19 南京农业大学 Quinazoline-4 (3H) -ketone derivative containing 1,3, 4-oxadiazole, preparation method and application
CN112898223A (en) * 2021-02-01 2021-06-04 贵州大学 1,3, 4-oxadiazole compound containing sulfonate/carboxylate structure and preparation method and application thereof
CN113045562A (en) * 2021-03-29 2021-06-29 扬州市普林斯医药科技有限公司 Thiazole compound for plant bacteriostasis and application thereof
CN113563281A (en) * 2021-07-06 2021-10-29 贵州大学 Benzophenone compound containing 1,3, 4-thiadiazole thioether structure and application thereof
CN113880768A (en) * 2021-09-07 2022-01-04 贵州大学 Synthesis method of 1, 5-disubstituted-1H-pyrazole-4-ethyl formate
CN114751889A (en) * 2022-05-11 2022-07-15 贵州大学 N-heterocycle-1, 5-disubstituted-4-pyrazolecarboxamide compounds and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812034A (en) * 2010-05-11 2010-08-25 贵州大学 2-substituent-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole derivative, synthetic method and application thereof
CN102079730A (en) * 2010-09-06 2011-06-01 贵州大学 Derivatives containing 2, 5-substituted heterocyclic radical sulphone and synthesis method and application thereof
CN103788015A (en) * 2014-01-22 2014-05-14 贵州大学 Derivatives containing thiadiazole or oxadiazole and application of derivatives in prevention and control of agricultural plant diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812034A (en) * 2010-05-11 2010-08-25 贵州大学 2-substituent-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole derivative, synthetic method and application thereof
CN102079730A (en) * 2010-09-06 2011-06-01 贵州大学 Derivatives containing 2, 5-substituted heterocyclic radical sulphone and synthesis method and application thereof
CN103788015A (en) * 2014-01-22 2014-05-14 贵州大学 Derivatives containing thiadiazole or oxadiazole and application of derivatives in prevention and control of agricultural plant diseases

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
B. M. KHUTOVA，等: "CONVERSIONS OF 7-ARYL-7H -PYRAZOLO[3,4-d]-[1,2,3]TRIAZIN-4-OLS BY THE ACTION OF PHOSPHORUS PENTOXIDE, PENTASULFIDE, AND OXYCHLORIDE", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 *
WANGWEN-YAN,等: "Syntheses of 1, 3, 4-Thia(oxa)diazole-substituted Pyrazole Derivatives and Their Fungicidal Activities", 《CHEM. RES. CHINESE U.》 *
孙娜波，等: "含吡唑环的1,3,4-噁二唑类衍生物的合成及杀菌活性研究", 《有机化学》 *

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