Preparation and application of 1-substituted phenyl-5-methyl-1H-pyrazole-3-formamide derivative

Abstract

The invention relates to a novel compound as well as a preparation method and application thereof, in particular to preparation and application of a 1-substituted phenyl-5-methyl-1H-pyrazole-3-formamide derivative. The structural formula of the compound 1-substituted phenyl-5-methyl-1H-pyrazole-3-formamide derivative is as shown in a formula I which is described in the specification. In the formula (I), R1 is selected from 4-chlorine or 2, 4-dichloro; r2 is selected from H, methyl, methoxyl and cyclopropyl; and R3 is selected from the group consisting of 3-methyl phenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorphenyl, 2-(5-chloro-1H-indole-3-yl) ethyl and N-(4-chlorphenyl)-2-phenyl. Experiments show that the compound disclosed by the invention has relatively good antifungal activity on botryosphaeria dothidea, pythium aphanidermatum, fusarium oxysporum, pyricaria grisea, alternaria alternata, Sclerotinia sclerotiorum and botrytis cinerea, so that more choices can be provided for research and development of the antifungal drugs, and the compound disclosed by the invention has a wide application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a new type of compound and a preparation method and application thereof, in particular to the preparation and application of 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives. Background Art

[0002] Plant diseases caused by pathogens have led to crop yield reduction and deterioration in agricultural product quality, causing significant losses to agricultural production. Pathogens are prone to develop resistance and are difficult to prevent and control. At present, the common prevention and control method is to use fungicides for spraying. However, the long-term use of certain fungicides will not only cause pathogens to gradually develop resistance and reduce the prevention and control effect, but also have a certain impact on the environment and non-target organisms. Therefore, finding green and efficient fungicides with novel mechanisms of action has become the focus of current pesticide research.

[0003] Pyrazole amide compounds are easy to synthesize, have diverse molecular structures, good biological activity and selectivity, making them a hot spot for the creation of new pesticides. In 2006, BASF launched the fluopyram, which is an antifungal drug developed with pyrazole amide as the skeleton. Fluopyram has the characteristics of high efficiency, broad spectrum and strong selectivity, and has good preventive and therapeutic activity. It is used to prevent and control fungal diseases in crops such as cereals, soybeans, cotton, fruits and vegetables, and can be sprayed on the leaves or used as seed treatment (Chinese patent CN101115723A).

[0004]

[0005] However, although fluopicolide exhibits strong inhibitory effects on many fungi, it still needs to be used with caution in consideration of issues such as drug resistance, environmental impact, and potential harm to non-target organisms. Rational use and adoption of appropriate application strategies, as well as rational rotation with other pesticides are important measures to ensure its long-term effectiveness and environmental friendliness.

[0006] Therefore, it is of great significance to develop a new 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivative and explore its antifungal activity. Summary of the invention

[0007] The purpose of the present invention is to provide a new pyrazole amide compound 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivative and a preparation method and application thereof.

[0008] 1-Substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives shown in chemical structural formula I:

[0009]

[0010] Wherein, R1 is selected from: 4-chloro or 2,4-dichloro; R2 is selected from: H, methyl, methoxy or cyclopropyl; R3 is selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1H-indol-3-yl)ethyl or N-(4-chlorophenyl)-2-phenyl.

[0011] Preferably, the N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide derivative is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 or A12; wherein,

[0012] A1 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0013] A2 is N-(3-methylphenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0014] A3 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide A4 is N-(4-nitrobenzyl)-N-methoxy-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0015] A5 is N-(4-chlorophenyl)-N-methyl-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0016] A6 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A7 is N-(3-methylphenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0017] A8 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0018] A9 is N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0019] A10 is N-(4-nitrobenzyl)-N-methoxy-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0020] A11 is N-(3-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0021] A12 is N-(4-chlorophenyl)-N-methyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide.

[0022] The preparation method of the above 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives is as follows:

[0023]

[0024] Among them, R1 is selected from: 4-chloro or 2,4-dichloro; R2 is selected from: H, methyl, methoxy, cyclopropyl; R3 is selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1H-indol-3-yl)ethyl, N-(4-chlorophenyl)-2-phenyl.

