Pyrazole carboxamide group-containing fluoromethyl thioester compounds, and preparation method and application thereof

Abstract

This invention discloses fluoromethyl thiobenzoate compounds containing pyrazole carboxamide groups. The target product is obtained by combining the pyrazole carboxamide skeleton with an active fluoromethyl thio group, and its bactericidal activity has been evaluated, aiming to provide highly efficient novel candidate compounds for the creation of novel bactericides. This invention also discloses a simple method for preparing the above-mentioned fluoromethyl thiobenzoate compounds containing pyrazole carboxamide groups, which is easy to synthesize in large quantities.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, and also to the preparation method and application of the above-mentioned benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups. Background Technology

[0002] Fluoromethylthio groups (SCH2F, SCF2H, SCF3), as common fluorine-containing groups, possess unique lipophilicity, membrane permeability, and metabolic stability, demonstrating great potential in the development of pesticides and pharmaceutical molecules. Several bioactive molecules containing fluoromethylthio groups have been reported. For example, among SCF3-containing molecules, Cefazafiu is a cephalosporin antibiotic used to treat bacterial infections; Toltrazuril is a triazinone compound with broad-spectrum anticoccal activity, widely used for coccidiosis in chickens; and Fipronil is a commonly used commercially available insecticide. Among SCF2H-containing bioactive molecules, Pyriprole is a derivative of the insecticide fipronil, used to control hemiptera and coleopteran pests; and Flomoxef sodium is an oxazone antibiotic with good antibacterial activity against various Gram-positive bacteria. Among SCH2F-containing bioactive molecules, Fluticasone and Fluticasone propionate are anti-inflammatory drug molecules that can treat asthma and allergic rhinitis.

[0003] Succinate dehydrogenase inhibitors (SDHIs) are a widely used class of fungicides, ranking among the top three in the fungicide market alongside methoxyacrylates and triazoles. Pyrazole carboxamide is an important active skeleton of SDHIs, present in almost half of all SDHI fungicides, and chemical modification based on this skeleton has become an important direction for the development of novel fungicides.

[0004] This invention employs a molecular combination strategy, combining the pyrazole carboxamide skeleton with an active fluoromethyl thio group. By using computer simulations to determine the binding energy with succinate dehydrogenase, a class of fluoromethyl thioester compounds containing pyrazole carboxamide groups were designed and synthesized. Their bactericidal activity was evaluated, aiming to provide highly efficient novel candidate compounds for the creation of novel bactericides. Summary of the Invention

[0005] The purpose of this invention is to provide benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, which have simple structures, are easy to synthesize, and provide highly efficient novel candidate compounds for the creation of new bactericides.

[0006] The second and third objectives of this invention are to provide a method for preparing fluoromethyl thiobenzoate compounds containing pyrazole carboxamide groups in general formula 1 or general formula 2, with a simple synthetic route.

[0007] A fourth objective of this invention is to provide the application of the above-mentioned benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups in the field of plant pathogen fungicides.

[0008] The first technical solution adopted in this invention is: a fluoromethyl thiobenzoate compound containing a pyrazole carboxamide group, the structure of which is as shown in general formula 1 or general formula 2:

[0009] or , where R F1 It is difluoromethyl or trifluoromethyl; R F2 It is any one of monofluoromethyl, difluoromethyl, and trifluoromethyl; R is any one of methyl, 4-chlorophenyl, or 3,4-difluorophenyl.

[0010] The first technical solution of this invention is also characterized by:

[0011] The fluoromethyl thiobenzoate compound of general formula 1 containing a pyrazole carboxamide group is any one of compounds 1-1 to 1-12, and its structure is as follows:

[0012] , , , , , , , , , , , .

[0013] The fluoromethyl thiobenzoate compound of general formula 2 containing a pyrazole carboxamide group is any one of compounds 2-1 to 2-6, and its structure is as follows:

[0014] , , ,

[0015] , , .

