Fluorine-containing coumarin compound containing chalcone structure as well as preparation method and application of fluorine-containing coumarin compound

Abstract

The invention provides a fluorine-containing coumarin compound containing a chalcone structure as well as a preparation method and application of the fluorine-containing coumarin compound, and belongs to the technical field of organic synthetic chemistry. The structural formula of the compound is # imgabs0, wherein R1 and R2 are independently selected from H, F, Cl, Br, Me, OMe, or a naphthalene ring, or a heterocyclic ring of thiophene, furan and pyridine; the preparation method comprises the following steps: mixing and dissolving a fluorine-containing coumarin compound 1a, a benzoyl trifluoroacetone compound 2a, a solvent and an additive, then carrying out a reaction, and after the reaction is finished, carrying out separation to obtain the fluorine-containing coumarin compound. According to the invention, trifluoromethyl is introduced through a synthesis method of alpha-beta unsaturated ketone, then a chalcone structure is introduced to change the properties of coumarin, the structure is modified, and the antibacterial activity of coumarin is enhanced.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a preparation method and application of a coumarin compound containing a chalcone structure. Background Art

[0002] Fungal diseases seriously threaten global food security and are one of the main reasons for global crop yield reduction and quality decline. At present, agricultural fungicides play an important role in inhibiting fungal diseases, solving the food crisis and ensuring agricultural safety. Traditional agricultural fungicides are mostly chemical fungicides. These fungicides have a quick effect and high efficiency, but they are extremely likely to cause environmental pollution, have high residues, produce drug resistance and have a narrow scope of application. Therefore, it is crucial to develop new, efficient and environmentally friendly agricultural fungicides. Natural products and their derivatives play a crucial role in the development of new agricultural fungicides. Many new green agricultural fungicides come from natural products or are developed based on natural products.

[0003] Coumarin is a natural product widely distributed in higher plants such as Rutaceae, Umbelliferae, Compositae, Leguminosae, etc. It has attracted people's attention due to its unique structure and diverse biological activities. Current research shows that coumarin compounds provide important help in antibacterial and pest control. Some simple coumarins have been widely used in the development of natural source pesticides and applied in agricultural production. For example, the following compounds disclosed below:

[0004]

[0005] 4-Hydroxycoumarin (Compound 1) is often used as an intermediate for synthesizing anticoagulant rodenticides; 7-Hydroxycoumarin (Compound 2) has obvious inhibitory effects on various bacteria and fungi; 6-Methylcoumarin (Compound 3) shows high aphicidal activity against Aphis gossypii, one of the agricultural economic pests, and has no toxicity to bees, and is a green aphicide with broad prospects. In addition, coumarin derivatives also play an important role in resisting agricultural pathogens. In 2022, Compound 4 synthesized by Zhang et al. showed strong bactericidal activity against Botrytis cinerea; in 2023, Compound 5 synthesized by Jiang et al. showed excellent antibacterial activity against Rhizoctonia solani, with an EC 50 value of 10.9 μg / mL, comparable to the commercial fungicide triadimefon (EC 50 = 6.1 μg / mL). According to relevant reports, coumarin compounds not only play an important role in the development of new pesticides, but are also widely used in the medical field. In the early 20th century, based on the significant anticoagulant function of 4-hydroxycoumarin, researchers developed new preparations such as warfarin (Compound 6), etc., which have been widely used clinically.

[0006] Chalcone compounds belong to a type of natural product flavonoids. Existing research shows that chalcone compounds have various biological activities such as insect resistance, antibacterial, and anti-inflammatory properties, and are widely used in fields such as pesticides and medicine. According to available information, for example, the following series of compounds are disclosed:

[0007]

[0008] Compounds 1 and 2 generated by combining the chalcone skeleton with the Strobilurin pharmacophore have a better inhibitory effect on cucumber downy mildew than the positive control drug azoxystrobin, and have potential application prospects in the control of downy mildew. In addition, the synthetic compounds 3 and 4 reported by Ye Yiqiang et al. had inhibition rates of 98.7% and 99.2% respectively against Xanthomonas oryzae pv. oryzae at a concentration of 200 μg / mL. In addition, chalcone compounds are also widely used in the medical field. Since chalcone compounds can inhibit α-glucosidase and improve insulin sensitivity, they are often used to synthesize anti-diabetic drugs. Currently, commonly used chalcone drugs include acarbose tablets, metformin hydrochloride tablets, etc.

