Preparation and Application of 1-Substituted Phenyl-5-Methyl-1H-Pyrazole-3-Carboxamide Derivatives

Abstract

The present application relates to a kind of new compound and its preparation method and application, specifically 1-substituted phenyl-5-methyl-1 H Preparation and application of pyrazole-3-formamide derivatives. The structural formula of the compound 1-substituted phenyl-5-methyl-1 H Pyrazole-3-formamide derivatives is as shown in formula I. Wherein, R1 selected from: 4-chloro or 2,4-dichloro;R2 selected from: H, methyl, methoxy, cyclopropyl;R3 selected from: 3-methylphenyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-chlorophenyl, 2-(5-chloro-1 H Indole-3-yl) ethyl, N-(4-chlorophenyl)-2-phenyl. Test shows that the compound of the application shows good antifungal activity to grape cavity fungus (Botryosphaeria dothidea) (Botryosphaeria dothidea), Pythium aphanidermatum (Pythium aphanidermatum), Fusarium oxysporum (Fusarium oxysporum), Gray pear spot fungus (Gymnosporangium japonicum), Alternaria alternata (Alternaria alternata), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum), Botrytis cinerea (Botrytis cinerea), and has wide application prospect. Botryosphaeria dothidea Pythium aphanidermatum Fusarium oxysporum Phyricularia grisea Alternaria nees Sclerotinia sclerotiorum Botrytis cinerea ​​​​​​​

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 result in significant losses in agricultural production, resulting in reduced crop yields and lowered agricultural product quality. Pathogens are also prone to developing resistance, making them difficult to prevent and control. Currently, the most common control method is spraying with fungicides. However, the long-term use of certain fungicides alone not only leads to the gradual development of resistance in pathogens, reducing control effectiveness, but also has certain impacts on the environment and non-target organisms. Therefore, the search for green, highly effective fungicides with novel mechanisms of action has become a key focus of pesticide research.

[0003] Pyrazoleamide compounds are easy to synthesize, possess diverse molecular structures, and exhibit excellent biological activity and selectivity, making them a hot topic for the development of new pesticides. In 2006, BASF launched fluopyram, an antifungal drug developed with a pyrazoleamide backbone. Fluopyram boasts high efficacy, broad spectrum, and strong selectivity, exhibiting excellent preventive and therapeutic activity. It is used to control fungal diseases in crops such as cereals, soybeans, cotton, and fruits and vegetables, and can be applied as a foliar spray or seed treatment (Chinese Patent CN101115723A).

[0004]

[0005] However, although flupyraclostrobin shows strong inhibitory effects on many fungi, it still needs to be used with caution considering 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 its preparation method and application.

[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-mentioned 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives is as follows:

[0023]

[0024] Wherein, 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, or 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 concentrate, 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 novel class of 1-substituted phenyl-5-methyl-1H-pyrazole-3-carboxamide derivatives of the pyrazole amide class, as well as preparation methods and applications thereof. Experiments have shown that the compounds of the present invention exhibit good antifungal activity against Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, and Botrytis cinerea. The antifungal activity of some compounds is comparable to that of the marketed drug flupyroxam. The compounds of the present invention will provide more options for the development of antifungal drugs and have broad application prospects. DETAILED DESCRIPTION

[0042] The present invention will be further described below with reference to the following 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. The reagents used in the examples are all analytically pure or chemically pure and are commercially available or prepared by methods well known to those skilled in the art. The following examples all achieve the objectives of the present invention.

[0044] Example 1

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

[0046]

[0047] To a two-necked flask, add 4.80 g (0.03 mol) of compound A ethyl pyruvate, 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. Heat under reflux for 24 hours. TLC indicates the reaction is complete. The mixture is dried under reduced pressure, ethyl acetate is added, and the mixture is filtered. The filter cake is removed and the filtrate is dried. Chromatographic column chromatography is used to separate the product into an off-white solid, yielding 4.50 g of B1 (50% yield).

