A thiodifluoride derivative, a preparation method thereof and application thereof in bacteriostasis

Abstract

The application belongs to the field of organic synthesis and particularly relates to a thio difluoro ester derivative, a preparation method thereof and application thereof in bacteriostasis. The preparation method of the thio difluoro ester derivative comprises the following steps: mixing styrene, BrF2COOEt, CS2, morpholine, a chlorocholine and glycerol mixed solvent and CuOTf in an air atmosphere, and irradiating under light for 24 h; after the reaction is completed, cooling to room temperature; and collecting the precipitate to obtain the thio difluoro ester. The preparation method is simple, efficient, green and pollution-free, and can be widely applied in the field of inhibiting wheat Helminthosporium leaf spot or apple canker.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a thiodifluoroester derivative, its preparation method, and its application in antibacterial properties. Background Technology

[0002] Sulfur-containing compounds (Green Chem., 2021, 23: 496), especially organodithiocarbamates, are ubiquitous in a wide range of bioactive compounds (Org. Lett., 2019, 21: 7938). For example, they are frequently used in medicinal chemistry and have been applied in cancer treatment (Bioorg. Med. Chem. Lett., 2006, 16: 4214). The biological properties of sulfur-containing compounds play a crucial role in agriculture, thus promoting their synthesis. Therefore, developing efficient and green methods to synthesize these important sulfur-containing compounds will be of great value in the screening of bioactive molecules.

[0003] Difluoroalkyl functional groups are an important scaffold, and various bioactive drugs containing the CF2 moiety have been reported (Antiviral Therapy, 2009, 14: 607). In recent years, ethyl difluorobromoacetate, in particular, has become an important reagent for introducing difluoroalkyl groups into organic compounds (Chin. J. Org. Chem., 2020, 40: 806-807.).

[0004] In 1994, Bessho et al. reported that pyrrolidine dithiocarbamate is an effective inhibitor of nuclear factor κB (NF-κB) activation, which can prevent apoptosis of human promyelocytic leukemia HL-60 cells and thymocytes; NF-κB activation plays an important role in the apoptosis of human hematopoietic cells (Biochem. Pharmacol., 1994, 48: 1883).

[0005] In 2015, Ren et al. synthesized three series of novel dithiocarbamate analogs and evaluated their cytotoxic activity against four human cancer cell lines in vitro (Eur. J. Med. Chem., 2015, 93: 321). The dithiocarbamate analogs with phenyl terminals showed excellent inhibitory activity against the tested cancer cell lines.

[0006] The above methods not only require expensive metal catalysts such as palladium, but also necessitate heating, resulting in high energy consumption and environmental unfriendliness. Therefore, developing an environmentally friendly and low-cost method for preparing thiodifluoroester derivatives has broad economic and social benefits. Summary of the Invention

[0007] To address the problems existing in the prior art, the present invention adopts the following technical solution:

[0008] The preparation method of thiodifluoro ester derivatives includes the following steps: styrene, BrF₂COOEt, CS₂, morpholine, choline chloride, and a mixed solvent of glycerol, along with CuOTf, are reacted in air under light irradiation for 24 h. After the reaction is complete, the mixture is cooled to room temperature, and the precipitate is collected as the thiodifluoro ester. The specific reaction formula is as follows:

[0009]

[0010] In the above formula, R is 4-CH3, 3-CH3, 4-Br, 3-Br, 4-Cl, 3-Cl, 2-Cl, 4-F, 4-CH3O, 4-tBu, or 2, 3, 4, 5, 6-pentafluorine; R 1 for R 2 for .

[0011] Preferably, the molar ratio of styrene, BrF2COOEt, CS2 and morpholine is 1:2:2:1.

[0012] Preferably, the room temperature is 25°C.

[0013] Preferably, the ratio of choline chloride to glycerol in the mixed solvent of choline chloride and glycerol is 1:2.

[0014] Preferably, the light source for illumination is blue light.

[0015] A thiodifluoroester derivative prepared by the above method.

