CN110615764A - N- (2-benzamide) -1H-pyrazole-4-formamide compound and preparation method and application thereof - Google Patents
N- (2-benzamide) -1H-pyrazole-4-formamide compound and preparation method and application thereof Download PDFInfo
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- 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
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- 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
Abstract
The invention discloses N- (2-benzamide) -1H-pyrazole-4-carboxamides, processes for their preparation and their use. N- (2-benzamide) -1HPyrazole-4-carboxamides, i.e. N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamides of formula (i):in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy. The invention discloses N- (2-benzamide) -3- (difluoro)Methyl) -1-methyl-1HThe-pyrazole-4-formamide compound is a new compound with bactericidal activity, has a better inhibition rate on rhizoctonia solani at a concentration of 50ppm, and provides a foundation for the research and development of new pesticides.
Description
Technical Field
The invention relates to an N- (2-benzamide) -1H-pyrazole-4-formamide compound and a preparation method and application thereof.
Background
Nowadays, pyrazole amide compounds usually have excellent and wide biological activity such as low toxicity, high efficiency and the like because of containing high-activity structural groups such as pyrazole, amide and the like, and a pyrazole ring is an important member of nitrogen-containing heterocycles, has a very unique structural form, and has high biological activity to various microorganisms, pathogenic factors and diseases, so that the pyrazole amide compounds are not only used in the fields of sterilization, disinsection and acaricidal action, but also widely applied in the field of weeding, and even applied in the field of anticancer in medicine. In recent years, some overseas pesticides have been interested in the development of bisamide pesticides, and chlorantraniliprole and cyantraniliprole developed by DuPont and flubendiamide developed by Bayer and Japanese pesticide Kabushiki Kaisha are on the market. There are developed Tetraniliprol of Bayer, Bromocha fluorobenzenediamide developed by Pasv and Mitsui chemistry, and the like. The compound has the advantages of low residue on plants, small phytotoxicity, low acute toxicity on mammals and the like.
The design and synthesis of the novel pyrazole diacyl fungicide have important significance for developing novel pesticides with high efficiency, low toxicity and low residue.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound and a preparation method and application thereof. The invention designs and synthesizes a series of compounds such as pyrazole diacyl and the like based on the structure of SDH inhibitors such as fluxapyroxad and the like, introduces modes such as extension and substituted benzamide and the like by taking a pyrazole amide structure as a matrix, and introduces difluoromethyl at the 3-position of a pyrazole ring to investigate the influence on the biological activity of the compounds.
The N- (2-benzamide) -1H-pyrazole-4-formamide compound, namely the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound, is characterized in that the structural formula is shown as the formula (I):
in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.
The N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that R in the formula (I) is one of the following compounds: 2-methylphenyl, 2, 6-dichlorophenyl, 2, 3-dichlorophenyl, 4-methoxyphenyl, 2, 4-dichlorophenyl and phenyl.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized by comprising the following steps:
1) heating ethyl difluoroacetoacetate and triethyl orthoformate in an organic solvent A to reflux reaction, concentrating to remove the solvent after the reaction is finished, adding the concentrated residue into a mixed solution of a methylhydrazine aqueous solution and an organic solvent B, stirring and reacting at the temperature of 45-60 ℃, and tracking the reaction process by TLC; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in a formula (II);
2) adding the 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in the formula (II) obtained in the step 1) into a NaOH aqueous solution with the mass concentration of 8-12%, stirring and reacting at the temperature of 55-70 ℃ until a reaction liquid system is transparent, naturally cooling to room temperature, adding acid to adjust the pH of the reaction liquid to 1.5-3.0, separating out a solid, performing suction filtration, and drying filter residues to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III);
3) heating the 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) obtained in the step 2) in thionyl chloride to reflux reaction, concentrating to remove excessive thionyl chloride after the reaction is finished, stirring and reacting the concentrated residue with N-Boc-ethylenediamine and triethylamine in an organic solvent C at room temperature, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled and concentrated residue by column chromatography to obtain (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamido) ethyl) carbamic acid tert-butyl ester shown in the formula (IV);
4) heating the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate obtained in the step 3) and trifluoromethyl acetic acid in an organic solvent D to reflux reaction, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled concentrate by column chromatography to obtain the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V);
