Difluoromethylthiazole amide compounds and their use as fungicides

Abstract

The present invention relates to the field of pesticide fungicides, and discloses a difluoromethyl thiazole amide compound and its application as a fungicide. The difluoromethyl thiazole amide compound has a structure shown in formula (I). The present invention introduces a difluoromethyl thiazole structure and a diphenyl ether fragment to design a difluoromethyl thiazole amide compound with high activity against diseases such as rice sheath blight, and the compound can be used as a new succinate dehydrogenase inhibitor or fungicide.

Description

Technical Field

[0001] The present invention relates to difluoromethyl thiazole amide compounds and their application as fungicides, in particular to their application in preventing and treating plant diseases caused by pathogenic bacteria. Background Art

[0002] Rice is one of the most important food crops in my country, with its planting area accounting for about 30% of the total food crop area and its output close to 50% of the total national grain output. Rice sheath blight is one of the most common major rice diseases, ranking first among the three major rice diseases in my country, and seriously restricts the high and stable yield of rice.

[0003] Succinate dehydrogenase inhibitors (SDHIs) are excellent candidate drugs for overcoming fungicide resistance and improving plant disease control (J. Agric. Food Chem. 2022, 70, 957-975). Among them, thiofuranamide has strong systemic conductivity and long-lasting effect, and has been used as a specific drug for rice sheath blight. However, due to various factors such as the price of the original drug, the promotion of thiofuranamide in China is not ideal. In order to develop a new thiazole SDHIs fungicide that is more efficient, green, low-toxic and relatively low-cost for rice sheath blight, this laboratory used thiofuranamide as the lead compound and carried out a series of structural modifications on it, replacing the trifluoromethyl group on the thiazole ring with a difluoromethyl group and introducing a diphenyl ether fragment into the structure.

[0004]

[0005] Prior art CN 114560826A and CN1226244A respectively disclose the general formula of thiazole amide compounds used as fungicides, and disclose some specific thiazole amide compounds containing diphenyl ether structure in the examples.

[0006] For example, CN1226244A discloses the following thiazole amide compound 10 containing a diphenyl ether structure.

[0007] For example, CN 114560826 A discloses the following two compounds 13 and 19 with the best activity against rice sheath blight pathogen.

[0008] Summary of the invention

[0009] The object of the present invention is to provide a difluoromethylthiazole amide compound with higher activity for preventing and treating rice sheath blight and other diseases.

[0010] The inventors of the present invention have screened and studied thiazole amide compounds and found that the difluoromethyl thiazole amide compounds represented by general formula (I) have very excellent fungicidal effects. Compared with other thiazole amide compounds, they can effectively prevent and control crop diseases, especially rice sheath blight.

[0011] The present invention provides a difluoromethyl thiazole amide compound as shown in formula (I):

[0012]

[0013] Where:

[0014] R is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a monofluoromethyl group, a difluoromethyl group, a difluoromethoxy group, a trifluoromethyl group, and a trifluoromethoxy group.

[0015] The preferred technical solution of the present invention is that the structure of the compound represented by formula (I) is at least one of the following:

[0016]

[0017] On the other hand, the present invention provides a method for preparing the compound represented by formula (I) and the key intermediate 2-methyl-4-difluoromethyl-5-thiazolecarboxylic acid.

[0018] Reaction (1):

[0019]

[0020] Reaction (2):

[0021]

[0022] The 1-methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid described in reaction formula (2) is a raw material for preparing more than ten common succinate dehydrogenase inhibitor fungicides such as fluopicolide and fluopicolide hydroxylamide. However, the synthesis of 1-methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid must use highly toxic and explosive methylhydrazine, resulting in certain safety hazards in its industrial production. In the present invention, the reaction formula (1) uses thioacetamide instead of methylhydrazine to avoid the safety hazards caused by the use of highly toxic and explosive methylhydrazine in industrial production and has lower raw material costs.

[0023] The present invention also provides the use of the compound represented by formula (I) in preventing and controlling crop diseases, wherein the plant disease is at least one of rice sheath blight, cucumber powdery mildew, wheat sheath blight, wheat powdery mildew, corn rust, corn sheath blight, soybean rust, rice blast and cucumber downy mildew.