[0016] An application of the above-mentioned thiodifluoro ester derivative, wherein the thiodifluoro ester derivative is used in the field of inhibiting wheat take-all pathogen or apple rot pathogen.

[0017] Beneficial effects: The synthesis method described in this invention is simple, efficient, green, and pollution-free. Comprehensive analysis of the initial activity screening data shows that compounds M4, M10, M11, and M12 exhibited better inhibition rates against wheat take-all pathogens at concentrations of 50 mg / L and 100 mg / L than the control drug Hymexazol, with inhibition rates exceeding 80%. Compounds M10, M11, and M12 also showed better inhibitory effects against apple rot pathogens at concentrations of 50 mg / L and 100 mg / L than the control drug, with compound M12 achieving an inhibition rate exceeding 80% at 50 mg / L. Attached Figure Description

[0018] Figure 1 The inhibitory effects of M4, M10, M11 and M12 on wheat take-all pathogen. Detailed Implementation

[0019] The present invention will be further illustrated below with specific embodiments. It should be understood that the preparation methods of the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Under the premise of the concept of the present invention, simple improvements to the preparation methods of the present invention are all within the scope of protection claimed by the present invention.

[0020] It should also be noted that the various preferred technical features of the method of the present invention mentioned above, as well as the various specific technical features in the embodiments described below, can be combined together. All combinations of these technical features fall within the scope of the present invention, with the numerical values ​​specifically disclosed in the present invention serving as upper and lower limits.

[0021] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0022] Unless otherwise specified, the materials and reagents used in the following examples can be obtained commercially or synthesized from commercially available raw materials.

[0023] The specific embodiments of the present invention are described in detail below with reference to the technical solutions, but the process conditions are not limited to these embodiments.

[0024] Example 1

[0025]

[0026] Styrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M1 (ethyl 2,2-difluoro-4-((4-morpholinylcarbothio)thio)-4-phenylbutyrate), in 85% yield.

[0027] 1 H NMR (500 MHz, DMSO) δ 7.43 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz,2H), 7.33 – 7.28 (m, 1H), 5.29 (dd, J = 10.5, 3.9 Hz, 1H), 4.20 (d, J= 24.2 Hz, 2H), 4.04 (q, J = 7.0 Hz, 2H), 3.84 (s, 2H), 3.64 (s, 4H), 3.20 – 2.95 (m, 2H),1.20 (t, J = 7.1 Hz, 3H).

[0028] 13 C NMR (126 MHz, DMSO) δ 193.37 (s), 163.52 (s), 163.26 (s), 163.00(s), 138.42 (s), 129.07 (s), 128.91 (s), 128.59 (s), 117.41 (s), 115.40 (s),113.41 (s), 66.03 (dd, J = 24.2, 3.4 Hz), 63.48 (s), 51.48 (d, J = 3.9 Hz), 50.67(d, J = 4.5 Hz), 49.55 (t, J = 3.9 Hz), 14.04 (s).

[0029] HRMS: m / z calcd for C 17 H 22 F2NO3S2[M+H] + : 390.1003; found: 390.1008.

[0030] Example 2

[0031]

[0032] p-Methylstyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out at 25 °C under light irradiation for 24 h in air. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M₂ (ethyl 2,2-difluoro-4-((4-morpholinylcarbothio)thio)-4-phenylbutyrate), in 76% yield.

[0033] 11H NMR (500 MHz, DMSO) δ 7.30 (d, J J = 8.0 Hz, 2H), 7.16 (d, J J = 7.9 Hz,2H), 5.23 (dd, J J = 10.6, 4.2 Hz, 1H), 4.20 (dd, J J = 13.0, 3.8 Hz, 2H), 4.04 (q, J J =7.1 Hz, 2H), 3.83 (s, 2H), 3.64 (d, J J = 4.1 Hz, 4H), 3.17 – 2.92 (m, 2H), 2.29(s, 3H), 1.20 (t, J J = 7.1 Hz, 3H).