[0016] The second technical solution adopted in this invention is a method for preparing benzoic acid fluoromethyl thioester compounds of general formula 1 containing pyrazole carboxamide groups, the synthesis steps of which are as follows:

[0017] Step 1: Under ice bath, oxygen-free and water-free conditions, anhydrous triethylamine is slowly added to a dichloromethane solution of 4-aminobenzaldehyde and stirred for 30 minutes to obtain mixed solution I;

[0018] Step 2: Continue to add the dichloromethane solution of acyl chloride compound B dropwise to mixed solution I under ice bath conditions, and react at room temperature for 12 hours. After the reaction is completed, the reaction system is post-processed to obtain aldehyde compound D.

[0019] Step 3: Add fluoromethyl thiobenzenesulfinate E, aldehyde compound D prepared in step 2, acetonitrile and tert-butyl hydroperoxide (TBHP) sequentially to a flask, and reflux at 84°C for 24 h. After the reaction is completed, remove the solvent by vacuum distillation to obtain the remaining mixture III. Separate and purify the remaining mixture III by silica gel column chromatography to obtain the compound described in general formula 1.

[0020] The synthesis route is as follows:

[0021] .

[0022] The second technical solution of the present invention is further characterized by:

[0023] In step 1, the molar concentration of the dichloromethane solution of 4-aminobenzaldehyde is 1.5 mmol / mL, and the molar ratio of 4-aminobenzaldehyde to anhydrous triethylamine is 1:1.2.

[0024] The post-treatment process of the reaction system in step 2 is as follows: water is added to the reaction system, the organic phase is extracted with ethyl acetate, then the organic phase is washed three times with water and saturated brine respectively, and dried with anhydrous sodium sulfate for 30 min; finally, the excess solvent is evaporated under reduced pressure to obtain the remaining mixture II, and the remaining mixture II is separated by silica gel column chromatography to obtain compound D;

[0025] The concentration of the dichloromethane solution of acyl chloride compound B is 3.0 mmol / mL; the molar ratio of acyl chloride compound B to 4-aminobenzaldehyde is 1:1.

[0026] Step 3: The molar ratio of aldehyde compound D: fluoromethyl thiobenzenesulfinate 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.

[0027] The third technical solution adopted in this invention is a method for preparing benzoic acid fluoromethyl thioester compounds of general formula 2 containing pyrazole carboxamide groups, the synthesis steps of which are as follows:

[0028] Step A: Under ice bath, oxygen-free and water-free conditions, anhydrous triethylamine is slowly added dropwise to a dichloromethane solution of 2-iodoaniline. After stirring for 30 minutes, mixed solution IV is obtained.

[0029] Step B: Under ice bath conditions, the dichloromethane solution of acyl chloride compound B was slowly added dropwise to mixed solution IV. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, water was added, and the organic phase was extracted three times with ethyl acetate. Then, the organic phase was washed three times with saturated brine. After drying with anhydrous sodium sulfate for 30 minutes, the solution was filtered and the filtrate was concentrated by rotary evaporation. The solution was then purified by silica gel column chromatography with a mesh size of 200-300 to obtain compound G.

[0030] Step C: Compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene (dppf), sodium carbonate, 1,4-dioxane, and water were added sequentially to a flask. The mixture was placed in an oil bath at 65°C and reacted 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 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 using a rotary evaporator. The filtrate was then purified by silica gel column chromatography using a 200-300 mesh screen to obtain compound I.

[0031] Step D: Add fluoromethyl thiobenzenesulfinate E, compound I, acetonitrile, and tert-butyl hydroperoxide (TBHP) sequentially to a flask. React under continuous reflux at 84°C for 24 hours. After the reaction, remove the solvent by vacuum distillation. The remaining mixture V is then purified by silica gel column chromatography to obtain the compound described in general formula 2. The synthetic route is as follows:

[0032] .

[0033] 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.

[0034] In step B, the molar ratio of compound B to 2-iodoaniline is 1:1; the molar concentration of the dichloromethane solution of acyl chloride compound B is 2.8 mmol / mL.

[0035] In step C, the molar ratio of compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene (dppf), and sodium carbonate is 1:2.1:0.08:0.16:6.5, and the volume ratio of solvent 1,4-dioxane to 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.

