CN107935929A - 3 trifluoromethyl 1H pyrazoles of a kind of 1 methyl, 4 amide derivatives and preparation method and application - Google Patents

3 trifluoromethyl 1H pyrazoles of a kind of 1 methyl, 4 amide derivatives and preparation method and application Download PDF

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CN107935929A
CN107935929A CN201711250600.3A CN201711250600A CN107935929A CN 107935929 A CN107935929 A CN 107935929A CN 201711250600 A CN201711250600 A CN 201711250600A CN 107935929 A CN107935929 A CN 107935929A
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methyl
trifluoromethyl
pyrazoles
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刘幸海
金涛
王翰
谭成侠
翁建全
韩亮
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

The invention discloses 1 methyl, 3 trifluoromethyl 1H4 amide derivatives of pyrazoles and preparation method and application.It, which is added to after being flowed back by trifluoroacetic ethyl acetoacetate and triethyl orthoformate in acetic anhydride in methyl hydrazine, is made 1 methyl, 3 trifluoromethyl 1H pyrazoles, 4 Ethyl formate, and adding hydrochloric acid after the hydrolysis of 1 methyl, 3 trifluoromethyl 1H pyrazoles, 4 Ethyl formate is made 1 methyl, 3 trifluoromethyl 1H4 carboxylic acid of pyrazoles, 1 methyl, 3 trifluoromethyl 1H4 carboxylic acid of pyrazoles adds aryl alkanamine and 1 methyl, 3 trifluoromethyl 1 is made in triethylamine with adding dichloromethane dilution after thionyl chloride reactionH4 amide derivatives of pyrazoles.Preparation method of the present invention is simple and convenient to operate, obtained compound is best to peanut Cercospora bacteria, Sclerotinia sclerotiorum inhibitory activity under 50ppm, inhibiting rate has respectively reached 96% and 100%, it is preferable to Botryosphaeria berengeriana f. sp inhibiting rate, bacteriostasis rate is above comparison medicament bacteriostasis rate more than 10%, provides the foundation for the research and development of novel pesticide.

Description

A kind of 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives and its preparation side Method and application
Technical field
The present invention relates to a kind of pyrazole compound of new amide containing, that is, 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Amide derivatives and preparation method and application.
Background technology
Nowadays, pyrazole amide and carbamide compounds are due to containing pyrazoles, acid amides and urea bridge grade height active structure group, usually Equally also there is extensive bioactivity with excellent and extensive bioactivity, the thiourea such as low toxicity, efficient, it is such as anti- The height of allergy, anti-inflammatory, antibacterial, desinsection and weeding etc., end of the sixties in last century thiourea thiophanate and thiophanate methyl Effect, widely using for less toxic fungicide more push to a new high the bactericidal activity research of thiourea derivatives, up to the present, state Some outer pharmaceutical companies successfully develop in succession the fungicide of dozens of Thiourea, insecticide, plant growth regulator and The new varieties such as rat poison, such as fungicide Thiophamine, insecticide C-9140, acaricide methamidophos, plant growth regulator furan benzene sulphur Urea, rat poison ANTU etc..Such compound has that low to the residual of plant, poisoning is small, low to the acute toxicity of mammal etc. Advantage.
The content of the invention
The structure based on the SDH inhibitor such as fluxapyroxad of the invention, by carrying out alkyl to the amido link of pyrazole ring 4 Change extension mode, and in 3 introducing trifluoromethyls of pyrazole ring to investigate influence of the fluorine element number to chemical combination microbic activity, if Meter has synthesized 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives, and have studied its preparation method and application.
A kind of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- amide derivatives, it is characterised in that its structural formula is such as Shown in formula (I)：
In formula (I)：R0For hydrogen or methyl, R1For phenyl or substituted-phenyl, the substituent of the substituted-phenyl is halogen, first Epoxide, nitro, methyl, ethyl, butyl.
A kind of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- amide derivatives, it is characterised in that R in formula (I)1 To be one of following：N- benzyls, (S)-N- (1- phenethyls), (R)-N- (1- phenethyls), (S)-N- (1- (4- chlorphenyls) ethyl), N- (- 2 butyl of 4- butyl benzenes), N- phenethyls, N- (- 5 nitrobenzyl of 2- methoxyl groups), N- (naphthalene -1- methylene), N- (3,4,5- Trimethoxy benzyl), N- (pyridine -3- methylene),.