[0034] 13 13C NMR (126 MHz, DMSO) δ 193.52 (s), 163.54 (s), 163.29 (s), 163.03(s), 137.98 (s), 135.24 (s), 129.59 (s), 128.79 (s), 117.43 (s), 115.44 (s),113.45 (s), 65.98 (d, J J = 19.7 Hz), 63.48 (s), 51.49 – 51.45 (m), 51.01 (dd, J J =96.2, 3.7 Hz), 49.34 (s), 21.15 (s), 14.02 (s).

[0035] HRMS: m / z calcd for C 18 18 24 H15F2NO3S2[M+H] + : 404.1160; found: 404.1165.

[0036] Example 3

[0037]

[0038] 3-Methylstyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography, and the target product M3 (ethyl 2,2-difluoro-4-((4-morpholinylcarbothio)thio)-4-(m-methylphenyl)butyrate) was obtained in 70% yield.

[0039] 1 H NMR (500 MHz, DMSO) δ 7.27 – 7.18 (m, 3H), 7.12 (d, J = 7.2 Hz, 1H), 5.24 (dd, J = 10.7, 4.1 Hz, 1H), 4.20 (dd, J = 25.7, 3.9 Hz, 2H), 4.03 (q, J = 7.1Hz, 2H), 3.83 (d, J = 0.5 Hz, 2H), 3.63 (d, J = 4.4 Hz, 4H), 3.16 – 2.94 (m, 2H), 2.30 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

[0040] 13 C NMR (126 MHz, DMSO) δ 193.47 (s), 163.53 (s), 163.27 (s), 163.02(s), 138.35 (s), 138.18 (s), 129.32 (d, J = 17.4 Hz), 128.97 (s), 125.98 (s), 117.40 (s), 115.40 (s), 113.41 (s), 66.03 (d, J = 24.8 Hz), 65.92 – 64.88 (m), 63.46 (s), 51.04 (d, J = 100.4 Hz), 49.57 (t, J = 3.9 Hz), 21.36 (s), 14.02 (s).

[0041] HRMS: m / z calcd for C 18 H 24 F2NO3S2[M+H] + : 404.1160; found: 404.1167.

[0042] Example 4

[0043]

[0044] 4-Bromostyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography, yielding the target product M (ethyl 4-(4-bromophenyl)-2,2-difluoro-4-((4-morpholinyl carbthioyl)thio)butyrate), in 71% yield.

[0045] 1 H NMR (500 MHz, DMSO) δ 7.55 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 5.29 (dd, J = 10.5, 4.4 Hz, 1H), 4.19 (d, J = 1.8 Hz, 2H), 4.11 (q, J = 7.1Hz, 2H), 3.83 (s, 2H), 3.63 (d, J = 3.3 Hz, 4H), 3.18 – 2.95 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0046] 13 C NMR (126 MHz, DMSO) δ 192.96 (s), 163.49 (s), 163.46 – 163.25 (m), 163.10 (d, J= 32.0 Hz), 138.31 (s), 131.94 (s), 131.10 (s), 121.69 (s), 117.38(s), 115.38 (s), 113.38 (s), 67.06 – 66.34 (m), 65.99 (d, J = 32.7 Hz), 63.60(s), 51.16 (dd, J = 111.1, 9.1 Hz), 48.80 (s), 14.06 (s).

[0047] HRMS: m / z calcd for C 17 H 21 BrF₂NO₃S₂[M+H] + : 468.0108; found: 468.0117.

[0048] Example 5

[0049]

[0050] 0.2 mmol of 4-chlorostyrene, 0.4 mmol of BrF₂COOEt, 0.4 mmol of CS₂, 0.2 mmol of morpholine, 2 mol% of CuOTf, and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out at 25 °C under light irradiation for 24 h in air. After the reaction was complete, the reaction mixture was cooled to room temperature and 5 mL of cold water was added. The precipitate was collected. The product was purified by column chromatography to the target product M5 (ethyl 4-(4-chlorophenyl)-2,2-difluoro-4-((4-morpholinyl carbthioyl)thio)butyrate), in 72% yield.