[0036] In step D, the molar ratio of compound I, fluoromethyl thiobenzenesulfinate E, and tert-butyl hydroperoxide (TBHP) is 1:1.5:4, and acetonitrile is added at a rate of 10 mL per mmol of compound I.

[0037] The fourth technical solution adopted in this invention is a benzoic acid fluoromethyl thioester compound containing a pyrazole carboxamide group, which can effectively inhibit apple ring rot fungus, wheat scab 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 new fungicides.

[0038] The beneficial effects of this invention are:

[0039] (1) The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group of the present invention has a novel compound structure and good inhibitory activity against plant pathogens and fungi. It can effectively inhibit apple ring rot fungus, wheat scab fungus, grape gray mold fungus, rice sheath blight fungus and rapeseed sclerotinia fungus. It can provide efficient new candidate compounds for the creation of new fungicides.

[0040] (2) The method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups of the present invention designs and synthesizes 3-fluoromethylpyrazole-4-carboxamide compounds substituted with fluoromethyl thioyl groups as a source of novel succinate dehydrogenase inhibitors (SDHI), which not only helps to enrich the structural diversity of bactericides, but also may improve their broad-spectrum and high-efficiency properties. By introducing fluoromethyl thioyl molecules, the novel SDHI can bind to the target enzyme more precisely, thereby effectively inhibiting its activity and achieving the purpose of bactericidal action. At the same time, the introduction of fluoromethyl thioyl molecules may also endow the novel SDHI with better stability, enabling it to maintain a stable bactericidal effect in complex and changing ecological environments. Moreover, the entire preparation method is simple, the synthetic route is short, and it is easy to prepare in large quantities. Attached Figure Description

[0041] Figure 1 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compound 1-1 was prepared in Example 1. 1 H NMR spectrum;

[0042] Figure 2 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compounds 1-2 prepared in Example 1 are examples of compounds prepared in this invention. 1 H NMR spectrum;

[0043] Figure 3 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compounds 1-3 were prepared in Example 1. 1 H NMR spectrum;

[0044] Figure 4 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compounds 1-4 were prepared in Example 1. 1H NMR spectrum;

[0045] Figure 5 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compounds 1-5 were prepared in Example 1. 1 H NMR spectrum;

[0046] Figure 6 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compounds 1-6 were prepared in Example 1. 1 H NMR spectrum;

[0047] Figure 7 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Example 2 describes compound 2-1 prepared from these compounds. 1 H NMR spectrum;

[0048] Figure 8 This invention relates to benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, their preparation methods, and applications. Compound 2-2 is the compound prepared in Example 2. 1 H NMR spectrum. Detailed Implementation

[0049] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0050] The synthetic methods for compounds 1-1 to 1-12 of general formula 1 all follow route one, as shown below:

[0051]

[0052] Compound B is obtained by reacting compound A with sulfoxide (SOCl2). The preparation process of compound B is as follows:

[0053] Under ice bath conditions and in an anhydrous and oxygen-free environment, thionyl chloride was slowly added dropwise to a dichloromethane solution of compound A, and then the mixture was 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. The molar ratio of compound A to thionyl chloride was 1:10, and the molar concentration of compound A in the dichloromethane solution was 1.5 mmol / mL.

[0054] Compound B used in all the following examples was prepared by the above preparation process. The structural formulas of compound A used in the preparation process and compounds B, D, E, G, I, and compounds of general formula 1 (1-1~1-12) and general formula 2 (2-1~2-6) are shown below:

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] Example 1:

[0064] The synthetic steps of compound 1-1 are as follows:

[0065] Step 1: Dissolve 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. Under ice bath, anaerobic and anhydrous conditions, slowly add 36 mmol of anhydrous triethylamine to the dichloromethane solution of 4-aminobenzaldehyde C and stir for 30 min to obtain mixed solution I.