5) uniformly stirring and mixing the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) obtained in the step 4), an organic solvent E and triethylamine, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, performing rotary evaporation and concentration after the reaction is finished to remove the solvent, and performing column chromatography separation and purification on the rotary evaporation and concentration residue to obtain the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (I);
wherein the number of the substituent groups on the benzene ring of the substituted benzoyl chloride is one or more, and each substituent group is independently selected from H, halogen, C1-C3 alkyl or C1-C3 alkoxy.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that the organic solvent A in the step 1) is acetic anhydride, and the organic solvent B is ethanol; the organic solvent C in the step 3), the organic solvent D in the step 4) and the organic solvent E in the step 5) are all dichloromethane.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 1), the feeding molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and methylhydrazine is 1: 1.1-1.5.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 3), the feeding molar ratio of 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) to N-Boc-ethylenediamine is 1: 1.1-1.5; in the step 4), the feeding molar ratio of the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate shown in the formula (IV) to the trifluoromethyl acetic acid is 1: 1.05-1.2.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that in the step 5), the feeding molar ratio of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) to the substituted benzoyl chloride is 1: 1.05-1.2.
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that the molar ratio of the organic solvent A to the ethyl difluoroacetoacetate in the step 1) is 2-4: 1, and the volume usage of the organic solvent B is 0.3-0.8 ml/mmol based on the mass of the ethyl difluoroacetoacetate; the volume dosage of the organic reagent C in the step 3) is 0.5-1.0 ml/mmol based on the amount of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid shown in the formula (III); the volume usage amount of the organic reagent D in the step 4) is 5-8 ml/mmol based on the substance amount of (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamic acid tert-butyl ester shown in a formula (IV); the volume usage amount of the organic reagent E in the step 5) is 5-8 ml/mmol based on the amount of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide shown in the formula (V).
The preparation method of the N- (2-benzamide) -1H-pyrazole-4-formamide compound is characterized in that eluents for column chromatography separation in the steps 3), 4) and 5) are mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1: 0.5-2.
The N- (2-benzamide) -1H-pyrazole-4-formamide compound is applied to preparation of a bactericide.
The synthetic process route of the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound is as follows:
compared with the prior art, the invention has the following beneficial effects: the invention provides an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide compound, a preparation method thereof and application thereof in preparing a bactericide, the preparation method is simple, the operation is convenient, the obtained compound has the best inhibition activity on rhizoctonia solani under the concentration of 50ppm, and the inhibition rate reaches 54.3%.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
EXAMPLE 13 preparation of- (difluoromethyl) -1-methyl-N- (2- (2-methylbenzamido) ethyl) -1H-pyrazole-4-carboxamide
1) Synthesis of ethyl 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate (II):
after ethyl difluoroacetoacetate (50.0mmol) and triethyl orthoformate (60mmol) were reacted in acetic anhydride (150.0mmol) under reflux for 8 hours (detection of complete conversion of the reaction product), the reaction solution was concentrated by distillation under reduced pressure to remove excess triethyl orthoformate and acetic anhydride solvent, the concentrated residue was added to a mixed solution of 8.3g of 40% aqueous methylhydrazine solution and 25mL of ethanol under ice-bath conditions, heating to 50 ℃ for reaction, tracking the reaction process by TLC (thin layer chromatography), distilling and concentrating to remove the solvent after the reaction is finished, adding 20mL ethyl acetate and 20mL saturated saline solution into the distilled concentrate for extraction and layering, washing an organic layer for 2 times by using the saturated saline solution (the volume of the saturated saline solution adopted in each washing is 20mL), drying by anhydrous magnesium sulfate, and then performing rotary evaporation to remove the residual solvent to prepare 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in formula (II);
2) synthesis of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (iii):
adding 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate (38mmol) shown in formula (II) into a 100mL reaction bottle, then adding 30mL NaOH aqueous solution with the mass concentration of 10%, heating to 60 ℃, stirring until the reaction liquid is transparent, naturally cooling to room temperature, adding acid into the reaction liquid to adjust the pH to about 2.0, separating out a solid, carrying out suction filtration, washing filter residues with water, and drying to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in formula (III).
