Thiodifluoroester derivative, preparation method thereof and application of thiodifluoroester derivative in antibacterial aspect

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a sulfo-difluoro ester derivative, a preparation method thereof and application of the sulfo-difluoro ester derivative in the aspect of bacteriostasis. The preparation method of the thiodifluoroester derivative comprises the following steps: reacting styrene, a mixed solvent of BrF2COOEt, CS2, morpholine, choline chloride and glycerol and CuOTf in an air atmosphere under light irradiation for 24 hours, cooling to room temperature after the reaction is completed, and collecting a precipitate, namely thiodifluoroester, the preparation method disclosed by the invention is simple, efficient, green and pollution-free; the compound can be widely applied to the field of inhibition of gaeumannomyces graminis or valsa mali.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a thiodifluoroester derivative and a preparation method thereof and an application thereof in antibacterial properties. Background Art

[0002] Sulfur-containing compounds (Green Chem., 2021, 23: 496), especially organic dithiocarbamates, are ubiquitous in various biologically active compounds (Org. Lett., 2019, 21: 7938). For example, they are often used in medicinal chemistry and have been used in cancer treatment (Bioorg. Med. Chem. Lett., 2006, 16: 4214). The biological properties of sulfur-containing compounds play a key role in agriculture, which has promoted the development of the synthesis of these compounds. Therefore, the development of efficient and green methods to synthesize this important sulfur-containing compound will be of great value for the screening of bioactive molecules.

[0003] Difluoroalkyl functional groups are an important class of basic scaffolds, and a variety of bioactive drugs containing CF2 moieties have been reported (Antiviral Therapy, 2009, 14: 607). In recent years, especially difluoroethyl bromoacetate is 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 and 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). Dithiocarbamate analogs with phenyl end groups showed excellent inhibitory effects on the tested cancer cell lines.

[0006] The above methods not only require the use of expensive metal catalysts such as palladium, but also require heating, high energy consumption, and are environmentally unfriendly. Therefore, developing an environmentally friendly, low-cost method for preparing thiodifluoroester derivatives has extensive economic and social benefits. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the present invention adopts the following technical solutions: The preparation method of thiodifluoroester derivatives comprises the following steps: styrene, BrF 2 COOEt, CS 2 , morpholine, choline chloride and propylene glycol mixed solvent and CuOTf were reacted under air atmosphere and light irradiation for 24 h. After the reaction was completed, it was cooled to room temperature and the precipitate was collected to obtain difluorothioate; the specific reaction formula is: In the above formula, R is 4-CH 3 , 3-CH 3 ,4-Br,3-Br,4-Cl,3-Cl,2-Cl,4-F,4-CH 3 O, 4-tBu or 2,3,4,5,6-pentafluoro; R 1 for , R 2 for .

[0008] Preferably, the styrene, BrF 2 The molar ratio of COOEt, CS2 and morpholine is 1:2:2:1.

[0009] Preferably, the room temperature is 25°C.

[0010] Preferably, the ratio of choline chloride to glycerol in the choline chloride and glycerol mixed solvent is 1:2.

[0011] Preferably, the light source of the light irradiation is blue light.

[0012] A thiodifluoroester derivative prepared by the above method.

[0013] 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.

[0014] Beneficial effects: The synthesis method of the present invention is simple, efficient, green and pollution-free. Comprehensive analysis of the preliminary screening data of activity shows that the inhibition rates of compounds M4, M10, M11 and M12 at 50 mg / L and 100 mg / L against wheat take-all pathogen are better than those of the control drug hymexazol, with an inhibition rate of more than 80%; the inhibition effects of compounds M10, M11 and M12 at 50 mg / L and 100 mg / L against apple rot pathogen are better than those of the control drug, among which the inhibition rate of compound M12 at 50 mg / L can reach more than 80%. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1The inhibitory effects of M4, M10, M11 and M12 on wheat take-all pathogen. DETAILED DESCRIPTION

[0016] The present invention is further illustrated by specific examples below. It should be understood that the preparation methods of the examples of the present invention are only used to illustrate the present invention, rather than 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 fall within the scope of protection required by the present invention.

[0017] It should also be noted that the various preferred technical features of the method of the present invention mentioned above and the various specific technical features in the embodiments described in detail below can be combined together, and all combinations of all these technical features with all numerical ranges with the numerical values ​​specifically disclosed in the present invention as upper and lower limits, etc., fall within the scope of the present invention.

[0018] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0019] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources or synthesized from raw materials obtained from commercial sources.

[0020] The specific embodiments of the present invention are described in detail below in conjunction with the technical solutions, but the process conditions are not limited to these embodiments.