[0066] Step 2: 30 mmol of the acyl chloride compound (compound B-1) was dissolved in 10 mL of dichloromethane to obtain a dichloromethane solution of the acyl chloride compound (compound B-1) with a molar concentration of 3.0 mmol / mL. The dichloromethane solution of the acyl chloride compound (compound B-1) was slowly added dropwise to mixed solution I under ice bath conditions. The reaction was carried out at room temperature for 12 h. After the reaction was completed, 50 mL of water was added to the reaction system, and the organic phase was extracted three times with 100 mL of ethyl acetate each time. The organic phase was then washed three times with water and saturated brine, respectively, and dried over anhydrous sodium sulfate for 30 min. Finally, excess solvent was evaporated under reduced pressure to obtain the remaining mixture II. The remaining mixture II was separated by silica gel column chromatography using a 200-300 mesh screen to obtain the aldehyde compound (compound D-1).

[0067] Step 3: In a 100 mL round-bottom flask, add fluoromethyl thiobenzenesulfinic acid (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). Reflux the reaction system at 84 °C for 24 hours. After the reaction is complete, remove the solvent by vacuum distillation to obtain the remaining mixture III. Separate and purify the remaining mixture III by silica gel column chromatography to obtain a white solid, namely compound 1-1,4-(1-methyl-3-difluoromethyl-pyrazole-4-carboxamido)benzoic acid fluoromethyl thiobenzene.

[0068] like Figure 1 As shown, the yield of compound 1-1, R f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0069] Compound 1-1: Yield 62%. Eluant: dichloromethane (R f = 0.3). 1 H 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.

[0070] Example 2:

[0071] The preparation method and the amounts and reaction parameters of each substance in this embodiment are consistent with those in Example 1. The difference from Example 1 is that the fluoromethyl thiobenzenesulfinic acid 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 thiobenzenesulfinic acid. Figure 2 As shown, the yields and R of compounds 1-2 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0072] Compounds 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), 39.74 ppm; 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) for C 14 H 11 F4N3O2S(M+Na + ): Calcd: 384.0400, Found: 384.0387.

[0073] Example 3:

[0074] The preparation method and the amounts and reaction parameters of each substance in this embodiment are consistent with those in Example 1. The difference is that the fluoromethyl thiobenzenesulfinic acid 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 thiobenzenesulfinic acid. Figure 3 As shown, the yields and R values ​​of compounds 1-3 are... f The values, proton NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0075] Compounds 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.

[0076] Example 4:

[0077] The preparation method and the amounts and reaction parameters of each substance in this embodiment 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 compounds 1-4 are 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. Figure 4 As shown, the yields and R of compounds 1-4 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0078] Compounds 1-4: Yield 56%. Eluant: dichloromethane (R f = 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; 19F 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.

[0079] Example 5:

[0080] The preparation method and the amounts and reaction parameters of each substance in this embodiment 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 fluoromethyl thiobenzenesulfinic acid compound used is E-2, and the prepared compounds 1-5 are 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thioester. Figure 5 As shown, the yields and R of compounds 1-5 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0081] Compounds 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) for C 14 H 10 F5N3O2S(M+Na + ): Calcd: 402.0306, Found: 402.0308.

[0082] Example 6:

[0083] The preparation method and the amounts and reaction parameters of each substance in this embodiment 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 fluoromethyl thiobenzenesulfinic acid compound used is E-3, and the prepared compounds 1-6 are 4-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thiobenzenesulfinic acid. Figure 6 As shown, the yields and R of compounds 1-6 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0084] Compounds 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.

[0085] Example 7:

[0086] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-3, and compounds 1-7 are 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. The yield and R of compounds 1-7 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0087] Compounds 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 12 F4N3O2S(M+Na + ): Calcd: 480.0167, Found: 480.0158.

[0088] Example 8:

[0089] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-3, the fluoromethyl thiobenzenesulfinic acid compound is E-2, and compounds 1-8 are 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thiobenzenesulfinic acid. The yields and R of compounds 1-8 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0090] Compounds 1-8: Yield 45%. Eluant: dichloromethane (R f = 0.3). 1H 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.

[0091] Example 9:

[0092] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-3, the fluoromethyl thiobenzenesulfinic acid compound is E-3, and compounds 1-9 are 4-(1-(4-chlorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thiobenzenesulfinic acid. The yields and R of compounds 1-9 are...f The values, proton NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0093] Compounds 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.

