A coumarin thiazole derivative, its preparation method and application

Abstract

The present invention discloses a coumarin thiazole derivative, which is a compound having the structure shown in the following general formula (I) obtained by modifying the hydroxyl group of 7-hydroxycoumarin. This type of compound has fungicidal activity and has a certain antibacterial or bactericidal effect on sesame pathogenic fungi such as Macrophomina phaseolina, Fusarium oxysporum, and Corynespora cassiicola at a concentration of 500 μg / mL. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of pesticides, relates to coumarin derivatives, and particularly relates to a coumarin thiazole derivative and a preparation method thereof, as well as the application of the derivative in fungicides. Background Art

[0002] Structural modification and transformation of natural products is one of the important methods for discovering new green pesticides. Some natural compounds have been used for the prevention and control of plant diseases. For example, Shi Zhiqi et al. (Preliminary study on the inhibitory mechanism of osthole against plant pathogenic fungi [J]. Acta Phytophylacica Sinica, 2004(04): 28-32.) reported that osthole is registered for the prevention and control of wheat powdery mildew, rice damping-off and rice sheath blight, etc. Dingxiangjunzhi developed by Shenyang Research Institute of Chemical Industry has a strong control effect on apple canker and cucumber downy mildew, etc. (Guan Aiying et al. The creation context of the fungicide dingxiangjunzhi [J]. Agrochemicals, 2011, 50(02): 90-92.).

[0003] Coumarin is a class of compounds containing a benzopyran structure that widely exists in nature, and has broad-spectrum biological activities such as antioxidant, anticoagulant, anti-inflammatory, anti-tumor, anti-HIV, anti-blood sugar and antibacterial. In the research and development of agricultural fungicides, coumarin compounds have also received increasing attention.

[0004] Thiazole is a class of five-membered aromatic heterocyclic compounds containing nitrogen and sulfur atoms, and has activities such as herbicidal, insecticidal and bactericidal. There are already multiple commercial fungicides containing thiazole structures, such as thiabendazole, thifluzamide, boscalid, etc.

[0005] Chen Naiyuan et al. (Synthesis and antibacterial activity of dehydroabietic acid-based B-ring fused thiazole-amide compounds [J]. Fine Chemicals, 2016, 33(07): 8-11.) introduced a thiazole group into dehydroabietic acid for structural modification, and synthesized a series of novel dehydroabietic acid-based B-ring fused thiazole-amide compounds with significant antifungal activity. Ding Chengrong et al. (Synthesis and biological activities of aryl thiazole-linked piperidine amide compounds [J]. Chinese Journal of Organic Chemistry, 2020, 40(02): 528-535.) synthesized a series of aryl thiazole-linked piperidine amide compounds, and the compounds showed high antifungal and insecticidal activities.

[0006] There have been a large number of reports on introducing thiazole groups into the coumarin parent body and studying its antibacterial activity. However, most of these studies have focused on the 3-position structure of coumarin (Coumarin thiazoles as unique structural skeleton of potential antimicrobial agents[J]. Bioorganic Chemistry, 2022, 124: 105855.; Novel chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids as potential antibacterial repressors against methicillin-resistant Staphylococcus aureus[J]. European Journal of Medicinal Chemistry, 2021, 222: 113628.). Summary of the Invention

[0007] Aiming at the problem that the bactericidal and antibacterial activities of natural active molecular compounds are generally average, the purpose of the present invention is to provide a coumarin thiazole derivative with excellent activity and bactericidal effect, as well as a preparation method of the coumarin thiazole derivative.

[0008] Providing the application of the coumarin thiazole derivative in agricultural fungicides is another object of the present invention.

[0009] The coumarin thiazole derivative described in the present invention is a compound with the chemical structure shown in the following general formula (I).

[0010]

[0011] Wherein:

[0012] The substituent R is or .

[0013] Specifically, R1 represents one or more substituents connected to the benzene ring, selected from hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, tribromomethyl, tribromomethoxy, trichloromethyl or trichloromethoxy, and n is 1 or 2.

[0014] Specifically, R2 represents a substituent connected to the thiophene ring, selected from hydrogen, methyl, formyl, acetyl, halogen or phenyl.

[0015] Further preferably, in the coumarin thiazole derivative of the present invention, the substituent R is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 4-ethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-trichloromethylphenyl, 4-trichloromethoxyphenyl, 3-tribromomethylphenyl, 3-tribromomethoxyphenyl, 2-thienyl, 2-(3-methylthienyl) group, 2-(3-formylthienyl) group, 2-(3-acetylthienyl) group, 2-(3-chlorothienyl) group, 2-(3-bromothienyl) group or 2-(3-phenylthienyl) group.

[0016] Still further, in the coumarin thiazole derivative of the present invention, the substituent R is selected from 3,4-dichlorophenyl or 2-thienyl.

[0017] According to the principle of active substructure splicing, the present invention introduced a thiazole ring into the 7-position structure of the natural active substance coumarin, designed and synthesized a series of novel coumarin thiazole derivatives, discovered compounds with high bactericidal activity, and for the first time applied this coumarin thiazole derivative as an agricultural fungicide.

[0018] Furthermore, the present invention also provides a preparation method of the coumarin thiazole derivative, specifically using an α-bromoacetone derivative shown in the following structural general formula (V) as a raw material,

[0019]

[0020] Carrying out a cyclization reaction with thiourea to prepare a fourth intermediate shown in the following structural general formula (VI);

[0021]

[0022] Then, carrying out an amidation reaction between a third intermediate shown in the following structural formula (IV) and the fourth intermediate shown in the above structural general formula (VI) to prepare a target product of the coumarin thiazole derivative shown in the structural general formula (I);

[0023]

[0024] Among them, the definition of R is the same as that in the structural general formula (I).