[0051] 1 H NMR (500 MHz, DMSO) δ 7.48 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 5.31 (dd, J = 10.5, 4.4 Hz, 1H), 4.19 (d, J = 1.7 Hz, 2H), 4.11 (q, J = 7.1Hz, 2H), 3.84 (s, 2H), 3.63 (d, J= 5.3 Hz, 4H), 3.19 – 2.95 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0052] 13 C NMR (126 MHz, DMSO) δ 192.99 (s), 163.23 (t, J = 32.1 Hz), 137.87(s), 133.13 (s), 130.79 (s), 129.01 (s), 115.38 (s), 66.45 – 65.14 (m), 63.60(s), 51.59 (s), 50.69 (s), 48.73 (d, J = 4.0 Hz), 14.06 (s).

[0053] HRMS: m / z calcd for C 17 H 22 ClF2NO3S2[M+H] + : 424.0619; found: 424.0626.

[0054] Example 6

[0055]

[0056] 4-Methoxystyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M6 (ethyl 2,2-difluoro-4-(4-methoxyphenyl)-4-((4-morpholinyl carbthioyl)thio)butyrate) in 88% yield.

[0057] 1 H NMR (500 MHz, DMSO) δ 7.34 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.21 (dd, J = 10.7, 4.3 Hz, 1H), 4.20 (dd, J= 19.6, 5.4 Hz, 2H), 4.04 (q, J =7.1 Hz, 2H), 3.82 (s, 2H), 3.75 (s, 3H), 3.63 (s, 4H), 3.14 – 2.95 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[0058] 13 C NMR (126 MHz, DMSO) δ 193.62 (s), 163.54 (s), 163.29 (s), 163.03 (s), 159.46 (s), 130.17 (s), 129.93 (s), 117.44 (s), 115.43 (s), 114.39 (s),113.44 (s), 65.99 (dd, J = 22.8, 7.7 Hz), 63.46 (s), 55.61 (s), 51.43 (s), 51.43 – 50.07 (m), 49.13 (d, J = 4.0 Hz), 14.02 (s).

[0059] HRMS: m / z calcd for C 18 H 24 F2NO4S2[M+H] + : 420.1115; found: 420.1120.

[0060] Example 7

[0061]

[0062] 0.2 mmol of 4-tert-butylstyrene, 0.4 mmol of BrF₂COOEt, 0.4 mmol of CS₂, 0.2 mmol of morpholine, 2 mol% of CuOTf, and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and 5 mL of cold water was added. The precipitate was collected. The product was purified by column chromatography to the target product M7 (ethyl 4-(4-tert-butylphenyl)-2,2-difluoro-4-((4-morpholinylcarbothio)thio)butyrate), in 86% yield.

[0063] 11H NMR (500 MHz, DMSO) δ 7.37 (d, J J = 8.5 Hz, 2H), 7.33 (d, J J = 8.5 Hz,2H), 5.24 (dd, J J = 10.6, 4.2 Hz, 1H), 4.20 (dd, J J = 35.0, 2.7 Hz, 2H), 3.93 (q, J J=7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (d, J J = 5.1 Hz, 4H), 3.15 – 2.96 (m, 2H), 1.26(s, 9H), 1.15 (t, J J = 7.1 Hz, 3H).

[0064] 13 13C NMR (126 MHz, DMSO) δ 193.51 (s), 163.51 (s), 163.25 (s), 163.00(s), 151.04 (s), 135.10 (s), 128.65 (s), 125.82 (s), 117.39 (s), 115.39 (d, J J=2.6 Hz), 113.39 (s), 66.01 (dd, J J = 24.8, 7.6 Hz), 63.40 (s), 51.03 (dd, J J=102.2, 4.2 Hz), 49.19 (s), 34.75 (s), 31.47 (s), 13.99 (s).

[0065] HRMS: m / z calcd for C 21 19 30 [[ID=P3]]F2NO3S2[M+H] + : 446.1629; found: 446.1638.

[0066] Example 8

[0067]

[0068] 3-Bromostyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M8 (ethyl 4-(3-bromophenyl)-2,2-difluoro-4-((4-morpholinyl carbthioyl)thio)butyrate), in 78% yield.