[0024] The results of biological activity tests show that the selected representative compounds I-1 and I-2 exhibited high-efficiency activity, whether in enzyme activity inhibition test, in vitro assay test of drug-containing culture medium, rice leaf test or in vivo pot test, and their biological activities were better than those of the marketed drug thiofuranil; at the same time, the cytotoxicity test showed that compound I-1 had lower toxicity than similar fungicides thiofuranil and fluphenazine. Therefore, the compounds described in formula (I), especially compound I-1 or I-2, have the prospect of being developed as a special, low-toxic green fungicide for the prevention and control of rice sheath blight.

[0025] The above contents of the present invention are further described in detail below through specific implementation modes, but this should not be construed as limiting the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the drawings without creative labor. Among them:

[0027] Figure 1 Schematic diagram of the in vitro experiment (plate) of compound I-1 and thiophanate-methyl on rice sheath blight pathogenic bacteria in the examples of the present invention (the concentrations from left to right are 10 mg / L, 2 mg / L, 0.4 mg / L, 0.1 mg / L, 0.02 mg / L, 0.005 mg / L and 0.001 mg / L, respectively). DETAILED DESCRIPTION

[0028] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0029] Synthesis Example

[0030] Example 1 Preparation of 2-methyl-4-difluoromethyl-5-thiazolecarboxylic acid

[0031]

[0032] Ethyl difluoroacetoacetate (27 g, 162.6 mmol) and 10 mL of dichloromethane were added to the reaction flask, and sulfonyl chloride (24.2 g, 179.3 mmol) was slowly added dropwise under stirring in an ice-water bath. After the addition was completed, the temperature was raised to room temperature for reaction for 12 hours. After the reaction was completed, the reaction solution was poured into ice water, extracted with dichloromethane (30 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. After desolvation, 33.5 g of ethyl 2-chlorodifluoroacetoacetate was obtained, which was directly used in the next step.

[0033] Thioacetamide (14.2 g, 189.3 mmol) and 30 mL of acetonitrile were added to the reaction flask, and a mixed solution of ethyl 2-chlorodifluoroacetoacetate (31.5 g, 157.5 mmol) and 20 mL of acetonitrile was slowly added dropwise under stirring at room temperature. After the addition, the mixture was reacted at room temperature for 3 hours, and then triethylamine (47.7 g, 472.3 mmol) was added dropwise. After the addition, the mixture was heated to reflux for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, acetonitrile and triethylamine were removed, and 20% sodium hydroxide aqueous solution was added to continue reflux reaction for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and thioacetamide and other substances were extracted with ethyl acetate. The aqueous layer was adjusted to pH 2-3 with hydrochloric acid, stirred for 0.5 hours, allowed to stand, filtered and dried to obtain 21.5 g of 2-methyl-4-difluoromethyl-5-thiazolecarboxylic acid.

[0034] Example 2 Preparation of difluoromethylthiazole amide compounds shown in compounds I-1 and I-2

[0035]

[0036] Add o-(2-chloro-4-trifluoromethylphenoxy)aniline (0.575g, 2.0mmol, synthesis method reference WO 2015 / 058444Al) to the reaction flask, dissolve in 10mL of dichloromethane, then add triethylamine (0.606g, 6.0mmol), slowly add 4-(difluoromethyl)-2-methylthiazole-5-carbonyl chloride (0.508g, 2.4mmol, synthesis method reference patent CN 106349183 A) in 10mL of dichloromethane solution while stirring under ice-water bath conditions. After the drop is completed, warm to room temperature and react for 5 hours. After the reaction is completed, pour the reaction solution into 30mL of water, extract with dichloromethane, wash the organic layer with saturated sodium bicarbonate aqueous solution and saturated brine, dry with anhydrous sodium sulfate, and recover dichloromethane by rotary evaporation. The residue was purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:7) to obtain 0.725 g of compound I-1.

[0037] The preparation method of compound I-2 is the same as the synthesis method of compound I-1.

[0038] NMR and mass spectrometry data of compound I-1: light yellow solid, melting point 117.0–118.1℃. 1H NMR(400MHz,Chloroform-d)δ8.49(d,J=7.4Hz,2H),7.77(s,1H),7.49(d,J=8.7Hz,1H),7.25(s,1H) ,7.15(d,J=7.8Hz,1H),7.23–6.98(m,1H),7.05(d,J=8.6Hz,1H),6.88(d,J=8.1Hz,1H),2.75(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.05,157.47,154.73,148.53(t,J=25.0Hz),144.73,133.49,129.14,128.49(q,J=3.8Hz),127.46(q ,J=33.6Hz),125.80,125.53,125.51,125.48,123.29(q,J=273.2Hz),121.94,119.35,117.96,109.98(t,J=237.7Hz),19.59.ESI-MS m / z461.09[M-H] － .