[0009] Due to the special properties of fluorine atoms, fluorine-containing compounds have attracted wide attention from medicinal chemists. Introducing fluorine atoms or fluorine-containing groups into drugs can increase the lipophilicity, biocompatibility of drugs, and improve the stability of drug metabolism, etc. Compounds containing a trifluoromethyl structure (CF 3 ) play an important role among them. According to available information, currently about 40% of fluorine-containing pesticides contain a trifluoromethyl structure. The following compounds are some currently marketed pesticides containing fluorine atoms and trifluoromethyl groups:

[0010]

[0011] Currently, the synthesis of coumarin compounds and derivatives containing a chalcone structure mainly uses salicylaldehyde and ethyl acetoacetate as raw materials, and 3-acetylcoumarin is obtained through the Knoevenagel reaction, and then the obtained 3-acetylcoumarin and benzaldehydes with different substituents are synthesized by the Claisen-Schmidt condensation method; or salicylaldehyde is used as a raw material to obtain the corresponding coumarin compounds through the Wittig reaction and formylation reaction, and then synthesized with acetophenones containing different substituents through the Claisen-Schmidt reaction. Using the Knoevenagel reaction requires the use of strong bases or strong acids, which is polluting. Using the Wittig reaction, the reaction rate is slow, the reaction is relatively complex and causes serious environmental pollution. And currently, there is no reported data on the determination of the activity of agricultural pathogens of fluorine-containing coumarin compounds and derivatives containing a chalcone structure. Summary of the Invention

[0012] In view of the above technical problems, the present invention provides a fluorinated coumarin compound containing a chalcone structure, a preparation method and an application thereof. Using coumarin as a skeleton, a trifluoromethyl group is introduced through a synthesis method of α-β unsaturated ketone, and then a chalcone structure is introduced to change the properties of coumarin, modify its structure and enhance its antibacterial activity.

[0013] In order to achieve the above object, the technical solution of the present invention is realized as follows:

[0014] A preparation method of a fluorinated coumarin compound containing a chalcone structure, the reaction equation of which is:

[0015]

[0016] Wherein R 1 and R 2 are independently selected from H, F, Cl, Br, Me, OMe, or a naphthalene ring, or a heterocycle of thiophene, furan, pyridine;

[0017] The preparation method includes the following steps: dissolving a fluorinated coumarin compound 1a, a benzoyltrifluoroacetone compound 2a, a solvent and an additive, and then carrying out a reaction, and separating after the reaction is completed to obtain the product.

[0018] Specifically, put the benzoyltrifluoroacetone compound, the solvent and the additive into a reaction tube with a magnetic stirrer, heat and stir until dissolved, add the fluorinated coumarin compound, the reaction time is about 2 hours, the reaction temperature is 40 - 70 °C, and TLC is used to monitor the reaction until the reaction is complete. After the reaction is completed, pour the reaction solution into a beaker, add dilute hydrochloric acid, distilled water and n-hexane. Stir vigorously until the solid completely precipitates, filter and dry the solid. If purification is required, recrystallize in dichloromethane / n-hexane. If the product has a pyridine ring etc. resulting in no solid precipitation, separate the aqueous phase, add saturated sodium carbonate solution to adjust the pH to alkaline, extract with ethyl acetate and collect the organic phase, dry with anhydrous sodium sulfate and separate the product by column chromatography.

