Fluoromethyl benzoate thioester compound containing pyrazolecarboxamide as well as preparation method and application of fluoromethyl benzoate thioester compound

Abstract

The invention discloses a pyrazolecarboxamide-containing fluoromethyl thiobenzoate compound, a target product is obtained by combining a pyrazolecarboxamide skeleton with an active fluoromethyl thio group, and the bactericidal activity of the pyrazolecarboxamide-containing fluoromethyl thiobenzoate compound is evaluated, so that an efficient novel candidate compound is expected to be provided for the creation of a novel bactericide. The invention also discloses a preparation method of the pyrazolecarboxamide-containing fluoromethyl benzoate thioester compound, the synthesis route is simple, and the pyrazolecarboxamide-containing fluoromethyl benzoate thioester compound is easy to prepare on a large scale.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to benzoic acid fluoromethyl thioester compounds containing pyrazolecarboxamide groups, and also relates to a preparation method and application of the benzoic acid fluoromethyl thioester compounds containing pyrazolecarboxamide groups. Background Art

[0002] As a common fluorinated group, fluoromethylthio (SCH2F, SCF2H, SCF3) has unique lipophilicity, membrane permeability and metabolic stability, and has shown great potential in the development of pesticides and pharmaceutical molecules. At present, several fluoromethylthio-containing bioactive molecules have been reported. For example, among the molecules containing SCF3, Cefazafiu is a cephalosporin antibiotic that can be used to treat bacterial infections; Toltrazuril is a triazone compound with broad-spectrum anticoccidial activity and is widely used for chicken coccidiosis; Fipronil is a commonly used commercial insecticide. Among the bioactive molecules containing SCF2H, Pyriprole is a derivative of the insecticide fipronil, which can be used to control hemiptera and coleoptera pests; Flomoxef sodium is an oxadiazole antibiotic that has good antibacterial activity against a variety of Gram-positive bacteria. Among the bioactive molecules containing SCH2F, Fluticasone and Fluticasone propionate have anti-inflammatory effects and are drug molecules that can treat asthma and allergic rhinitis.

[0003] Succinate dehydrogenase inhibitors (SDHI) are a widely used fungicide, and together with methoxyacrylates and triazole fungicides, they occupy the top three positions in the fungicide market. Pyrazole carboxamide is an important active skeleton of SDHI, which exists in almost half of SDHI fungicides. Chemical modification based on this skeleton has become an important direction for the research and development of new fungicides.

[0004] The present invention adopts a molecular splicing strategy to combine the pyrazolecarboxamide skeleton with an active fluoromethylthio group, and designs and synthesizes a class of benzoic acid fluoromethylthioester compounds containing pyrazolecarboxamide groups through computer simulation of the binding energy with succinate dehydrogenase, and evaluates their fungicidal activity, in order to provide efficient new candidate compounds for the creation of new fungicides. Summary of the invention

[0005] The invention aims to provide a benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group, which has a simple structure and is easy to synthesize, and provides a highly efficient new candidate compound for the creation of a new fungicide.

[0006] The second and third objectives of the present invention are to provide a method for preparing benzoic acid fluoromethyl thioester compounds containing a pyrazolecarboxamide group in general formula 1 or general formula 2, and the synthetic route is simple.

[0007] The fourth object of the present invention is to provide the use of the above-mentioned pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compounds in plant pathogenic fungicides.

[0008] The first technical solution adopted by the present invention is: a benzoic acid fluoromethyl thioester compound containing a pyrazole carboxamide group, whose structure is as shown in general formula 1 or general formula 2: or , where R F1 is difluoromethyl or trifluoromethyl; R F2 is any one of monofluoromethyl, difluoromethyl and trifluoromethyl; R is any one of methyl, 4-chlorophenyl and 3,4-difluorophenyl.

[0009] The first technical solution of the present invention is also characterized in that: The benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group of general formula 1 is any one of compounds 1-1 to 1-12, and has the following structure: , , , , , , , , , , , .

[0010] The benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group of general formula 2 is any one of compounds 2-1 to 2-6, and has the following structure: , , , , , .

[0011] The second technical solution adopted by the present invention is a method for preparing a pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound of general formula 1, and the synthesis steps are as follows: Step 1, in an ice bath, in the absence of oxygen and water, slowly add anhydrous triethylamine to a dichloromethane solution of 4-aminobenzaldehyde, and stir for 30 minutes to obtain a mixed solution I; Step 2, continue to add the dichloromethane solution of the acyl chloride compound B dropwise to the mixed solution I under ice bath conditions, react at room temperature for 12 hours, and after the reaction is completed, post-treat the reaction system to obtain an aldehyde compound D; Step 3, adding benzenesulfinic acid fluoromethyl thioester E, the aldehyde compound D prepared in step 2, acetonitrile and tert-butyl hydroperoxide (TBHP) in a flask in sequence, and conducting reflux reaction at 84° C. for 24 hours. After the reaction, the solvent is removed by reduced pressure distillation to obtain a residual mixture III, and the residual mixture III is separated and purified by silica gel column chromatography to obtain the compound of formula 1; The synthetic route is as follows: .

[0012] The second technical solution of the present invention is also characterized in that: The molar concentration of the dichloromethane solution of 4-aminobenzaldehyde in step 1 is 1.5 mmol / mL, and the molar ratio of 4-aminobenzaldehyde to anhydrous triethylamine is 1:1.2.

[0013] The post-treatment process of the reaction system in step 2 is: adding water to the reaction system, extracting the organic phase with ethyl acetate, then washing the organic phase three times with water and saturated brine respectively, and drying over anhydrous sodium sulfate for 30 minutes; finally, distilling off the excess solvent under reduced pressure to obtain the remaining mixture II, and separating the remaining mixture II by silica gel column chromatography to obtain compound D; The concentration of the dichloromethane solution of the acyl chloride compound B is 3.0 mmol / mL; the molar ratio of the acyl chloride compound B to 4-aminobenzaldehyde is 1:1.

[0014] Step 3: The molar ratio of aldehyde compound D: fluoromethylbenzenesulfinate E: tert-butyl hydroperoxide (TBHP) is 1:1.5:4, and the amount of acetonitrile added is 10 mL of acetonitrile per mmol of aldehyde compound D.