[0025] In the above preparation method of the present invention, specifically, the cyclization reaction is carried out in an ethanol solvent system at 75 - 85 °C, and the reaction time is preferably 1 - 2 h.

[0026] In the above preparation method of the present invention, specifically, the amidation reaction is carried out in a toluene solvent system containing potassium carbonate at 100-110 °C, and its preferred reaction time is 1-2 h.

[0027] In the synthesis process of the target product of the coumarin thiazole derivative of the present invention, referring to the literature (Papadopoulou MV, Bloomer WD, Rosenzweig HS, et al. European journal of medicinal chemistry, 2016, 117: 179-186.; Geronikaki AA, Lagunin AA, Hadjipavlou-Litina DI, et al. Journal of medicinal chemistry, 2008, 51(6): 1601-1609.; Geronikaki A, Theophilidis G. European journal of medicinal chemistry, 1992, 27(7): 709-716.), three different solvent systems of dichloromethane / triethylamine, DMF / potassium carbonate and toluene / potassium carbonate were respectively tried. In the first two systems, the reaction was not complete enough, and even some did not react; while when non-polar toluene was used as the solvent and potassium carbonate was used as the acid-binding agent, although the solubility of the raw materials in the solvent was poor, the high temperature was sufficient to promote the reaction to proceed, making the reaction relatively complete and the product yield relatively high.

[0028] Furthermore, the present invention does not limit any way to obtain the third intermediate shown in the structural formula (IV) for preparing the target product of the coumarin thiazole derivative, and the compound of the structure can be prepared by adopting various feasible synthetic routes or methods.

[0029] However, based on the fact that there is no report on the preparation method of this compound in the existing literature, the present invention further provides a preparation method of the third intermediate shown in the structural formula (IV), specifically prepared according to the following method.

[0030] 1) Using 7-hydroxycoumarin and ethyl chloroacetate as raw materials, carry out the Williamson ether synthesis reaction to prepare the first intermediate shown in the following structural formula (II);

[0031]

[0032] 2) Carry out the hydrolysis reaction of the carboxylic acid ester for the first intermediate to prepare the second intermediate shown in the following structural formula (III);

[0033]

[0034] 3), perform the acyl chloride reaction of the carboxylic acid with the second intermediate to prepare a third intermediate represented by the structural formula (IV).

[0035] Specifically, the Williamson ether synthesis reaction is carried out in an acetone solvent system containing potassium carbonate with 7-hydroxycoumarin and ethyl chloroacetate at 50 - 60 °C.

[0036] More specifically, the preferred reaction time for the Williamson ether synthesis reaction is 6 - 9 h.

[0037] Specifically, for the hydrolysis reaction, first react at 75 - 85 °C in an alkaline aqueous solution for 1 - 2 h, and then carry out an acidification reaction to prepare the second intermediate.

[0038] Specifically, the acyl chloride reaction is carried out with thionyl chloride in benzene solvent at 75 - 80 °C for 2 - 2.5 h.

[0039] During the acyl chloride reaction process, referring to the literature (Ozcan S, Kazi A, Marsilio F, et al. Journal of medicinal chemistry, 2013, 56(10): 3783 - 3805.; Hu L, Zhao Y. Organic & Biomolecular Chemistry, 2018, 16(31): 5580 - 5584.), two solvent systems of tetrahydrofuran and benzene were respectively tried. When tetrahydrofuran was used as the solvent, the product yield was low and there were many impurity spots; while in the non-polar benzene solvent, although the solubility of the raw materials was poor, the reaction was milder, and the product had high purity and high yield.

[0040] The specific preparation method of the coumarin thiazole derivative of the present invention can be carried out according to the following synthetic route.

[0041]

[0042] Furthermore, the present invention also provides the application of the coumarin thiazole derivative in inhibiting or killing crop pathogenic fungi.

[0043] Specifically, the crop pathogenic fungi in the present invention involve Macrophomina phaseolina Macrophomina phaseolina Fusarium oxysporum Fusarium oxysporum Corynespora cassiicola Corynespora cassiicola

[0044] More specifically, the coumarin thiazole derivatives of the present invention are mainly used to inhibit or kill pathogenic fungi on sesame crops, especially pathogenic fungi such as Macrophomina phaseolina, Fusarium oxysporum, and Corynespora cassiicola.

[0045] Furthermore, the present invention also provides a crop fungicide, which contains the coumarin thiazole derivative of the present invention as a pharmaceutically active ingredient, and the mass percentage content of the pharmaceutically active ingredient is 0.1 - 99.9%.

[0046] The crop fungicide of the present invention can be prepared into various conventional pesticide fungicides by combining the pharmaceutically active ingredient with any necessary adjuvants. For example, but not limited to, it can be prepared into any one of a suspension concentrate, an emulsion in water, a dispersible oil suspension, a wettable powder, a water dispersible granule, an emulsifiable concentrate, or a microemulsion.

[0047] The coumarin thiazole derivative provided by the present invention has a novel structure, is easy to synthesize, and has bactericidal activity. In particular, it has a good bactericidal effect on sesame crop diseases caused by pathogenic fungi such as Macrophomina phaseolina, Fusarium oxysporum, and Corynespora cassiicola, thus providing a new crop fungicide. Description of the Drawings

[0048] Figure 1 It shows the effect of the coumarin thiazole derivative of the present invention on inhibiting the activity of Macrophomina phaseolina. From left to right are the compound of Example 1, the compound of Example 11, and dimethomorph.