[0019] Those with better reactions are as described in the examples: In a pressure-resistant reaction tube, 4 mL of sulfolane, compound 2a (1.5 mmol), and 4-dimethylaminopyridine (DMAP) (1.65 mmol) were added. After stirring at 50 °C for 30 min, compound 1a (1.5 mmol) was added, and the reaction was stirred at 60 °C for about 2 h. When the molar ratio of compound 1a to compound 2a is 1:1, the effect is better, but it is not limited to this. The molar ratio of the two can be adjusted to be between 1:(1 - 4); when the reaction compound solvent is sulfolane, the reaction effect is the best, but it is not limited to this. Reactions can also occur when using solvents such as chloroform, 1,4-dioxane, dichloroethane (DCE), ethyl acetate (EA), ethanol (EtOH), etc. When the additive is DMAP, the catalytic effect is the best, but it is not limited to this. When using triethylamine (Et 3 N), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium bicarbonate (NaHCO 3 ) etc. as additives, the reaction can also proceed smoothly. When the additive feeding ratio is 1.1 equivalents, the catalytic effect is the best, but it is not limited to this. The additive feeding ratio can be adjusted to be between 0.8 - 2.0. When the reaction temperature is 60 °C, the reaction effect is the best, but it is not limited to this. The reaction can still occur when the temperature is reduced to 40 °C or increased to 120 °C. The reaction time of 2 h has the best effect, but it is not limited to this. The target product can still be obtained when the reaction time is shortened to 1 h or extended to 15 h.

[0020] Advantages of the present invention: The present invention combines coumarin, chalcone, and fluorine-containing compounds, uses fluorine-containing coumarin compounds with different substituents, fluorine-containing 1,3-diketone compounds and derivatives as raw materials, and selects green sulfolane as the solvent to synthesize novel fluorine-containing coumarin compounds containing chalcone structure. As a green solvent, sulfolane is more suitable for the development of green pesticides. The synthesized compounds 3aa - 3bh of the present invention were used to measure the activities against five pathogenic bacteria, namely Fusarium oxysporum, Fusarium graminearum, Fusarium moniliforme, Phytophthora parasitica var. nicotianae, and Rhizoctonia solani. All compounds have certain bactericidal activities against the five pathogenic bacteria, and the antibacterial effect against Rhizoctonia solani is the best. Among them, the bactericidal property of compound 3aa against Rhizoctonia solani can reach more than 80%. Then, the activities of eight compounds, namely 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3bg, and 3ch synthesized in the examples, against the above five pathogenic bacteria were measured. Among them, these eight compounds all have obvious inhibitory effects on Rhizoctonia solani and have broad application prospects. Description of the Drawings

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or in the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0022] Figure 1 1H NMR spectrum of compound 3aa 1

[0023] Figure 2 13C NMR spectrum of compound 3aa 13

[0024] Figure 3 1H NMR spectrum of compound 3ab 1

[0025] Figure 4 13C NMR spectrum of compound 3ab 13

[0026] Figure 5 1H NMR spectrum of compound 3ac 1

[0027] Figure 6 13C NMR spectrum of compound 3ac 13

[0028] Figure 7 1H NMR spectrum of compound 3ad 1

[0029] Figure 8 13C NMR spectrum of compound 3ad 13

[0030] Figure 9 1H NMR spectrum of compound 3ae 1

[0031] Figure 10 13C NMR spectrum of compound 3ae 13

[0032] Figure 11 1H NMR spectrum of compound 3af 1

[0033] Figure 12 13C NMR spectrum of compound 3af 13

[0034] Figure 13 1H NMR spectrum of compound 3bg 1 ​​​​​​​​​​​​​

[0035] Figure 14 1H NMR spectrum of compound 3bg 13 13C spectrum.

[0036] Figure 15 1H NMR spectrum of compound 3bh 1 1H spectrum.

[0037] Figure 16 13C NMR spectrum of compound 3bh 13 13C spectrum.

[0038] Figure 17 Is the antibacterial rate of the fluorinated coumarin compounds containing chalcone structure prepared in Examples 1-8 against Rhizoctonia solani.

[0039] Figure 18 Is the antibacterial rate of the fluorinated coumarin compounds containing chalcone structure prepared in Examples 1-8 against Fusarium graminearum.

[0040] Figure 19 Is the antibacterial rate of the fluorinated coumarin compounds containing chalcone structure prepared in Examples 1-8 against Fusarium moniliforme.

[0041] Figure 20 Is the antibacterial rate of the fluorinated coumarin compounds containing chalcone structure prepared in Examples 1-8 against Phytophthora parasitica var. nicotianae.