[0048] Example 2

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

[0050]

[0051] To a two-necked flask, 4.50 g (0.15 mol) of compound B1, 2.40 g (0.60 mol) of sodium hydroxide, 30 mL of anhydrous tetrahydrofuran, and 30 mL of distilled water were added. The reaction temperature was 40°C and the reaction time was 4 hours. The reaction was complete by TLC. The mixture was dried under reduced pressure, filtered, and washed three times with distilled water. The filter cake was placed in an eggplant-shaped flask, 1 mol / L hydrochloric acid was added, and the pH was adjusted to 2-3. The mixture was stirred for 0.50 hours and filtered. The filter cake was placed in a vacuum drying oven at 55°C for 5 hours to obtain 4.00 g of C1, with a yield of 98%.

[0052] Example 3

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

[0054]

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

[0056] Example 4

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

[0058]

[0059] To a two-necked flask were added 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. The reaction temperature was 30°C for 24 hours. The reaction was complete by TLC. The mixture was evaporated to dryness under reduced pressure, ethyl acetate was added, and the mixture was filtered. The filter cake was removed and the filtrate was dried. H was isolated by column chromatography to obtain 0.20 g of H (47% yield).

[0060] Example 5

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

[0062]

[0063] To a two-necked flask were added 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, and acetonitrile 20 mL. The reaction temperature was 30°C and the reaction time was 24 hrs. The reaction was complete by TLC. The mixture was evaporated under reduced pressure, ethyl acetate was added, and the mixture was filtered. The filter cake was removed and the filtrate was evaporated. The product was separated by column chromatography to obtain 0.22 g of compound J, in a 49% yield.

[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] To a two-necked flask, add 0.30 g (1.10 mmol) of compound C1, 0.32 g (1.65 mmol) of EDCI, 0.22 g (1.65 mmol) of HOBt, 0.39 g (3.85 mmol) of triethylamine, and 12 mL of dichloromethane. Stir at room temperature for 0.5 hr. Then add 0.21 g (1.10 mmol) of compound K. Stir at room temperature for 24 hrs. The reaction is complete by TLC. The mixture is evaporated to dryness under reduced pressure, ethyl acetate is added, and the filter cake is removed. The filtrate is then dried and separated by column chromatography to yield 0.10 g of A1 as an off-yellow solid in a 20% yield. Melting point: 159.0-159.7°C.

[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 an overall 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] Preparation method as example 6, reaction for 24 hrs, to get A3, light purple solid, total yield 51%. Melting point: 100.3-101.2 °C.

[0078] 1 H NMR (600 MHz, CDC13) δ 2.67 (s, 3H, CH3-1H-pyrazole), 3.97 (s, 1H, -NH), 6.55 (s, 1H, CH3-1H-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 = 12.0 Hz, 2H, p-Cl-C6H4), 7.90 (dd, J = 6.0 Hz, 12.0 Hz, 1H, -C6H4-), 8.07 (d, J = 6.0 Hz, 1H, -C6H4-), 8.35 (d, J = 6.0 Hz, 1H, 2,4-2Cl-C6H3), 9.40 (s, 1H, -CO-NH-); 13 C NMR (101 MHz, CDC13) δ 11.53, 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. 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] To a flask was added compound C10 0.30 g (1.10 mmol), PyBOP 2.00 g (3.85 mmol), triethylamine 0.39 g (3.85 mmol), dichloromethane 12 mL, stirred at room temperature for 0.5 hr, added compound H 0.20 g (1.10 mmol), stirred at room temperature for 24 hrs, TLC monitored the completion of reaction. The reaction mixture was concentrated under reduced pressure, added ethyl acetate, filtered, removed the filter cake, concentrated the filtrate, chromatography column separation gave A4, 0.15 g, yellowish oil, yield 31%. 1 H NMR (600 MHz, CDC13) δ 2.17 (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 = 6.0 Hz, 1H, 2,4-2Cl-C6H3), 7.39 (dd, J = 6.0 Hz, 12.0 Hz, 1H, 2,4-2Cl-C6H3), 7.56 (d, J = 12.0 Hz, 3H, p-NO2-C6H4, 2,4-2Cl-C6H3), 8.17 (d, J = 12.0 Hz, 2H, p-NO2-C6H4); 13 C NMR (101 MHz, CDC13) δ 11.35, 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. Formula: C 19 H 16 Cl2N4O4, HRMS-EST m / 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] Preparation method same as example 9, reaction 24 hrs, gave A5, yellowish oil, overall yield 42%.