[0021] Example 1 Styrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M1 (ethyl 2,2-difluoro-4-((4-morpholinylcarbonylsulfanyl)sulfanyl)-4-phenylbutyrate) was obtained with a yield of 85%.

[0022] 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). 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). HRMS: m / z calcd for C 17 H 22 F 2 NO 3 S 2 [M+H] + : 390.1003; found: 390.1008. Example 2 p-Methylstyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M2 (ethyl 2,2-difluoro-4-((4-morpholinylcarbonylsulfanyl)sulfanyl)-4-phenylbutyrate) was obtained with a yield of 76%.

[0023] 1 H NMR (500 MHz, DMSO) δ 7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz,2H), 5.23 (dd, J = 10.6, 4.2 Hz, 1H), 4.20 (dd, J = 13.0, 3.8 Hz, 2H), 4.04 (q, J =7.1 Hz, 2H), 3.83 (s, 2H), 3.64 (d, J = 4.1 Hz, 4H), 3.17 – 2.92 (m, 2H), 2.29(s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C 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 = 19.7 Hz), 63.48 (s), 51.49 – 51.45 (m), 51.01 (dd, J =96.2, 3.7 Hz), 49.34 (s), 21.15 (s), 14.02 (s). HRMS: m / z calcd for C 18 H 24 F 2 NO 3 S 2 [M+H] + : 404.1160; found: 404.1165. Example 3 3-Methylstyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2(0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M3 (ethyl 2,2-difluoro-4-((4-morpholinylcarbonylsulfanyl)sulfanyl)-4-(m-methylphenyl)butyrate) was obtained with a yield of 70%.

[0024] 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). 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). HRMS: m / z calcd for C 18 H24 F 2 NO 3 S 2 [M+H] + : 404.1160; found: 404.1167. Example 4 4-Bromostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M (ethyl 4-(4-bromophenyl)-2,2-difluoro-4-((4-morpholinylcarbonylsulfonyl)sulfanyl)butyrate) was obtained with a yield of 71%.

[0025] 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). 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). HRMS: m / z calcd for C 17 H 21 F 2 NO 3 S 2 [M+H] + : 468.0108; found: 468.0117. Example 5 4-Chlorostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M5 (ethyl 4-(4-chlorophenyl)-2,2-difluoro-4-((4-morpholinylcarbonylsulfanyl)sulfanyl)butyrate) was obtained with a yield of 72%.

[0026] 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). 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). HRMS: m / z calcd for C 17 H 22 CIF 2 NO 3 S 2 [M+H] + : 424.0619; found: 424.0626. Example 6 4-Methoxystyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M6 (ethyl 2,2-difluoro-4-(4-methoxyphenyl)-4-((4-morpholinylcarbonylsulfanyl)sulfanyl)butyrate) was obtained with a yield of 88%.

[0027] 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). 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). HRMS: m / z calcd for C 18 H 24 F 2 NO 4 S 2 [M+H] + : 420.1115; found: 420.1120 . Example 7 4-tert-Butylstyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M7 (ethyl 4-(4-tert-butylphenyl)-2,2-difluoro-4-((4-morpholinylcarbonylsulfonyl)sulfanyl)butyrate) was obtained with a yield of 86%.

[0028] 1H NMR (500 MHz, DMSO) δ 7.37 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz,2H), 5.24 (dd, J = 10.6, 4.2 Hz, 1H), 4.20 (dd, J = 35.0, 2.7 Hz, 2H), 3.93 (q, J =7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (d, J = 5.1 Hz, 4H), 3.15 – 2.96 (m, 2H), 1.26(s, 9H), 1.15 (t, J = 7.1 Hz, 3H). 13 C 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 =2.6 Hz), 113.39 (s), 66.01 (dd, J = 24.8, 7.6 Hz), 63.40 (s), 51.03 (dd, J =102.2, 4.2 Hz), 49.19 (s), 34.75 (s), 31.47 (s), 13.99 (s). HRMS: m / z calcd for C 21 H 30 F 2 NO 3 S 2 [M+H] + : 446.1629; found: 446.1638. Example 8 3-Bromostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2(0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M8 (ethyl 4-(3-bromophenyl)-2,2-difluoro-4-((4-morpholinylcarbonylsulfonyl)sulfanyl)butyrate) was obtained with a yield of 78%.

[0029] 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). 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). HRMS: m / z calcd for C 17 H 21 F 2 NO 3 S 2 [M+H] + : 468.0108; found: 468.0118. Example 9 3-Chlorostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M9 (ethyl 4-(3-chlorophenyl)-2,2-difluoro-4-((morpholine-4-carbonylthio)thio)butyrate) was obtained with a yield of 65%.