[0042] Figure 21 Is the antibacterial rate of the fluorinated coumarin compounds containing chalcone structure prepared in Examples 1-8 against Fusarium oxysporum. Detailed implementation mode

[0043] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.,

[0044] Example 1

[0045] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is as follows:

[0046]

[0047] In a pressure-resistant reaction tube, 4 mL of sulfolane, 1.5 mmol of benzoyltrifluoroacetone (2a) and 1.65 mmol of DMAP were added. After stirring at 40 °C for 30 min, 1.5 mmol of unsubstituted fluorinated coumarin (1a) was added, and the mixture was stirred at 40 °C for about 2 h. The reaction was monitored by TLC until it was complete. After separation and purification, the target product 3aa was obtained with a yield of 46.7%. The NMR spectrum of the product is as Figure 1-2 shown. 1 H NMR(400MHz,DMSO-d 6 )δ8.22(s,1H),8.07(s,1H),7.99(d,J=6.8Hz,2H),7.80(d,J=9.4Hz,1H),7.67(q,J=7.3Hz,1H),7.55(t,J=7.7Hz,2H),7.46-7.34(m,2H)ppm. 13 C NMR(100MHz,DMSO-d 6 )δ189.92,158.50,153.62,143.66,136.36,134.75,133.99(q,J=4.8Hz),133.52,132.73(q,J=31.8Hz),129.58,129.42,129.30,125.50,122.97(q,J=274.7Hz),120.05,118.51,116.73ppm. 19 F NMR(376MHz,DMSO-d 6 ):δ-65.14ppm.

[0048] Example 2

[0049] A method for preparing a fluorinated coumarin compound containing a chalcone structure, the reaction equation of which is:

[0050]

[0051] In a pressure-resistant reaction tube, 4 mL of sulfolane, 1.5 mmol of 4,4,4-trifluoro-1-(naphthalen-2-yl)butane-1,3-dione (2b) and 3.0 mmol of N,N-dimethylpyridin-4-amine were added. After stirring at 50 °C for 30 min, 1.5 mmol of unsubstituted fluorinated coumarin (1a) was added, and the mixture was stirred at 60 °C for about 2 h. The reaction was monitored by TLC until it was complete. After separation and purification, the target product 3ab was obtained with a yield of 80.0%. The NMR spectrum of the product is as Figure 3-4 shown. 1 H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.25(s,2H),8.19(d,J=8.0Hz,1H),8.02(t,J=8.5Hz,2H),7.92(d,J=8.7Hz,1H),7.81(d,J=7.7Hz,1H),7.75 - 7.61(m,3H),7.48 - 7.36(m,2H)ppm. 13 C NMR(100MHz,DMSO - d 6 )δ189.57,158.53,153.62,143.50,135.94,133.84(q,J=4.5Hz),133.78,133.55,132.83(q,J=31.7Hz),132.55,132.21,130.38,129.86,129.59,129.21,128.26,127.73,125.56,123.94,123.06(q,J=275.4Hz),120.27,118.56,116.77ppm. 19 F NMR(376MHz,DMSO - d 6 ):δ - 65.02ppm.

[0052] Example 3

[0053] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is as follows:

[0054]

[0055] In a pressure - resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of 4,4,4 - trifluoro - 1 - (pyridin - 3 - yl)butane - 1,3 - dione (2c) and 3.0 mmol of N,N - dimethyl - 4 - pyridinamine. After stirring at 50 °C for 30 min, add 1.5 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 60 °C for about 2 h, and use TLC to monitor the reaction until it is complete. Separate and purify to obtain the target product 3ac with a yield of 70.0%. The NMR spectrum of the product is as Figure 5-6 shown. 1 H NMR(400MHz,DMSO - d 6)δ9.16(d, J = 2.2Hz, 1H), 8.83(dd, J = 4.8, 1.7Hz, 1H), 8.33(dt, J = 8.1, 2.0Hz, 1H), 8.26(s, 1H), 8.11(d, J = 1.6Hz, 1H), 7.82(dd, J = 7.8, 1.6Hz, 1H), 7.69(ddd, J = 8.7, 7.4, 1.7Hz, 1H), 7.59(dd, J = 8.0, 4.8Hz, 1H), 7.48 - 7.37(m, 2H) ppm. 13 C NMR(100MHz, DMSO - d 6 )δ189.37, 158.54, 154.68, 153.62, 150.38, 143.74, 136.72, 133.66, 133.45(q, J = 4.8Hz), 133.12(q, J = 32.0Hz), 131.91, 129.67, 125.59, 124.51, 122.89(q, J = 276.1Hz), 119.84, 118.50, 116.78 ppm. 19 F NMR(376MHz, DMSO - d 6 ):δ - 65.18 ppm.