[0049] Figure 2 It shows the effect of the coumarin thiazole derivative of the present invention on inhibiting the activity of Fusarium oxysporum. From left to right are the compound of Example 1 and dimethomorph.

[0050] Figure 3 It shows the effect of the coumarin thiazole derivative of the present invention on inhibiting the activity of Corynespora cassiicola. From left to right are the compound of Example 1 and dimethomorph. Embodiments

[0051] The following further describes in detail the specific embodiments of the present invention with reference to the drawings and examples. The following examples are only used to more clearly illustrate the technical solutions of the present invention, so that those skilled in the art can well understand and utilize the present invention, rather than limiting the protection scope of the present invention.

[0052] The production processes, experimental methods, or detection methods involved in the embodiments of the present invention are all conventional methods in the prior art without special instructions, and their names and / or abbreviations are all conventional names in the field. They are very clear and definite in the relevant application fields, and those skilled in the art can understand the conventional process steps according to the names and apply the corresponding equipment, and implement them under conventional conditions or the conditions recommended by the manufacturer.

[0053] There are no special restrictions on the sources of various instruments, equipment, raw materials or reagents used in the embodiments of the present invention. They are all conventional products that can be obtained through regular commercial channels, and can also be prepared according to the conventional methods well-known to those skilled in the art.

[0054] The coumarin thiazole derivatives in the following embodiments of the present invention are specifically prepared from commercially available chemical reagents such as 7-hydroxycoumarin, ɑ-bromoacetone derivatives, ethyl chloroacetate and thiourea.

[0055] (1) Synthesis of Intermediate (II)

[0056] Add 7-hydroxycoumarin, potassium carbonate, ethyl chloroacetate and acetone into a flask, react at 50 - 60 °C for 6 - 9 h, monitor the reaction completion by TLC, concentrate under reduced pressure to remove acetone, dissolve the residue with ethyl acetate, wash the organic layer three times with saturated sodium hydroxide solution and saturated brine respectively, dry over anhydrous sodium sulfate, and distill off ethyl acetate under reduced pressure to obtain Intermediate (II).

[0057] (2) Synthesis of Intermediate (III)

[0058] Add Intermediate (II), sodium hydroxide, water and ethanol into a flask, react at 75 - 85 °C for 1 - 2 h, monitor the reaction completion by TLC, add 2 mol / L hydrochloric acid for acidification, a large amount of white solid is produced, filter, wash with water and dry to obtain Intermediate (III).

[0059] (3) Synthesis of Intermediate (IV)

[0060] Add Intermediate (III), thionyl chloride and benzene into a flask, react at 75 - 80 °C for 2 - 2.5 h, monitor the reaction completion by TLC, distill off benzene under reduced pressure to obtain Intermediate (IV).

[0061] (4) Synthesis of Thiazole Derivative (VI)

[0062] Add ɑ-bromoacetone derivative, thiourea and ethanol into a flask, react at 75 - 85 °C for 1 - 2 h, after monitoring the reaction completion by TLC, distill off ethanol under reduced pressure, wash the residue three times with saturated sodium bicarbonate solution and water respectively, dry to obtain Thiazole Derivative (VI) with a yield of 80 - 95%.

[0063] (5) Synthesis of the Target Product

[0064] Add Intermediate (IV), Thiazole Derivative (VI), potassium carbonate and toluene into a flask, react at 110 °C for 1 - 2 h, monitor the reaction completion by TLC, wait for the system to cool to room temperature, filter, wash the filter cake with saturated sodium bicarbonate solution and water respectively, and finally obtain the target product by silica gel column chromatography.

[0065] Example 1

[0066] N-(4-(3,4-dichlorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, the structural formula is as follows, molecular formula C 20 H 12 Cl2N2O4S.

[0067]

[0068] Add 20 mmol (3.24 g) of 7-hydroxycoumarin, 30 mmol (4.14 g) of potassium carbonate, and 40 mL of acetone to a 100 mL flask. After stirring at room temperature for 15 min, add 30 mmol (3.68 g) of ethyl chloroacetate and react at 50 °C for 7 h.

[0069] Monitor the reaction by TLC, concentrate under reduced pressure to remove acetone, dissolve the residue in ethyl acetate, wash the ethyl acetate organic phase three times with saturated sodium hydroxide solution and saturated brine respectively, dry over anhydrous sodium sulfate, and then distill off ethyl acetate under reduced pressure to obtain the intermediate (II) as a white solid with a yield of 72%.

[0070] Add 16.3 mmol (3.58 g) of the above intermediate (II), 28.5 mmol (1.14 g) of sodium hydroxide, 5 mL of water and 15 mL of ethanol to a 50 mL flask and react at 85 °C for 1 h.

[0071] Monitor the reaction by TLC, add 2 mol / L hydrochloric acid for acidification, a large amount of white solid is produced, filter, wash with water, and dry to obtain the intermediate (III) as a white solid with a yield of 94%.

[0072] Add 1.5 mmol (0.33 g) of the above intermediate (III), 9 mmol (0.774 mL) of thionyl chloride, and 10 mL of benzene to a 25 mL flask and react at 80 °C for 2 h.

[0073] Monitor the reaction by TLC, distill off benzene under reduced pressure to obtain the intermediate (IV) as a light red solid with a yield of 90%.