[0025] The present invention also provides the use of the above 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives in the preparation of antifungal drugs.

[0026] Preferably, the fungus is Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, Botrytis cinerea.

[0027] Preferably, the 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivative is selected from A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 or A12, wherein:

[0028] A1 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0029] A2 is N-(3-methylphenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0030] A3 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide A4 is N-(4-nitrobenzyl)-N-methoxy-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0031] A5 is N-(4-chlorophenyl)-N-methyl-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0032] A6 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A7 is N-(3-methylphenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0033] A8 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0034] A9 is N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0035] A10 is N-(4-nitrobenzyl)-N-methoxy-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0036] A11 is N-(3-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0037] A12 is N-(4-chlorophenyl)-N-methyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide.

[0038] The present invention also provides a fungicide, which contains a fungicide-effective amount of at least one of the above-mentioned 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives, and optionally contains auxiliary materials.

[0039] Furthermore, the formulation of the fungicide is selected from at least one of emulsifiable concentrate, suspension, wettable powder, dust, granule, aqueous solution, mother liquor or mother powder.

[0040] The beneficial effects of the present invention are:

[0041] The present invention provides a new class of 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives of pyrazole amide compounds and a preparation method and application thereof. Experiments show that the compounds of the present invention have good antifungal activity against Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotiniasclerotiorum and Botrytis cinerea, and the antifungal activity of some compounds is equivalent to that of the listed drug fluopyraclostrobin. The compounds of the present invention will provide more options for the research and development of antifungal drugs and have broad application prospects. DETAILED DESCRIPTION

[0042] The present invention is further described below in conjunction with examples. The following examples are only for illustration and are not intended to limit the scope of protection of the present invention in any way.

[0043] The processes and methods not described in detail in the following examples are conventional methods known in the art, and the reagents used in the examples are all analytically pure or chemically pure, and can be purchased commercially or prepared by methods well known to those of ordinary skill in the art. The following examples all achieve the purpose of the present invention.

[0044] Example 1

[0045] Synthesis of 1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (B1):

[0046]

[0047] Add 4.80 g (0.03 mol) of ethyl pyruvate of compound A, 5.30 g (0.03 mol) of 2,4-dichlorophenylhydrazine, 2.80 g (0.03 mol) of sodium acetate, and 40 mL of anhydrous ethanol to a two-necked bottle, heat and reflux for 24 hrs, and the reaction is complete after TLC detection. Dry under reduced pressure, add ethyl acetate, filter, remove the filter cake, dry the filtrate, and separate the off-white solid product by chromatographic column to obtain B1, 4.50 g, with a yield of 50%.

[0048] Example 2

[0049] Synthesis of 1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (C1):

[0050]

[0051] Add compound B1 4.50g (0.15mol), sodium hydroxide 2.40g (0.60mol), anhydrous tetrahydrofuran 30mL, distilled water 30mL into a two-necked bottle, reaction temperature 40℃, reaction time 4hrs, TLC detection reaction completion. Reduce pressure and spin dry, filter, wash with distilled water 3 times, put the filter cake into an eggplant-shaped bottle, add 1mol / L hydrochloric acid, adjust its pH to 2-3, stir for 0.50hrs, filter, put the filter cake into a vacuum drying oven, set the temperature to 55℃, time 5hrs, and obtain C1, 4.00g, yield 98%.

[0052] Example 3

[0053] Synthesis of N-cyclopropyl-N-(4-nitrophenyl)methanamine (G):

[0054]

[0055] Cyclopropylamine 0.80g (14.0mmol), p-nitrobenzyl bromide 0.50g (2.33mmol), anhydrous potassium carbonate 1.94g (14.00mmol), potassium iodide, acetonitrile 20mL were added to a two-necked bottle, the reaction temperature was 30°C, the reaction time was 24hrs, and the reaction was completed by TLC detection. The mixture was dried under reduced pressure, ethyl acetate was added, filtered, the filter cake was removed, the filtrate was dried, and the yellowish oily product was separated by chromatographic column to obtain G, 0.22g, with a yield of 49%.