[0069] 1 H NMR (500 MHz, DMSO) δ 7.68 (t, J = 1.7 Hz, 1H), 7.51 (ddd, J = 8.0,1.8, 0.8 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 5.32 (dd, J =10.6, 4.4 Hz, 1H), 4.34 (q, J = 7.1 Hz, 1H), 4.28 – 4.13 (m, 1H), 4.10 (q, J =7.1 Hz, 2H), 3.86 (s, 2H), 3.66 (d, J = 28.4 Hz, 4H), 3.19 (qd, J = 15.2, 10.8Hz, 1H), 3.01 (qd, J = 16.3, 4.3 Hz, 1H), 1.29 (t, J = 7.1 Hz, 1H), 1.23 (t, J =7.1 Hz, 2H).

[0070] 13 C NMR (126 MHz, DMSO) δ 192.91 (s), 184.91 (s), 163.47 (s), 163.22(s), 162.96 (s), 141.62 (s), 131.45 (d, J= 4.2 Hz), 131.19 (s), 128.12 (s),122.17 (s), 117.37 (s), 115.37 (s), 113.38 (s), 66.55 – 65.19 (m), 64.50 (s),63.61 (s), 52.32 (s), 52.11 – 51.81 (m), 51.18 (dd, J = 115.9, 3.2 Hz), 49.75(s), 48.83 (d, J = 4.0 Hz), 14.04 (d, J = 7.5 Hz).

[0071] HRMS: m / z calcd for C 17 H 21 BrF₂NO₃S₂[M+H] + : 468.0108; found: 468.0118.

[0072] Example 9

[0073]

[0074] 3-Chlorostyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M9 (ethyl 4-(3-chlorophenyl)-2,2-difluoro-4-((morpholine-4-carbonylthio)thio)butyrate), in 65% yield.

[0075] 1 H NMR (500 MHz, DMSO) δ 7.55 (d, J = 1.0 Hz, 1H), 7.41 (ddd, J = 7.7,3.8, 1.9 Hz, 1H), 7.39 – 7.38 (m, 1H), 7.38 – 7.35 (m, 1H), 5.32 (dd, J = 10.6, 4.4 Hz, 1H), 4.33 (q, J= 7.1 Hz, 1H), 4.20 (dd, J = 10.9, 7.1 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 3.73 – 3.58 (m, 4H), 3.25 – 3.10 (m, 1H), 3.01(qd, J = 16.3, 4.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 1H), 1.23 (t, J = 7.1 Hz, 2H).

[0076] 13 C NMR (126 MHz, DMSO) δ 192.91 (s), 184.91 (t, J = 5.2 Hz), 163.48(s), 163.22 (s), 162.97 (s), 160.84 (s), 160.60 (s), 141.37 (s), 133.61 (s),130.92 (s), 128.59 (d, J = 14.5 Hz), 127.73 (s), 121.14 (s), 118.92 (s), 117.37(s), 115.37 (s), 113.37 (s), 67.20 – 65.37 (m), 64.50 (s), 63.60 (s), 52.32(s), 51.17 (dd, J = 114.9, 2.1 Hz), 49.75 (s), 48.87 (t, J = 3.8 Hz), 14.03 (d, J =5.4 Hz).

[0077] HRMS: m / z calcd for C 17 H 21 ClF2NO3S2[M+H] + : 424.0614; found: 424.0624.

[0078] Example 10

[0079]

[0080] 0.2 mmol of 4-fluorostyrene, 0.4 mmol of BrF₂COOEt, 0.4 mmol of CS₂, 0.2 mmol of morpholine, 2 mol% of CuOTf, and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out at 25 °C under light irradiation for 24 h in air. After the reaction was complete, the reaction mixture was cooled to room temperature and 5 mL of cold water was added. The precipitate was collected. The product was purified by column chromatography to the target product M10 (ethyl 2,2-difluoro-4-(4-fluorophenyl)-4-((morpholine-4-carbonylthio)thio)butyrate), in 65% yield.