3) Synthesis of tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamido) ethyl) carbamate (IV):
mixing 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid (30mmol) shown in formula (III) with 10mL of thionyl chloride, heating to reflux for reaction, continuing to react for 30min after the reaction solution turns from turbid to clear and transparent, cooling to room temperature after the reaction is stopped, concentrating to remove redundant thionyl chloride, diluting and mixing the concentrated residue with 10mL of dichloromethane, and preparing to obtain a solution A for later use.
Dropwise adding the prepared solution A into a mixed solution of 15mL of dichloromethane, N-Boc-ethylenediamine (40.0mmol) and 4mL of triethylamine, stirring at room temperature for reaction, and tracking the reaction process by TLC; after the reaction is finished, concentrating to remove the solvent, and carrying out column chromatography separation and purification on the concentrated residue (eluent is petroleum ether and ethyl acetate with the volume ratio of 1: 1) to obtain (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamic acid tert-butyl ester shown in the formula (IV);
4) synthesis of N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide (v):
adding 10mL of dichloromethane into tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate (1.5mmol) shown in the formula (IV), stirring uniformly, adding trifluoromethyl acetic acid (1.6mmol), heating up, refluxing for 2H, and tracking the reaction process by TLC; after the reaction is finished, the solvent is removed by concentration, and the concentrated residue is separated and purified by column chromatography (eluent is petroleum ether and ethyl acetate with the volume ratio of 1: 1) to obtain the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V).
5) Synthesis of 3- (difluoromethyl) -1-methyl-N- (2- (2-methylbenzamido) ethyl) -1H-pyrazole-4-carboxamide (G1):
adding 10mL of dichloromethane and 1mL of triethylamine into N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide (1.5mmol) shown in formula (V), uniformly stirring, dropwise adding 2-methylbenzoyl chloride (1.6mmol), stirring at room temperature for reaction, and tracking the reaction process by TLC; after the reaction is finished, the solvent is removed by concentration, and the concentrated residue is separated and purified by column chromatography (eluent is petroleum ether and ethyl acetate with the volume ratio of 1: 1) to prepare the 3- (difluoromethyl) -1-methyl-N- (2- (2-methylbenzamido) ethyl) -1H-pyrazole-4-formamide shown as the formula (G1).
3- (difluoromethyl) -1-methyl-N- (2- (2-methylbenzamido) ethyl) -1H-pyrazole-4-carboxamide: white solid, yield: 68.3%, melting point: 113 ℃ and 116 ℃;1HNMR(CDCl3,500MHz),δ:7.85(s,1H,py),7.37-7.29(m,1H,ph),7.28(s,1H,ph),7.23-7.17(m,2H,ph),7.05(t,J＝54.0Hz,1H,CHF2),6.65(s,1H,NH),3.85(s,3H,CH3),3.66-3.75(m,4H,CH2),2.40(s,3H,CH3)。
example 2N- (2- (2, 6-Dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide
The procedure of example 1 was otherwise the same as that of example 1 except that 2-methylbenzoyl chloride in step 5) of example 1 was replaced with an equimolar amount of 2, 6-dichlorobenzoyl chloride, to obtain the objective compound, N- (2- (2, 6-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by formula (G2);
n- (2- (2, 6-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide: white solid, yield: 63.5%, melting point: 109-113 ℃;1H NMR(CDCl3,500MHz),δ:7.86(s,1H,py),7.35-7.31(m,2H,ph),7.29(s,1H,ph),7.12-6.89(m,2H,ph,CHF2),6.52(s,1H,NH),3.94(s,3H,CH3),3.75-3.68(m,4H,CH2).