[0074] Add 5 mmol (1.34 g) of 2-bromo-3',4'-dichloroacetophenone, 5 mmol (0.38 g) of thiourea and 15 mL of ethanol to a 50 mL flask and react at 85 °C for 2 h.

[0075] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(3,4-dichlorophenyl)thiazol-2-amine with a yield of 93%.

[0076] 1.3 mmol (0.285 g) of the above intermediate (IV), 1 mmol (0.25 g) of 4-(3,4-dichlorophenyl)thiazol-2-amine, 1.5 mmol (0.205 g) of potassium carbonate and 10 mL of toluene were added to a 50 mL flask, and the reaction was carried out at 110 °C for 1.5 h.

[0077] The reaction was monitored by TLC. After the system was cooled to room temperature, it was filtered. The filter cake was washed with saturated sodium bicarbonate solution and water respectively. The obtained crude product was separated and purified by column chromatography with (methanol∶dichloromethane = 1∶14) to obtain the white solid target product N-(4-(3,4-dichlorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with a yield of 79%.

[0078] 1 H NMR (600 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.92 – 7.86 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.31 (d, J = 9.6 Hz, 1H), 5.03 (s, 2H).

[0079] 13 C NMR (101 MHz, DMSO-d6) δ 167.08, 161.30, 160.64, 158.08, 155.65, 146.85, 144.67, 135.19, 132.07, 131.50, 130.61, 130.03, 127.85, 126.20, 113.43, 113.11, 110.99, 102.10, 66.81.

[0080] Example 2

[0081] N-(4-(3-methoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, the structural formula is as follows, molecular formula C 21 H 16 N2O5S.

[0082]

[0083] The synthesis of intermediates (II), (III) and (IV) was the same as that in Example 1.

[0084] Add 6.5 mmol (1.49 g) of α-bromo-3-methoxyacetophenone, 6.5 mmol (0.49 g) of thiourea and 19.5 mL of ethanol to a 50 mL flask and react at 85 °C for 2 h.

[0085] Monitor the reaction by TLC, remove ethanol by distillation under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(3-methoxyphenyl)thiazol-2-amine with a yield of 91%.

[0086] Add 1.69 mmol (0.37 g) of intermediate (IV), 1.3 mmol (0.27 g) of 4-(3-methoxyphenyl)thiazol-2-amine, 1.95 mmol (0.27 g) of potassium carbonate and 13 mL of toluene to a 50 mL flask and react at 110 °C for 1.5 h.

[0087] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶22) to obtain the white solid target product N-(4-(3-methoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide with a yield of 56%.

[0088] 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.90 (dd, J = 8.2, 2.7 Hz, 1H), 6.31 (d, J = 9.5 Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H).

[0089] 13 C NMR (101 MHz, DMSO-d6) δ 166.43, 160.86, 160.15, 159.62, 157.12, 155.17, 148.82, 144.18, 135.54, 129.81, 129.54, 118.07, 113.68, 112.92, 112.62, 110.95, 108.79, 101.59, 66.32, 55.09.

[0090] Example 3

[0091] N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 20 H 13 ClN2O4S.

[0092]

[0093] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0094] Add 7.15 mmol (1.60 g) of α-bromo-4-chloroacetophenone, 7.15 mmol (0.54 g) of thiourea and 21.5 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0095] Monitor the reaction by TLC, distill off the ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(4-chlorophenyl)thiazol-2-amine with a yield of 89%.

[0096] Add 1.86 mmol (0.41 g) of intermediate (IV), 1.43 mmol (0.30 g) of 4-(4-chlorophenyl)thiazol-2-amine, 2.15 mmol (0.30 g) of potassium carbonate and 14.3 mL of toluene into a 50 mL flask, and react at 110 °C for 2 h.

[0097] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶16) to obtain the target product N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a pale yellow solid with a yield of 33%.

[0098] 1 H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.05 – 7.02 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.03 (s, 2H).

[0099] 1313C NMR (101 MHz, DMSO-d6) δ 166.50, 160.84, 160.14, 157.42, 155.16, 147.72, 144.19, 133.03, 132.32, 129.54, 128.77, 127.40, 112.93, 112.62, 109.17, 101.60, 66.32。

[0100] Example 4

[0101] N-(4-(4-Methoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, the structural formula is as follows, molecular formula C 21 H 16 N2O5S。

[0102]

[0103] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0104] Add 10.30 mmol (2.36 g) of α-bromo-4-methoxyacetophenone, 10.30 mmol (0.78 g) of thiourea and 30.9 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0105] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(4-methoxyphenyl)thiazol-2-amine with a yield of 90%.

[0106] Add 2.68 mmol (0.59 g) of intermediate (IV), 2.06 mmol (0.42 g) of 4-(4-methoxyphenyl)thiazol-2-amine, 3.10 mmol (0.43 g) of potassium carbonate and 20.6 mL of toluene into a 50 mL flask, and react at 110 °C for 2 h.

[0107] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶21) to obtain the target product N-(4-(4-methoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a pale yellow solid with a yield of 54%.

[0108] 11H NMR (600 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.07 – 7.02 (m, 2H), 7.02 – 6.95 (m, 2H), 6.32 (d, J = 9.5 Hz, 1H), 5.02 (s, 2H), 3.79 (s, 3H).