[0081] 1 H NMR (500 MHz, DMSO) δ 7.52 – 7.46 (m, 2H), 7.19 (t, J = 8.8 Hz, 2H), 5.30 (dd, J = 10.7, 4.3 Hz, 1H), 4.20 (dd, J = 8.8, 2.9 Hz, 2H), 4.09 (q, J = 7.1Hz, 2H), 3.84 (s, 2H), 3.63 (s, 4H), 3.19 – 2.96 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0082] 13 C NMR (126 MHz, DMSO) δ 193.16 (s), 163.50 (s), 163.12 (t, J = 16.0Hz), 161.17 (s), 134.89 (d, J = 3.1 Hz), 131.02 (d, J = 8.3 Hz), 117.40 (s), 115.94 (s), 115.77 (s), 115.39 (s), 113.40 (s), 66.00 (ddd, J = 16.9, 5.8, 4.0Hz), 63.54 (s), 51.10 (dd, J = 106.6, 5.1 Hz), 48.74 (t, J = 3.7 Hz), 14.05 (s).

[0083] HRMS: m / z calcd for C 17 H 21 F3NO3S2[M+H] + : 408.0909; found: 408.0919.

[0084] Example 11

[0085]

[0086] 2-Chlorostyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M11 (ethyl 4-(4-chlorophenyl)-2,2-difluoro-4-((morpholine-4-carbonylthio)thio)butyrate), in 60% yield.

[0087] 1 H NMR (500 MHz, DMSO) δ 7.67 (dd, J = 5.6, 3.4 Hz, 1H), 7.53 – 7.46(m, 1H), 7.40 – 7.30 (m, 2H), 5.77 (dd, J = 11.1, 3.9 Hz, 1H), 4.34 (q, J = 7.1Hz, 1H), 4.21 (s, 1H), 4.07 (hd, J = 10.7, 7.1 Hz, 2H), 3.85 (d, J = 9.8 Hz, 2H), 3.65 (d, J = 32.5 Hz, 4H), 3.31 – 3.16 (m, 1H), 3.01 (qd, J = 16.5, 3.8 Hz, 1H), 1.29 (d, J = 7.1 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H).

[0088] 13C NMR (126 MHz, DMSO) δ 193.09 (s), 184.91 (t, J = 5.2 Hz), 163.47(s), 163.21 (s), 162.96 (s), 135.29 (s), 133.27 (s), 130.86 (s), 130.30 (d, J =3.1 Hz), 127.76 (s), 117.27 (s), 115.27 (s), 113.27 (s), 66.86 – 65.02 (m), 64.50 (s), 63.57 (s), 52.32 (s), 51.70 – 50.60 (m), 49.75 (s), 45.98 (d, J =4.7 Hz), 39.04 (d, J = 22.8 Hz), 38.76 (s), 14.02 (d, J = 2.3 Hz).

[0089] HRMS: m / z calcd for C 17 H 21 ClF2NO3S2[M+H] + : 424.0614; found: 424.0623.

[0090] Example 12

[0091]

[0092] 2,3,4,5,6-pentafluorostyrene (0.2 mmol), BrF₂COOEt (0.4 mmol), CS₂ (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%), and the solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnetic stir bar. The reaction was carried out in air at 25 °C under light irradiation for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. The product was purified by column chromatography to the target product M12 (ethyl 2,2-difluoro-4-((morpholine-4-carbonylthio)thio)-4-(perfluorophenyl)butyrate), in 61% yield.

[0093] 1 H NMR (500 MHz, CDCl3) δ 5.98 – 5.87 (m, 1H), 4.25 (q, J= 7.1 Hz, 2H), 3.85 (ddd, J = 11.7, 6.9, 3.2 Hz, 2H), 3.69 (s, 4H), 3.44 (s, 2H), 2.99 – 2.85(m, 2H), 1.33 (dt, J = 14.3, 8.9 Hz, 3H).