[0056] Example 4

[0057] Synthesis of O-methyl-N-(4-nitrophenyl)hydroxylamine (H)

[0058]

[0059] Add 0.80 g (9.58 mmol) of methoxyamine hydrochloride, 0.50 g (2.33 mmol) of p-nitrobenzyl bromide, 1.32 g (9.58 mmol) of anhydrous potassium carbonate, potassium iodide, and 20 mL of acetonitrile to a two-necked bottle, and perform the reaction at 30°C for 24 hrs. The reaction is complete after TLC detection. The mixture is dried under reduced pressure, ethyl acetate is added, filtered, the filter cake is removed, the filtrate is dried, and H is separated by a chromatographic column to obtain 0.20 g of H with a yield of 47%.

[0060] Example 5

[0061] Synthesis of N-cyclopropyl-N-(3-nitrophenyl)methylamine (J)

[0062]

[0063] Cyclopropylamine 0.80 g (14.0 mmol), m-nitrobenzyl bromide 0.50 g (2.33 mmol), anhydrous potassium carbonate 1.94 g (14.0 mmol), potassium iodide, acetonitrile 20 mL were added to a two-necked bottle, the reaction temperature was 30 ° C, the reaction time was 24 hrs, and the reaction was completed by TLC detection. The mixture was dried under reduced pressure, ethyl acetate was added, filtered, the filter cake was removed, the filtrate was dried, and J was separated by chromatographic column, 0.22 g, and the yield was 49%.

[0064] Example 6

[0065] Synthesis of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A1):

[0066]

[0067] Add compound C1 0.30g (1.10mmol), EDCI 0.32g (1.65mmol), HOBt 0.22g (1.65mmol), triethylamine 0.39g (3.85mmol), dichloromethane 12mL into a two-necked bottle, stir for 0.5hr at room temperature, add compound K 0.21g (1.10mmol), stir for 24hrs at room temperature, and the reaction is complete by TLC detection. Dry under reduced pressure, add ethyl acetate, filter, remove the filter cake, dry the filtrate, separate by chromatographic column to obtain A1, 0.10g, yellowish solid, yield 20%. Melting point: 159.0~159.7℃.

[0068] 1 H NMR(600MHz, CDCl3)δ2.15(s,3H,CH3-1H-pyrazole),3.00(t,J=6.0Hz,2H,-CH2-),3.73(q,J=6.0H z,2H,N-CH2-),6.73(s,1H,pyrazole),6.98(t,J=6.0Hz,1H,indol),7.07(s,1H,indol),7.11(d,J= 6.0Hz,1H,indol),7.24(d,J=12.0Hz,1H,indol),7.31(d,J=6.0Hz,1H,2,4-2Cl-C6H3),7.39(d,J= 12.0Hz,1H,2,4-2Cl-C6H3),7.55(s,1H,indol),7.56(s,1H,2,4-2Cl-C6H3),8.24(s,1H,-CO-NH-); 13C NMR (101MHz,CDCl3)δ11.48,25.52,39.71,106.52,112.33,112.97,118.38,122.33,123.59,125.14,128.20,128.66,130.39,130.51,133.37,134.79,135.48,136.48,142.76,147.76,162.11.Molecular formula: C 21 H 17 Cl3N4O,HRMS-EST m / z calcd for[M+H] + 447.0541, found 447.0548.

[0069] Example 7

[0070] Synthesis of N-(3-methylphenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A2):

[0071]

[0072] The preparation method was the same as that of Example 6. The reaction was continued for 24 hrs to obtain A2 as a yellowish oil with a total yield of 42%.

[0073] 1 H NMR (600MHz, CDCl3) δ2.19(s,3H,-CH3),2.35(s,3H,CH3-1H-pyrazole),6.82(s,1H,pyrazole),6.92(d,J=6.0Hz,1H,-C6H4-),7.22(t,J=6.0Hz,1H,-C6H4 -),7.38(d,J=6.0Hz,1H,-C6H4-),7.44(d,J=12.0Hz,2H,2,4-2Cl-C6H3),7.5 3(s,1H,-C6H4-),7.61(d,J=6.0Hz,1H,2,4-2Cl-C6H3),8.61(s,1H,-CO-NH-); 13 C NMR (101MHz,CDCl3)δ11.573,21.64,106.81,116.87,120.44,124.97,128.29,128.92,130.51,133.46,135.43,136.69,137.88,138.98,143.18,147.98,159.69.Molecular formula: C 18 H 15 Cl2N3O,HRMS-EST m / z calcd for[M+H]+ 360.0665, found 360.0675.

