A fluorine-containing quinazolinone compound, a preparation method and application thereof

Abstract

This invention discloses a fluoroquinazolinone compound, its preparation method, and its applications, belonging to the fields of organic synthetic chemistry and agricultural fungicide technology. The method uses 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid and oxime ether compounds as raw materials. Under the action of the condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the catalyst 4-dimethylaminopyridine, the reaction is carried out at 20-30℃ for 8-16 h to construct a target compound in one step, fusing multiple active fragments including quinazolinone, trifluoromethyl, oxime ether, and amide. This invention features mild reaction conditions, simple operation, good functional group compatibility, a wide range of substrate applicability, and good product yield. The eight compounds prepared all exhibit certain fungicidal activity against *Rhizoctonia solani*, *Tricholoma mater*, and *Rhizoctonia solani*. Compound 3d showed an inhibition rate of up to 90.7% against *Tricholoma mater*, providing important lead compounds and new synthetic ideas for the development of novel green agricultural fungicides.

Description

Technical Field

[0001] This invention belongs to the technical field of organic synthetic chemistry and agricultural fungicides, and particularly relates to a quinazolinone compound. Background Technology

[0002] Food is the foundation of the nation, and food security is a matter of paramount importance. Ensuring food security is not only a core national strategic requirement but also a fundamental support for safeguarding people's livelihoods. Currently, fungal diseases have become a significant threat to crop production, causing substantial annual yield reductions and economic losses. Agricultural fungicides are the most important and commonly used technical means for controlling crop fungal diseases. While traditional fungicides offer advantages such as rapid onset and high efficacy, long-term and excessive application can easily induce drug resistance in pathogens and lead to a series of ecological and food safety problems, including excessive pesticide residues and soil and water pollution. Therefore, developing novel green fungicides that are highly efficient, low in toxicity, and environmentally compatible has become a key research direction in the field of pesticide innovation. Among these, structural modification and optimization using natural products as active lead compounds is a highly promising strategy for green pesticide development.

[0003] The quinazolinone skeleton, composed of a fused benzene and pyrimidine ring, is one of the most desirable heterocyclic skeletons, widely found in natural products, drugs, and bioactive molecules. Quinazolinones form the structural basis of over 150 natural alkaloids, and their unique structure and diverse biological activities have made them a "privileged structure" for drug development in both pharmaceutical and pesticide fields. In the late 20th century, researchers developed compound raltitrexate, a specific thymidylate synthase (TS) inhibitor, which is currently widely used clinically to treat advanced rectal cancer. In the field of pesticides, quinazoline ketones have often been regarded as key active ingredients in naturally derived pesticides in recent years. Compound II, benquitrione, is a herbicide discovered by Professor Yang Guangfu's research group in 2013. It is the world's first commercially available quinazoline dione pesticide, highly safe for sorghum, and characterized by high efficiency, broad spectrum of weed control, low toxicity, and low residue. It is particularly effective against major noxious weeds in sorghum fields such as wild millet and tiger tail grass. In 2024, compound III, synthesized by Kang Lei et al., showed an inhibition rate of over 90% against crabgrass and foxtail grass. Through molecular mechanism studies such as membrane permeability assessment, transcriptome analysis, and ACC enzyme activity detection, compound III was confirmed to be a novel ACC enzyme inhibitor and can serve as a lead compound for the development of novel ACC enzyme inhibitors. In 2025, compounds IV and V, synthesized by Bao Xiaoping et al., showed an inhibitory effect on EC50 of Rhizoctonia solani. 50 The values ​​were 0.41 and 0.47 μg / mL, respectively, compared to the commercial fungicide cyazofamid (EC). 50= 0.49 μg / mL) is equivalent to the above-mentioned active molecule containing quinazolinone, and the structural formula is shown below:

[0004] .

[0005] Oxime ethers, as a class of highly efficient active fragments, possess excellent and broad-spectrum biological activities in drug development, such as antitumor, antiviral, insecticidal, and fungicidal effects. Currently, oxime ether fragments are widely used in the structural optimization of pesticide fungicides. Oximetridium, cymoxanil, oximetriazine, and enoximetridium are all commercially successful, highly active oxime ether fungicides widely used in various crops. Among them, enoximetriazine, independently developed by the Shenyang Chemical Research Institute in 1997, is a methoxyacrylate fungicide with broad-spectrum fungicidal activity. It is the first agent capable of simultaneously controlling powdery mildew and downy mildew, and also shows excellent control efficacy against black spot, anthracnose, and leaf spot diseases, with low toxicity and good environmental compatibility. In 2024, Xia Qing et al. designed a series of novel oxime ether coumarin derivatives, among which compound I showed the most significant inhibition rate against Rhizoctonia solani, EC 100%. 50 The value was 0.46 μg / mL, comparable to the commercially available fungicide boscalid; in the same year, Luo Bo et al. designed and synthesized compound II, and the succinate dehydrogenase (SDH) enzyme inhibition assay showed that compound II produced a significant SDH inhibitory effect, EC 100%. 50 The value was 2.04 μM, significantly stronger than fluopyram (EC). 50 = 6.15 μM), these findings suggest that compound II is a promising candidate for a highly effective SDHI-based bactericide against Rhizoctonia solani. The structural formula of the active molecule containing the oxime ether structure is shown below: .