[0015] The third technical solution adopted by the present invention is a method for preparing a pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound of general formula 2, wherein the synthesis steps are as follows: Step A, in an ice bath, under oxygen-free and water-free conditions, slowly dropwise add anhydrous triethylamine to a dichloromethane solution of 2-iodoaniline, and stir for 30 minutes to obtain a mixed solution IV; Step B, slowly dropwise add the dichloromethane solution of the acyl chloride compound B to the mixed solution IV under ice bath conditions, react at room temperature for 8 hours, add water after the reaction is completed, extract the organic phase three times with ethyl acetate, then wash the organic phase three times with saturated brine, dry it with anhydrous sodium sulfate for 30 minutes, filter and concentrate the filtrate with a rotary evaporator, and purify it by 200-300 mesh silica gel column chromatography to obtain compound G; Step C, compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene (dppf), sodium carbonate, 1,4-dioxane and water were added to a flask in sequence, and the mixture was placed in an oil bath at 65°C for reaction for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate. After the extraction was completed, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate for 30 minutes, filtered, and the filtrate was concentrated by a rotary evaporator, and purified by 200-300 mesh silica gel column chromatography to obtain compound I; Step D: Add fluoromethylbenzenesulfinate E, compound I, acetonitrile and tert-butyl hydroperoxide (TBHP) in a flask in sequence, and carry out continuous reflux reaction at 84° C. for 24 hours. After the reaction, remove the solvent by reduced pressure distillation to obtain the remaining mixture V, and separate and purify the remaining mixture V by silica gel column chromatography to obtain the compound of formula 2. The synthetic route is as follows: .

[0016] In step A, the molar ratio of 2-iodoaniline to anhydrous triethylamine is 1:1.2, and the concentration of the dichloromethane solution of 2-iodoaniline is 1.5 mmol / mL; The molar ratio of compound B to 2-iodoaniline in step B is 1:1; the molar concentration of the dichloromethane solution of acyl chloride compound B is 2.8 mmol / mL; In step C, the molar ratio of compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene (dppf), and sodium carbonate is 1:2.1:0.08:0.16:6.5, and the volume ratio of solvent 1,4-dioxane and water is 2.5:1; the amount of dioxane and water added is 5 mL of dioxane and 2 mL of water per mmol of compound G.

[0017] In step D, the molar ratio of compound I, fluoromethyl benzenesulfinate E, and tert-butyl hydroperoxide (TBHP) is 1:1.5:4, and the amount of acetonitrile added is 10 mL of acetonitrile per mmol of compound I.

[0018] The fourth technical solution adopted by the present invention is that benzoic acid fluoromethyl thioester compounds containing pyrazolecarboxamide can effectively inhibit apple ring rot fungus, wheat fusarium rust fungus, grape gray mold fungus, rice sheath blight fungus and rapeseed sclerotinia fungus, and can provide highly efficient new candidate compounds for the creation of new fungicides.

[0019] The beneficial effects of the present invention are: (1) The pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compounds of the present invention have novel compound structures and good inhibitory activity against plant pathogenic fungi. They can effectively inhibit apple ring rot fungus, wheat fusarium rust fungus, grape gray mold fungus, rice sheath blight fungus and rapeseed sclerotinia fungus, and can provide highly efficient new candidate compounds for the creation of new fungicides.

[0020] (2) The preparation method of the pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compounds of the present invention, and the design and synthesis of fluoromethylthioyl-substituted 3-fluoromethylpyrazole-4-carboxamide compounds as a source of new succinate dehydrogenase inhibitors (SDHIs) not only help to enrich the structural diversity of fungicides, but also may improve their broad spectrum and high efficiency. By introducing fluoromethylthioyl molecules, the new SDHI can bind to the target enzyme more accurately, thereby effectively inhibiting its activity and achieving the purpose of sterilization. At the same time, the introduction of fluoromethylthioyl molecules may also give the new SDHI better stability, so that it can still maintain a stable bactericidal effect in a complex and changeable ecological environment, and the entire preparation method is simple, the synthetic route is short, and it is easy to prepare in large quantities. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The benzoic acid fluoromethyl thioester compound containing pyrazolecarboxamide group of the present invention and the preparation method and application method of the compound 1-1 prepared in Example 1 1 H NMR spectra; Figure 2 The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention and its preparation method and application example 1 prepared in compound 1-2 1 H NMR spectra; Figure 3 The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention and the preparation method and application example 1 of compound 1-3 prepared 1 H NMR spectra; Figure 4 The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention and the preparation method and application example 1 of the compound 1-4 prepared 1 H NMR spectra; Figure 5 The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention and the preparation method and application example 1 of the compound 1-5 prepared 1 H NMR spectra; Figure 6 The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention and the preparation method and application example 1 of the compound 1-6 prepared 1 H NMR spectra; Figure 7 The benzoic acid fluoromethyl thioester compound containing pyrazolecarboxamide group of the present invention and its preparation method and application example 2 prepared in compound 2-1 1 H NMR spectra; Figure 8 The benzoic acid fluoromethyl thioester compound containing pyrazolecarboxamide group of the present invention and the preparation method and application method of the compound 2-2 prepared in Example 2 1 H NMR spectra. DETAILED DESCRIPTION

[0022] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0023] The synthetic methods of compounds 1-1 to 1-12 of formula 1 all adopt route 1, and the specific route is as follows:

[0024] Compound B is obtained by reacting compound A with thionyl chloride (SOCl2). The preparation process of compound B is as follows: Under ice bath, anhydrous and oxygen-free conditions, thionyl chloride was slowly added dropwise to the dichloromethane solution of compound A, and then refluxed at 40°C for 4 hours. During this process, the reaction system changed from a white turbid state to a yellow transparent liquid. After the reaction was completed, the reaction system was cooled to room temperature, and then the solvent was evaporated under reduced pressure to obtain compound B, wherein the molar ratio of compound A to thionyl chloride was 1:10, and the molar solubility of the dichloromethane solution of compound A was 1.5 mmol / mL.