[0094] Example 10:

[0095] The preparation method and the amounts of each substance and reaction parameters used in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-4, and compounds 1-10 are 4-(1-(3,4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid monofluoromethyl thioester. The yield and R of compounds 1-10 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0096] Compounds 1-10: Yield 59%. Eluant: ethyl acetate / petroleum ether (1:6, R) f = 0.40). 11H NMR (400 MHz, Acetone-d6) δ 9.91 (s, 1H), 9.19 (s, 1H), 8.03 (d, J J = 8.9 Hz, 2H), 7.96 (d, J J = 8.8 Hz, 2H), 7.97–7.90 (m, 1H), 7.76–7.80 (m, 1H), 7.58–7.65 (m, 1H), 6.09 (d, J J = 50.3 Hz, 2H) ppm; 13 13C NMR (101 MHz, Acetone-d6) δ 186.11, 158.58, 151.64, 150.89 (m), 149.17 – 148.43 (m), 144.52, 142.32 (q, J J = 38.7 Hz), 135.50 – 135.38 (m), 131.45, 131.02, 128.89, 120.74 (q, J J = 270.0 Hz), l19.32, 118.65 (d, J J = 18.8 Hz), 118.45, 116.40 – 116.30 (m), 109.82 (d, J J = 22.3 Hz), 80.69 (d, J J = 212.5 Hz) ppm; 19 19F NMR (376 MHz, Acetone-d6) δ -61.89, -136.07 – -136.38 (m), -139.60 – -139.74 (m), -192.22 – -192.66 (q, J J = 48.8 Hz) ppm. IR: 2361, 1675, 1594, 1520, 1321, 1217, 1176, 1145, 1045, 906, 752, 597 cm -1 . HRMS (ESI) for C 19 18 11 H + 6F6N3O2S (M+H

[0097] Example 11:

[0098] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-4, the fluoromethyl thiobenzenesulfinic acid compound is E-2, and compound 1-11 is 4-(1-(3,4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid difluoromethyl thiobenzenesulfinic acid. The yield and R of compound 1-11 are... f The values, proton NMR spectrum, carbon NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0099] Compounds 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.

[0100] Example 12:

[0101] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 1. The difference is that in this embodiment, compound B is B-4, the fluoromethyl thiobenzenesulfinic acid compound is E-3, and compounds 1-12 are 4-(1-(3,4-difluorophenyl)-3-trifluoromethyl-pyrazole-4-carboxamido)benzoic acid trifluoromethyl thiobenzenesulfinic acid. The yield and R of compounds 1-12 are... f The values, proton NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0102] Compounds 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.

[0103] The synthetic methods for compounds 2-1 to 2-6 of general formula 2 all follow route two, as shown below:

[0104]

[0105] Example 13:

[0106] The synthetic steps of compound 2-1 are as follows:

[0107] Step A: Add 30 mmol / L 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. Under ice bath, oxygen-free and anhydrous conditions, slowly add 36 mmol of anhydrous triethylamine to the dichloromethane solution of 2-iodoaniline. After stirring for 30 min, a mixed solution IV is obtained.

[0108] Step B: Dissolve the acyl chloride compound (compound B-1) (5.4 g, 28 mmol / L) in 10 mL of dichloromethane to obtain a dichloromethane solution of the acyl chloride compound with a molar concentration of 2.8 mmol / mL. Under ice bath conditions, slowly add the dichloromethane solution of the acyl chloride compound dropwise to mixed solution IV and react at room temperature for 8 h. After the reaction is complete, add 50 mL of water and extract the organic phase three times with ethyl acetate, each time with 100 mL of ethyl acetate. Then wash the organic phase three times with saturated brine, dry with anhydrous sodium sulfate for 30 min, filter, concentrate the filtrate using a rotary evaporator, and purify by silica gel column chromatography with a 200-300 mesh to obtain a white solid compound G-1.