[0056] Example 4

[0057] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is:

[0058]

[0059] In a pressure - resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of 4,4,4 - trifluoro - 1 - (4 - fluorophenyl)butane - 1,3 - dione (2d) and 3.0 mmol of N,N - dimethyl - 4 - pyridinamine. After stirring at 50 °C for 30 min, add 1.5 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 60 °C for about 2 h, and use TLC to monitor the reaction until it is complete. Separate and purify to obtain the target product 3ad with a yield of 69.0%. The NMR spectrum of the product is as Figure 7-8 shown. 1 H NMR(400MHz, DMSO - d 6)δ8.96(s,1H),8.53(d,J=8.4Hz,1H),8.23(d,J=9.1Hz,1H),8.12(d,J=1.5Hz,1H),8.12 - 8.06(m,2H),8.05(d,J=8.1Hz,1H),7.72(ddd,J=8.4,6.9,1.4Hz,1H),7.62(t,J=7.0Hz,1H),7.58(d,J=9.0Hz,1H),7.37(t,J=8.8Hz,2H)ppm. 13 C NMR(100MHz,DMSO - d 6 )δ188.48,166.07(d,J=254.2Hz),158.57,153.73,140.02,134.91,133.82(q,J=4.5Hz),133.48(q,J=31.8Hz),133.24(d,J=2.8Hz),132.52(d,J=10.0Hz),130.45,129.41,129.26 - 128.99(m),126.87,122.98(q,J=274.9Hz),122.80,119.29,116.98,116.54(d,J=21.9Hz),112.73ppm. 19 F NMR(376MHz,DMSO - d 6 ):δ - 64.96, - 103.86ppm.

[0060] Example 5

[0061] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is as follows:

[0062]

[0063] In a pressure - resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of 1 - (4 - chlorophenyl) - 4,4,4 - trifluorobutane - 1,3 - dione (2e) and 3.0 mmol of N,N - dimethyl - 4 - pyridinamine. After stirring at 50 °C for 30 min, add 1.5 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 60 °C for about 2 h, and monitor the reaction by TLC until the reaction is complete. Separate and purify to obtain the target product 3ae with a yield of 78.0%. The NMR spectrum of the product is as Figure 9-10 shown. 1 H NMR(400MHz,DMSO - d 6)δ8.98(s,1H),8.55(d,J=8.4Hz,1H),8.27(d,J=9.1Hz,1H),8.12(d,J=1.6Hz,1H),8.08(d,J=8.5Hz,1H),8.03 - 7.99(m,2H),7.75(t,J=7.0Hz,1H),7.67 - 7.59(m,4H)ppm. 13 C NMR(101MHz,DMSO - d 6 )δ188.94,158.56,153.77,140.12,139.73,135.14,135.00,133.78(q,J=4.6Hz),133.60(q,J=32.0Hz),131.25,130.50,129.57,129.46,129.19,129.14,126.94,122.95(q,J=276.1Hz),122.85,119.20,117.02,112.75ppm. 19 F NMR(376MHz,DMSO - d 6 )δ - 64.93ppm.

[0064] Example 6

[0065] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is:

[0066]

[0067] In a pressure - resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of 1 - (4 - bromophenyl) - 4,4,4 - trifluoro - 1,3 - butanedione (2f) and 3.0 mmol of N,N - dimethyl - 4 - pyridinamine. After stirring at 50 °C for 30 min, add 1.5 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 60 °C for about 2 h, and use TLC to monitor the reaction until it is complete. Separate and purify to obtain the target product 3af with a yield of 72.2%. The NMR spectrum of the product is as Figure 11-12 shown. 1 H NMR(400MHz,DMSO - d 6 )δ8.96(s,1H),8.52(d,J=8.4Hz,1H),8.23(d,J=9.1Hz,1H),8.10(d,J=1.5Hz,1H),8.05(d,J=6.9Hz,1H),7.92(d,J=8.6Hz,2H),7.77 - 7.69(m,3H),7.62(t,J=7.5Hz,1H),7.58(d,J=9.0Hz,1H)ppm. 1313C NMR (101 MHz, DMSO-d 6 ) δ 189.15, 158.56, 153.75, 140.09, 135.45, 134.96, 133.73 (q, J = 4.5 Hz), 133.60 (q, J = 31.3 Hz), 132.50, 131.26, 130.46, 129.42, 129.14, 129.11, 129.03, 126.89, 122.96 (q, J = 275.3 Hz), 122.81, 119.17, 116.98, 112.73 ppm. 19 19F NMR (376 MHz, DMSO-d 6 ): δ -64.94 ppm.