[0025] The compound B used in all the following examples is prepared by the above-mentioned preparation process. The structures of the compound A used in the preparation process and the prepared compound B, compound D, compound E, compound G, compound I, compounds 1-1 to 1-12 of formula 1, and compounds 2-1 to 2-6 of formula 2 are shown below:

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] Embodiment 1: The synthesis steps of compound 1-1 are as follows: Step 1, dissolving 30 mmol of 4-aminobenzaldehyde (compound C) in 20 mL of dichloromethane to obtain a dichloromethane solution of 4-aminobenzaldehyde with a molar concentration of 1.5 mmol / mL, slowly adding 36 mmol of anhydrous triethylamine to the dichloromethane solution of 4-aminobenzaldehyde C in an ice bath in an oxygen-free and water-free condition, and stirring for 30 minutes to obtain a mixed solution I; Step 2, 30mmol of the acyl chloride compound (compound B-1) was dissolved in 10mL of dichloromethane to obtain a dichloromethane solution of the acyl chloride compound (compound B-1) with a molar concentration of 3.0mmol / mL, and the dichloromethane solution of the acyl chloride compound (compound B-1) was slowly added dropwise to the mixed solution I under ice bath conditions, and reacted at room temperature for 12h. After the reaction was completed, 50mL of water was added to the reaction system, and the organic phase was extracted with ethyl acetate three times, each time with 100mL of ethyl acetate, and then the organic phase was washed with water and saturated brine three times, respectively, and dried over anhydrous sodium sulfate for 30min; finally, the excess solvent was evaporated under reduced pressure to obtain the remaining mixture II, and the remaining mixture II was separated by 200-300 mesh silica gel column chromatography to obtain an aldehyde compound (compound D-1); Step 3. In a 100 mL round-bottom flask, benzenesulfinic acid fluoromethyl thioester (compound E-1, 1.5 mmol, 1.0 equiv), aldehyde compound D-1 (2.0 mmol, 0.6 equiv), acetonitrile (20 mL), and tert-butyl hydroperoxide (TBHP) (8.0 mmol, 4.0 equiv) were added in sequence, and the reaction system was refluxed at 84 ° C for 24 hours. After the reaction, the solvent was removed by reduced pressure distillation to obtain the remaining mixture III. The remaining mixture III was separated and purified by silica gel column chromatography to obtain a white solid, i.e., compound 1-1, 4-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester.

[0034] like Figure 1 As shown, the yield of compound 1-1, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-1: Yield 62%. Eluant: dichloromethane (R f = 0.3). 1H NMR (400 MHz, Acetone-d6) δ 9.66 (s, 1H), 8.39–8.40 (m, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.94(d, J = 9.2 Hz, 2H), 7.34 (t, J = 54.2 Hz, 1H), 6.07 (d, J = 50.3 Hz, 2H), 3.99 (s,3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 186.81, 161.12, 146.76 (t, J = 23.9 Hz),145.53, 133.28, 131.39, 129.51, 120.07, 116.89, 110.55 (t, J = 234.7 Hz), 81.43(d, J = 212.4 Hz), 39.77 ppm; 19 F NMR (376 MHz, ) δ -115.44 (d, J = 54.9 Hz), -192.05 (t, J = 48.9Hz) ppm. IR: 3318, 2925, 2349, 1668, 1591, 1523, 1409, 1317,1217, 1173, 1060, 901, 843, 799, 733, 647cm -1 . HRMS (ESI) for C 14 H 12 F3N3O2S(M+Na + ): Calcd: 366.0495, Found: 366.0485.