[0074] Example 8

[0075] Synthesis of N-(N-(4-chlorophenyl)-2-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A3):

[0076]

[0077] The preparation method is the same as that of Example 6. After reacting for 24 hours, A3 is obtained as a light purple solid with a total yield of 51%. Melting point: 100.3-101.2°C.

[0078] 1 H NMR(600MHz, CDCl3)δ2.67(s,3H,CH3-1H-pyrazole),3.97(s,1H,-NH),6.55(s,1H,CH3-1 H-pyrazole),7.25(m,1H,-C6H4-),7.28(s,1H,-C6H4-),7.67–7.52(m,4H,p-Cl-C6H4,2,4 -2Cl-C6H3),7.76(d,J=12.0Hz,2H,p-Cl-C6H4),7.90(dd,J=6.0Hz,12.0Hz,1H,-C6H4-),8 .07(d,J=6.0Hz,1H,-C6H4-),8.35(d,J=6.0Hz,1H,2,4-2Cl-C6H3),9.40(s,1H,-CO-NH-); 13 C NMR (101MHz,CDCl3)δ11.53,106.87,117.92,122.81,123.37,124.31,124.72,125.84,128.22,129.20,130.42,130.44,130.72,133.21,134.64,135.27,136.61,143.21,143.27,147.41,160.26.Molecular formula: C 23 H 17 Cl3N4O,HRMS-EST m / z calcd for[M+H] + 471.0541, found 471.0539.

[0079] Example 9

[0080] Synthesis of N-(4-nitrobenzyl)-N-methoxy-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A4):

[0081]

[0082] Add 0.30 g (1.10 mmol) of compound C1, 2.00 g (3.85 mmol) of PyBOP, 0.39 g (3.85 mmol) of triethylamine, and 12 mL of dichloromethane to a two-necked flask, stir at room temperature for 0.5 hr, add 0.20 g (1.10 mmol) of compound H, stir at room temperature for 24 hrs, and the reaction is complete after TLC detection. Dry under reduced pressure, add ethyl acetate, filter, remove the filter cake, dry the filtrate, and separate by chromatographic column to obtain A4, 0.15 g, a yellowish oil, with a yield of 31%. 1 H NMR (600MHz, CDCl3) δ2.17(s,3H,CH3-1H-pyrazole),3.74(s,3H,N-CH3),5.19(s,2H,p-NO2-C6H4),6.74(s,1H,pyrazole),7.33(d,J=6.0Hz,1H,2,4 -2Cl-C6H3),7.39(dd,J=6.0Hz,12.0Hz,1H,2,4-2Cl-C6H3),7.56(d,J=12.0Hz,3H,p-NO2-C6H4, 2,4-2Cl-C6H3),8.17(d,J=12.0Hz,2H,p-NO2-C6H4); 13 C NMR (101MHz,CDCl3)δ11.35,51.31,62.57,108.90,123.82,128.17,129.21,130.40,133.29,135.45,136.50,141.87,144.11,145.81,147.56,162.77.Molecular formula: C 19 H 16 Cl2N4O4,HRMS-ESTm / z calcd for[M+H] + 435.0621, found 435.0632.

[0083] Example 10

[0084] Synthesis of N-(4-chlorophenyl)-N-methyl-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A5):

[0085]

[0086] The preparation method was the same as that of Example 9. The reaction was continued for 24 hrs to obtain A5 as a yellowish oil with a total yield of 42%.