[0068] Example 7

[0069] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is as follows:

[0070]

[0071] In a pressure-resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of thienoyltrifluoroacetone (2 g) and 3.0 mmol of N,N-dimethyl-4-pyridylamine. After stirring at 60 °C for 30 min, add 1.5 mmol of 8-methoxy-3-(trifluoroacetyl)-2H-chromen-2-one (1b), stir and react at 60 °C for about 2 h, and use TLC to monitor the reaction until it is complete. Separate and purify to obtain 3b g of the target product, with a yield of 73%. The NMR spectrum of the product is as Figure 13-14 shown. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (dd, J = 4.0, 1.2 Hz, 1H), 8.18 - 8.13 (m, 2H), 8.00 (d, J = 1.6 Hz, 1H), 7.38 (q, J = 4.2, 3.4 Hz, 1H), 7.35 - 7.30 (m, 3H), 3.93 (s, 3H) ppm. 13 13C NMR (101 MHz, DMSO-d 6 ) δ 181.27, 158.18, 146.92, 144.31, 143.14, 142.89, 138.30, 136.25, 133.56 (q, J = 32.2 Hz), 131.76 (q, J = 4.7 Hz), 129.79, 125.51, 122.88 (q, J = 275.7 Hz), 120.70, 120.52, 119.12, 115.63, 56.67 ppm. 19FNMR(376MHz,DMSO-d 6 ):δ - 65.50ppm.

[0072] Example 8

[0073] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is:

[0074]

[0075] In a pressure-resistant reaction tube, add 4 mL of sulfolane, 1.5 mmol of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2 g) and 3.0 mmol of N,N-dimethyl-4-pyridinamine. After stirring at 60 °C for 30 min, add 1.5 mmol of 8-methoxy-3-(trifluoroacetyl)-2H-chromen-2-one (1b), stir and react at 60 °C for about 2 h, and use TLC to monitor the reaction until it is complete. Separate and purify to obtain the target product 3bh with a yield of 64%. The NMR spectrum of the product is as Figure 15-16 shown. 1 H NMR(400MHz,DMSO-d 6 )δ 8.15(s,1H),8.13(d,J = 1.6Hz,1H),7.88(d,J = 3.7Hz,1H),7.82(d,J = 1.6Hz,1H),7.40 - 7.35(m,1H),7.33(d,J = 5.4Hz,2H),6.82(dd,J = 3.7,1.7Hz,1H),3.94(s,3H)ppm. 13 C NMR(101MHz,DMSO-d 6 )δ 175.53,158.17,152.47,150.43,146.92,143.06,142.90,133.75(q,J = 31.9Hz),131.17(q,J = 4.7Hz),125.49,122.82(q,J = 274.8Hz),122.41,120.70,120.50,119.14,115.60,113.80,56.66ppm. 19 F NMR(376MHz,DMSO-d 6 ):δ - 65.79ppm.

[0076] Bactericidal activity test:

[0077] Take 33 mg of the synthesized drug above and dissolve it in 3.3 mL of DMSO. Similarly, weigh 33 mg of carbendazim as the positive control for this experiment, and use 3.3 mL of DMSO as the negative control. Add 2.66 mL of Tween 80 to 250 mL of water, stir well, and seal it with plastic sealing film and kraft paper for later use. Next to the alcohol lamp flame, add 0.66 mL of the medicinal liquid and 2.65 mL of Tween water to each culture medium, shake well, sterilize the bottle mouth by burning, and then pour it evenly into three culture media. After the culture medium solidifies, cut along the edge of the bacterial cake with a puncher next to the alcohol lamp flame, pick it out with an inoculation needle, and invert and inoculate it in the petri dish. After inoculation, seal it with sealing film and invert it. Incubate it in a constant temperature incubator at 25 °C.

