A pyrazole carboxamide derivative containing isoxazole and preparation method and application thereof

Abstract

The application discloses a pyrazole carboxamide derivative containing isoxazole and a preparation method and application thereof, and belongs to the technical field of organic synthesis. 1 is selected from hydrogen, 4-fluoro, 5-fluoro, R 2 is selected from hydrogen, 4-fluoro, 4-chloro, 4-methyl or 4-methoxy. The application modifies a difluoro pyrazole carboxamide lead structure by introducing an isoxazole ring, and the target product is prepared through four steps, the synthesis route is simple, the conditions are mild, the yield is good, and the compound of the application exhibits excellent fungicidal activity and a wide fungicidal spectrum on various plant pathogenic fungi. The compound of the application can be used as a new SDHI fungicide candidate compound for the prevention and treatment of plant pathogenic fungi in the fields of agriculture, horticulture, forestry or health.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a pyrazole carboxamide derivative containing isoxazole, its preparation method and application. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Succinate dehydrogenase inhibitors (SDHIs) are a class of fungicides that act on the mitochondrial respiratory chain complex II of pathogens. They inhibit the activity of succinate dehydrogenase, blocking electron transport and the tricarboxylic acid cycle, leading to bacterial death due to impaired respiration. Pyrazolamide compounds are an important skeleton type in SDHI fungicides, and several varieties, such as fluopyram and fluopyram aniline, have been commercialized. Existing pyrazolamide SDHI fungicides typically consist of three parts: an acid fragment, an amine fragment, and an amide bond. Structural modifications mainly focus on the transformation of substituents on both sides of the amide bond.

[0004] However, existing pyrazole carboxamide-based SDHI fungicides still have shortcomings in application. On the one hand, long-term single-use has led to varying degrees of resistance in some target pathogens to existing varieties, resulting in decreased control efficacy. On the other hand, some varieties have relatively narrow fungicidal spectra, and their activity against multiple important plant pathogens is not ideal, making it difficult to meet the needs of synergistic control of multiple diseases in agricultural production. Therefore, there is an urgent need to develop a novel pyrazole carboxamide-based SDHI fungicide to address the problem of pathogen resistance and broaden the fungicidal spectrum. Summary of the Invention

[0005] In view of this, the present invention provides a pyrazole carboxamide derivative containing isoxazole, its preparation method and application.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: In a first aspect, the present invention provides a pyrazole carboxamide derivative containing isoxazole, the structure of which is shown in Formula I:

[0007] Equation I, where R 1 Selected from: hydrogen, 4-fluoro, 5-fluoro; R 2 Selected from: hydrogen, 4-fluorine, 4-chloro, 4-methyl, 4-methoxy.

[0008] Preferably, the pyrazole carboxamide derivative is selected from the following compounds: (I-1) (I-2) (I-3) (I-4) (I-5) (I-6) (I-7) (I-8) (I-9) (I-10) (I-11) (I-12) (I-13) (I-14).

[0009] Secondly, the present invention provides a method for preparing the above-mentioned isoxazole-containing pyrazole carboxamide derivatives, the reaction route of which is as follows:

[0010] Among them, R 1 Selected from: hydrogen, 4-fluoro, 5-fluoro; R 2 Selected from: hydrogen, 4-fluorine, 4-chloro, 4-methyl, 4-methoxy.

[0011] Preferably, the reaction route includes: (1) Compound 1 was dissolved in dichloromethane, and an aqueous solution of hydroxylamine hydrochloride and sodium carbonate was added. The mixture was stirred at room temperature and filtered to obtain compound 2. (2) Dissolve compound 2 in ethanol, add compound A, add sodium hypochlorite and DIPEA in sequence at room temperature, react overnight at room temperature, and filter to obtain compound 3; (3) Compound 3 and palladium on carbon were dissolved in anhydrous ethanol, hydrazine hydrate was added dropwise, the mixture was heated under reflux, filtered, filtered again, concentrated, extracted, dried, and purified by column chromatography to obtain compound 4; (4) Compound 4 was dissolved in dichloromethane, and triethylamine and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride solution were added. The reaction was carried out at room temperature, and the compound of formula I was obtained by extraction, washing, drying and column chromatography purification.

[0012] Preferably, in step (1), the molar ratio of compound 1 to hydroxylamine hydrochloride and sodium carbonate is 1:(1~3):(1~3), and the reaction time is 4-6 h with stirring at room temperature.