[0087] 1 H NMR (600MHz, CDCl3) δ2.05(s,3H,CH3-1H-pyrazole),3.47(s,3H,-CH3),6.20(s,1H,pyrazole),7.09(m,3H,p-Cl-C6H4, 2,4-2Cl-C6H3),7.24(d,J=12.0Hz,2H,p-Cl-C6H4),7.31(d,J=12.0Hz,2H,2,4-2Cl-C6H3),7.49(s,1H,2,4-2Cl-C6H3); 13 C NMR (101MHz,CDCl3)δ11.30,38.34,107.64,127.98,128.38,129.23,130.22,130.44,132.39,133.20,135.43,136.16,141.16,143.49,147.59,164.31.Molecular formula: C 18 H 14 Cl3N3O,HRMS-EST m / zcalcd for[M+H] + 394.0275, found 394.0283.

[0088] Embodiment 11

[0089] Synthesis of 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (B2):

[0090]

[0091] Add 4.80g (0.03mol) of compound A ethyl pyruvate, 4.30g (0.03mol) of p-chlorophenylhydrazine, 2.80g (0.03mol) of sodium acetate, and 40mL of anhydrous ethanol to a two-necked bottle, heat and reflux for 24hrs, and the reaction is complete after TLC detection. Dry under reduced pressure, add ethyl acetate, filter, remove the filter cake, dry the filtrate, and separate the off-white solid product by chromatographic column to obtain B2, 3.0g, with a yield of 38%.

[0092] Example 12

[0093] Synthesis of 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (C2):

[0094]

[0095] Add compound B2 3.00g (11.4mmol), sodium hydroxide 2.40g (45.4mmol), anhydrous tetrahydrofuran 30mL, distilled water 30mL into a two-necked bottle, reaction temperature 40℃, reaction time 4hrs, TLC detection reaction completion. Reduce pressure and spin dry, filter, wash with distilled water 3 times, put the filter cake into an eggplant-shaped bottle, add 1mol / L hydrochloric acid, adjust its pH to 2-3, stir for 0.5hr, filter, put the filter cake into a vacuum drying oven, set the temperature to 55℃, time 5hrs, and obtain C2, 2.00g, yield 65%.

[0096] Example 13

[0097] Synthesis of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A6):

[0098]

[0099] Add compound C2 0.30g (1.27mmol), EDCI 0.37g (1.91mmol), HOBt 0.26g (1.91mmol), triethylamine 0.45g (4.45mmol), dichloromethane 12mL into a two-necked bottle, stir at room temperature for 0.5hr, add compound K 0.25g (1.27mmol), stir at room temperature for 24hrs, and the reaction is complete by TLC detection. Dry under reduced pressure, add ethyl acetate, filter, remove the filter cake, dry the filtrate, separate by chromatographic column to obtain a white solid product, and obtain A6, 0.14g, white solid, yield 27%. Melting point: 144.6-145.3℃.

[0100] 1 H NMR(600MHz, CDCl3)δ2.33(s,3H,CH3-1H-pyrazole),3.01(t,J=6.0Hz,2H,-CH2-),3.73(q, J=6.0Hz,2H,N-CH2-),6.73(s,1H,pyrazole),7.05(t,J=6.0Hz,1H,indol),7.07(s,1H,indo l),7.12(dd,J=6.0,12.0Hz,1H,indol),7.25(d,J=12.0Hz,1H,indol),7.35(d,J=12.0Hz,2H ,p-Cl-C6H4),7.45(d,J=12.0Hz,2H,p-Cl-C6H4),7.57(s,1H,indol),8.24(s,1H,-CO-NH-); 13C NMR (101MHz,CDCl3)δ12.61,25.54,39.74,107.76,112.33,113.07,118.45,122.38,123.60,125.21,126.37,128.71,129.51,134.34,134.79,137.84,141.00,147.08,162.19.Molecular formula: C 21 H 18 Cl2N4O,HRMS-EST m / z calcd for[M+H] + 413.0930, found 413.0940.

[0101] Embodiment 14

[0102] Synthesis of N-(3-methylphenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A7):

[0103]

[0104] The preparation method was the same as that of Example 13. The reaction was continued for 24 hrs to obtain A7 as a colorless oil with an overall yield of 32%.