EXAMPLE 3 preparation of N- (2- (2, 3-Dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide
The 2-methylbenzoyl chloride in step 5) of example 1 was replaced with an equimolar amount of 2, 3-dichlorobenzoyl chloride, and the other procedures were the same as in example 1 to obtain N- (2- (2, 3-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by the formula (G3);
n- (2- (2, 3-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide: white solid, yield: 53.1%, melting point: 105 ℃ and 107 ℃;1H NMR(CDCl3,500MHz),δ:7.88(s,1H,py),7.53-7.58(m,1H,ph),7.39-7.45(m,1H,ph),7.25(t,J＝8.0Hz,1H,ph),7.08-6.85(m,2H,ph,CHF2),6.82(s,1H,NH),3.93(s,3H,CH3),3.69-3.75(m,4H,CH2).
EXAMPLE 43 preparation of N- (difluoromethyl) -N- (2- (4-methoxybenzamido) ethyl) -1-methyl-1H-pyrazole-4-carboxamide
The 2-methylbenzoyl chloride in step 5) of example 1 was replaced with an equimolar amount of 4-methoxybenzoyl chloride, and the other procedures were carried out as in example 1 to obtain 3- (difluoromethyl) -N- (2- (4-methoxybenzoylamino) ethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by the formula (G4);
3- (difluoromethyl) -N- (2- (4-methoxybenzamido) ethyl) -1-methyl-1H-pyrazole-4-carboxamide: white solid, yield: 47.5%, melting point: 96-98 ℃;1H NMR(CDCl3,500MHz),δ:7.88(d,J＝9.0Hz,2H,py,ph),7.84(s,1H,ph),7.08(s,1H,ph),6.94(t,J＝54.0Hz,1H,CHF2),6.81(d,J＝9.0Hz,1H,ph),6.65(s,1H,NH),3.78(s,3H,CH3),3.75(s,3H,CH3O),3.69-3.74(m,4H,CH2).
EXAMPLE 5 preparation of N- (2- (2, 4-Dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide
The same procedure as in example 1 was repeated except for replacing 2-methylbenzoyl chloride in step 5) of example 1 with an equimolar amount of 2, 4-dichlorobenzoyl chloride to obtain N- (2- (2, 4-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by the formula (G5);
n- (2- (2, 4-dichlorobenzamide) ethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide: white solid, yield 46.2%, melting point: 93-97 ℃;1H NMR(CDCl3,500MHz),δ:7.86(s,1H,py),7.63-7.59(m,1H,ph),7.52(d,J＝8.0Hz,1H,ph),7.20(t,J＝8.0Hz,1H,ph),7.03-6.80(m,2H,ph,CHF2),6.61(s,1H,NH),3.82(s,3H,CH3),3.73-3.78(m,4H,CH2).
EXAMPLE 6 preparation of N- (2-Benzoamidoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide
The 2-methylbenzoyl chloride in step 5) of example 1 was replaced with an equimolar amount of benzoyl chloride, and the other procedures were the same as in example 1 to obtain N- (2-benzamidoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by the formula (G6);
n- (2-benzamidoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide: white solid, yield: 51.7%, melting point: 103-106 ℃;1H NMR(CDCl3,500MHz),δ:7.94-8.04(m,2H,py,ph),7.84(s,1H,ph),7.47(m,1H,ph),7.34(t,J＝8.0Hz,2H,ph),6.93(t,J＝54.0Hz,1H,CHF2),6.67(s,1H,NH),3.77(s,3H,CH3),3.71-3.76(m,4H,CH2).
example 7 bactericidal Activity test
Test subjects: early blight of tomato (Alternaria solani), Gibberella zeae (Gibberella zeae), late blight of potato (Phytophthora infestans), Phytophthora capsici (Phytophthora capsici), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum), Botrytiscineria cucumeri (Botrytiscineria), Rhizoctonia solani (Riziocotinia solani), Fusarium oxysporum cucumerinum (Fusarium oxysporum), Pseudocercospora arachidicola (Cercospora arachidicola) and Phyllospora malalis (Boyosphaeriererengiana).