[0013] Preferably, in step (2), the molar ratio of compound 2 to compound A, sodium hypochlorite, and DIPEA is 1:1:1~3:1~3, and the overnight reaction time is 10h; In step (2), the sodium hypochlorite is an aqueous solution of sodium hypochlorite with a mass fraction of 5-15%, preferably 10%.

[0014] Preferably, in step (3), the hydrazine hydrate is an aqueous solution of hydrazine hydrate with a mass fraction of 75-85%, preferably 80%; The mass ratio of compound 3, palladium on carbon, and hydrazine hydrate aqueous solution is 1:0.05~0.1:0.8~1.2, the heating reflux temperature is 75-85℃, and the reflux reaction time is 2-4h.

[0015] Preferably, in step (4), the molar ratio of compound 4, triethylamine and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is 1:1.0~1.1:1.2~1.5, and the reaction time at room temperature is 2-3h; The 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride solution is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride dissolved in dichloromethane.

[0016] Preferably, in steps (3) and (4), the extraction is performed using dichloromethane and water, the washing is performed using saturated brine to wash the organic phase obtained from the extraction, the drying is performed using anhydrous sodium sulfate, and the eluent for column chromatography purification is ethyl acetate / petroleum ether with a volume ratio of 1:4~6.

[0017] Thirdly, the present invention provides the application of the isoxazole-containing pyrazole carboxamide derivatives described above or the isoxazole-containing pyrazole carboxamide derivatives prepared by the above method in the preparation of fungicides for the prevention and control of plant pathogens in the fields of agriculture, horticulture, forestry or health.

[0018] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) This invention introduces isoxazole into the lead structure of difluoropyrazole carboxamide and designs and synthesizes a class of isoxazole-containing pyrazole carboxamide derivatives. The structure is novel, the preparation process is simple and efficient, it exhibits excellent bactericidal activity against a variety of plant pathogens and has a broad bactericidal spectrum. The raw materials are readily available, the production cost is low, the overall yield is good, and it has great application prospects.

[0019] (2) The compounds of this invention have a broad fungicidal spectrum and excellent activity, exhibiting good inhibitory activity against a variety of important plant pathogens, including *Syndromea hygrostis*, *Botrytis cinerea*, *Anthracnose*, *Fusarium graminearum*, *Rhizoctonia solani*, *Rhizoctonia solani*, and *Sclerotinia sclerotiorum*. Specifically, compounds I-2 and I-3 showed inhibitory activity against *Rhizoctonia solani* comparable to that of commercially available varieties such as fluopyram, thifluzamide, and cyazofamid; compounds I-4 and I-10 showed significantly better inhibitory activity against *Sclerotinia sclerotiorum* than cyazofamid. This indicates that the isoxazole-containing pyrazolecarbamide derivatives of this invention can serve as candidate compounds for novel SDHI fungicides, used in the control of plant pathogens in agriculture, horticulture, forestry, or public health, with significant application potential, particularly in the control of rice sheath blight and rapeseed sclerotiorum. Detailed Implementation

[0020] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0021] Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention. Specific conditions not specified in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Components whose manufacturers are not specified are all commercially available conventional products.

[0022] Example 1 (1) Preparation of intermediate compound 2: Compound 1 (o-nitroacetophenone, 10.0 mmol) was dissolved in dichloromethane (30 mL), and an aqueous solution of hydroxylamine hydrochloride (15.0 mmol) and potassium carbonate (15.0 mmol) (20 mL) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered and dried to give compound 2 as a white solid.

[0023] (2) Preparation of intermediate compound 3: The compound 2 (8.0 mmol) obtained in step (1) was dissolved in ethanol (25 mL), and compound A (phenylacetylene, R) was added. 2 =H, 9.6 mmol), and 10% sodium hypochlorite aqueous solution (16.0 mmol) and DIPEA (16.0 mmol) were added sequentially at room temperature, and the mixture was stirred overnight at room temperature for 12 hours. After the reaction was completed, the mixture was filtered and dried to obtain compound 3.

[0024] (3) Preparation of intermediate compound 4: Compound 3 (5.0 mmol) obtained in step (2) and palladium on carbon (0.25 g) were dissolved in anhydrous ethanol (30 mL), and 80% hydrazine hydrate aqueous solution (4.0 g) was slowly added dropwise. The mixture was heated to 80 °C and refluxed for 6 hours. After the reaction was completed, palladium on carbon was removed by filtration, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was extracted with dichloromethane and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated to remove the solvent, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1, volume ratio) to obtain compound 4.