[0030] 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). 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). HRMS: m / z calcd for C 17 H 21 CIF 2 NO 3 S 2 [M+H] + : 424.0614; found: 424.0624. Example 10 4-Fluorostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2(0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M10 (ethyl 2,2-difluoro-4-(4-fluorophenyl)-4-((morpholine-4-carbonylthio)thio)butyrate) was obtained with a yield of 65%.

[0031] 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). 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). HRMS: m / z calcd for C 17 H 21 F 3 NO 3 S2 [M+H] + : 408.0909; found: 408.0919. Embodiment 11 2-Chlorostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M11 (ethyl 4-(4-chlorophenyl)-2,2-difluoro-4-((morpholine-4-carbonylthio)thio)butyrate) was obtained with a yield of 60%.

[0032] 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). 13 C 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). HRMS: m / z calcd for C 17 H 21 CIF 2 NO 3 S 2 [M+H] + : 424.0614; found: 424.0623. Example 12 2,3,4,5,6-pentafluorostyrene (0.2 mmol), BrF 2 COOEt (0.4 mmol), CS 2 (0.4 mmol), morpholine (0.2 mmol), CuOTf (2 mol%) and solvent choline chloride / glycerol (1:2, 1 mL) were added to a 25 mL reaction tube equipped with a magnet. The reaction was carried out at 25 °C under air atmosphere and light irradiation for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected. After column chromatography purification, the target product M12 (ethyl 2,2-difluoro-4-((morpholine-4-carbonylthio)thio)-4-(perfluorophenyl)butyrate) was obtained with a yield of 61%.

[0033] 1 H NMR (500 MHz, CDCl 3 ) 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). 13 C NMR (126 MHz, CDCl 3 ) 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). HRMS: m / z calcd for C 17 H 17 F 7 NO 3 S 2 [M+H] + : 480.0532; found: 480.0543. After the reaction of the above examples 1-12 is completed, choline chloride / glycerol can be recovered by evaporating water under reduced pressure. The recovered choline chloride / glycerol can be used in subsequent experiments. After the solvent is used for 8 consecutive times, the yield does not decrease significantly. The specific results are shown in Table 1: Table 1 application 1. Experimental Methods The method for determining the in vitro antibacterial activity of the target compound used the mycelium growth rate method, and selected wheat rot pathogen and apple rot pathogen as the test strains. Experimental steps: First, the PDA prepared in a conical flask according to the proportion was sealed with a breathable sealing film, placed in a high-pressure sterilizer at a temperature of 120 ℃, and sterilized for 30 minutes. Before inoculation, the compounds prepared in Examples 1-12 and the control drug solution were also prepared, using DMSO (dimethyl sulfoxide) as the solvent. In the experiment, each drug concentration culture dish was measured with 3 parallel repetitions. The colony diameter was measured using the cross method, and the inhibition rate was calculated.

[0034] 2. Preliminary screening results of antibacterial activity In the activity determination of thiodifluoro ester compounds, the antibacterial activity of two pathogenic fungi, G. graminsis and V. mali, was tested at concentrations of 50 mg / L and 100 mg / L. The test results are shown in Table 2: Table 2 Antibacterial activity of thiodifluoroester compounds (inhibition rate %) Comprehensive analysis of the preliminary screening data showed that the inhibition rates of compounds M4, M10, M11, and M12 at 50 mg / L and 100 mg / L against the wheat take-all pathogen G. graminsis were better than those of the control drug Hymexazol, with inhibition rates exceeding 80%. The inhibition effects of compounds M10, M11, and M12 at 50 mg / L and 100 mg / L against the apple rot pathogen V. mali were better than those of the control drug Hymexazol, with the inhibition rate of compound M12 at 50 mg / L reaching over 80%.

Claims

1. A method for preparing a thiodifluoroester derivative, characterized in that: The following steps are adopted: styrene, BrF2COOEt, CS2, morpholine, choline chloride and glycerol mixed solvent and CuOTf are reacted under air atmosphere and light irradiation for 24 hours. After the reaction is completed, it is cooled to room temperature and the precipitate is collected to be thiodifluoroester; the specific reaction formula is: ； 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-pentafluoro; R 1 for , R 2 for .

2. The preparation method according to claim 1, characterized in that: The molar ratio of 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 preparation method according to claim 1, characterized in that: The ratio of choline chloride to glycerol in the choline chloride and glycerol mixed solvent is 1:

2.

5. The preparation method according to claim 1, characterized in that: The light source of the light irradiation is blue light.

6. A thiodifluoroester derivative prepared by the method according to any one of claims 1 to 5.

7. Use of the thiodifluoroester derivative according to claim 6, characterized in that: The thiodifluoroester derivative is used in the field of inhibiting wheat take-all pathogen or apple rot pathogen.

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