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives, it is characterised in that including Following steps：
1) methyl hydrazine and ethanol are added to after being flowed back by trifluoroacetic ethyl acetoacetate and triethyl orthoformate in acetic anhydride Mixed liquor in be made as shown in formula (II) 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylate solutions；
2) the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates hydrolysis shown in the formula (II) obtained step 1) 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- the carboxylic acids as shown in formula (III) are made in addition hydrochloric acid afterwards；
3) 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylic acids and protochloride shown in the formula (III) obtained step 2) Organic solvent diluting is added after sulfone reaction, then adds aryl alkanamine and triethylamine, stirred overnight at room temperature, extraction, column chromatography, system Obtain the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives as shown in formula (I).
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylate solutions, it is characterised in that step It is rapid 1) in triethyl orthoformate dosage with the gauge of material, the material of the trifluoroacetic ethyl acetoacetate and triethyl orthoformate The ratio between amount be 1~2:2~5, it is preferably 2:3；The dosage of methyl hydrazine aqueous solution is with the gauge of methyl hydrazine material, the trifluoro second The ratio between amount of ethyl acetoacetic acid ethyl ester and methyl hydrazine material is 1~2:3~5, it is preferably 2:3.
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives, it is characterised in that step 3) dosage of thionyl chloride is with the gauge of material, the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylic acids and thionyl chloride in The ratio between amount of material is 1:1~200, it is preferably 1:10；The aryl alkanamine is with the gauge of material, the 1- methyl -3- trifluoros The ratio between amount of methyl isophthalic acid H- pyrazoles -4- carboxylic acids and aryl alkanamine material is 1:1~3, it is preferably 1:1.05.
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylate solutions, it is characterised in that step Rapid organic solvent 3) is tetrahydrofuran, dichloromethane, dioxane, toluene or dimethylbenzene.Preferably dichloromethane.
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylate solutions, it is characterised in that step Rapid organic solvent 3) is dichloromethane.
The preparation method of the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- amide derivatives, it is characterised in that step 3) extractant is that volume ratio is 1 in:1 dichloromethane and water mixed liquid, column chromatography use volume ratio as 2:1 EA and PE is mixed Close liquid.
The present invention also provides the preparation of the Trifluoromethyl-1 H- pyrazoles -4- amide derivatives of 1- methyl -3- shown in a kind of formula (I) Method, described method includes following steps：
1) by trifluoroacetic ethyl acetoacetate, triethyl orthoformate is when back flow reaction 8 is small in organic solvent A, gas phase tracking Reactant is evaporated under reduced pressure to the reaction was complete, removes unnecessary triethyl orthoformate, obtain crude product after reaction；Under ice bath, dropwise Crude product is added dropwise in 40% methyl hydrazine and organic solvent B mixed liquor, when back flow reaction 6 is small, TLC (EA/PE=1/1 (V)) Tracking is reacted, and is evaporated under reduced pressure after question response, is added ethyl acetate and is extracted three times with saturated salt solution, the anhydrous sulphur of organic layer Sour sodium water removal rear overhang steams, and 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates shown in formula (II) are made；
2) formula (II) compound will be added in 5% sodium hydrate aqueous solution, when 60 DEG C of reactions 3 are small, to reactant It is transparent, then adds hydrochloric acid neutralization and pH is adjusted to faintly acid, separate out solid, reaction stops, and filters shown in obtained formula (III) 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylic acids；
3) added after the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylic acids shown in formula (III) are reacted with thionyl chloride Organic solvent C dilutes, and then adds aryl alkanamine and triethylamine, stirred overnight at room temperature, extraction, column chromatography, is made such as formula (I) institute 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- the amide derivatives shown；The extractant is methylene chloride/water=1:1, column Chromatograph (EA:PE=2:1(V)).