[0025] (4) Preparation of target compound I-1: Compound 4 (1.5 mmol) obtained in step (3) was dissolved in dichloromethane (15 mL), and triethylamine (1.65 mmol) was added. 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. The filtrate was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 4:1, volume ratio) to obtain the target compound I-1.

[0026] 3-(Difluoromethyl)-1-methyl- N -(2-(5-phenylisoxazol-3-yl)phenyl)-1 H -pyrazole-4-carboxamide, white solid; yield, 44%; mp: 163-165 °C; 1 H NMR (CDCl3, 400 MHz) δ 10.98 (s, 1H), 8.79 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.92– 7.81 (m, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.51 (dd, J = 19.1, 7.2 Hz, 4H), 7.37(s, 1H), 7.29 – 7.16 (m, 2H), 6.96 (s, 1H), 4.08 (s, 3H); 13 C NMR (CDCl3, 101MHz) δ 171.92, 169.88, 163.31, 160.10, 137.33, 131.20 (d, J= 3.9 Hz), 130.88,129.22, 128.90, 126.70, 126.05, 123.61, 121.25, 117.71, 116.15, 109.45 (t, J =236.6 Hz), 100.01, 98.61, 39.95; HRMS(m / z) calcd for C 21 H 16 F2N4O2(M+H) + :395.1309, found: 395.1320. Example 2 Following the synthesis method of Example 1, except that phenylacetylene was replaced with p-chlorophenylacetylene in step (2), the rest of the operation was the same, and the target compound I-2 was obtained.

[0027] N -(2-(5-(4-chlorophenyl)isoxazol-3-yl)phenyl)-3-(difluoromethyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield 30%; mp: 155-156 °C; 1 HNMR(CDCl3, 400 MHz) δ 10.94 (s, 1H), 8.80 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 3H), 7.38(s, 1H), 7.33 – 7.15 (m, 1H), 6.97 (s, 1H), 4.10 (s, 3H); 13 C NMR (CDCl3, 101MHz) δ 168.73, 163.39, 160.08, 137.31, 137.04, 131.35, 131.17, 129.58,128.91, 127.30, 125.12, 123.67, 121.31, 115.95, 111.81, 109.46, 98.95, 39.98;HRMS(m / z) calcd for C 21 H15 ClF2N4O2(M+H) + : 429.0930, found: 429.0921. Example 3 Following the synthesis method of Example 1, except that phenylacetylene was replaced with p-fluorophenylacetylene in step (2), the rest of the operation was the same, and the target compound I-3 was obtained.

[0028] 3-(Difluoromethyl)- N -(2-(5-(4-fluorophenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield 25%; mp: 175-177 °C; 1 HNMR(DMSO, 400 MHz) δ 10.44 (s, 1H), 8.44 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.99 (dd, J = 8.3, 5.4 Hz, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.32 (s, 1H), 4.01 (s, 3H); 13 C NMR (DMSO, 101 MHz) δ 168.08, 164.53, 162.55, 162.06, 159.93,144.98 (t, J = 23.8 Hz), 136.08, 132.54, 130.67, 129.63, 128.21 (d, J = 8.9 Hz),124.80, 123.54, 123.16 (d, J = 2.9 Hz), 119.47, 116.59, 116.37, 116.26, 109.62(t, J = 234.7 Hz), 99.99, 99.50; HRMS(m / z) calcd for C 21H 15 F3N4O2(M+H) + : 413.1225, found: 413.1220. Example 4 Following the synthesis method of Example 1, except that phenylacetylene was replaced with p-methylphenylacetylene in step (2), the rest of the operation was the same, and the target compound I-4 was obtained.

[0029] 3-(Difluoromethyl)-1-methyl- N -(2-(5-(p-tolyl)isoxazol-3-yl)phenyl)-1 H -pyrazole-4-carboxamide, white solid; yield, 32%; mp: 186-188 °C; 1 H NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.78(d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.40 (s,1H), 7.34 (s, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.91 (s, 1H), 4.09 (s, 3H), 2.47(s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 170.01, 163.26, 160.10, 146.72, 141.35,137.32, 131.15 (d, J = 2.7 Hz), 129.90, 128.90, 125.96, 123.94, 123.57, 121.12,116.16, 109.45 (t, J = 236.6 Hz), 97.98, 39.97, 21.59; HRMS(m / z) calcd forC 22 H 18 F2N4O2(M+H) + : 409.1476, found: 409.1468. Example 5 Following the synthesis method of Example 1, except that phenylacetylene was replaced with p-methoxyphenylacetylene in step (2), the rest of the operation was the same, and the target compound I-5 was obtained.