[0035] Embodiment 2: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the benzenesulfinic acid fluoromethyl thioester compound used in this embodiment is E-2, and the prepared compound 1-2 is 4-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thioester. Figure 2 As shown, the yield of compound 1-2, R fThe values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-2: Yield 58%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.71 (s, 1H), 8.39 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.91 (d, J =8.7 Hz, 2H), 7.64 (t, J = 55.2 Hz, 1H), 7.33 (t, J = 54.1 Hz, 1H), 3.99 (s, 3H)ppm; 13 C NMR (101 MHz, Acetone-d6) δ 185.64, 161.13, 146.98 – 146.51 (m), 146.04, 133.28, 130.77, 129.53, 121.79 (t, J = 268.2 Hz), 120.11, 116.78,110.50 (t, J = 234.9 Hz), 39.74ppm; 19 F NMR (376 MHz, ) δ -100.05 (d, J = 53.8 Hz),-115.49 (d, J = 53.6 Hz)ppm; IR: 3319, 3125, 2924, 2349, 1673, 1591, 1522,1409, 1319, 1217, 1174, 1053, 896, 842, 786, 732, 644cm -1 . HRMS (ESI) forC 14 H 11 F4N3O2S(M+Na + ): Calcd: 384.0400, Found: 384.0387. Embodiment 3: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the benzenesulfinic acid fluoromethyl thioester compound used in this embodiment is E-3, and the prepared compound 1-3 is 4-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thioester. Figure 3 As shown, the yields of compounds 1-3, R f The values, H NMR spectrum, F NMR spectrum, IR spectrum and high resolution mass spectrum data are shown below: Compound 1-3: Yield 42%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.76 (s, 1H), 8.42 (s, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.93 (d, J =8.9 Hz, 2H), 7.33 (t, J = 54.1 Hz, 1H), 4.00 (s, 3H) ppm; 19 F NMR (376 MHz, ) δ -40.16, -115.51 (d, J = 54.3 Hz) ppm; IR:2361, 1682, 1593, 1526, 1411, 1335,1155, 1106, 891, 798, 644cm -1 .HRMS (ESI) for C 14 H 10 F5N3O2S(M+Na + ): Calcd:402.0306, Found: 402.0292. Embodiment 4: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-2, and the prepared compound 1-4 is 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. Figure 4 As shown, the yields of compounds 1-4, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-4: Yield 56%. Eluant: dichloromethane (Rf = 0.3). 1 HNMR (400 MHz, Acetone-d6) δ 9.79 (s, 1H), 8.47 (s, 1H), 8.00 (d, J = 9.0 Hz, 2H), 7.96 (d, J =9.0 Hz, 2H), 6.08 (d, J = 50.3 Hz, 2H), 4.03 (s, 3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 186.96 – 186.94 (m), 159.97, 145.76, 141.38 (q, J = 38.4 Hz),134.77, 131.61, 129.67, 121.94 (q, J = 269.7 Hz), 120.16, 117.44, 81.57 (d, J =212.3 Hz), 40.04 ppm; 19 F NMR (376 MHz, Acetone-d6) δ -61.43, -192.31 (t, J =50.7 Hz) ppm. IR: 3318, 3126, 2926, 2349, 2323, 1669, 1592, 1542, 1523, 1496,1446, 1407, 1320, 1217, 1170, 1135, 1047, 985, 904, 843, 823, 733, 647cm -1 .HRMS (ESI) for C 14 H 11 F4N3O2S(M+Na + ): Calcd: 384.0400, Found: 384.0391. Embodiment 5: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-2, the benzenesulfinic acid fluoromethyl thioester compound used is E-2, and the prepared compound 1-5 is 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thioester. Figure 5 As shown, the yields of compounds 1-5, R fThe values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-5: Yield 51%. Eluant: dichloromethane (R f = 0.3). 1 HNMR (400 MHz, Acetone-d6) δ 9.80 (s, 1H), 8.45 (s, 1H), 7.96 (d, J = 1.3 Hz, 1H), 7.94 (d, J =9.3 Hz, 2H), 7.66 (t, J = 55.2 Hz, 1H), 4.03 (s, 3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 185.88, 160.05, 146.34, 141.45 (q, J = 38.4 Hz), 134.81, 131.09 –131.06 (m), 129.82, 122.03 (t, J = 269.7 Hz), 121.96 (q, J = 269.7 Hz), 120.27,117.40, 40.10 ppm; 19 F NMR (376 MHz, ) δ -60.98, -100.16 (d, J = 56.4 Hz)ppm. IR:3318, 3125, 2919, 2349, 1673, 1592, 1543, 1523, 1407, 1321, 1292, 1217, 1171,1136, 1074, 1045, 902, 842, 821, 786, 759, 689, 670, 643cm -1 . HRMS (ESI) forC 14 H 10 F5N3O2S(M+Na + ): Calcd: 402.0306, Found: 402.0308. Embodiment 6: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-2, the benzenesulfinic acid fluoromethyl thioester compound used is E-3, and the prepared compound 1-6 is 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thioester. Figure 6 As shown, the yields of compounds 1-6, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-6: Yield 41%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.86 (s, 1H), 8.47 (s, 1H), 8.00 (d, J = 9.0 Hz, 2H), 7.94 (d, J =9.0 Hz, 2H), 4.04 (s, 3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 181.78, 160.03,146.65, 141.44 (q, J = 37.8 Hz), 134.77, 130.28 – 130.25(m), 129.99, 129.44 (q, J = 309.1 Hz), 121.90 (q, J = 269.7 Hz), 120.34, 117.28, 40.07 ppm; 19 F NMR (376MHz, Acetone-d6) δ -40.40, -61.50ppm. IR: 2361, 1695, 1593, 1523, 1408, 1322,1102, 1048, 896, 821, 761, 669cm -1 . HRMS (ESI) for C 14 H9F6N3O2S(M+H + ): Calcd:398.0393, Found: 398.0394. Embodiment 7: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-3, and the prepared compound 1-7 is 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. The yield of compound 1-7, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-7: Yield 51%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.93 (s, 1H), 9.21 (s, 1H), 8.03 (d, J = 8.9 Hz, 2H), 7.97 (d, J =8.9 Hz, 2H), 7.93 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 6.09 (d, J = 50.3Hz, 2H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 187.01, 159.57, 145.53, 143.17 (q, J = 38.4 Hz), 138.47, 134.37, 132.06, 131.88, 130.80, 129.78, 121.26 (q, J =270.7 Hz),122.13, 120.25, 119.22, 81.60 (d, J = 212.5 Hz) ppm; 19 F NMR (376 MHz, Acetone-d6) δ -61.66, -192.12 (t, J = 50.9 Hz)ppm. IR: 2926, 2361, 1674, 1593,1528, 1491, 1408, 1320, 1217, 1172, 1143, 1045, 904, 830, 757, 647cm -1 . HRMS(ESI) for C 19 H 12F4N3O2S(M+Na + ): Calcd: 480.0167, Found: 480.0158. Embodiment 8: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-3, the benzenesulfinic acid fluoromethyl thioester compound used is E-2, and the prepared compound 1-8 is 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thioester. The yield of compound 1-8, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-8: Yield 45%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.94 (s, 1H), 9.20 (s, 1H), 7.99 (d, J = 9.1 Hz, 2H), 7.96 (d, J =9.1 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 7.66 (t, J = 56.0 Hz, 1H), 7.65 (d, J = 9.0Hz, 2H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 185.79 (t, J = 3.3 Hz), 159.51,145.95, 143.46 (q, J = 38.4 Hz), 138.32, 134.27, 131.98, 131.19 – 131.15 (m),130.69, 129.74, 124.27 (q, J = 270.7Hz), 121.88 (t, J = 269.7 Hz), 122.02,120.21, 118.99 ppm; 19 F NMR (376 MHz, ) δ -61.69, -100.06 (d, J= 55.2 Hz)ppm.IR: 2924, 2361, 1679, 1530, 1492, 1324, 1175, 1076, 906, 830, 670cm -1 . HRMS(ESI) for C 19 H 11 F5N3O2S(M+Na + ): Calcd: 498.0073, Found: 498.0071. Embodiment 9: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-3, the benzenesulfinic acid fluoromethyl thioester compound used is E-3, and the prepared compound 1-9 is 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thioester. The yield of compound 1-9, R f The values, H NMR spectrum, F NMR spectrum, IR spectrum and high resolution mass spectrum data are shown below: Compound 1-9: Yield 43%. Eluant: dichloromethane (R f = 0.3). 1 H NMR (400 MHz, Acetone-d6) δ 9.98 (s, 1H), 9.19 (s, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.96 (d, J =8.9 Hz, 2H), 7.92 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H)ppm; 19 F NMR (376 MHz, )δ -40.18, -61.69ppm. IR: 2926, 2361, 1696, 1593, 1527, 1491, 1322, 1100, 896,830, 739, 644cm -1 . HRMS (ESI) for C 19 H 10 F6N3O2S(M+Na + ): Calcd: 515.9979, Found: 515.9966. Embodiment 10: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-4, and the prepared compound 1-10 is 4-(1-(3,4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. The yield and R of compound 1-10 are f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 1-10: Yield 59%. Eluant: ethyl acetate / petroleum ether (1: 6, R f = 0.40). 1 H NMR (400 MHz, Acetone-d6)δ9.91 (s, 1H), 9.19 (s, 1H), 8.03 (d, J =8.9 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.97–7.90 (m, 1H), 7.76–7.80 (m, 1H), 7.58–7.65 (m, z, 1H), 6.09 (d, J = 50.3 Hz, 2H)ppm; 13 C NMR (101 MHz, Acetone-d6)δ 186.11, 158.58, 151.64150.89 (m), 149.17 – 148.43 (m), 144.52, 142.32 (q, J =38.7 Hz), 135.50 – 135.38 (m), 131.45, 131.02, 128.89, 120.74 (q, J = 270.0Hz), 119.32, 118.65 (d, J = 18.8 Hz), 118.45, 116.40 – 116.30 (m), 109.82 (d, J =22.3 Hz), 80.69 (d, J = 212.5 Hz)ppm; 19 F NMR (376 MHz, Acetone-d6) δ -61.89, -136.07 – -136.38 (m), -139.60 – -139.74 (m), -192.22 – -192.66 (q,J = 48.8 Hz)ppm. IR: 2361, 1675, 1594, 1520, 1321, 1217, 1176, 1145, 1045, 906, 752, 597cm -1 . HRMS (ESI) for C 19 H 11 F6N3O2S (M+H + ): Calcd: 460.0549, Found: 460.0533. Embodiment 11: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-4, the benzenesulfinic acid fluoromethyl thioester compound used is E-2, and the prepared compound 1-11 is 4-(1-(3, 4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thioester. The yield and R of compound 1-11 are f The values, H NMR spectrum, C NMR spectrum, IR spectrum and high resolution mass spectrum data are shown below: Compound 1-11: Yield 56%. Eluant: ethyl acetate / petroleum ether (1: 6, R f = 0.40). 1 H NMR (400 MHz, Acetone-d6) δ 9.97 (s, 1H), 9.20 (s, 1H), 8.00 –7.97 (m, 4H), 7.95 – 7.90(m, 1H), 7.79 – 7.76 (m, 1H), 7.67 (t, J = 54.0 Hz,1H), 7.65 – 7.58 (m, 1H)ppm; 13 C NMR (101 MHz, Acetone-d6) δ 185.92, 159.56,152.57 – 151.83 (m), 150.10 – 149.36 (m), 146.00, 143.27 (q, J = 39.4Hz),136.41 – 136.29 (m), 132.44, 131.35, 129.90, 122.00 (t, J = 268.7 Hz), 121.63(q, J= 269.7Hz), 120.33, 119.68 – 119.49 (m), 119.28, 117.62 – 117.27 (m), 110.75 (d, J = 22.3 Hz)ppm. IR: 2361, 2343, 1678, 1594, 1520, 1324, 1217, 1177,1149, 1079, 907, 593 cm-1. HRMS (ESI) for C 19 H 10 F7N3O2S (M+H + ): Calcd: 478.0455, Found: 478.0459. Embodiment 12: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 1. The difference from Example 1 is that the compound B used in this embodiment is B-4, the benzenesulfinic acid fluoromethyl thioester compound used is E-3, and the prepared compound 1-12 is 4-(1-(3, 4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thioester. The yield and R of compound 1-12 are f The values, H NMR spectra, IR spectra and high-resolution mass spectrometry data are shown below: Compound 1-12: Yield 38%. Eluant: ethyl acetate / petroleum ether (1: 6, R f = 0.40). 1 H NMR (400 MHz, Acetone-d6) δ 9.99 (s, 1H), 9.21 (s, 1H), 8.03– 7.89 (m, 5H), 7.81 – 7.74 (m, 1H), 7.66 (dt, J = 10.3, 8.8 Hz, 1H) ppm; IR: 2361, 2342, 1697, 1565, 1521, 1324, 1152, 1106, 1064, 894, 762, 645cm -1 . HRMS (ESI) for C 19 H9F8N3O2S (M+H + ): Calcd: 496.0360, Found: 496.0365. The synthetic methods of compounds 2-1 to 2-6 of formula 2 all adopt route 2, and the specific route is as follows:

[0036] Embodiment 13: Synthesis steps of compound 2-1: Step A, add 30 mmol of 2-iodoaniline (compound F) to 20 ml of dichloromethane to obtain a dichloromethane solution of 2-iodoaniline with a molar concentration of 1.5 mmol / ml, slowly add 36 mmol of anhydrous triethylamine dropwise to the dichloromethane solution of 2-iodoaniline in an ice bath, in the absence of oxygen and water, and stir for 30 minutes to obtain a mixed solution IV; Step B, dissolve the acyl chloride compound (Compound B-1) (5.4g, 28mmoL) in 10ml of dichloromethane to obtain a dichloromethane solution of the acyl chloride compound with a molar concentration of 2.8mmol / mL, slowly dropwise add the dichloromethane solution of the acyl chloride compound to the mixed solution IV under ice bath conditions, react at room temperature for 8h, after the reaction is completed, add 50mL of water, extract the organic phase with ethyl acetate 3 times, each time with 100mL of ethyl acetate, then wash the organic phase three times with saturated brine, dry it with anhydrous sodium sulfate for 30min, filter and concentrate the filtrate with a rotary evaporator, and purify it by 200-300 mesh silica gel column chromatography to obtain a white solid compound G-1.

[0037] Step C, compound G-1 (10 mmol), 4-formylphenylboronic acid (compound H, 6.5 mmol), Pd(OAc)2 (0.25 mmol, 0.06 g), dppf (0.5 mmol, 0.28 g), Na2CO3 (20.0 mmol, 2.12 g), 1,4-dioxane (15.0 mL) and water (6.0 mL) were added to a 100 mL double-necked flask, and the flask was placed in an oil bath at 65 ° C for 12 hours. After the reaction, the reaction system was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate 3 times, each time using 50 mL of ethyl acetate. After the extraction, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate for 30 minutes, filtered and the filtrate was concentrated by rotary evaporator, and purified by 200-300 mesh silica gel column chromatography to obtain a yellow solid compound I-1; Step D: In a 100 mL round-bottom flask, benzenesulfinic acid fluoromethyl thioester (i.e., compound E-1, added in an amount of 1.5 mmol, 1.0 equiv), compound I-1 (2.0 mmol, 0.6 equiv), acetonitrile (20 mL), and tert-butyl hydroperoxide (i.e., TBHP, added in an amount of 8.0 mmol, 4.0 equiv) were added in sequence, and the reaction system was refluxed at 84° C. for 24 hours. After the reaction was completed, the solvent was removed by reduced pressure distillation to obtain the remaining mixture V. The remaining mixture V was separated and purified by silica gel column chromatography to obtain a white solid compound 2-1,2ʹ-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid monofluoromethyl thioester.