The reaction process of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- amide derivatives of the present invention is as follows：
The present invention also provides a kind of Trifluoromethyl-1 H- pyrazoles -4- amide derivatives of 1- methyl -3- shown in formula (I) to exist The application in fungicide is prepared, the specific fungicide is prevention fusarium graminearum (FusaHum graminearum Sehw), phytophthora infestans (Phytophthora infestans (Mont.) de Bary), P. capsici (Phytophthora capsici Leonian), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum (Lib.) de Bary), Rhizoctonia solani Kuhn (Thanatephoruscucumeris), tomato early blight bacterium (Alternariasolani), Huang Melon ash arrhizus bacteria (Botrytis cinerea), cucumber fusarium axysporum (Fusarium oxysporum.sp.cucumebrium Owen), peanut Cercospora bacteria (Cercospora arachidicola Hori), Botryosphaeria berengeriana f. sp (Botryosphaeria Dothidea fungicide).
Further, the Trifluoromethyl-1 H- pyrazoles -4- amide derivatives of 1- methyl -3- shown in formula (I) of the present invention are being made Concentration in standby fungicide is 50ppm.
Further, the Trifluoromethyl-1 H- pyrazoles -4- amide derivatives of 1- methyl -3- shown in formula (I) of the present invention are being made Application in standby prevention peanut Cercospora bacteria, Sclerotinia sclerotiorum, compound shown in the formula (I) is chemical combination shown in (K1~10) Thing, compound most preferably shown in (K2).
Further, the Trifluoromethyl-1 H- pyrazoles -4- amide derivatives of 1- methyl -3- shown in formula (I) of the present invention are being made Application in standby prevention Botryosphaeria berengeriana f. sp, compound shown in the formula (I) is compound shown in (K1~10), most preferably (K5) Shown compound.
Compared with prior art, the beneficial effects are mainly as follows：The present invention provides a kind of 1- methyl -3- three Methyl fluoride -1H- pyrazoles -4- amide derivatives and preparation method thereof prepare the application in fungicide with it, its preparation method is simple, Easy to operate, obtained compound shows preferable suppression to peanut Cercospora bacteria, Sclerotinia sclerotiorum at 50 ppm concentration Property processed, inhibiting rate have respectively reached 96% and 100%, preferable to Botryosphaeria berengeriana f. sp inhibiting rate, and bacteriostasis rate is above comparison medicine Agent bacteriostasis rate more than 10%；Compound of the present invention is the noval chemical compound with bactericidal activity, is provided for the research and development of novel pesticide Basis.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in This：
The preparation of embodiment 1N- benzyl -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
(1) synthesis of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- Ethyl formates (II)：
By trifluoroacetic ethyl acetoacetate (7.36g, 40mmol), triethyl orthoformate (8.88g, 60mmol) is in acetic anhydride When back flow reaction 8 is small in (12.24g, 0.12mol), gas phase following response thing is evaporated under reduced pressure after reaction to the reaction was complete, Unnecessary triethyl orthoformate is removed, obtains crude product formula 1；Under ice bath, formula 1 (9.6g, 40mmol) is added dropwise to 40% methyl dropwise In hydrazine (6.9g, 60mmol) and ethanol (20ml) mixed liquor, when back flow reaction 6 is small, TLC (EA/PE=1/1 (V)) tracking reactions, It is evaporated under reduced pressure after question response, adds ethyl acetate (20ml) and extracted three times with saturated salt solution, organic layer anhydrous slufuric acid Sodium water removal rear overhang steams, and the 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates shown in formula (II) are made；
(2) synthesis of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylic acids formulas (III)：
1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates (8.88g, 40mmol) shown in formula (II) are added It is transparent to reaction system when 60 DEG C of reactions 3 are small into 5% sodium hydrate aqueous solution (100ml), then add hydrochloric acid and neutralize PH is adjusted to faintly acid, separates out solid, reaction stops, filtering 1- methyl -3- Trifluoromethyl-1 H- pyrazoles shown in formula (III) - 4- carboxylic acids.