[0030] 3-(Difluoromethyl)- N -(2-(5-(4-methoxyphenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 26%; 1 H NMR (CDCl3, 400MHz) δ 11.03 (s, 1H), 8.80 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.40 (s, 1H), 7.22(t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 4.08 (s, 3H), 3.91(s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 169.80, 163.25, 161.62, 160.10, 146.70,137.31, 131.13 (d, J = 8.8 Hz), 128.88, 127.67, 123.55, 121.08, 119.37, 117.91– 117.52 (m), 116.21, 114.60, 109.46 (t, J = 236.5 Hz), 97.18, 55.50, 39.95;HRMS(m / z) calcd for C 22 H 18 F2N4O3(M+H) + : 425.1425, found: 425.1417. Example 6 Following the synthesis method of Example 1, except that 4-fluoro-2-nitroacetophenone was used instead of o-nitroacetophenone in step (1) and phenylacetylene was used in step (2), the rest of the operations were the same, and the target compound I-6 was obtained.

[0031] 3-(Difluoromethyl)- N -(4-fluoro-2-(5-phenylisoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 23%; mp: 169-171 °C; 1 H NMR (CDCl3, 400 MHz) δ 10.85 (s, 1H), 8.78 (dd, J = 9.1, 5.3 Hz, 1H), 8.05 (s,1H), 7.89 (d, J = 4.1 Hz, 2H), 7.56 (d, J = 4.2 Hz, 3H), 7.43 – 7.37 (m, 1H),7.35 (s, 1H), 7.21 (t, J = 7.1 Hz, 1H), 6.92 (s, 1H), 4.09 (s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 170.29, 162.42, 159.96, 159.62, 157.20, 146.62, 133.52,131.14 (d, J = 14.7 Hz), 129.26, 126.45, 126.06, 123.13 (d, J = 7.7 Hz), 117.89,117.75, 117.68, 117.44, 115.33, 115.09, 109.48 (t, J = 236.6 Hz), 100.00,98.53, 39.93; HRMS(m / z) calcd for C 21 H 15 F3N4O2(M+H) + : 413.1225, found: 413.1215. Example 7 Following the synthesis method of Example 1, except that 4-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-fluoroacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-7 was obtained.

[0032] 3-(Difluoromethyl)- N -(4-fluoro-2-(5-(4-fluorophenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide; white solid, yield, 35%; mp:143-144 °C; 1 H NMR (CDCl3, 400 MHz) δ 10.77 (s, 1H), 8.74 (dd, J = 9.2, 5.3 Hz,1H), 8.01 (s, 1H), 7.85 (dd, J = 8.8, 5.2 Hz, 2H), 7.35 (dd, J = 9.1, 2.9 Hz,1H), 7.30 (s, 1H), 7.23 – 7.16 (m, 3H), 6.84 (s, 1H), 4.05 (s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 169.34, 165.52, 162.51, 159.97, 157.23, 138.78, 133.54,131.23, 128.25 (d, J = 8.7 Hz), 123.29 (d, J = 7.5 Hz), 122.87, 117.91 (d, J = 21.7Hz), 116.70, 116.48, 115.22 (d, J = 24.3 Hz), 109.48, 99.99, 98.39, 39.96; HRMS(m / z) calcd for C 21 H 14 F4N4O2(M+H) + : 431.1131, found: 431.1123. Example 8 Following the synthesis method of Example 1, except that 4-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-methylacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-8 was obtained.