[0038] like Figure 7 As shown, the yield of compound 2-1, R f The values, H NMR spectrum, C NMR spectrum, IR spectrum and high resolution mass spectrum data are shown below: Compound 2-1: Yield 45%. Eluant: ethyl acetate / petroleum ether (1: 2, R f =0.40). 1 H NMR (400 MHz, Acetone-d6) δ 8.77 (s, 1H), 8.11 (s, 1H), 8.05 (d, J =8.6 Hz, 2H), 7.89 – 7.80 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.50 – 7.46 (m,1H), 7.45 – 7.44 (m, 1H), 7.42 – 7.41 (m, 1H), 7.20 (t, J = 54.3 Hz, 1H), 6.11(d, J = 50.2 Hz, 3H), 3.91 (s, 3H)ppm; 13 C NMR (101 MHz, Acetone-d6) δ 188.15,161.18, 146.47, 146.40 – 145.85 (m), 135.81, 135.45, 133.27, 131.02, 130.59,129.60, 128.62, 127.22, 126.94, 117.11, 110.78 (t, J = 234.3 Hz), 81.57 (d, J=212.7 Hz), 39.76ppm; IR: 3280, 2924, 2853, 1679, 1605, 1617, 1524, 1484,1446, 1214, 1178, 1036, 903, 765, 652cm -1 . HRMS (ESI) for C 20 H 16 F3N3O2S (M+Na + ):Calcd: 442.0808, Found: 442.0819. Embodiment 14: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 13. The difference from Example 13 is that the benzenesulfinic acid fluoromethyl thioester compound used in this embodiment is E-2, and the prepared compound 2-2 is 2ʹ-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid difluoromethyl thioester. Figure 8 As shown, the yield of compound 2-2, R f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 2-2: Yield 47%. Eluant: ethyl acetate / petroleum ether (1: 2, R f =0.40). 1 H NMR (400 MHz, Acetone-d6) δ 8.79 (s, 1H), 8.10 (s, 1H), 7.99 (d, J =8.5 Hz, 2H), 7.82 – 7.80 (m, 1H), 7.69 (t, J = 52Hz, 1H), 7.69 – 7.67 (m, 2H),7.49 – 7.45 (m, 1H), 7.43 – 7.41 (m, 1H), 7.38 – 7.34 (m, 1H),7.19 (t, J = 54.2Hz, 1H), 3.91 (s, 3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 187.12, 161.20,147.24, 146.18, 135.67 (d, J= 31.7 Hz), 134.99, 133.30, 131.07, 130.80,129.78, 128.66, 127.35, 127.05, 121.85 (t, J = 268.8 Hz), 117.15, 110.81 (t, J =234.3 Hz), 39.80ppm; 19 F NMR (376 MHz, Acetone-d6) δ -100.38 (d, J = 56.6 Hz), -114.81 (d, J = 55.1 Hz) ppm; IR: 3280, 2925, 2361, 1682, 1546, 1447, 1214,1077, 901, 744, 650cm -1 . HRMS (ESI) for C 20 H 15 F4N3O2S (M+H + ): Calcd: 438.0894,Found: 438.0887. Embodiment 15: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 13. The difference from Example 13 is that the benzenesulfinic acid fluoromethyl thioester compound used in this embodiment is E-3, and the prepared compound 2-3 is 2ʹ-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid trifluoromethyl thioester. The yield and R of compound 2-3 are f The values, H NMR spectrum, F NMR spectrum, IR spectrum and high resolution mass spectrum data are shown below: Compound 2-3: Yield 47%. Eluant: ethyl acetate / petroleum ether (1: 2, R f =0.40). 1 H NMR (400 MHz, Acetone-d6) δ 8.89 (s, 1H), 8.12 (s, 1H), 7.97 (d, J =8.5 Hz, 2H), 7.74– 7.77 (m, 1H), 7.69 (d, J= 8.5 Hz, 2H), 7.49– 7.45 (m, 1H), 7.44 – 7.40 (m, 1H), 7.38 – 7.34 (m, 1H), 7.17 (t, J = 54.2 Hz, 1H), 3.91 (s,3H) ppm; 19 F NMR (376 MHz, Acetone-d6) δ -40.56, -114.90 (d, J = 53.8 Hz) ppm; IR: 3301, 2974, 1710, 1658, 1603, 1546, 1448, 1242, 1160, 1107, 891, 762,650cm -1 . HRMS (ESI) for C 20 H 14 F5N3O2S (M+Na + ): Calcd: 478.0619, Found: 478.0620. Embodiment 16: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 13. The difference from Example 13 is that the compound B used in this embodiment is B-2, and the prepared compound 2-4 is 2ʹ-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid monofluoromethyl thioester. The yield and R of compound 2-4 are f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 2-4: Yield 54%) Eluant: ethyl acetate / petroleum ether (1: 2, R f =0.40). 1 H NMR (400 MHz, Acetone-d6) δ 8.85 (s, 1H), 8.15 (s, 1H), 8.05 (d, J =8.6 Hz, 2H), 7.84 – 7.80 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.48 – 7.44 (m,1H), 7.43 – 7.41 (m, 1H), 7.38 – 7.34 (m, 1H), 6.11 (d, J= 50.2 Hz, 2H), 3.93(s, 3H) ppm; 13 C NMR (101 MHz, Acetone-d6) δ 188.22, 160.05, 146.56, 135.95,135.60, 135.54, 134.38, 131.07, 130.63, 129.69, 128.66, 127.18, 127.03,121.97 (q, J = 269.7 Hz), 117.66, 81.61 (d, J = 212.5 Hz), 39.91ppm; 19 F NMR (376MHz, Acetone-d6) δ -61.19, -192.75 (t, J = 50.3 Hz)ppm; IR: 3268, 2925, 1679,1605, 1547, 1522, 1307, 1214, 1175, 1137, 902, 763,652cm-1.HRMS (ESI) forC20H15F4N3O2S (M+Na+): Calcd: 460.0713, Found: 460.0709. Embodiment 17: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 13. The difference from Example 13 is that the compound B used in this embodiment is B-2, the benzenesulfinic acid fluoromethyl thioester compound used is E-2, and the prepared compound 2-5 is 2ʹ-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid difluoromethyl thioester. The yield and R of compound 2-5 are f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 2-5: Yield 48%. Eluant: ethyl acetate / petroleum ether (1: 2, R f =0.40). 1 HNMR (400 MHz, Acetone-d6) δ 8.85 (s, 2H), 8.15 (s, 1H), 7.99 (d, J =8.6 Hz, 2H), 7.82–7.78 (m, 1H), 7.68 (d, J= 8.6 Hz, 2H), 7.69 (t, J = 52Hz, 1H),7.49–7.44 (m, 1H), 7.43–7.41 (m, 1H), 7.39–7.35 (m, 1H), 3.94 (s, 3H) ppm. 13 CNMR (101 MHz, Acetone-d6) δ 187.15, 160.05, 147.32, 135.97, 135.63, 135.03,134.40, 131.09, 130.82, 129.84, 128.68, 127.32, 127.14, 121.98 (q, J =269.7Hz), 121.87 (t, J = 268.8 Hz), 117.68, 39.95ppm; 19 F NMR (376 MHz, Acetone-d6) δ -61.19, -100.40 (d, J = 55.2 Hz) ppm; IR: 3268, 1682, 1651, 1604, 1547,1522, 1494, 1446, 1308, 1214, 1175, 1136, 1079, 1055, 901, 762, 743, 650cm -1 .HRMS (ESI) for C 20 H 14 F5N3O2S (M+Na + ): Calcd: 478.0619, Found: 478.0616. Embodiment 18: The preparation method of this embodiment and the amount of each substance taken during the preparation process and the reaction parameters are consistent with those in Example 13. The difference from Example 13 is that the compound B used in this embodiment is B-2, the benzenesulfinic acid fluoromethyl thioester compound used is E-3, and the prepared compound 2-6 is 2ʹ-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid trifluoromethyl thioester. The yield and R of compound 2-6 are f The values, hydrogen NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum and high-resolution mass spectrum data are as follows: Compound 2-6: Yield 45%. Eluant: ethyl acetate / petroleum ether (1: 2, R f=0.40). 1 H NMR (400 MHz, Acetone-d6) δ 8.87 (s, 1H), 8.15 (s, 1H), 7.98 (d, J =8.1 Hz, 2H), 7.79 – 7.77 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.51 – 7.45 (m,1H), 7.45 – 7.40 (m, 1H), 7.40 – 7.35 (m, 1H), 3.94 (s, 3H) ppm; 13 C NMR (101MHz, Acetone-d6) δ 183.19, 160.07, 147.86, 140.84 (q, J = 37.8 Hz), 135.95,135.64, 134.41, 131.10, 131.00, 129.96, 129.37 (q, J = 309.1Hz), 128.84,127.41, 127.21, 121.99 (q, J = 268.7Hz), 117.67, 39.97 ppm; 19 F NMR (376 MHz, Acetone-d6) δ -40.56, -61.23 ppm; IR: 3268, 2923, 1705, 1655, 1546, 1495,1308, 1150, 1105, 1052, 891, 762, 743, 649cm -1 . HRMS (ESI) for C 20 H 14 F5N3O2S (M+Na + ): Calcd: 496.0525, Found: 496.0526. The verification experiment of the use of the product prepared in this application is as follows: Experiment 1: Determination of the inhibitory activity of compounds 1-1~1-12 and compounds 2-1~2-6 against apple ring rot (Physalosporapiricola, Pg), wheat fusarium (FusaHum graminearum Sehw, Fg), grape gray mold (Botrytis cinerea, Bc), rice sheath blight (T-hanatephoruscucumeris, Ps) and rapeseed sclerotinia (Sclerotinia sclerotiorum, Ss).