[0094] 13 C NMR (126 MHz, CDCl3) δ 193.17 (s), 163.37 (s), 163.11 (s), 162.86(s), 146.44 – 146.11 (m), 144.47 – 144.18 (m), 142.12 (s), 140.68 (s), 140.16(s), 138.63 (dd, J = 25.5, 11.3 Hz), 136.66 (d, J = 10.4 Hz), 116.33 (s), 114.32(s), 113.39 – 112.92 (m), 112.31 (s), 66.43 – 65.94 (m), 63.47 (s), 51.90 –51.39 (m), 50.83 – 50.23 (m), 39.02 – 38.63 (m), 38.53 (s), 31.43 (s), 30.19(s), 29.33 (s), 13.87 (s).

[0095] HRMS: m / z calcd for C 17 H 17 F7NO3S2[M+H] + : 480.0532; found: 480.0543.

[0096] After the reactions in Examples 1-12 above were completed, choline chloride / glycerol could be recovered by evaporating water under reduced pressure. The recovered choline chloride / glycerol could be reused in subsequent experiments. The yield did not decrease significantly after the solvent was used eight times consecutively. Specific results are shown in Table 1.

[0097] Table 1

[0098]

[0099] application

[0100] 1. Experimental Methods

[0101] The mycelial growth rate method was used to determine the in vitro antibacterial activity of the target compound, and *Tricholoma materia malata* and *Pseudomonas aeruginosa* were selected as test strains. Experimental procedure: First, PDA prepared in a conical flask according to the specified ratio was sealed with a breathable sealing film and placed in an autoclave at 120 °C for 30 min. Before inoculation, the solutions of the compound and control drug prepared in Examples 1-12 were prepared using DMSO (dimethyl sulfoxide) as the solvent. Three replicates were performed for each drug concentration culture dish. The colony diameter was measured using the cross-multiplication method, and the inhibition rate was calculated.

[0102] 2. Initial screening results of antibacterial activity

[0103] In the activity assay of dithiofluoride compounds, the antifungal activity against two pathogenic fungi, *Gastropoda graminsis* and *V. mali*, was mainly tested at concentrations of 50 mg / L and 100 mg / L. The test results are shown in Table 2.

[0104] Table 2. Antibacterial activity (inhibition rate %) of thiodifluoroester compounds

[0105]

[0106] Comprehensive analysis of the initial activity screening data revealed that compounds M4, M10, M11, and M12 exhibited superior inhibition rates (over 80%) against *G. graminsis*, the wheat take-all pathogen, at concentrations of 50 mg / L and 100 mg / L. Compounds M10, M11, and M12 also showed superior inhibitory effects against *V. mali*, the apple rot pathogen, at concentrations of 50 mg / L and 100 mg / L, compared to *Hymexazol*. Compound M12, in particular, achieved an inhibition rate exceeding 80% at 50 mg / L.

Claims

1. A process for the preparation of a thiodifluorocarbonate derivative, characterized in that, The following steps were used: R-substituted styrene, BrF₂COOEt, CS₂, morpholine, choline chloride, and glycerol mixed solvent, along with CuOTf, were reacted in air under light irradiation for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the precipitate was collected as difluorothioester. The specific reaction formula is as follows: ； In the above formula, R is 4-CH3, 3-CH3, 4-Br, 3-Br, 4-Cl, 3-Cl, 2-Cl, 4-F, 4-CH3O, 4-tBu or 2, 3, 4, 5, 6-pentafluorine.

2. The production method according to claim 1, characterized by, The molar ratio of the R-substituted styrene, BrF2COOEt, CS2 and morpholine is 1:2:2:

1.

3. The preparation method according to claim 1, characterized in that, The room temperature is 25°C.

4. The production method according to claim 1, characterized by, The ratio of choline chloride to glycerol in the mixed solvent of choline chloride and glycerol is 1:

2.

5. The preparation method according to claim 1, characterized in that, The light source for the illumination is blue light.

6. Use of a thiodifluorocarbonate derivative prepared according to the process of any one of claims 1 to 5, characterized in that, The thiodifluoroester derivative is used in the field of inhibiting wheat take-all pathogens or apple rot pathogens.

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