(3) synthesis of N- benzyls -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides formula (K1)：
1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- carboxylic acids (7.76g, 40mmol) and thionyl chloride shown in formula (III) When (47.6g, 0.4mol) reflux 4 is small, when question response system is changed into light yellow transparent liquid, the reaction was continued 30min, reaction stops Only, 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- acyl chlorides is evaporated under reduced pressure to after being cooled to room temperature, by 1- methyl -3- fluoroforms Base -1H- pyrazoles -4- acyl chlorides (2mmol) is added in 15ml dichloromethane, is added phenylmethanamine (2.1mmol), is then slowly added dropwise Triethylamine (0.3g, 3mmol) stirred overnight at room temperature；TLC(EA:PE=2:1 (V)) tracking, after complete reaction with dichloromethane/ Water=1:1 (V) system extracts three times, concentration of organic layers, toluene or the extraction of 75% ethanol, column chromatography (EA:PE=2:1 (V)), obtain (K1) N- benzyl -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides shown in
Formula K1) shown in N- benzyl -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamide structural formulas it is as follows：
N- benzyl -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：White solid, yield：54.3%, melt Point：122~123 DEG C,1HNMR(400MHz,CDCl3)δ:3.97(s,3H,CH3), 4.62 (d, J=5.6Hz, 2H, CH2), 6.37 (s, 1H, NH), 7.29~7.33 (m, 2H, Ph), 7.35~7.40 (m, 3H, Ph), 7.96 (s, 1H, CH)
The preparation of embodiment 2 (S) -1- methyl-N- (1- phenethyls) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
Phenylmethanamine in 1 step 3) of embodiment is changed to (S) -1- phenethyl -1- amine, trifluoroacetic ethyl acetoacetate and original The ratio between amount of formic acid triethyl material is 1:The ratio between 2,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and amount of thionyl chloride material are 1:The ratio between amount of 1,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and (S) -1- phenethyl -1- amine materials is 1:1, organic solvent is used Dioxane, other are operated with embodiment 1, and 1- methyl-(S)-N- (1- phenethyls) shown in obtained target compounds of formula (K2)- 3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
(S) -1- methyl-N- (1- phenethyls) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown solid, yield： 62.2%, fusing point：95~96 DEG C,1HNMR(400MHz,CDCl3)δ:1.57 (d, J=5.6Hz, 3H, CH3),3.96(s,3H, CH3), 5.22~5.28 (m, 1H, CH), 6.33 (s, 1H, NH), 7.28~7.30 (m, 1H, Ph), 7.34~7.38 (m, 4H, Ph),7.95(s,1H,CH).
The preparation of embodiment 3 (R) -1- methyl-N- (1- phenethyls) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
Phenylmethanamine in 1 step 3) of embodiment is changed to (R) -1- phenethyl -1- amine, trifluoroacetic ethyl acetoacetate and original The ratio between amount of formic acid triethyl material is 1:The ratio between 5,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and amount of thionyl chloride material are 1:The ratio between amount of material of 195,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and (R) -1- phenethyl -1- amine is 1:3, You Jirong Agent dimethylbenzene, other operations obtain 1- methyl-(R)-N- (1- phenethyls) -3- (three as shown in formula (K3) with embodiment 1 Methyl fluoride) -1H- pyrazole-4-carboxamides
(R) -1- methyl-N- (1- phenethyls) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown solid, yield： 43.5%, fusing point：99~100 DEG C,1HNMR(400MHz,CDCl3)δ:1.57 (d, J=5.6Hz, 3H, CH3),3.95(s,3H, CH3), 5.23~5.27 (m, 1H, CH), 6.34 (s, 1H, NH), 7.28~7.30 (m, 1H, Ph), 7.35~7.38 (m, 4H, Ph),7.94(s,1H,CH).
Embodiment 4 (S)-N- (1- (4- chlorphenyls) ethyl) -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides Preparation
Phenylmethanamine in 1 step 3) of embodiment is changed to 1- (4- chlorphenyls) ethyl -1- amine, trifluoroacetic ethyl acetoacetate It is 1 with the ratio between the amount of triethyl orthoformate material:The amount of 4,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and thionyl chloride material it Than for 1:The ratio between amount of material of 5,1,3- dimethyl -1H- pyrazoles -4- carboxylic acids and 1- (4- chlorphenyls) ethyl -1- amine is 1:2, Organic solvent tetrahydrofuran, other operations obtain (S)-N- (1- (4- chlorphenyls) second as shown in formula (K4) with embodiment 1 Base) -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
(S)-N- (1- (4- chlorphenyls) ethyl) -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown is consolidated Body, yield：70.4%, fusing point：105~106 DEG C,1HNMR(400MHz,CDCl3)δ:1.57 (d, J=5.8Hz, 3H, CH3), 3.99(s,3H,CH3), 5.21~5.24 (m, 1H, CH), 6.31 (s, 1H, NH), 7.32~7.34 (m, 4H, Ph), 8.00 (s, 1H,CH).