[0039] Preparation of test materials and culture medium: Plant fungi: Physalospora piricola (Pg), FusaHum graminearum (Fg), Botrytis cinerea (Bc), T-hanatephoruscucumeris (Ps), and Sclerotinia sclerotiorum (Ss) Control agent: Flupyraclostrobin (98% original drug, Kaiwei Chemical).

[0040] Prepare PDA culture medium: weigh a certain amount of PDA culture medium, add deionized water, stir and heat to boil until completely dissolved, divide into Erlenmeyer flasks, autoclave at 121 ℃ for 20 min, cool and set aside.

[0041] Preparation of drug solution: Weigh 4.0 mg of the compound to be tested and dissolve it in 2.0 mL DMSO. Transfer it to a 50 mL centrifuge tube containing 18.0 mL sterile Tween water in a sterile clean bench, and then add it to 180 mL sterilized PDA medium and mix well to make the final concentration of the drug solution 20 μg / mL. Pour the medium evenly into 15 culture dishes and cool them for later use. Use an equal amount of DMSO Tween water as a blank control and the commercial drug fluopicolide as a control drug.

[0042] Activity test of compounds against plant pathogens: The inhibitory activity of the target compounds against five plant pathogenic fungi was determined by the mycelium growth rate method. The edge of the pre-activated fungus was punched to make a fungus cake with a diameter of 5.0 mm, which was transferred to the center of the drug-containing culture medium with a sterile inoculation needle and placed in a constant temperature incubator at 28 °C for 2-6 days. When the colony of the blank control group grows to about 5.0 cm, the mycelium diameter is measured with a vernier caliper using the cross method. The inhibition rate is calculated according to the following formula, where C is the measured diameter of the blank control mycelium and T is the measured diameter of the drug treatment group.

[0043] The formula for calculating the inhibition rate of mycelium growth is: inhibition rate I (%) = (CA) / (CB) × 100%, where I is the inhibition rate, A is the measured diameter of the drug treatment group; B is the mycelium disk diameter, which is 5.0 mm; C is the measured diameter of the blank control mycelium. The inhibition rate results are shown in Table 1.

[0044] Table 1 Inhibition rate of compounds against five plant pathogens at a concentration of 20 μg / mL (%) a

[0045] Notes: Pg: apple ring rot; Fg: wheat fusarium rust; Bc: grape gray mold; Ps: rice sheath blight; Ss: rapeseed sclerotinia.

[0046] As shown in Table 1, at a concentration of 20 μg / mL, all compounds showed certain fungicidal activity. For apple ring rot, compounds 1-1 and 1-5 showed an inhibition rate close to 100%, which was significantly higher than the positive control flupyraclostrobin (inhibition rate of 47.5%); for wheat fusarium head blight, compounds 1-1 and 2-1 showed high activity, with inhibition rates exceeding 80%; for grape gray mold, compound 1-8 showed high antibacterial activity, with an inhibition rate of 80%; for rice sheath blight, except for 1-8, all compounds showed high inhibitory activity, with inhibition rates greater than 70%, among which compound 1-4 had an inhibition rate of 90%; for rapeseed sclerotinia, except for 1-5 and 1-7, the remaining compounds showed high activity, with inhibition rates greater than 80%, among which compounds 1-3 and 2-4 had inhibition rates greater than 90%.