[0039] Compound I-2 NMR and mass spectrometry data: light yellow solid, melting point 133.4–134.6℃. 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.3Hz,1H),8.30(s,1H),7.97(s,1H),7.73(d,J=8.7Hz,1H ),7.31(t,J=8.0Hz,1H),7.23–7.15(m,1H),7.12(t,J=54.1Hz,1H),7.05–6.99(m,2H),2.75(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.09,157.59,157.31,149.12(t,J=24.9Hz),143.98,132.83(d,J=4.2Hz),130.99(d,J=3.9Hz),129.87,126.42,125.9 8,125.82,125.64,123.35(q,J=272.0Hz),122.71(d,J=272.9Hz),122.33,1 21.30(q,J=32.3Hz),119.53,117.81,109.72(t,J=237.7Hz),19.59.ESI-MS m / z 495.09[M-H] － .

[0040] Preparation Example 1

[0041] Thiazole amide compounds shown in the following formula II were synthesized by the method of patent CN 114560826 A and a synthesis method similar to that of Example 1 and Example 2. The numbers are shown in Table 1.

[0042]

[0043] Table 1

[0044]

[0045]

[0046]

[0047] Some of the NMR data of the above compounds are as follows:

[0048] Compound II-2: 1 H NMR (400MHz, Chloroform-d) δ8.42(s,1H),7.91(s,1H),7.34(s,1H),7.25–6.96(m,3H),6.88–6.69(m,2H),2.60(s,6H). 13 C NMR(101MHz,Chloroform-d)δ167.08,159.76,155.57,155.32,144.66,133.78,131.49, 129.88,127.69,126.49,125.42,124.81,121.39,120.14,118.53,117.62,19.56,17.42.

[0049] Compound II-3: 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.1Hz,1H),8.03(s,1H),7.20(t,J=7.8Hz,1H),7.16(d,J= 9.1Hz,1H),7.13–7.06(m,1H),6.93–6.84(m,2H),6.77(d,J=9.1Hz,1H),2.69(s,3H),2.67(s,3H). 13C NMR(101MHz,Chloroform-d)δ167.10,159.74,155.16,152.39(dd,J=8.2,2.5Hz),150.79(dd,J=250.5,13.9Hz),147.17(dd,J=244.9,12.5Hz), 145.17,129.70,126.64,125.10,124.73,121.27,118.09(d,J=18.8Hz), 118.05, 113.98 (dd, J = 6.0, 3.6Hz), 108.24 (d, J = 20.4Hz), 19.54, 17.37.

[0050] Compound II-4: 1 H NMR(400MHz,Chloroform-d)δ8.50(d,J=8.2Hz,1H),7.91(s,1H),7.29–7.22(m,1H),7 .18–7.07(m,1H),6.96(d,J=8.3Hz,1H),6.76–6.59(m,2H),2.69(s,3H),2.67(s,3H). 13 C NMR(101MHz,Chloroform-d)δ167.07,159.75,155.56,153.19–150.44(m),144.18,140.65,138.80–13 4.21(m),130.04,126.27,125.90,124.92,121.61,118.90,102.76(dd,J=17.9,6.2Hz),19.56,17.39.

[0051] Compound II-17: 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.0Hz,1H),8.41(s,1H),7.42(d,J=8.8H z,1H),7.22(t,J=7.8Hz,1H),7.17–7.10(m,2H),6.96–6.85(m,2H),2.75(s,3H).

[0052] Compound II-18: 1 H NMR (400MHz, Chloroform-d) δ8.48(d,J=8.5Hz,1H),8.45(s,1H),7.24–7.08(m,3H),6.94–6.83(m,2H),6.76(d,J=8.9Hz,1H),2.75(s,3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.00, 156.62, 152.13 (dd, J = 8.3, 2.9 Hz), 150.75 (d, J = 236.3, 13.7 Hz), 147.28 (dd, J = 245.0, 12.5 Hz), 145.68, 140.60 (d, J = 36.5 Hz), 136.12, 128.95 (d, J = 3.7 Hz), 125.57, 124.85, 121.38, 120.32 (q, J = 272.2 Hz), 118.02 (dd, J = 19.2, 1.2 Hz), 117.73, 114.35 (dd, J = 6.2, 3.7 Hz), 108.54 (d, J = 20.2 Hz), 19.45.