[0109] 13 13C NMR (101 MHz, DMSO-d6) δ 166.32, 160.87, 160.16, 159.04, 157.08, 155.16, 148.87, 144.18, 129.54, 127.03, 114.11, 113.79, 112.92, 112.61, 106.36, 101.60, 66.34, 55.13.

[0110] Example 5

[0111] N-(4-(2,5-Dimethoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, the structural formula is as follows, molecular formula C 22 H 18 N2O6S.

[0112]

[0113] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0114] Add 12.01 mmol (3.11 g) of α-bromo-2,5-dimethoxyacetophenone, 12.01 mmol (0.91 g) of thiourea and 36.0 mL of ethanol into a 100 mL flask, and react at 85 °C for 2 h.

[0115] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(2,5-dimethoxyphenyl)thiazol-2-amine, with a yield of 88%.

[0116] Add 3.12 mmol (0.69 g) of intermediate (IV), 2.

[0117] The reaction was monitored by TLC. After the system was cooled to room temperature, it was filtered. The filter cake was washed with saturated sodium bicarbonate solution and water respectively. The obtained crude product was separated and purified by column chromatography with (methanol∶dichloromethane = 1∶25) to obtain the white solid target product N-(4-(2,5-dimethoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with a yield of 66%.

[0118] 1 H NMR (600 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.73 (s, 1H), 7.69 – 7.64 (m, 2H), 7.08 – 7.01 (m, 3H), 6.89 (dd, J = 8.9, 3.2 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 5.03 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H).

[0119] 13 C NMR (101 MHz, DMSO-d6) δ 166.36, 160.89, 160.16, 155.61, 155.17, 153.06, 150.95, 144.68, 144.18, 129.54, 123.09, 113.93, 112.95, 112.92, 112.62, 112.47, 101.59, 66.35, 55.89, 55.41.

[0120] Example 6

[0121] N-(4-(3-fluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 20 H 13 FN2O4S.

[0122]

[0123] The synthesis of intermediates (II), (III) and (IV) was the same as that in Example 1.

[0124] 10.81 mmol (2.35 g) of α-bromo-3-fluorophenacyl ketone, 10.81 mmol (0.82 g) of thiourea and 32.4 mL of ethanol were added to a 50 mL flask, and the reaction was carried out at 85 °C for 2 h.

[0125] The reaction was monitored by TLC, ethanol was removed by distillation under reduced pressure, and the residue was washed three times with saturated sodium bicarbonate solution and water respectively, and then dried to obtain 4-(3-fluorophenyl)thiazol-2-amine with a yield of 92%.

[0126] 2.81 mmol (0.55 g) of intermediate (IV), 2.17 mmol (0.42 g) of 4-(3-fluorophenyl)thiazol-2-amine, 3.25 mmol (0.45 g) of potassium carbonate and 21.7 mL of toluene were added to a 50 mL flask, and the mixture was reacted at 110 °C for 2.0 h.

[0127] The reaction was monitored by TLC. After the system was cooled to room temperature, the mixture was filtered. The filter cake was washed with saturated sodium bicarbonate solution and water respectively. The obtained crude product was separated and purified by column chromatography with (methanol∶dichloromethane = 1∶12) to obtain the target product N-(4-(3-fluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a pale yellow solid with a yield of 56%.

[0128] 1 H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H),7.80 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (dt, J = 10.5, 2.2 Hz, 1H), 7.67(d, J = 8.3 Hz, 1H), 7.48 (td, J = 8.0, 6.1 Hz, 1H), 7.17 (td, J = 8.6, 2.7Hz, 1H), 7.07 – 7.01 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.04 (s, 2H).

[0129] 13 C NMR (101 MHz, DMSO-d6) δ 166.54, 162.58 (d, J = 242.5 Hz), 160.84,160.15, 157.38, 155.16, 147.63, 144.18, 136.54 (d, J = 8.3 Hz), 130.79 (d, J= 8.3 Hz), 129.54, 121.71, 114.52 (d, J = 21.1 Hz), 112.93, 112.62, 112.24(d, J = 23.0 Hz), 109.83, 101.60, 66.31.

[0130] Example 7

[0131] N-(4-(4-Fluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 20 H 13 FN2O4S.

[0132]

[0133] The synthesis of intermediates (II), (III) and (IV) is the same as in Example 1.

[0134] Add 7.78 mmol (1.69 g) of α-bromo-4-fluorophenacyl ketone, 7.78 mmol (0.59 g) of thiourea and 23.3 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0135] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(4-fluorophenyl)thiazol-2-amine with a yield of 87%.

[0136] Add 2.02 mmol (0.40 g) of intermediate (IV), 1.56 mmol (0.30 g) of 4-(4-fluorophenyl)thiazol-2-amine, 2.35 mmol (0.32 g) of potassium carbonate and 15.6 mL of toluene into a 50 mL flask, and react at 110 °C for 2.0 h.

[0137] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶13) to obtain the target product N-(4-(4-fluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a white solid with a yield of 31%.

[0138] 1 H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.69 – 7.64 (m, 2H), 7.31 – 7.24 (m, 2H), 7.07 – 7.01 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.03 (s, 2H).

[0139] 1313C NMR (101 MHz, DMSO-d6) δ 166.45, 161.81 (d, J = 244.9 Hz), 160.85, 160.15, 157.35, 155.16, 147.95, 144.18, 130.81, 129.54, 127.71 (d, J = 8.1 Hz), 115.60 (d, J = 21.7 Hz), 112.93, 112.62, 108.20, 101.60, 66.33。

[0140] Example 8

[0141] N-(4-(4-Trifluoromethoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 21 H 13 F3N2O5S。

[0142]

[0143] The synthesis of intermediates (II), (III) and (IV) is the same as in Example 1.