[0047] Compounds 1-1 and 1-4 showed high inhibitory effects on five plant pathogens, with inhibition rates exceeding 75%, demonstrating good broad-spectrum antibacterial activity.

Claims

1. A benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group, characterized in that: The structure of the benzoic acid fluoromethyl thioester compound containing pyrazolecarboxamide group is as shown in Formula 1 or Formula 2: or , where R F1 is difluoromethyl or trifluoromethyl; R F2 is any one of monofluoromethyl, difluoromethyl and trifluoromethyl; R is any one of methyl, 4-chlorophenyl and 3,4-difluorophenyl.

2. The pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 1, characterized in that: The benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group described in general formula 1 is any one of compounds 1-1 to 1-12, and has the following structure: 、 、 、 、 、 、 、 、 、 、 、 。 3. The pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 1, characterized in that: The benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group described in general formula 2 is any one of compounds 2-1 to 2-6, and has the following structure: 、 、 、 、 、 。 4. A method for preparing a benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group, characterized in that: The synthesis steps of general formula 1 are as follows: Step 1, in an ice bath, in the absence of oxygen and water, slowly add anhydrous triethylamine to a dichloromethane solution of 4-aminobenzaldehyde, and stir for 30 minutes to obtain a mixed solution I; Step 2, continue to add the dichloromethane solution of the acyl chloride compound B dropwise to the mixed solution I under ice bath conditions, react at room temperature for 12 hours, and after the reaction is completed, post-treat the reaction system to obtain an aldehyde compound D; Step 3, adding benzenesulfinic acid fluoromethyl thioester E, the aldehyde compound D prepared in step 2, acetonitrile and tert-butyl hydroperoxide (TBHP) in a flask in sequence, and conducting reflux reaction at 84° C. for 24 hours. After the reaction, the solvent is removed by reduced pressure distillation to obtain a residual mixture III, and the residual mixture III is separated and purified by silica gel column chromatography to obtain the compound of formula 1; The synthetic route is as follows: 。 5. The method for preparing the pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 4, characterized in that: The molar concentration of the dichloromethane solution of 4-aminobenzaldehyde in step 1 is 1.5 mmol / mL, and the molar ratio of 4-aminobenzaldehyde to anhydrous triethylamine is 1:1.

2.

6. The method for preparing the pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 4, characterized in that: The post-treatment process of the reaction system described in step 2 is: adding water to the reaction system, extracting the organic phase with ethyl acetate, then washing the organic phase three times with water and saturated brine respectively, and drying over anhydrous sodium sulfate for 30 minutes; finally, distilling off the excess solvent under reduced pressure to obtain a residual mixture II, and separating the residual mixture II by silica gel column chromatography to obtain an aldehyde compound D; The concentration of the dichloromethane solution of the acyl chloride compound B is 3.0 mmol / mL; the molar ratio of the acyl chloride compound B to 4-aminobenzaldehyde is 1:

1.

7. The method for preparing the pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 4, characterized in that: The molar ratio of the aldehyde compound D in step 3: fluoromethylbenzenesulfinate E: tert-butyl hydroperoxide is 1:1.5:4, and the amount of acetonitrile added is 10 mL of acetonitrile per mmol of the aldehyde compound D.

8. A method for preparing a benzoic acid fluoromethyl thioester compound containing a pyrazolecarboxamide group, characterized in that: The synthesis steps of general formula 2 are as follows: Step A, in an ice bath, under oxygen-free and water-free conditions, slowly dropwise add anhydrous triethylamine to a dichloromethane solution of 2-iodoaniline, and stir for 30 minutes to obtain a mixed solution IV; Step B, slowly dropwise add the dichloromethane solution of the acyl chloride compound B to the mixed solution IV under ice bath conditions, react at room temperature for 8 hours, add water after the reaction is completed, extract the organic phase three times with ethyl acetate, then wash the organic phase three times with saturated brine, dry it with anhydrous sodium sulfate for 30 minutes, filter and concentrate the filtrate with a rotary evaporator, and purify it by 200-300 mesh silica gel column chromatography to obtain compound G; Step C, compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, sodium carbonate, 1,4-dioxane and water were added to a flask in sequence, and the mixture was placed in an oil bath at 65°C for reaction for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate. After the extraction was completed, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate for 30 minutes, filtered, and the filtrate was concentrated by a rotary evaporator, and purified by 200-300 mesh silica gel column chromatography to obtain compound I; Step D: Add fluoromethylbenzenesulfinate E, compound I, acetonitrile and tert-butyl hydroperoxide to a flask in sequence, and continue to reflux at 84° C. for 24 hours. After the reaction, remove the solvent by reduced pressure distillation to obtain a residual mixture V, and separate and purify the residual mixture V by silica gel column chromatography to obtain the compound of formula 2; the synthetic route is as follows: 。 9. The method for preparing the pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to claim 8, characterized in that: The molar ratio of 2-iodoaniline to anhydrous triethylamine described in step A is 1:1.2, and the concentration of the dichloromethane solution of 2-iodoaniline is 1.5 mmol / mL; The molar ratio of compound B to 2-iodoaniline in step B is 1:1; the molar concentration of the dichloromethane solution of acyl chloride compound B is 2.8 mmol / mL; The molar ratio of the compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, and sodium carbonate in step C is 1:2.1:0.08:0.16:6.5, and the volume ratio of the solvent 1,4-dioxane and water is 2.5:1; the amount of dioxane and water added is 5 mL of dioxane and 2 mL of water per mmol of compound G; The molar ratio of compound I, benzenesulfinic acid fluoromethyl thioester E, and tert-butyl hydroperoxide described in step D is 1:1.5:4, and the amount of acetonitrile added is 10 mL of acetonitrile per mmol of compound I.

10. The pyrazolecarboxamide-containing benzoic acid fluoromethyl thioester compound according to any one of claims 1 to 9 can effectively inhibit apple ring rot fungus, wheat fusarium rust fungus, grape gray mold fungus, rice sheath blight fungus and rapeseed sclerotinia fungus, and can provide a highly efficient new candidate compound for the creation of a new fungicide.

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