[0109] Step C: In a 100 mL double-necked flask, add 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). Place the flask in an oil bath at 65°C and react for 12 h. After the reaction is complete, cool the reaction system to room temperature, filter, and extract the filtrate three times with ethyl acetate, using 50 mL of ethyl acetate each time. After extraction, wash the organic phase three times with saturated brine, dry with anhydrous sodium sulfate for 30 min, filter, concentrate the filtrate using a rotary evaporator, and purify by silica gel column chromatography (200-300 mesh) to obtain a yellow solid compound I-1.

[0110] Step D: In a 100 mL round-bottom flask, fluoromethyl thiobenzenesulfinic acid (i.e., compound E-1, 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, 8.0 mmol, 4.0 equiv) were added sequentially. The reaction system was refluxed at 84 °C for 24 hours. After the reaction was completed, the solvent was removed by vacuum distillation. 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 fluoromethyl thiobenzenesulfinic acid.

[0111] like Figure 7 As shown, the yield of compound 2-1, R f The values, proton NMR spectrum, carbon NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0112] 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.

[0113] Example 14:

[0114] The preparation method and the amounts and reaction parameters of each substance in this embodiment are consistent with those in Example 13. The difference is that the fluoromethyl thiobenzenesulfinic acid 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 thiobenzenesulfinic acid. Figure 8 As shown, the yield of compound 2-2, R f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0115] 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.

[0116] Example 15:

[0117] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 13. The difference is that the fluoromethyl thiobenzenesulfinic acid 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, proton NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0118] Compounds 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.

[0119] Example 16:

[0120] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 13. The difference is that in this embodiment, compound B is B-2, and 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, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0121] Compounds 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.

[0122] Example 17:

[0123] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 13. The difference is that in this embodiment, compound B is B-2, the fluoromethyl thiobenzenesulfinic acid compound is E-2, and 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, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0124] Compounds 2-5: Yield 48%. Eluant: ethyl acetate / petroleum ether (1:2, R) f =0.40). 11H NMR (400 MHz, Acetone-d6) δ 8.85 (s, 2H), 8.15 (s, 1H), 7.99 (d, J J = 8.6 Hz, 2H), 7.82–7.78 (m, 1H), 7.68 (d, J J = 8.6 Hz, 2H), 7.69 (t, J 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 13C NMR (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 J = 269.7Hz), 121.87 (t, J J = 268.8 Hz), 117.68, 39.95ppm; 19 19F NMR (376 MHz, Acetone-d6) δ -61.19, -100.40 (d, J 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.

[0125] Example 18:

[0126] The preparation method and the amounts of each substance and reaction parameters in this embodiment are consistent with those in Example 13. The difference is that in this embodiment, compound B is B-2, the fluoromethyl thiobenzenesulfinic acid compound is E-3, and compound 2-6 is 2ʹ-(1-methyl-3-trifluoromethyl-pyrazole-4-carboxamido)-1,1ʹ-biphenyl-4-carboxylic acid trifluoromethyl thiobenzenesulfinic acid. The yield and R of compound 2-6 are... f The values, proton NMR spectrum, carbon NMR spectrum, fluorine NMR spectrum, infrared spectrum, and high-resolution mass spectrometry data are shown below:

[0127] Compounds 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 C20 H 14 F5N3O2S (M+Na + ): Calcd: 496.0525, Found: 496.0526.

[0128] The following experiments were conducted to verify the use of the product prepared in this application:

[0129] Experiment 1: Determination of the inhibitory activities of compounds 1-1~1-12 and compounds 2-1~2-6 against Physalosporapiricola (Pg), FusaHum graminearum Sehw (Fg), Botrytis cinerea (Bc), Thanatephorus cucumeris (Ps), and Sclerotinia sclerotiorum (Ss).

[0130] Preparation of experimental materials and culture media:

[0131] Plant fungi: *Physalospora piricola* (Pg), the causal agent of apple ring rot; *FusaHum graminearum* (Fg), the causal agent of wheat scab; *Botrytis cinerea* (Bc), the causal agent of grape gray mold; *T. hanatephorus cucumeris* (Ps), the causal agent of rice sheath blight; and *Sclerotinia sclerotiorum* (Ss), the causal agent of rapeseed sclerotiorum.