[0144] Add 11.67 mmol (3.30 g) of α-bromo-4-trifluoromethoxyacetophenone, 11.67 mmol (0.89 g) of thiourea and 35.0 mL of ethanol into a 100 mL flask, and react at 85 °C for 2 h.

[0145] Monitor the reaction by TLC, remove ethanol by distillation under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine with a yield of 85%.

[0146] Add 3.03 mmol (0.60 g) of intermediate (IV), 2.34 mmol (0.61 g) of 4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine, 3.53 mmol (0.48 g) of potassium carbonate and 23.4 mL of toluene into a 50 mL flask, and react at 110 °C for 2.0 h.

[0147] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶15) to obtain the white solid target product of N-(4-(4-trifluoromethoxyphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide with a yield of 61%.

[0148] 11H NMR (600 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.05 – 7.97 (m, 3H), 7.76(s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.07 – 7.01 (m,2H), 6.31 (d, J = 9.5 Hz, 1H), 5.03 (s, 2H).

[0149] 13 13C NMR (101 MHz, DMSO-d6) δ 166.52, 160.85, 160.15, 157.52, 155.17,147.80, 147.52, 144.19, 133.43, 129.54, 127.49, 121.32, 118.82, 112.93,112.62, 109.44, 101.60, 66.32.

[0150] Example 9

[0151] N-(4-(3-Trifluoromethylphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, the structural formula is as follows, molecular formula C 21 H 13 F3N2O4S.

[0152]

[0153] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0154] Add 13.42 mmol (3.80 g) of α-bromo-3-trifluoromethylacetophenone, 13.42 mmol (1.02 g) of thiourea and 40.2 mL of ethanol into a 100 mL flask, and react at 85 °C for 2 h.

[0155] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(3-(trifluoromethoxy)phenyl)thiazol-2-amine, with a yield of 87%.

[0156] Add 3.03 mmol (0.60 g) of intermediate (IV), 2.34 mmol (0.61 g) of 4-(3-(trifluoromethoxy)phenyl)thiazol-2-amine, 3.48 mmol (0.55 g) of potassium carbonate and 26.9 mL of toluene into a 50 mL flask, and react at 110 °C for 2.0 h.

[0157] The reaction was monitored by TLC. After the reaction system was cooled to room temperature, it was filtered. The filter cake was washed with saturated sodium bicarbonate solution and water respectively. The obtained crude product was separated and purified by column chromatography with (methanol∶dichloromethane = 1∶15) to obtain the target product, N-(4-(3-trifluoromethylphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, as a pale yellow solid, with a yield of 33%.

[0158] 1 H NMR (600 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.26 (s, 1H), 8.24 – 8.18(m, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.93 (s, 1H), 7.72 – 7.62 (m, 3H), 7.07 –7.02 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.04 (s, 2H).

[0159] 13 C NMR (101 MHz, DMSO-d6) δ 166.58, 160.83, 160.15, 157.62, 155.16,147.20, 144.18, 135.06, 129.95, 130.27 – 128.79 (m), 129.54, 129.42, 124.60 –123.97 (m), 122.30 – 121.89 (m), 112.94, 112.62, 110.25, 101.61, 66.32.

[0160] Example 10

[0161] N-(4-(2,4-difluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, and the molecular formula C 20 H 12 F2N2O4S.

[0162]

[0163] The synthesis of intermediates (II), (III) and (IV) was the same as that in Example 1.

[0164] 9.13 mmol (2.15 g) of α-bromo-2,4-difluoroacetophenone, 9.13 mmol (0.69 g) of thiourea and 27.3 mL of ethanol were added to a 50 mL flask and reacted at 85 °C for 2 h.

[0165] The reaction was monitored by TLC, ethanol was removed under reduced pressure, and the residue was washed three times with saturated sodium bicarbonate solution and water respectively, and then dried to obtain 4-(2,4-difluorophenyl)thiazol-2-amine with a yield of 85%.

[0166] 2.06 mmol (0.41 g) of intermediate (IV), 1.59 mmol (0.34 g) of 4-(2,4-difluorophenyl)thiazol-2-amine, 2.37 mmol (0.37 g) of potassium carbonate and 18.3 mL of toluene were added to a 50 mL flask, and the mixture was reacted at 110 °C for 1.8 h.

[0167] The reaction was monitored by TLC. After the system was cooled to room temperature, it was filtered. The filter cake was washed with saturated sodium bicarbonate solution and water respectively. The obtained crude product was separated and purified by column chromatography with (methanol∶dichloromethane = 1∶10) to obtain the target product N-(4-(2,4-difluorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a white solid with a yield of 41%.

[0168] 1 H NMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.06 (td, J = 8.9, 6.7 Hz,1H), 8.00 (d, J = 9.5 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.6 Hz,1H), 7.37 (ddd, J = 11.7, 9.2, 2.6 Hz, 1H), 7.21 (td, J = 8.5, 2.6 Hz, 1H),7.06 – 7.01 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.04 (s, 2H).

[0169] 13 C NMR (101 MHz, DMSO-d6) δ 166.55, 160.84, 160.15, 158.56 – 158.11(m), 156.88, 155.16, 144.18, 141.88, 129.54, 129.45, 118.90 – 118.54 (m),112.93, 112.62, 112.31 (d, J = 13.6 Hz), 104.66 (t, J = 26.2 Hz), 101.65,101.60, 66.32.