[0087] 1 H NMR (600 MHz, CDC13) δ 2.05 (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 = 12.0 Hz, 2H, p-Cl-C6H4), 7.31 (d, J = 12.0 Hz, 2H, 2,4-2Cl-C6H3), 7.49 (s, 1H, 2,4-2Cl-C6H3); 13 C NMR (101 MHz, CDC13) δ 11.30, 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. Formula: C 18 H 14 Cl3N3O, HRMS-EST m / z calcd for [M+H] + 394.0275, found 394.0283.

[0088] Example 11

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

[0090]

[0091] Two-mouth flask was charged with compound A ethyl pyruvate 4.80 g (0.03 mol), p-chlorophenylhydrazine 4.30 g (0.03 mol), sodium acetate 2.80 g (0.03 mol), anhydrous ethanol 40 mL, heated to reflux for 24 hrs, TLC test reaction complete. Dry under reduced pressure, add ethyl acetate, filter, remove filter cake, dry the filtrate, column chromatography to get white solid product, B2, 3.0 g, yield 38%.

[0092] Example 12

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

[0094]

[0095] Two-mouth flask was charged with compound B2 3.00 g (11.4 mmol), sodium hydroxide 2.40 g (45.4 mmol), anhydrous tetrahydrofuran 30 mL, distilled water 30 mL, reaction temperature 40 °C, reaction time 4 hrs, TLC for reaction completion. Rotovap under reduced pressure, filter, wash with distilled water 3 times, put the filter cake into a jar, add 1 mol / L hydrochloric acid, adjust the pH to 2-3, stir for 0.5 hrs, filter, put the filter cake into a vacuum drying oven, set the temperature to 55 °C, time 5 hrs, get C2, 2.00 g, yield 65%.

[0096] Example 13

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

[0098]

[0099] Two-mouth flask was charged with compound C2 0.30 g (1.27 mmol), EDCI 0.37 g (1.91 mmol), HOBt 0.26 g (1.91 mmol), triethylamine 0.45 g (4.45 mmol), dichloromethane 12 mL, room temperature, stir for 0.5 hrs, add compound K 0.25 g (1.27 mmol), room temperature, stir for 24 hrs, TLC for reaction completion. Rotovap under reduced pressure, add ethyl acetate, filter, remove the filter cake, rotovap the filtrate, column chromatography to get white solid product, get A6, 0.14 g, white solid, yield 27%. Melting point: 144.6-145.3 °C.

[0100] 1 H NMR (600 MHz, CDC13) δ 2.33 (s, 3H, CH3-lH-pyrazole), 3.01 (t, J = 6.0 Hz, 2H, -CH2-), 3.73 (q, J = 6.0 Hz, 2H, N-CH2-), 6.73 (s, 1H, pyrazole), 7.05 (t, J = 6.0 Hz, 1H, indol), 7.07 (s, 1H, indol), 7.12 (dd, J = 6.0, 12.0 Hz, 1H, indol), 7.25 (d, J = 12.0 Hz, 1H, indol), 7.35 (d, J = 12.0 Hz, 2H, p-Cl-C6H4), 7.45 (d, J = 12.0 Hz, 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] Example 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] Example 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 was the same as that of Example 13. The reaction lasted for 24 hours to obtain A8 as a light purple solid with an overall yield of 63%. The melting point was 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] To a two-necked flask, add 0.30 g (1.10 mmol) of compound C2, 2.00 g (3.85 mmol) of PyBOP, 0.39 g (3.85 mmol) of triethylamine, and 12 mL of dichloromethane. Stir at room temperature for 0.5 hr. Then add 0.2 g (1.10 mmol) of compound G. Stir at room temperature for 24 hrs. The reaction is complete by TLC. The mixture is evaporated to dryness under reduced pressure, ethyl acetate is added, and the filter cake is removed. The filtrate is then dried and separated by column chromatography to afford 0.15 g of A9 as a yellowish oil in a 41% yield.