[0053] Compound II-19: 1 1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.69–6.64 (m, 2H), 2.75 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.19, 156.62, 151.87–151.50 (m), 153.15–150.33 (m), 144.65, 140.94–135.42 (m), 138.32–137.92 (m), 129.60, 129.34, 125.77, 125.70, 121.70, 120.27 (q, J = 273.1 Hz), 118.67, 103.04 (dd, J = 17.6, 10.6 Hz), 19.47.

[0054] Compound II-38: 1 1H NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.25–7.19 (m, 1H), 7.18–7.12 (m, 2H), 7.04 (d, J = 54.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 2.74 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 169.05, 157.38, 155.52, 148.03 (t, J = 25.4 Hz), 145.07, 133.90, 133.67, 131.41, 129.44, 127.67, 125.47, 125.27, 121.61, 120.31, 118.48, 117.82, 110.20 (t, J = 237.7 Hz), 19.56.

[0055] Compound II-39: 1 H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 7.26–6.97 (m, 4H), 6.94–6.85 (m, 2H), 6.80–6.73 (m, 1H), 2.75 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.00, 157.39, 152.30 (dd, J = 8.2, 2.8 Hz), 150.74 (dd, J = 250.3, 14.0 Hz), 147.97 (d, J = 25.2 Hz), 147.19 (dd, J = 244.8, 12.5 Hz), 145.59, 133.88, 129.22, 125.39, 124.92, 121.50, 117.98 (d, J = 19.3 Hz), 117.97, 114.15 (dd, J = 6.1, 3.7 Hz), 110.15 (t, J = 237.6 Hz), 108.43 (d, J = 20.2 Hz), 19.56.

[0056] Compound II-40: 1 H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 54.2 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.67 (dd, J = 8.3, 5.7 Hz, 2H), 2.75 (s, 3H). 13C NMR(101MHz,Chloroform-d)δ169.21,157.36,151.88(td,J=11.2,3.6Hz),151.75(ddd,J=250.9,10.9,5.8Hz),147.70(t,J=25.7Hz),144 .51,136.76(d,J=247.7Hz),134.11,129.66,125.77,125.55,121.79,118.94,110.41(t,J=237.6Hz),102.85(dd,J=17.7,6.7Hz),19.54.

[0057] Test Example 1

[0058] This test example is used to determine the in vitro antibacterial activity of the compounds prepared in Example 2 and Preparation Example 1 against Rhizoctonia solani.

[0059] The plant pathogenic fungus tested was Rhizoctonia solani.

[0060] 1. Experimental Methods

[0061] The mycelium growth rate method was used. Dissolve the sample to be tested with dimethyl sulfoxide (DMSO) and dilute it to 1000 mg / L with a sterile aqueous solution of 0.1% Tween-80. Add 1 mL of the above solution to each conical flask and make the volume to 50 mL with PDA culture medium. Oscillate and mix evenly, pour into a culture dish to make drug-containing plates with different concentration gradients. Use DMSO as a blank control, use a 5 mm diameter puncher to cut the bacterial cake along the outer edge of the mycelium, and move it to the center of the drug-containing plate. Repeat each treatment 3 times. Place the culture dish in a constant temperature incubator at 25°C for culture. When the mycelium growth of the blank control group reaches 2 / 3 of the diameter of the culture dish, use a vernier caliper using the cross method to measure the diameter of the bacterial cake (mm), calculate the average value, and calculate the relative inhibition rate by comparing it with the blank control group. The calculation formula is as follows:

[0062]

[0063] 2. Experimental results

[0064] By testing the antibacterial activity of the thiazole amide compounds prepared in Example 2 and Preparation Example 1 against rice sheath blight, it was found that the inhibitory activity of compounds I-1 and I-2 in Example 2 against rice sheath blight was significantly better than that of all the compounds in Preparation Example 1 (including comparison compounds 10, 13 and 19).

[0065] The results of in vitro inhibitory activity test of difluoromethylthiazole amide compounds on rice sheath blight pathogen (see Table 2 and Table 3). As shown in Table 1, this type of compound still has a very good inhibitory effect on rice sheath blight pathogen at extremely low concentrations, especially when the concentration is 0.001 mg / L, the corresponding inhibition rate is significantly higher than that of thiofuranamide and fluorophenyletheramide. As shown in Table 3, compounds I-1 and I-2 showed very excellent inhibitory effects on rice sheath blight pathogen, which are significantly better than the similar fungicides.