[0170] Example 11

[0171] N-(4-(4-Thien-2-yl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, and the molecular formula C 18 H 12 N2O4S2.

[0172]

[0173] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0174] Add 6.5 mmol (1.34 g) of 2-bromo-1-thienyl ethanone, 6.5 mmol (0.49 g) of thiourea and 19.5 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0175] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(thien-2-yl)thiazol-2-amine with a yield of 91%.

[0176] Add 1.69 mmol (0.37 g) of intermediate (IV), 1.3 mmol (0.27 g) of 4-(thien-2-yl)thiazol-2-amine, 1.95 mmol (0.27 g) of potassium carbonate and 13 mL of toluene into a 50 mL flask, and react at 110 °C for 1.5 h.

[0177] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶11) to obtain the target product N-(4-(4-thien-2-yl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a yellow solid with a yield of 62%.

[0178] 1 H NMR (600 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.55 – 7.49 (m, 3H), 7.11 (dd, J = 5.1, 3.5 Hz, 1H), 7.06 – 7.00 (m, 2H), 6.31 (d, J = 9.5 Hz, 1H), 5.01 (s, 2H).

[0179] 1313C NMR (101 MHz, DMSO-d6) δ 166.44, 160.85, 160.15, 157.29, 155.16, 144.18, 143.80, 138.22, 129.55, 128.06, 125.61, 123.86, 112.93, 112.60, 106.80, 101.59, 101.54, 66.27。

[0180] Example 12

[0181] N-(4-Phenylthiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 20 H 14 N2O4S.

[0182]

[0183] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0184] Add 7.48 mmol (1.49 g) of α-bromoacetophenone, 7.48 mmol (0.56 g) of thiourea and 22.4 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0185] Monitor the reaction by TLC, distill off the ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-phenylthiazol-2-amine with a yield of 85%.

[0186] Add 1.94 mmol (0.43 g) of intermediate (IV), 1.50 mmol (0.26 g) of 4-phenylthiazol-2-amine, 2.24 mmol (0.31 g) of potassium carbonate and 35.6 mL of toluene into a 100 mL flask, and react at 110 °C for 1.5 h.

[0187] Monitor the reaction by TLC. After the system cools to room temperature, filter. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶18) to obtain the target product N-(4-phenylthiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide as a white solid with a yield of 26%.

[0188] 11H NMR (600 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.00 (d, J = 9.7 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.66 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 7.05 – 7.02 (m, 1H), 6.31 (d, J = 9.5 Hz, 1H), 5.02 (s, 2H).

[0189] 13 13C NMR (101 MHz, DMSO-d6) δ 166.42, 160.86, 160.15, 157.24, 155.17, 148.97, 144.18, 134.17, 129.54, 128.74, 127.85, 125.69, 112.92, 112.61, 108.41, 101.60, 66.33.

[0190] Example 13

[0191] N-(4-(4-Trifluoromethylphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with the structural formula as follows, molecular formula C 21 H 13 F3N2O4S.

[0192]

[0193] The synthesis of intermediates (II), (III) and (IV) is the same as that in Example 1.

[0194] Add 6.36 mmol (1.70 g) of α-bromo-4-trifluoromethylacetophenone, 6.36 mmol (0.48 g) of thiourea and 19.0 mL of ethanol into a 50 mL flask, and react at 85 °C for 2 h.

[0195] Monitor the reaction by TLC, distill off ethanol under reduced pressure, wash three times with saturated sodium bicarbonate solution and water respectively, and dry to obtain 4-(4-(trifluoromethyl)phenyl)thiazol-2-amine, with a yield of 83%.

[0196] Add 1.65 mmol (0.37 g) of intermediate (IV), 1.28 mmol (0.31 g) of 4-(4-(trifluoromethyl)phenyl)thiazol-2-amine, 1.90 mmol (0.26 g) of potassium carbonate and 30.5 mL of toluene into a 100 mL flask, and react at 110 °C for 1.5 h.

[0197] Monitor the reaction by TLC. After the system cools to room temperature, filter it. Wash the filter cake with saturated sodium bicarbonate solution and water respectively. The obtained crude product is separated and purified by column chromatography with (methanol∶dichloromethane = 1∶14) to obtain the white solid target product of N-(4-(4-trifluoromethylphenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, with a yield of 23%.

[0198] 1 H NMR (600 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 8.00 (d, J = 9.4 Hz, 1H), 7.90 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 7.07 – 7.02 (m, 1H), 6.32 (d, J = 9.4 Hz, 1H), 5.04 (s, 2H).

[0199] 13 C NMR (101 MHz, DMSO-d6) δ 166.61, 160.84, 160.15, 157.66, 155.16, 147.38, 144.18, 137.86, 129.54, 128.51 – 127.54 (m), 126.25, 125.91 – 125.61 (m), 112.93, 112.63, 111.04, 101.61, 66.32.

[0200] Application Example

[0201] Use the coumarin thiazole derivatives prepared in the above examples as test materials, and adopt the mycelial growth rate method to conduct antibacterial experiments against plant pathogenic fungi to test the antifungal activities of different derivatives.

[0202] All inhibition activity tests are carried out in a laminar flow hood, and all materials used are sterilized by high temperature and high pressure.

[0203] Tested plant pathogenic fungi: Macrophomina phaseolina ( Macrophomina phaseolina ), Fusarium oxysporum (Fusarium oxysporum ), Corynespora cassiicola Corynespora cassiicola ), etc., sesame pathogenic fungi, provided by the Henan Academy of Agricultural Sciences.