[0132] Control agent: Fluopyram (98% technical grade, Kaiwei Chemical).

[0133] Preparation of PDA culture medium: Weigh a certain amount of PDA culture medium, add deionized water, stir and heat to boiling until completely dissolved, dispense into Erlenmeyer flasks, autoclave at 121 ℃ for 20 min, and cool for later use.

[0134] Preparation of the drug solution: Weigh 4.0 mg of the test compound and dissolve it in 2.0 mL of DMSO. Transfer the solution to a 50 mL centrifuge tube containing 18.0 mL of sterile Tween water in a sterile laminar flow hood. Then add the solution to 180 mL of sterile PDA medium and mix well to achieve a final concentration of 20 μg / mL. Pour the medium into 15 petri dishes and let cool for later use. Use an equal volume of DMSO and Tween water as a blank control and use the commercial drug fluopyram as a control.

[0135] Activity test of the compound against plant pathogens: The inhibitory activity of the target compound against five plant pathogenic fungi was determined using the mycelial growth rate method. Pre-activated fungal colonies were prepared by punching holes at the edges to create 5.0 mm diameter mycelial discs, which were then transferred to the center of the drug-containing culture medium using a sterile inoculation needle and incubated at 28 ℃ for 2-6 days. When the colonies in the blank control group reached approximately 5.0 cm in length, the mycelial diameter was measured using calipers using the cross-sectional method. The inhibition rate was calculated using the following formula, where C is the measured mycelial diameter of the blank control group and T is the measured diameter of the drug-treated group.

[0136] The formula for calculating the mycelial growth inhibition rate is: Inhibition rate I(%) = (CA) / (CB) × 100%, where I is the inhibition rate, A is the measured diameter of the drug-treated group, B is the mycelial disc diameter (5.0 mm), and C is the measured diameter of the blank control mycelium. The inhibition rate results are shown in Table 1.

[0137] Table 1. Inhibition rates (%) of the compounds against five plant pathogens at a concentration of 20 μg / mL. a

[0138]

[0139] Notes: Pg: Apple ring rot fungus; Fg: Wheat scab fungus; Bc: Grape gray mold fungus; Ps: Rice sheath blight fungus; Ss: Rapeseed sclerotinia rot fungus.

[0140] As shown in Table 1, all compounds exhibited certain fungicidal activity at a concentration of 20 μg / mL. For *Rhizoctonia solani*, the causal agent of apple ring rot, compounds 1-1 and 1-5 showed near 100% inhibition rates, significantly higher than the positive control fluopyram (inhibition rate 47.5%). For *Fusarium graminearum*, compounds 1-1 and 2-1 showed high activity, with inhibition rates exceeding 80%. For *Botrytis cinerea*, the causal agent of grape gray mold, compound 1-8 showed high antibacterial activity, with an inhibition rate reaching 80%. For *Rhizoctonia solani*, except for 1-8, all compounds showed high inhibitory activity, with inhibition rates greater than 70%, among which compound 1-4 achieved an inhibition rate of 90%. For *Sclerotinia 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 achieved inhibition rates greater than 90%.

[0141] Compounds 1-1 and 1-4 showed high inhibitory effects against all five plant pathogens, with inhibition rates exceeding 75%, demonstrating good broad-spectrum antibacterial activity.