Embodiment 5N- (1- (4- (sec-butyl) phenyl) ethyl) -1- methyl -3- (trifluoromethyl) -1H- pyrazoles -4- formyls The preparation of amine
Phenylmethanamine in 1 step 3) of embodiment is changed to 4- (sec-butyl) aniline, other operations are obtained with embodiment 1 N- (1- (4- (sec-butyl) phenyl) ethyl) -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides as shown in formula (K5)
N- (1- (4- (sec-butyl) phenyl) ethyl) -1- methyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown Solid, yield：54.6%, fusing point：84~85 DEG C,1HNMR(500MHz,CDCl3)δ:1.26 (d, J=6.5Hz, 3H, CH3), 1.82~1.87 (m, 2H, CH2), 2.68~2.72 (m, 2H, CH2),3.97(s,3H,CH3), 4.18~4.24 (m, 1H, CH), 5.86 (s, 1H, NH), 7.18~7.21 (m, 3H, Ph), 7.31 (d, J=7.5Hz, 2H, Ph), 7.91 (s, 1H, CH)
The preparation of embodiment 61- methyl-N- phenethyls -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
Phenylmethanamine in 1 step 3) of embodiment is changed to 2- phenyl -1- amine, other operations are obtained such as formula with embodiment 1 (K6) 1- methyl-N- phenethyls -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides shown in
1- methyl-N- phenethyls -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：White solid, yield：48.9%, melt Point：97~98 DEG C,1HNMR(500MHz,CDCl3)δ:2.91 (t, J=7.0Hz, 2H, CH2), 3.68~3.72 (m, 2H, CH2), 3.96(s,3H,CH3), 6.03 (d, J=3.0Hz, 1H, NH), 7.24 (t, J=7.0Hz, 3H, Ph), 7.33 (t, J=7.5Hz, 2H,Ph),7.90(s,1H,CH).
Embodiment 7N- (2- methoxyl group -5- nitrobenzyls)-N, 1- dimethyl -3- (trifluoromethyl) -1H- pyrazoles -4- formyls The preparation of amine
Phenylmethanamine in 1 step 3) of embodiment is changed to N- methyl isophthalic acids-(2- methoxyl group -5- nitrobenzophenones) methylamine, its He is operated with embodiment 1, obtains N- (2- methoxyl group -5- nitrobenzyls)-N as shown in formula (K7), 1- dimethyl -3- (trifluoros Methyl) -1H- pyrazole-4-carboxamides
N- (2- methoxyl group -5- nitrobenzyls)-N, 1- dimethyl -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown Solid, yield：70.5%, fusing point：143~144 DEG C,1HNMR(500MHz,CDCl3)δ:2.99(s,3H,CH3),3.99(s, 3H,CH3),4.02(s,3H,CH3),4.79(s,2H,CH2), 6.98 (d, J=11.5Hz, 2H, Ph), 7.65 (s, 1H, Ph), 8.10(s,1H,CH).
The preparation of embodiment 8N, 1- dimethyl-N-(naphthalene -1- methyl) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
Phenylmethanamine in 1 step 3) of embodiment is changed to N- methyl isophthalic acids-(naphthalene -1- bases) methylamine, other operations are the same as implementation Example 1, obtains the N shown in formula (K8), 1- dimethyl-N -s (naphthalene -1- methyl) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides
N, 1- dimethyl-N-(naphthalene -1- methyl) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Brown solid, yield： 40.1%, fusing point：103~104 DEG C,1HNMR(400MHz,CDCl3)δ:2.80(s,3H,CH3),3.98(s,3H,CH3),5.24 (s,2H,CH2), 7.54~7.57 (m, 3H, Ph), 7.88 (d, J=8.4Hz, 2H, Ph), 7.92 (d, J=7.2Hz, 2H, Ph), 8.15(s,1H,CH).
Embodiment 9N, 1- dimethyl -3- (trifluoromethyl)-N- (3,4,5- trimethoxy benzyl) -1H- pyrazoles -4- formyls The preparation of amine
Phenylmethanamine in 1 step 3) of embodiment is changed to N- methyl isophthalic acids-(3,4,5- trimethoxyphenyl) methylamine, other Operation obtains the N as shown in formula (K9), 1- dimethyl -3- (trifluoromethyl)-N- (3,4,5- trimethoxy benzyls with embodiment 1 Base) -1H- pyrazole-4-carboxamides
N, 1- dimethyl -3- (trifluoromethyl)-N- (3,4,5- trimethoxy benzyl) -1H- pyrazole-4-carboxamides：It is yellowish Color solid, yield：52.5%, fusing point：102~103 DEG C,1HNMR(400MHz,CDCl3)δ:2.88(s,3H,CH3),3.89(s, 3H,CH3),4.00(s,3H,CH3),4.69(s,2H,CH2),6.56(s,2H,Ph),7.57(s,1H,CH).