[0204] The culture medium used in the experiment was the prepared potato - dextrose - agar (PDA) medium.

[0205] Take a small amount of dimethyl sulfoxide (DMSO) to dissolve the compound to be tested, add it to the PDA medium, and dilute it into a drug - containing plate with a concentration of 500 μg / mL. Take an equal amount of DMSO and add it to the PDA medium, and use it as a blank control after cooling.

[0206] Use a punch with a diameter of 5 mm to punch out uniformly shaped and sized fungal discs in sequence. Use an inoculation loop to inoculate the cut fungal discs in the center of the plate. Set up a blank control and a positive control, and set three parallel controls for each experimental group. Place the inoculated petri dishes in a constant - temperature incubator at 25 °C with light (12 h darkness, 12 h light). When the mycelium in the blank control covers the entire plate, use the cross - method to measure the growth diameter of the colonies in each experimental group, and calculate the inhibition rate of the test compound.

[0207] Inhibition rate (%) = (Growth diameter of colonies in blank control - Growth diameter of colonies in medicament - treated group) / (Growth diameter of colonies in blank control - Stalk diameter) × 100%

[0208] The determination results of the antibacterial activities of the coumarin thiazole derivatives and dimethomorph against sesame pathogenic fungi in each example are as Figures 1-3 shown, and the calculated results are shown in Table 1.

[0209]

[0210] It can be seen from Table 1 that at a concentration of 500 μg / mL, each coumarin thiazole derivative has certain inhibitory activities against three fungi, Macrophomina phaseolina, Fusarium oxysporum, and Corynespora cassiicola. Among them, for Macrophomina phaseolina, the o - dichlorophenyl - substituted structure of the compound in Example 1 shows the best performance, with an inhibition rate reaching 86.09%, much higher than 48.15% of the positive control drug dimethomorph; the thiophene aromatic ring - substituted structure is second, and its inhibition rate is comparable to that of the control drug. For Fusarium oxysporum, the o - dichlorophenyl - substituted structure also has good activity, with an inhibition rate of 55.22%, comparable to that of dimethomorph. For Corynespora cassiicola, the o - dichlorophenyl - substituted structure has slightly better activity than dimethomorph, with an inhibition rate of 77.1%, and the inhibition effect of the thiophene aromatic ring - substituted structure is slightly worse than that of the control drug, with an inhibition rate of 51.43%. Among the others, except for the monofluorophenyl - substituted structure, the electron - withdrawing structures such as trifluoromethylphenyl - substituted and trifluoromethoxyphenyl - substituted structures have slightly worse activities than the thiophene aromatic ring - substituted structure, the phenyl - substituted structure has the second - best activity, and the electron - donating structures such as methoxyphenyl - substituted structure have the worst activity.

[0211] The above embodiments of the present invention do not describe all the details in detail, nor do they limit the present invention to the above-described embodiments. All changes, modifications, substitutions, and variations made to these embodiments by those of ordinary skill in the art without departing from the principles and spirit of the present invention shall be included within the protection scope of the present invention.

Claims

1. A coumarin thiazole derivative, the chemical name of the derivative being N-(4-(3,4-dichlorophenyl)thiazol-2-yl)-2-(2-oxo-coumarin-7-yloxy)acetamide, and the chemical structural formula being as follows: ； Molecular formula C 20 H 12 Cl2N2O4S.

2. The preparation method of the coumarin thiazole derivative according to claim 1, which is to carry out a cyclization reaction between 2-bromo-3',4'-dichloroacetophenone and thiourea to prepare 4-(3,4-dichlorophenyl)thiazol-2-amine, and then carry out an amidation reaction with a third intermediate shown in the following structural formula (IV) to prepare the target product of the coumarin thiazole derivative: 。 3. The preparation method of the coumarin thiazole derivative according to claim 2, characterized in that The cyclization reaction is carried out at 75-85 °C for 1-2 h in an ethanol solvent system; the amidation reaction is carried out at 100-110 °C for 1-2 h in a toluene solvent system containing potassium carbonate.

4. The preparation method of the coumarin thiazole derivative according to claim 2, characterized in that The third intermediate shown in the structural formula (IV) is prepared according to the following method: 1). Carry out a Williamson ether synthesis reaction with 7-hydroxycoumarin and ethyl chloroacetate as raw materials to prepare a first intermediate shown in the following structural formula (II); ； 2). Carry out a hydrolysis reaction of the carboxylic acid ester for the first intermediate to prepare a second intermediate shown in the following structural formula (III); ； 3). Carry out an acyl chloride reaction of the carboxylic acid for the second intermediate to prepare the third intermediate shown in the structural formula (IV).

5. The preparation method of the coumarin thiazole derivative according to claim 4, characterized in that The Williamson ether synthesis reaction is carried out at 50-60 °C for 6-9 h in an acetone solvent system containing potassium carbonate; the hydrolysis reaction is carried out at 75-85 °C for 1-2 h in an alkaline aqueous solution and the second intermediate is prepared through acidification; the acyl chloride reaction is carried out in a benzene solvent at 75-80 °C and reacted with thionyl chloride for 2-2.5 h.

6. The application of the coumarin thiazole derivative according to claim 1 in inhibiting or killing crop pathogenic fungi, wherein the crop pathogenic fungi are Macrophomina phaseolina, Fusarium oxysporum or Corynespora cassiicola.

7. According to the application of claim 6, the crop is sesame.

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