[0033] I-8: 3-(Difluoromethyl)- N -(4-fluoro-2-(5-(p-tolyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 38%; mp: 28-29 °C; 1 HNMR(DMSO, 400 MHz) δ 10.36 (s, 1H), 8.44 (s, 1H), 8.13 (dd, J = 8.8, 5.4 Hz, 1H), 7.78 (t, J = 10.0 Hz, 3H), 7.59 (s, 1H), 7.42 (dd, J = 19.0, 7.7 Hz, 3H),7.31 (s, 1H), 4.01 (s, 3H), 2.39 (s, 3H); 13 C NMR(DMSO, 101 MHz) δ 169.37,161.53, 160.01, 157.56, 144.98, 144.75, 140.78, 132.59, 132.39 (d, J = 2.7 Hz), 129.90, 126.31 (d, J = 8.5 Hz), 125.58, 123.67, 122.15 (d, J = 8.1 Hz), 117.31(d, J = 22.1 Hz), 116.04, 115.80, 111.93, 110.31, 109.60, 107.27, 99.56, 21.00;HRMS(m / z) calcd for C 22 H 17 F3N4O2(M+H) + : 427.1382, found: 427.1374. Example 9 Following the synthesis method of Example 1, except that 4-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-methoxyacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-9 was obtained.

[0034] 3-(Difluoromethyl)- N -(4-fluoro-2-(5-(4-methoxyphenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 32%; mp:100-101 °C; 1 H NMR (DMSO, 400 MHz) δ 10.36 (s, 1H), 8.44 (s, 1H), 8.13 (dd, J =8.6, 5.5 Hz, 1H), 7.78 (t, J = 10.1 Hz, 3H), 7.59 (s, 1H), 7.42 (dd, J = 17.8,7.7 Hz, 3H), 7.31 (s, 1H), 4.01 (s, 3H), 2.39 (s, 3H); 13 C NMR(DMSO, 101 MHz) δ169.38, 161.55, 160.01, 157.56, 144.98, 140.78, 132.59, 132.38, 129.89,126.34, 125.58, 123.68, 122.11, 117.30 (d, J = 22.2 Hz), 116.04, 115.80, 109.60(t, J = 234.8 Hz), 99.56, 21.00; HRMS(m / z) calcd for C 22 H 17 F3N4O3(M+H) + : 443.1331, found: 443.1325. Example 10 Following the synthesis method of Example 1, except that 5-fluoro-2-nitroacetophenone was used instead of o-nitroacetophenone in step (1) and phenylacetylene was used in step (2), the rest of the operations were the same, and the target compound I-10 was obtained.

[0035] 3-(Difluoromethyl)- N -(5-fluoro-2-(5-phenylisoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 26%; mp: 163-165 °C; 1 H NMR (DMSO, 400 MHz) δ 10.72 (s, 1H), 8.47 (s, 1H), 8.30 – 8.15 (m, 1H), 8.00 (dd, J = 8.7, 6.5 Hz, 1H), 7.95 (d, J = 6.7 Hz, 2H), 7.73 (d, J = 3.2 Hz, 1H),7.66 – 7.53 (m, 3H), 7.32 (s, 1H), 7.29 – 7.21 (m, 1H), 4.02 (s, 3H); 13 C NMR(DMSO, 101 MHz) δ 169.57, 164.56, 162.52, 162.10, 160.55, 145.60, 138.70,138.58, 136.61, 133.15, 132.27 (d, J = 10.4 Hz), 131.38, 129.89, 126.81,126.24, 116.43, 115.34, 112.09, 111.87, 110.10, 109.55, 107.77, 100.53,100.00, 92.92, 21.00; HRMS(m / z) calcd for C 21 H 15 F3N4O2(M+H) + : 413.1225, found:413.1217. Example 11 Following the synthesis method of Example 1, except that 5-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-chlorophenylacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-11 was obtained.

[0036] N-(2-(5-(4-chlorophenyl)isoxazol-3-yl)-5-fluorophenyl)-3-(difluoromethyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield 23%;mp: 155-156 °C; 1 H NMR(CDCl3, 400 MHz) δ 10.68 (s, 1H), 8.46 (s, 1H), 8.20(t, J = 9.2 Hz,1H), 8.04 – 7.91 (m, 3H), 7.80 – 7.55 (m, 3H), 7.47 – 7.16 (m,2H), 4.03 (s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 169.32, 162.55, 160.01, 157.56,144.98, 140.78, 132.59, 132.38, 129.89, 126.34, 125.58, 123.68, 122.11,116.04, 115.80, 109.60 (t, J = 234.8 Hz), 98.56, 21.00; HRMS(m / z) calcd forC 21 H 14 ClF3N4O2(M+H) + : 447.0836, found: 447.0828. Example 12 Following the synthesis method of Example 1, except that 5-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-fluoroacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-12 was obtained.