The compounds represented by the formulae (G1) to (G6) prepared in examples 1 to 6 were labeled as test compounds, and the bactericidal activity test was performed in the following manner:
and (3) test treatment: each test compound was dissolved in DMSO to 1% EC stock solution for use. The indoor bactericidal activity of the compound to be tested to the test target under the dosage of 50ppm is evaluated by adopting a bacteriostatic ring method, and a solvent clean water control (QCK) and a fluxapyroxad control (FP) with the effective content of 50ppm are additionally arranged.
The test method comprises the following steps: 50 microliter of the prepared EC mother liquor is absorbed by a pipette gun and dissolved in 2.95mL of Tween water to prepare a liquid medicine with the effective concentration of the compound to be detected being 500 ppm. Sucking 1mL of the liquid medicine by using a pipette, putting the liquid medicine into a sterilized culture dish, putting 9mL of PDA culture medium into the culture dish, shaking up, and cooling. And (3) beating the round bacterial cake by using a puncher, picking the round bacterial cake to the center of a culture dish by using an inoculating needle, then placing the culture dish in an incubator at 27 ℃ for culture, and measuring the diameter of a bacterial colony after 48-72 hours. The pure growth amount of the bacterial colony is the difference value between the average diameter of the bacterial colony and the diameter of the bacterial cake, and the bacteria inhibition rate (%) calculation method is calculated according to the following formula.
The pure growth amount of the control colony in the above calculation formula refers to the pure growth amount of the colony under the test of the clear water control (QCK).
The bactericidal activity test results are shown in table 1.
Table 150 ppm fungicidal Activity of Compounds (% control)
As shown in Table 1, the G series compounds only have activity on wheat scab, cucumber gray mold and rice sheath blight, particularly the inhibition rate on the rice sheath blight, and the inhibition effects of the compounds G3, G5 and G6 can reach more than 50%. The compound G5 has the best inhibition effect on wheat scab, and reaches 53.6 percent. Except that the compound G3 has an inhibition rate of 54.3% on rice sheath blight disease. Except that the compound G6 has an inhibition rate of 50% on rice sheath blight disease, the compound G6 also has an inhibition rate of 43.9% on cucumber gray mold.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (10)
1. An N- (2-benzamide) -1H-pyrazole-4-carboxamide compound, namely an N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide compound, is characterized in that the structural formula is shown as the formula (I):
in formula (I): r is phenyl or substituted phenyl, the number of the substituent groups on the benzene ring of the substituted phenyl is one or more, and each substituent group is independently selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.
2. A N- (2-benzamide) -1H-pyrazole-4-carboxamide according to claim 1, characterized in that in formula (i) R is one of the following: 2-methylphenyl, 2, 6-dichlorophenyl, 2, 3-dichlorophenyl, 4-methoxyphenyl, 2, 4-dichlorophenyl and phenyl.