[0066] Table 2

[0067]

[0068] “-”Untested

[0069] like Figure 1 As shown in the figure, as the concentration of the compound decreases, the growth diameter of the rice sheath blight fungus gradually increases. It can be intuitively seen that the compound has a linear inhibitory effect on the growth of the rice sheath blight fungus.

[0070] EC of compounds against Rhizoctonia solani 50 The values ​​are shown in Table 3.

[0071] Table 3

[0072]

[0073]

[0074] Test Example 2

[0075] This test example is used to determine the control effects of Example Compound I-1 and positive controls hexaconazole and thiophanate-methyl on rice sheath blight.

[0076] The test method is as follows: weigh an appropriate amount of the compound to be tested and dissolve it with DMF, and prepare a 20000 mg / L mother solution with 0.1% Tween 80 aqueous solution. Then dilute it with 0.1% Tween 80 solution water to prepare the test solution. Use a throat sprayer to evenly spray the agent on the rice leaves in the two-leaf and one-heart stage, repeat 3 times for each treatment, and place it indoors to dry naturally after spraying. 24 hours after the agent treatment, place a 3cm×3cm rice sheath blight hyphae block at the base of the rice seedling stem, 2 hyphae blocks per pot of seedlings, and cultivate the hyphae facing the rice stem in a glass moisturizing cabinet, with a temperature of 25-28°C, humidity>90%, and a light / dark ratio of 12h / 12h. 4 days after inoculation of the fungus block, a graded survey was conducted according to the ratio of hyphae growth height to plant height.

[0077] The control effects of the compounds on rice sheath blight are shown in Table 4 below.

[0078] Table 4

[0079]

[0080] As can be seen from Table 4, compound I-1 has a good control effect on rice sheath blight, and its control effect on rice sheath blight is significantly better than that of the commercial fungicide hexaconazole. At high concentrations, the control effect of compound I-1 is equivalent to that of thiophanate-methyl, and at low concentrations (1 mg / L), it shows a higher control effect.

[0081] Test Example 3

[0082] This test example is used to determine the inhibitory activity of Example Compound I-1 and positive control Thiothiocarb against succinate dehydrogenase.

[0083] The test method is as follows: the pathogenic fungi cultured on the PDA plate are inoculated into a triangular flask containing 100 mL of potato dextrose liquid culture medium, and cultured in a shaker in the dark (25°C, 150 rpm) for 2 to 3 days, and then the prepared agent is added thereto to prepare a drug-containing culture medium with a corresponding concentration gradient. After 48 hours of drug treatment, the culture solution is filtered with two layers of gauze, and the obtained mycelium is filtered with a vacuum pump and rinsed with sterile water, and then the water is drained for use. According to the instructions of the kit (Solebo, BC0955), 0.1 g of mycelium is weighed in the grinder, and the corresponding reagents in the kit are added, and ground on ice for about 3 minutes. The liquid obtained after grinding is added to a 1.5 mL enzyme-free centrifuge tube, and centrifuged at 11000g for 10 minutes at 4°C to obtain the supernatant. Then, the enzyme activity is determined according to the instructions of the kit, and the enzyme activity inhibition rate of the corresponding agent on SDH is calculated. Each sample is repeated 3 times, and the average value is used to calculate the IC 50 value.

[0084] The data of the inhibitory activity of the compounds against succinate dehydrogenase are shown in Table 5 below.

[0085] Table 5

[0086] Compound <![CDATA[IC 50 (mg / L)]]> I-1 0.29 Thifluzamide 0.64

[0087] As can be seen from Table 5, the inhibitory effect of compound I-1 on succinate dehydrogenase is better than that of the fungicide thiofuranamide.

[0088] Test Example 4

[0089] This test example is used to determine the cytotoxicity of Example Compound I-1 and the positive control.

[0090] The tested cell lines were A549 (human non-small cell lung cancer cells) and HPAEpic (human alveolar epithelial cells).