[0037] 3-(Difluoromethyl)- N -(5-fluoro-2-(5-(4-fluorophenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield 25%; mp:175-177 °C; 1H NMR (DMSO, 400 MHz) δ 10.70 (s, 1H), 8.44 (s, 1H), 8.20 (dd, J =11.5, 2.3 Hz, 1H), 8.07 – 7.89 (m, 3H), 7.45 (t, J = 8.7 Hz, 2H), 7.33 (d, J =10.6 Hz, 1H), 7.29 – 7.16 (m, 2H), 4.02 (s, 43H); 13 C NMR (DMSO, 101 MHz) δ168.15, 164.61, 164.06, 162.87, 162.05, 161.61, 160.02, 145.01, 138.15 (d, J =11.8 Hz), 136.10, 132.61, 131.99 – 131.28 (m), 128.27 (d, J = 8.8 Hz), 123.03(d, J = 2.8 Hz), 116.54 (d, J = 22.2 Hz), 114.72 (d, J = 2.3 Hz), 112.93, 111.90 (d, J = 5.7 Hz), 111.43 (d, J = 22.5 Hz), 109.56 (d, J = 5.5 Hz), 109.27, 108.99,107.20, 99.93, 39.18; HRMS(m / z) calcd for C 21 H 14 F4N4O2(M+H) + : 431.1123, found:431.1131. Example 13 Following the synthesis method of Example 1, except that 5-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-methylacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-13 was obtained.

[0038] 3-(Difluoromethyl)- N -(5-fluoro-2-(5-(p-tolyl)isoxazol-3-yl)phenyl)-1-methyl-1H -pyrazole-4-carboxamide, white solid; yield, 24%; mp: 186-188 °C; 1 H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.63 (dd, J = 11.8, 2.4 Hz, 1H), 8.05(s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (dd, J = 8.5, 6.3 Hz, 1H), 7.36 – 7.29(m, 2H), 7.19 (s, 1H), 6.95 – 6.87 (m, 1H), 6.84 (s, 1H), 4.06 (s, 3H), 2.43(s, 3H); 13 C NMR (CDCl3, 101 MHz) δ 170.10, 162.68, 160.19, 151.93, 141.14 –139.26 (m), 131.25, 130.38, 130.28, 129.92, 125.99, 123.86, HRMS(m / z) calcd for C 22 H 17 F3N4O2(M+H) + : 427.1382, found: 427.1377. Example 14 Following the synthesis method of Example 1, except that 5-fluoro-2-nitroacetophenone was used to replace o-nitroacetophenone in step (1) and p-methoxyacetylene was used to replace phenylacetylene in step (2), the rest of the operations were the same, and the target compound I-14 was obtained.

[0039] 3-(Difluoromethyl)- N -(5-fluoro-2-(5-(4-methoxyphenyl)isoxazol-3-yl)phenyl)-1-methyl-1 H -pyrazole-4-carboxamide, white solid; yield, 17%;1 H NMR (DMSO, 400 MHz) δ 10.78 (s, 1H), 8.28 – 8.21 (m, 1H), 8.03 – 7.94 (m, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.32 (s, 1H), 7.21 (t, J = 8.4 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 4.03 (s, 3H), 3.86 (s, 3H); 13 C NMR(DMSO, 101 MHz) δ169.62, 163.39, 162.48, 162.05, 161.66, 160.52, 138.61, 136.61, 133.06,132.12, 127.98, 119.40, 116.46, 115.28, 115.03, 113.41, 111.78 (d, J = 22.2Hz), 110.07 (d, J = 5.5 Hz), 109.16, 107.76, 98.89; HRMS(m / z) calcd forC 22 H 17 F3N4O3(M+H) + : 443.1331, found: :443.1324. Bioactivity assay The mycelial growth rate method was used to determine the inhibitory activity of target compounds against various plant pathogenic fungi. *Alternaria solani* (A. s.), *Rhizoctonia solani* (R. s.), *Cercospora arachidicola* (C. a.), *Gibberella zeae* (G. z.), *Botrytis cinerea* (B. c.), *Physalospora piricola* (P. p.), and *Sclerotinia sclerotiorum* (S. s.) of rapeseed were used as test subjects. Fluopyram, thifluzamide, and boscalid were used as positive controls. The inhibition rates of each compound were determined at a concentration of 50 μg / mL. The inhibitory activity results of some compounds are shown in Table 1.