[0105] 1 H NMR (600MHz, CDCl3) δ2.36(s,3H,CH3-Ph),2.37(s,3H,CH3-1H-pyrazole),6.82(s,1H,pyrazole),6.93(d,J=7.5Hz,1H,-C6H4-),7.23(t,J=7.8Hz,1H,-C6H4- ),7.44(dd,J=6.6,4.7Hz,2H,p-Cl-C6H4),7.47(d,J=8.1Hz,1H,-C6H4-),7.51 (dd,J=9.0,2.2Hz,2H,p-Cl-C6H4),7.54(s,1H,-C6H4-),8.67(s,1H,-CO-NH-); 13 C NMR ((101MHz,CDCl3)δ12.60,21.62,107.97,116.84,120.39,124.96,126.46,128.93,129.59,134.56,137.73,137.88,138.99,141.45,147.27,159.74.Molecular formula: C 18 H 16 ClN3O,HRMS-EST m / z calcd for[M+H] +326.1055, found 326.1064.

[0106] Embodiment 15

[0107] Synthesis of N-(N-(4-chlorophenyl)-2-phenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A8):

[0108]

[0109] The preparation method is the same as that of Example 13. The reaction time is 24 hours to obtain A8 as a light purple solid with a total yield of 63%. Melting point: 175.1-176.1°C.

[0110] 1 H NMR(600MHz, CDCl3)δ2.33(s,3H,CH3-1H-pyrazole),5.95(s,1H,-NH),6.73(d,J =6.0Hz,2H,-C6H4-),6.76(s,1H,CH3-1H-pyrazole),7.11(d,J=6.0Hz,4H,Np-Cl- C6H4),7.24(d,J=12.0Hz,2H,p-Cl-C6H4),7.26(s,1H,-C6H4-),7.44(d,J=12.0H z,2H,p-Cl-C6H4),7.95(dd,J=6.0Hz,12.0Hz,1H,-C6H4-),8.99(s,1H,-CO-NH-); 13 C NMR (101MHz,CDCl3)δ12.67,108.02,117.49,122.92,123.50,124.62,124.82,125.65,126.16,129.24,129.47,131.42,133.82,134.39,137.64,141.37,143.43,146.73,160.25.Molecular formula: C 23 H 18 Cl2N4O,HRMS-EST m / z calcd for[M+H] + 437.0930, found 437.0940.

[0111] Example 16

[0112] Synthesis of N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A9):

[0113]

[0114] Compound C2 0.30 g (1.10 mmol), PyBOP 2.00 g (3.85 mmol), triethylamine 0.39 g (3.85 mmol), and dichloromethane 12 mL were added to a two-necked flask, stirred at room temperature for 0.5 hr, compound G 0.2 g (1.10 mmol) was added, stirred at room temperature for 24 hrs, and the reaction was completed by TLC detection. The mixture was dried under reduced pressure, ethyl acetate was added, filtered, the filter cake was removed, the filtrate was dried, and A9 was separated by chromatographic column, 0.15 g, a yellowish oil, with a yield of 41%.

[0115] 1 H NMR(600MHz,CDCl3)δ0.62(s,2H,cyclopropyl),0.74(s,2H,cyclopropyl),2.35(s,3H,CH3-1H-pyrazole),3.10(s,1H,cyclopropyl),4.87(s,2H,- CH2-),6.61(s,1H,pyrazole),7.37(m,2H,p-Cl-C6H4),7.43(d,J=6.0Hz,2H,p-Cl-C6H4),7.48(s,p-NO2-C6H4),8.17(d,J=12.0Hz,2H,p-NO2-C6H4); 13 C NMR (101MHz,CDCl3)δ10.20,12.44,32.39,50.81,109.04,123.88,126.20,128.43,129.44,134.16,137.88,139.60,145.85,147.22,147.44,166.66.Molecular formula: C 21 H 19 ClN4O3,HRMS-EST m / z calcd for[M+H] + 411.1218, found 411.1227.

[0116] Embodiment 17

[0117] Synthesis of N-(4-nitrobenzyl)-N-methoxy-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A10):

[0118]

[0119] The preparation method was the same as that of Example 16. The reaction was continued for 24 hrs to obtain A10 as a yellowish oil with a yield of 50%.