[0091] The test method is: A549 and HAPepic cells were cultured at 37°C and 5% CO 2Incubate the cells in DMEM complete medium (containing 10% fetal bovine serum + 1% Qinglian double antibody). 4 After overnight, discard the old culture medium, add the culture medium containing the compound to be tested, and place it in CO 2 The plates were cultured in a constant temperature incubator for 24 h, then the culture medium in the 96-well plate was discarded, and a 0.5 mg / mL MTT solution was added. The plates were incubated in a constant temperature incubator for another 4 h, and the solution was removed. 200 μL DMSO was added to each well, and the plates were shaken in the dark for 15 min. The absorbance of the solution was measured at a wavelength of 490 nm using an enzyme reader.

[0092] The cytotoxicity data of the compounds on A549 and HAPepic cells are shown in Table 6 below.

[0093] Table 6

[0094]

[0095] As can be seen from Table 6, compound I-1 is non-toxic to A549 and HAPepic cells at low concentrations, and both cells still have a high survival rate at high concentrations, which shows that compound I-1 is very safe for human cells; while cells treated with positive controls thiofuranil and flufenoxamide have a high survival rate at low concentrations, but the toxicity increases significantly with increasing concentrations. The data in Table 6 show that the compounds of the present invention have lower cytotoxicity than thiofuranil and flufenoxamide, and have the potential to be developed as green pesticides.

[0096] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A difluoromethylthiazole amide compound, characterized in that: The structure of the compound is shown in Formula I-1 or I-2, ; .

2. A method for preparing the difluoromethylthiazole amide compound according to claim 1, the method comprising: Will The compound represented by formula (A) or formula (B) is contacted with the compound represented by formula (C), wherein the compound represented by formula (C) can be obtained by contacting the compound represented by formula (D) with the compound represented by formula (E), , wherein R is selected from chlorine and trifluoromethyl, and X is selected from fluorine, chlorine, bromine and iodine.

3. The method according to claim 2, wherein: The conditions for the contact reaction of the compounds include: a reaction temperature of 0 to 150° C. and a reaction time of 0.5 to 48 h.

4. The method of claim 2, wherein the difluoromethylthiazole amide compound is The compound of formula (A) is prepared by the following reaction formula: .

5. The method of claim 4, wherein: The specific steps include: (1) In the presence of dichloromethane, chloroform or 1,2-dichloroethane, ethyl difluoroacetoacetate reacts with sulfonyl chloride to Ethyl 2-chlorodifluoroacetoacetate should be prepared, the molar ratio of ethyl difluoroacetoacetate to sulfonyl chloride is 1:1 to 1:1.5, and the reaction temperature is -15 to 25 °C; (2) Place 1,2-dichloroethane or acetonitrile in a reaction flask, add thioacetamide while stirring, and add dropwise at 20-30°C. 1,2-dichloroethane or acetonitrile solution of ethyl 2-chlorodifluoroacetoacetate, after the addition is complete, the reaction is continued for 1 to 3 hours, wherein the molar ratio of ethyl 2-chlorodifluoroacetoacetate to thioacetamide is 1:1 to 1:1.3; (3) Add the acid-binding agent triethylamine, tri-n-propylamine or tri-n-butylamine dropwise at 20-30°C. After the addition is complete, raise the temperature to reflux and maintain the reflux temperature. Flow for 1 to 3 hours to carry out the cyclization reaction; (4) After the reaction is completed, acetonitrile and acid binding agent are recovered by vacuum distillation. The reaction solution is cooled to room temperature and sodium hydroxide solution is added. Then raise the temperature to reflux for 1 to 3 hours; (5) After the hydrolysis reaction is completed, the temperature is lowered, and the reaction solution is extracted with an organic solvent to recover the remaining thioacetamide. The aqueous layer is dripped with Add hydrochloric acid for acidification, add dropwise, continue to cool, stir for 0.5-1 hour, filter with suction, and dry the filter cake.

6. Use of the difluoromethylthiazole amide compound according to claim 1 in the preparation of succinate dehydrogenase inhibitors.

7. Use of the difluoromethyl thiazole amide compound according to claim 1 in the preparation of an agent for preventing and controlling crop diseases, wherein: The crop disease is at least one of rice sheath blight, cucumber powdery mildew, wheat sheath blight, wheat powdery mildew, corn rust, corn sheath blight, soybean rust, rice blast and cucumber downy mildew.

8. A fungicide, comprising an active ingredient and an auxiliary material, wherein the active ingredient comprises at least one of the difluoromethylthiazole amide compounds according to claim 1.

9. The bactericide according to claim 8, wherein The dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspension, powder, granule and aqueous solution.

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