[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,found411.1227.

[0116] Example 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 in 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] Example 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 was continued 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] Example 19

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

[0128]

[0129] The preparation method was the same as that of Example 16. The reaction lasted for 24 hours to obtain A12 as a white solid in an 11% yield. The melting point was 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] Example 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 hyphal growth rate method was used. In a clean bench, the test compound dissolved in DMSO was mixed with PDA medium at a specific ratio, poured into a sterile Petri dish, and cooled to solidify before use. DMSO was used as a negative control. A 5 mm diameter sterile punch was used to cut a colony from the edge of a 7-day-old colony of Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, or Botrytis cinerea. The mycelial surface was placed in the center of the Petri dish and incubated in a 28°C incubator. The colony diameter was measured using the cross-hatch method. The difference between the treated group and the negative control was calculated to determine the antifungal inhibition rate.

[0135] 2. Antifungal Activity Experiment

[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, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, Botrytis cinerea.

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

[0141] Instruments: Thermo1300 series Class II A2 clean bench, DZF-6050 vacuum drying oven; ultrapure water preparation instrument (Milli-Q Company, 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 Procedure: Samples were tested for Botryosphaeria dothidea, Pythium aphanidermatum, Fusarium oxysporum, Phyricularia grisea, Alternaria nees, Sclerotinia sclerotiorum, and Botrytis cinerea. Each experiment was repeated twice, and conclusions were drawn using a negative control (dimethyl sulfoxide).

[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 cinerea; 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. Chemical structure shown in formula I: 1-substituted phenyl-5-methyl-1 H -Pyrazole-3-carboxamide derivatives: ； 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-1 H -indol-3-yl)ethyl or N-(4-chlorophenyl)-2-phenyl; when R1 is 4-chloro, R2 is H, and R3 is not 4-chlorophenyl.

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

3. 1-substituted phenyl-5-methyl-1- H -A method for preparing pyrazole-3-carboxamide derivatives, characterized in that: The reaction formula is as follows: ； Wherein, 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-1 H -indol-3-yl)ethyl, N-(4-chlorophenyl)-2-phenyl.

4. 1-substituted phenyl-5-methyl-1- H -Application of pyrazole-3-carboxamide derivatives in the preparation of antifungal drugs, wherein the fungus is Botrytis cinerea ( Botryosphaeria dothidea ), Pythium aphanidermatum ( Pythium aphanidermatum ), Fusarium oxysporum ( Fusarium oxysporum ) or Alternaria alternata ( Alternaria nees ).

5. 1-substituted phenyl-5-methyl-1- H -Application of pyrazole-3-carboxamide derivatives in the preparation of antifungal drugs, characterized in that, The fungus is Botrytis cinerea ( Botrytis cinerea ) or Sclerotinia sclerotiorum ( Sclerotinia sclerotiorum ), the derivative is selected from: A1, A4, A5, A6, A7, A9, A10 or A11, and the definition of A1, A4, A5, A6, A7, A9, A10 or A11 is as described in claim 2.

6. 1-substituted phenyl-5-methyl-1- H -Application of pyrazole-3-carboxamide derivatives in the preparation of antifungal drugs, characterized in that, The fungus is Pyricularia cinerea ( Phyricularia grisea ), the derivative is selected from: A1 or A5, and the definition of A1 or A5 is as described in claim 2.

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

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