[0120] 1H NMR (600MHz, CDCl3) δ2.35(s,3H,CH3-1H-pyrazole),3.78(s,3H,O-CH3),5.19(s,2H,-CH2-),6.75(s,1H,pyrazole),7.37(d,J=6 .0Hz,2H,p-Cl-C6H4),7.44(d,J=6.0Hz,2H,p-Cl-C6H4),7.57(d,J=12.0Hz,2H,p-NO2-C6H4),8.18(d,J=12.0Hz,2H,p-NO2-C6H4); 13 C NMR (101MHz,CDCl3)δ12.50,62.67,110.26,123.87,126.27,129.16,129.51,134.44,137.77,140.24,144.08,145.11,147.59,163.04.Molecular formula: C 19 H 17 ClN4O4,HRMS-ESTm / z calcd for[M+H] + 401.1011, found 401.1022.

[0121] Embodiment 18

[0122] Synthesis of N-(3-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A11):

[0123]

[0124] The preparation method was the same as that of Example 16. The reaction lasted for 24 hrs to obtain A11 as a white solid with a yield of 37% and a melting point of 88.6-89.2°C.

[0125] 1H NMR(600MHz,CDCl3)δ0.64(s,2H,cyclopropyl),0.76(s,2H,cyclopropyl),2.35(s,3H,CH3-1H-pyrazole),3.10(s,1H,cyclopropyl),4.87(s,2H,-CH2-),6.63(s,1H,pyrazole),7. 39(s,2H,p-Cl-C6H4),7.44(d,J=12.0Hz,2H,p-Cl-C6H4),7.49(t,J=6.0Hz,1H,m-NO2-C6H4 ),7.70(s,1H,m-NO2-C6H4),8.11(d,J=12.0Hz,1H,m-NO2-C6H4),8.19(s,1H,m-NO2-C6H4); 13 C NMR (101MHz,CDCl3)δ10.29,12.50,32.27,50.57,109.19,122.38,122.72,126.23,129.47,129.65,134.11,138.06,139.47,140.56,147.74,148.49,166.55.Molecular formula: C 21 H 19 ClN4O3,HRMS-EST m / z calcd for[M+H] + 411.1218, found 411.1229.

[0126] Embodiment 19

[0127] Synthesis of N-(4-chlorophenyl)-N-methyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (A12):

[0128]

[0129] The preparation method is the same as that of Example 16. The reaction time is 24 hours to obtain A12 as a white solid with a yield of 11%. Melting point: 180.2-181.9°C.

[0130] 1H NMR (600MHz, CDCl3) δ2.26(s,3H,CH3-1H-pyrazole),3.48(s,3H,N-CH3),6.27(s,1H,pyrazole),7.09(s,2H,Np-C l-C6H4),7.13(d,J=6.0Hz,2H,Np-Cl-C6H4),7.31(d,J=12.0Hz,2H,p-Cl-C6H4),7.37(d,J=6.0Hz,2H,p-Cl-C6H4); 13 C NMR (101MHz,CDCl3)δ12.53,38.48,109.47,125.74,128.67,129.24,129.27,132.53,133.79,137.88,139.15,143.78,146.85,163.75.Molecular formula: C 18 H 15 Cl2N3O,HRMS-EST m / z calcd for[M+H] + 360.0665, found 360.0674.

[0131] Embodiment 20

[0132] Determination of antifungal activity of 1-substituted phenyl-5-methyl-N-substituted benzyl-1H-pyrazole-3-carboxamides

[0133] 1. Principle of antifungal activity

[0134] The mycelium growth rate method was used. In the clean bench, the test compound dissolved in DMSO was mixed with PDA medium in a certain proportion, poured into a sterile culture dish after mixing, cooled and solidified for use, and DMSO was used as a negative control. A sterile punch with a diameter of 5 mm was used to cut the bacterial cake from the edge of the colony of Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, and Botrytis cinerea that had grown for 7 days, and the mycelium surface was attached to the center of the culture dish and placed in a constant temperature incubator at 28°C for culture. The colony diameter was determined by the cross method, and the difference between the drug-added group and the negative control was calculated to obtain the antifungal inhibition rate.