The system of embodiment 10N, 1- dimethyl-N-(pyridine -3- methyl) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides It is standby
Phenylmethanamine in 1 step 3) of embodiment is changed to N- methyl isophthalic acids-(pyridin-3-yl) methylamine, other operations are the same as real Example 1 is applied, obtains the N as shown in formula (K10), 1- dimethyl-N -s (pyridine -3- methyl) -3- (trifluoromethyl) -1H- pyrazoles -4- first Acid amides
N, 1- dimethyl-N-(pyridine -3- methyl) -3- (trifluoromethyl) -1H- pyrazole-4-carboxamides：Faint yellow solid, Yield：49.8%, fusing point：105~106 DEG C,1HNMR(500MHz,CDCl3)δ:2.87(s,3H,CH3),3.95(s,3H, CH3),4.71(s,2H,CH2), 7.28~7.32 (m, 1H, Ar), 7.57 (s, 1H, CH), 7.69 (s, 1H, CH), 8.55 (d, J= 3.5Hz,2H,Ar).
11 bactericidal activity of embodiment is tested
Subjects：Fusarium graminearum (FusaHum graminearum Sehw), phytophthora infestans (Phytophthora infestans (Mont.) deBary), P. capsici (Phytophthora capsici Leonian), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum (Lib.) de Bary), Rhizoctonia solani Kuhn (Thanatephoruscucumeris), tomato early blight bacterium (Alternariasolani), botrytis cinerea pers (Botrytis Cinerea), cucumber fusarium axysporum (Fusarium oxysporum.sp.cucumebrium Owen), peanut Cercospora bacteria (Cercospora arachidicola Hori), Botryosphaeria berengeriana f. sp (Botryosphaeria dothidea).
Test process：It is spare that each compound with DMSO is dissolved into 1%EC mother liquors.Using inhibition zone method, evaluation is for examination chemical combination Thing under 50ppm dosage to experiment target target indoor bactericidal activity, separately set solvent clear water control (QCK) and effective content as The fluxapyroxad active compound control (YCK) of 50ppm.
Test method：50 microlitres of mother liquor is drawn with liquid-transfering gun, is dissolved in the tween water of 2.95ml, is made into the medicine of 500ppm Liquid.1ml liquids are drawn with liquid-transfering gun to be put into sterilized culture dish, the PDA culture medium of 9ml is placed into, shakes up, and are cooled down.With Card punch is beaten to take and is chosen with transfer needle to culture dish center after circular bacteria cake, and then culture dish is placed in 27 DEG C of incubator and is cultivated, Colony diameter is measured after 48~72h.The pure increment of bacterium colony is bacterium colony average diameter in the difference of bacteria cake diameter, bacteriostasis rate (%) meter Calculation method is with reference to equation below.
Bactericidal activity test result is as shown in table 1.
The bactericidal activity (% preventive effects) of each compound under 1 50ppm of table
Drawn from table 1, to peanut Cercospora bacteria, Sclerotinia sclerotiorum inhibitory activity under compound 50ppm of the present invention Preferably, for example, K2, K4 compound are suitable with comparison medicament to the inhibiting rate of both germs, 96% He has been respectively reached 100%；Secondly it is preferable to Botryosphaeria berengeriana f. sp inhibiting rate, as K2, K5, compound bacteriostasis rate are above comparison medicament bacteriostasis rate More than 10%.

Claims (9)

  1. A kind of 1. 1- methyl -3- Trifluoromethyl-1sH- pyrazoles -4- amide derivatives, it is characterised in that its structural formula such as formula（Ⅰ）Institute Show：
    ,
    Formula（Ⅰ）In：R0For hydrogen or methyl, R1For phenyl or substituted-phenyl, the substituent of the substituted-phenyl is halogen, methoxyl group, Nitro, methyl, ethyl, butyl.