[0040] Table 1. Inhibitory activity of the compounds of this invention against seven plant pathogens (50 μg / mL, inhibition rate %)

[0041] As shown in Table 1, the compounds of this invention exhibited varying degrees of inhibitory activity against a variety of plant pathogenic fungi. Specifically, compounds I-2 and I-3 showed inhibition rates of 85% and 90% against rice sheath blight pathogens, respectively, which were comparable to the positive controls thifluzamide (87%), cyazofamid (86%), and fluopyram (89%). Compounds I-4 and I-10 showed inhibition rates of 52% and 51% against rapeseed sclerotinia stem rot pathogens, respectively, significantly superior to cyazofamid (29%).

[0042] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A pyrazole carboxamide derivative containing isoxazole, characterized in that, Its structure is shown in Equation I: Equation I, where R 1 Selected from: hydrogen, 4-fluoro, 5-fluoro; R 2 Selected from: hydrogen, 4-fluorine, 4-chloro, 4-methyl, 4-methoxy.

2. The isoxazole-containing pyrazole carboxamide derivative according to claim 1, characterized in that, The pyrazole carboxamide derivatives are selected from the following compounds: (I-1)、 (I-2)、 (I-3)、 (I-4)、 (I-5)、 (I-6)、 (I-7)、 (I-8)、 (I-9)、 (I-10)、 (I-11)、 (I-12)、 (I-13)、 (I-14)。 3. A method for preparing an isoxazole-containing pyrazole carboxamide derivative according to any one of claims 1-2, characterized in that, The reaction route is as follows: Among them, R 1 Selected from: hydrogen, 4-fluoro, 5-fluoro; R 2 Selected from: hydrogen, 4-fluorine, 4-chloro, 4-methyl, 4-methoxy.

4. The preparation method according to claim 3, characterized in that, The reaction route includes: (1) Compound 1 was dissolved in dichloromethane, and an aqueous solution of hydroxylamine hydrochloride and potassium carbonate was added. The mixture was stirred at room temperature and filtered to obtain compound 2. (2) Dissolve compound 2 in ethanol, add compound A, add sodium hypochlorite and DIPEA in sequence at room temperature, react overnight at room temperature, and filter to obtain compound 3; (3) Compound 3 and palladium on carbon were dissolved in anhydrous ethanol, hydrazine hydrate was added dropwise, the mixture was heated under reflux, filtered, filtered again, concentrated, extracted, dried, and purified by column chromatography to obtain compound 4; (4) Compound 4 was dissolved in dichloromethane, and triethylamine and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride solution were added. The reaction was carried out at room temperature, and the compound of formula I was obtained by extraction, washing, drying and column chromatography purification.

5. The preparation method according to claim 4, characterized in that, In step (1), the molar ratio of compound 1 to hydroxylamine hydrochloride and sodium carbonate is 1:(1~3):(1~3), and the reaction time is 4-6 h with stirring at room temperature.

6. The preparation method according to claim 4, characterized in that, In step (2), the molar ratio of compound 2 to compound A, sodium hypochlorite, and DIPEA is 1:1~2:1~3:1~3, and the overnight reaction time is 10h; In step (2), the sodium hypochlorite is an aqueous solution of sodium hypochlorite with a mass fraction of 5-15%, preferably 10%.

7. The preparation method according to claim 4, characterized in that, In step (3), the hydrazine hydrate is an aqueous solution of hydrazine hydrate with a mass fraction of 75-85%, preferably 80%; The mass ratio of compound 3, palladium on carbon, and hydrazine hydrate aqueous solution is 1:0.05~0.1:0.8~1.2, the heating reflux temperature is 75-85℃, and the reflux reaction time is 2-4h.

8. The preparation method according to claim 4, characterized in that, In step (4), the molar ratio of compound 4, triethylamine and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is 1:1.0~1.1:1.2~1.5, and the reaction time at room temperature is 2-3h; The 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride solution is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride dissolved in dichloromethane.

9. The preparation method according to claim 4, characterized in that, In steps (3) and (4), the extraction is performed using dichloromethane and water, the washing is performed using saturated brine to wash the organic phase obtained from the extraction, the drying is performed using anhydrous sodium sulfate, and the eluent for column chromatography purification is ethyl acetate / petroleum ether with a volume ratio of 1:4~6.

10. The use of isoxazole-containing pyrazole carboxamide derivatives according to any one of claims 1-2 or isoxazole-containing pyrazole carboxamide derivatives prepared by the method according to any one of claims 3-9 in the preparation of fungicides for the prevention and control of plant pathogens in the fields of agriculture, horticulture, forestry or health.

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