[0135] 2. Antifungal Activity Test

[0136] Sample: 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamides:

[0137]

[0138] Wherein, R1 is selected from: 4-chloro, 2,4-dichloro; R2 is selected from: H, methyl, methoxy, cyclopropyl; R3 is selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1H-indol-3-yl)ethyl, N-(4-chlorophenyl)-2-phenyl;

[0139] Fungi: Botryosphaeria dothidea, Pythiumaphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, Botrytis cinerea.

[0140] Reagents: PDA culture medium, antibiotics (Beijing Regen Biotechnology Co., Ltd.); dimethyl sulfoxide (Biyuntian Biotechnology Co., Ltd.).

[0141] Instruments: Thermo1300 series II Class A2 clean bench, DZF-6050 vacuum drying oven; ultrapure water preparation instrument (Milli-Q, USA); Sartorius BSA24S electronic analytical balance (Beijing Sartorius Scientific Instrument Co., Ltd.); LDZX-75KBS vertical steam sterilizer (Shanghai Shen'an Medical Equipment Factory).

[0142] Experimental operation: The samples were tested for Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, and Botrytis cinerea. In each experiment, the experiment was repeated twice, and the conclusion was drawn by comparing with the negative control dimethyl sulfoxide group.

[0143] 3. Evaluation of antifungal activity

[0144] 1) Calculation of fungal inhibition rate:

[0145]

[0146] Table 1 Inhibitory activity of the compounds of the present invention against pathogenic bacteria (%)

[0147]

[0148] a: 100 μg / mL; b: 400 μg / mL; / : inactive

[0149] Bd: Botrytis cinerea; Pa: Pythium aphanidermatum; Fo: Fusarium oxysporum; Pg: Pyricularia grisea; An: Alternaria alternata; Ss: Sclerotinia sclerotiorum; Bc: Botrytis cinerea;

[0150] The results in Table 1 show that the compounds of the present invention have good antifungal activity against Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotiniasclerotiorum and Botrytis cinerea, and can be used as potential fungicides.

Claims

1. 1-Substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives shown in chemical structural formula I: in, R1 is selected from: 4-chloro or 2,4-dichloro; R2 is selected from: H, methyl, methoxy or cyclopropyl; R3 is selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1H-indol-3-yl)ethyl or N-(4-chlorophenyl)-2-phenyl.

2. The 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivative according to claim 1, characterized in that: The N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 or A12; wherein A1 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A2 is N-(3-methylphenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A3 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A4 is N-(4-nitrobenzyl)-N-methoxy-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A5 is N-(4-chlorophenyl)-N-methyl-1-(2,4-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A6 is N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A7 is N-(3-methylphenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A8 is N-(N-(4-chlorophenyl)-2-phenyl)-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A9 is N-(4-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A10 is N-(4-nitrobenzyl)-N-methoxy-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A11 is N-(3-nitrobenzyl)-N-cyclopropyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide; A12 is N-(4-chlorophenyl)-N-methyl-1-(4-chlorophenyl)-5-methyl-1H-pyrazole-3-carboxamide.

3. The method for preparing the 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives according to claim 1, characterized in that: The reaction formula is as follows: Among them, R1 is selected from: 4-chloro or 2,4-dichloro; R2 is selected from: H, methyl, methoxy, cyclopropyl; R3 is selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1H-indol-3-yl)ethyl, N-(4-chlorophenyl)-2-phenyl.

4. Use of the 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives according to claim 1 or 2 in the preparation of antifungal drugs.

5. The use according to claim 4, characterized in that: The fungus is Botryosphaeria dothidea or Botrytis cinerea.

6. The use according to claim 4, characterized in that: The fungus is Pythium aphanidermatum or Fusarium oxysporum.

7. The use according to claim 4, characterized in that: The fungus is Sclerotinia sclerotiorum.

8. The use according to claim 4, characterized in that: The fungus is Phyricularia grisea.

9. The use according to claim 4, characterized in that: The fungus is Alternaria nees.

10. A bactericide, characterized in that: The bactericide contains a bactericidal effective amount of at least one of the 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives according to claim 1 or 2, and optionally contains auxiliary materials.

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