3. A process for the preparation of N- (2-benzamide) -1H-pyrazole-4-carboxamides according to claim 1 or 2, characterized by comprising the steps of:
1) heating ethyl difluoroacetoacetate and triethyl orthoformate in an organic solvent A to reflux reaction, concentrating to remove the solvent after the reaction is finished, adding the concentrated residue into a mixed solution of a methylhydrazine aqueous solution and an organic solvent B, stirring and reacting at the temperature of 45-60 ℃, and tracking the reaction process by TLC; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in a formula (II);
2) adding the 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate shown in the formula (II) obtained in the step 1) into a NaOH aqueous solution with the mass concentration of 8-12%, stirring and reacting at the temperature of 55-70 ℃ until a reaction liquid system is transparent, naturally cooling to room temperature, adding acid to adjust the pH of the reaction liquid to 1.5-3.0, separating out a solid, performing suction filtration, and drying filter residues to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III);
3) heating the 1-methyl-3-difluoromethyl-1H-pyrazole-4-formic acid shown in the formula (III) obtained in the step 2) in thionyl chloride to reflux reaction, concentrating to remove excessive thionyl chloride after the reaction is finished, stirring and reacting the concentrated residue with N-Boc-ethylenediamine and triethylamine in an organic solvent C at room temperature, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled and concentrated residue by column chromatography to obtain (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamido) ethyl) carbamic acid tert-butyl ester shown in the formula (IV);
4) heating the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate obtained in the step 3) and trifluoromethyl acetic acid in an organic solvent D to reflux reaction, tracking the reaction process by TLC, distilling and concentrating to remove the solvent after the reaction is finished, and separating the distilled concentrate by column chromatography to obtain the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V);
5) uniformly stirring and mixing the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (V) obtained in the step 4), an organic solvent E and triethylamine, then dropwise adding substituted benzoyl chloride, stirring and reacting at room temperature, tracking the reaction process by TLC, performing rotary evaporation and concentration after the reaction is finished to remove the solvent, and performing column chromatography separation and purification on the rotary evaporation and concentration residue to obtain the N- (2-benzamide) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamide shown in the formula (I);
wherein the number of the substituent groups on the benzene ring of the substituted benzoyl chloride is one or more, and each substituent group is independently selected from H, halogen, C1-C3 alkyl or C1-C3 alkoxy.
4. The process for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the organic solvent A in step 1) is acetic anhydride and the organic solvent B is ethanol; the organic solvent C in the step 3), the organic solvent D in the step 4) and the organic solvent E in the step 5) are all dichloromethane.
5. The method for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein in step 1), the molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and methylhydrazine is 1: 1.1-1.5.
6. The method for preparing an N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein in step 3), the charging molar ratio of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by formula (III) to N-Boc-ethylenediamine is 1: 1.1-1.5; in the step 4), the feeding molar ratio of the tert-butyl (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamate shown in the formula (IV) to the trifluoromethyl acetic acid is 1: 1.05-1.2.
7. The method for preparing an N- (2-benzamide) -1H-pyrazole-4-carboxamide according to claim 3, wherein in step 5), the molar ratio of N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide represented by formula (v) to the substituted benzoyl chloride is 1:1.05 to 1.2.
8. The process for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the molar ratio of organic solvent A to ethyl difluoroacetoacetate in step 1) is 2-4: 1, the volume of organic solvent B is 0.3-0.8 ml/mmol based on the amount of ethyl difluoroacetoacetate; the volume dosage of the organic reagent C in the step 3) is 0.5-1.0 ml/mmol based on the amount of the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid shown in the formula (III); the volume usage amount of the organic reagent D in the step 4) is 5-8 ml/mmol based on the substance amount of (2- (3- (difluoromethyl) -1-methyl-1H-pyrazole-4-formamido) ethyl) carbamic acid tert-butyl ester shown in a formula (IV); the volume usage amount of the organic reagent E in the step 5) is 5-8 ml/mmol based on the amount of the N- (2-aminoethyl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide shown in the formula (V).
9. The method for preparing N- (2-benzamide) -1H-pyrazole-4-carboxamide compound according to claim 3, wherein the eluents for column chromatography in step 3), step 4) and step 5) are mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 0.5-2.
10. Use of an N- (2-benzamide) -1H-pyrazole-4-carboxamide compound as claimed in claim 1 or 2 for the preparation of fungicides.
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| CN112175030A (en) * | 2020-11-11 | 2021-01-05 | 铜仁学院 | Acetyl glucose triazole benzamide compound and synthesis method and application thereof |
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