  2. A kind of 2. 1- methyl -3- Trifluoromethyl-1s according to claim 1H- pyrazoles -4- amide derivatives, its feature exist In formula（Ⅰ）Middle R1To be one of following：N- benzyls,（S）-N-（1- phenethyls）、（R）-N-（1- phenethyls）、（S）-N-（1- (4- chlorine Phenyl）Ethyl）, N- (- 2 butyl of 4- butyl benzenes), N- phenethyls, N-（- 5 nitrobenzyl of 2- methoxyl groups）、N-（Naphthalene -1- methylenes Base）、N-（3,4,5- trimethoxy benzyls）、N-（Pyridine -3- methylene）,.
  3. A kind of 3. 1- methyl -3- Trifluoromethyl-1s according to claim 1HThe preparation side of-pyrazoles -4- amide derivatives Method, it is characterised in that include the following steps：
    1）Mixing for methyl hydrazine and ethanol is added to after flow back by trifluoroacetic ethyl acetoacetate and triethyl orthoformate in acetic anhydride Close in liquid and be made such as formula（Ⅱ）Shown 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylate solutions；
    ,
    2）By step 1）Obtained formula（Ⅱ）Add after shown 1- methyl -3- Trifluoromethyl-1 H- pyrazoles -4- Ethyl formates hydrolysis Enter hydrochloric acid to be made such as formula（Ⅲ）Shown 1- methyl -3- Trifluoromethyl-1sH- pyrazoles -4- carboxylic acids；
    ,
    3）By step 2）Obtained formula（Ⅲ）Shown 1- methyl -3- Trifluoromethyl-1sH- pyrazoles -4- carboxylic acids and thionyl chloride are anti- Should after add organic solvent diluting, then add aryl alkanamine and triethylamine, stirred overnight at room temperature, extraction, column chromatography, is made such as Formula（Ⅰ）Shown 1- methyl -3- Trifluoromethyl-1sH- pyrazoles -4- amide derivatives.
  4. 4. the preparation method of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylate solutions according to claim 3, It is characterized in that step 1）The dosage of middle triethyl orthoformate is with the gauge of material, the trifluoroacetic ethyl acetoacetate and orthoformic acid The ratio between amount of material of triethyl is 1 ~ 2:2 ~ 5, it is preferably 2:3；The dosage of methyl hydrazine aqueous solution with the gauge of methyl hydrazine material, The ratio between amount of the trifluoroacetic ethyl acetoacetate and methyl hydrazine material is 1 ~ 2:3 ~ 5, it is preferably 2:3.
  5. 5. 1- methyl -3- Trifluoromethyl-1s according to claim 3HThe preparation method of-pyrazoles -4- amide derivatives, its It is characterized in that step 3）The dosage of middle thionyl chloride is with the gauge of material, the 1- methyl -3- Trifluoromethyl-1sH- pyrazoles -4- carboxylics The ratio between amount of acid and thionyl chloride material is 1:1 ~ 200, it is preferably 1:10；The aryl alkanamine is with the gauge of material, the 1- Methyl -3- Trifluoromethyl-1sHThe ratio between amount of-pyrazoles -4- carboxylic acids and aryl alkanamine material is 1:1 ~ 3, it is preferably 1:1.05.
  6. 6. the preparation method of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylate solutions according to claim 3, It is characterized in that step 3）Organic solvent be tetrahydrofuran, dichloromethane, dioxane, toluene or dimethylbenzene.
  7. 7. the preparation method of 1- methyl -3- Trifluoromethyl-1s H- pyrazoles -4- carboxylate solutions according to claim 3, It is characterized in that step 3）Organic solvent be dichloromethane.
  8. 8. 1- methyl -3- Trifluoromethyl-1s according to claim 3HThe preparation method of-pyrazoles -4- amide derivatives, its It is characterized in that step 3）Middle extractant is that volume ratio is 1:1 dichloromethane and water mixed liquid, column chromatography use volume ratio for 2:1 EA and PE mixed liquors.
  9. A kind of 9. 1- methyl -3- Trifluoromethyl-1s according to claim 1H- pyrazoles -4- amide derivatives are preparing sterilization Application in agent.
CN201711250600.3A 2017-12-01 2017-12-01 3 trifluoromethyl 1H pyrazoles of a kind of 1 methyl, 4 amide derivatives and preparation method and application Pending CN107935929A (en)

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