Claims

1. A method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, characterized in that, The structures of fluoromethyl thiobenzoic acid compounds containing pyrazole carboxamide groups are shown in general formula 1: Among them, R F1 It is difluoromethyl or trifluoromethyl; R F2 It is any one of monofluoromethyl, difluoromethyl, and trifluoromethyl; R is any one of methyl, 4-chlorophenyl, or 3,4-difluorophenyl; The synthesis steps of General Formula 1 are as follows: Step 1: Under ice bath, oxygen-free and water-free conditions, anhydrous triethylamine is slowly added to a dichloromethane solution of 4-aminobenzaldehyde and stirred for 30 minutes to obtain mixed solution I; Step 2: Continue to add the dichloromethane solution of acyl chloride compound B dropwise to mixed solution I under ice bath conditions, and react at room temperature for 12 hours. After the reaction is completed, the reaction system is post-processed to obtain aldehyde compound D. Step 3: Add fluoromethyl thiobenzenesulfinate E, aldehyde compound D prepared in step 2, acetonitrile and tert-butyl hydroperoxide (TBHP) sequentially to a flask, and reflux at 84°C for 24 h. After the reaction is completed, remove the solvent by vacuum distillation to obtain the remaining mixture III. Separate and purify the remaining mixture III by silica gel column chromatography to obtain the compound described in general formula 1. The synthesis route is as follows: 。 2. The method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups according to claim 1, characterized in that, In step 1, the molar concentration of the dichloromethane solution of 4-aminobenzaldehyde is 1.5 mmol / mL, and the molar ratio of 4-aminobenzaldehyde to anhydrous triethylamine is 1:1.

2.

3. The method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups according to claim 2, characterized in that, The post-treatment process of the reaction system described in step 2 is as follows: water is added to the reaction system, the organic phase is extracted with ethyl acetate, then the organic phase is washed three times with water and saturated brine respectively, and dried with anhydrous sodium sulfate for 30 min; finally, excess solvent is evaporated under reduced pressure to obtain the remaining mixture II, and the remaining mixture II is separated by silica gel column chromatography to obtain aldehyde compound D; The concentration of the dichloromethane solution of acyl chloride compound B is 3.0 mmol / mL; the molar ratio of acyl chloride compound B to 4-aminobenzaldehyde is 1:

1.

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

5. A method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups, characterized in that, The structures of fluoromethyl thiobenzoic acid compounds containing pyrazole carboxamide groups are shown in general formula 2. , where R F1 It is difluoromethyl or trifluoromethyl; R F2 It is any one of monofluoromethyl, difluoromethyl, and trifluoromethyl; R is methyl; The benzoic acid fluoromethyl thioester compound containing pyrazole carboxamide group described in Formula 2 is any one of compounds 2-1 to 2-6, and its structure is as follows: 、 、 、 、 、 ； The synthesis steps of general formula 2 are as follows: Step A: Under ice bath, oxygen-free and water-free conditions, anhydrous triethylamine is slowly added dropwise to a dichloromethane solution of 2-iodoaniline. After stirring for 30 minutes, mixed solution IV is obtained. Step B: Under ice bath conditions, the dichloromethane solution of acyl chloride compound B was slowly added dropwise to mixed solution IV. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, water was added, and the organic phase was extracted three times with ethyl acetate. Then, the organic phase was washed three times with saturated brine. After drying with anhydrous sodium sulfate for 30 minutes, the solution was filtered and the filtrate was concentrated by rotary evaporation. The solution was then purified by silica gel column chromatography with a mesh size of 200-300 to obtain compound G. Step C: Compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene, sodium carbonate, 1,4-dioxane, and water were added sequentially to a flask. The mixture was placed in an oil bath at 65°C and reacted 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 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 using a rotary evaporator. The filtrate was then purified by silica gel column chromatography using a 200-300 mesh screen to obtain compound I. Step D: Add fluoromethyl thiobenzenesulfinate E, compound I, acetonitrile, and tert-butyl hydroperoxide sequentially to a flask. React under continuous reflux at 84°C for 24 hours. After the reaction, remove the solvent by vacuum distillation. The remaining mixture V is then purified by silica gel column chromatography to obtain the compound described in general formula 2. The synthetic route is as follows:

6. The method for preparing benzoic acid fluoromethyl thioester compounds containing pyrazole carboxamide groups according to claim 5, characterized in that, The molar ratio of 2-iodoaniline to anhydrous triethylamine mentioned 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; In step C, the molar ratio of compound G, 4-formylphenylboronic acid H, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene, and sodium carbonate is 1:2.1:0.08:0.16:6.5, and the volume ratio of the solvent 1,4-dioxane to 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. In step D, the molar ratio of compound I, fluoromethyl thiobenzenesulfinate E, and tert-butyl hydroperoxide is 1:1.5:4, and acetonitrile is added at a rate of 10 mL per mmol of compound I.

Images