[0078] The calculation formula is: Inhibitory rate I = (D 0 - D t ) / D 0 × 100%.

[0079] D 0 is the average diameter of the mycelium on the control plate, and D t is the average diameter of the mycelium on the sample plate.

[0080] Select the compounds synthesized in Examples 1-8 to carry out activity determination on five pathogenic bacteria, namely Fusarium oxysporum, Fusarium graminearum, Fusarium moniliforme, Phytophthora parasitica var. nicotianae, and Rhizoctonia solani. As Figure 17-21 shown, all compounds have certain bactericidal activities against the five pathogenic bacteria, and the inhibitory effect on Rhizoctonia solani is the best. Among them, the bactericidal property of compound 3aa against Rhizoctonia solani can reach more than 80%. Then, carry out activity determination on the five pathogenic bacteria mentioned above for the eight compounds 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3bg, and 3ch synthesized in the examples. Among them, these eight compounds all have obvious inhibitory effects on Rhizoctonia solani and have broad application prospects.

[0081] Example 9

[0082] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is:

[0083]

[0084] In a pressure-resistant reaction tube, add 3 mL of chloroform, 1.5 mmol of benzoyltrifluoroacetone (2a), and 3 mmol of sodium bicarbonate. Stir at 40 °C for 30 min, then add 3 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 120 °C for about 1 h, and use TLC to monitor the reaction until the reaction is complete. Separate and purify to obtain the target product 3aa with a yield of 41.7%.

[0085] Example 10

[0086] A preparation method of a fluorinated coumarin compound containing a chalcone structure, and its reaction equation is as follows:

[0087]

[0088] In a pressure-resistant reaction tube, add 6 mL of dichloroethane, 1.5 mmol of benzoyltrifluoroacetone (2a) and 1.2 mmol of triethylamine. After stirring at 40 °C for 30 min, add 6 mmol of unsubstituted fluorinated coumarin (1a), stir and react at 80 °C for about 15 h, and use TLC to monitor the reaction until the reaction is complete. Separate and purify to obtain the target product 3aa with a yield of 49.1%.

[0089] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A fluorine-containing coumarin compound containing a chalcone structure, characterized in that: The structural formula of the compound is: Where R 1 and R 2 Independently selected from H, F, Cl, Br, Me, OMe, or a naphthalene ring, or a heterocyclic ring of thiophene, furan, or pyridine.

2. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 1, characterized in that: The reaction equation is: Where R 1 and R 2 independently selected from H, F, Cl, Br, Me, OMe, or a naphthalene ring, or a heterocyclic ring of thiophene, furan, or pyridine; The preparation method comprises the following steps: mixing and dissolving a fluorine-containing coumarin compound 1a, a benzoyltrifluoroacetone compound 2a, a solvent and an additive, then reacting, and separating to obtain the product after the reaction is completed.

3. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 2, characterized in that: The molar ratio of the fluorine-containing coumarin compound 1a to the benzoyltrifluoroacetone compound 2a is 1:1-4.

4. The method for preparing a fluorine-containing coumarin compound containing a chalcone structure according to claim 3, characterized in that: The molar ratio of the fluorine-containing coumarin compound 1a to the benzoyltrifluoroacetone compound 2a is 1:1-2.

5. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 2, characterized in that: The ratio of the fluorine-containing coumarin compound 1a to the solvent is 1:2-4 mmol / mL.

6. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 5, characterized in that: The solvent is sulfolane, chloroform, 1,4-dioxane, dichloroethane, ethyl acetate or ethanol.

7. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 2, characterized in that: The molar ratio of the fluorine-containing coumarin compound 1a to the additive is 1:0.8-2.

8. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 7, characterized in that: The additive is 4-dimethylaminopyridine, triethylamine, sodium bicarbonate or 1,8-diazabicycloundec-7-ene.

9. The method for preparing the fluorine-containing coumarin compound containing a chalcone structure according to claim 2, characterized in that: The reaction temperature is 40-120° C., and the reaction time is 1-15 h.

10. Use of the fluorine-containing coumarin compound containing a chalcone structure according to claim 1 in agricultural fungicides.

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