[0006] Fluorine atoms have the highest electronegativity and possess characteristics such as high lipophilicity, good hydrophobicity, and metabolic stability. Studies have shown that introducing fluorine-containing functional groups such as trifluoromethyl groups into specific positions of organic molecules can effectively increase the lipophilicity of molecules, improve the absorption, distribution, metabolism, and excretion properties of drugs, reduce their toxicity, and exhibit novel biological activities. Therefore, they are widely used in the field of pesticide chemistry. In the field of new pesticide development, more than 50% of pesticides launched in the past 20 years contain fluorine in their structure. Currently, about 40% of fluorine-containing pesticides on the market contain a trifluoromethyl structure. Common examples include the fungicide flufenoxuron, the insecticide fipronil, and the herbicide fluthiamethoxam. The structural formulas of pesticide molecules containing trifluoromethyl groups are shown below: .

[0007] Amide bonds are important structural units in agrochemicals and natural products. Introducing this structure can endow compounds with a wide range of activities, including herbicides, fungicides, insecticides, and antivirals. This structure can not only serve as a key pharmacophore in drug molecules but also as a bridging agent in the development of novel pesticides, connecting different pharmacophores to improve the overall stability and bioavailability of drug molecules. Amide fungicides control diseases such as powdery mildew and gray mold by inhibiting mitochondrial respiration or succinate dehydrogenase activity in pathogens. Currently, amide bonds are not only the "backbone" of active molecules in pesticides, but their application has been consistently present throughout the entire pesticide development process, from early traditional amide fungicides to recent novel ones. Common traditional amide fungicides include seffluzamide and carbendazim; novel amide fungicides include fluopyram, pyridaben, and cyazofamid. The structural formulas of agricultural fungicide molecules containing amide structures are shown below: These new amide fungicides have become important tools in modern integrated pest management and are widely used in agricultural production.

[0008] As quinazolinones, amides, and oxime ethers are three advantageous fragments with significant application value in antifungal activity, previous studies have mainly focused on single-skeletal or two-fragment combinations. However, studies on fusing three or more advantageous fragments and systematically evaluating their biological activity have not been reported. Current technologies lack simple and efficient synthetic methods for fusing multiple advantageous skeletons, failing to meet the demand for a rich compound library in the development of novel green fungicides. Therefore, developing a synthetic method with mild conditions, good functional group compatibility, and a wide substrate applicability, while simultaneously constructing novel compounds with excellent fungicidal activity, is a pressing technical problem that needs to be solved. Summary of the Invention

[0009] To address the technical problem of the inability to efficiently integrate multiple advantageous skeletons such as quinazolinones, oxime ethers, amides, and fluorinated functional groups, this invention proposes a fluorinated quinazolinone compound, its preparation method, and its application. This provides a new type of compound with excellent bactericidal activity for the development of novel green bactericides. The method is characterized by simple operation, mild conditions, strong functional group tolerance, and good yield.

[0010] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0011] A fluoroquinazoline ketone compound, the structural formula of which is shown below:

[0012] In the formula R 1=Me, i-Pr, 2-fluoroethyl, 3,4-F-PhCH2, 2-Br-PhCH2, s-Bu, PhCH2 or 4-Cl-PhCH2.

[0013] A method for preparing a fluoroquinazoline ketone compound includes the following steps: mixing 2-((2-(trifluoromethyl)quinazoline-4-yl)oxy)acetic acid, an oxime ether compound, a condensing agent, a catalyst, and a solvent to prepare a reaction solution, and reacting to obtain the fluoroquinazoline ketone compound;

[0014] The reaction formula is as follows:

[0015] ,

[0016] In the formula R 1 =Me, i-Pr, 2-fluoroethyl, 3,4-F-PhCH2, 2-Br-PhCH2, s-Bu, PhCH2 or 4-Cl-PhCH2.

[0017] The solvent is dichloromethane, or a mixture of dichloromethane and an auxiliary solvent; the auxiliary solvent is any one or more of ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, toluene, and chlorobenzene; the volume ratio of dichloromethane to the auxiliary solvent is 1:(1-4).

[0018] The condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or dicyclohexylcarbodiimide (DCC).

[0019] The catalyst is 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), or O-(benzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU).

[0020] The amount of the condensing agent is 1-3 equivalents of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid, preferably 1.5-2.5 equivalents, and most preferably 2 equivalents.

[0021] The catalyst is used in an amount of 0.3-0.7 equivalents of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid, preferably 0.4-0.6 equivalents, and most preferably 0.5 equivalents.

[0022] The molar ratio of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid to the oxime ether compound is 1:(1.5-2.5), preferably 1:(1.8-2.2), and most preferably 1:2.

[0023] The concentration of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid in the reaction solution is 0.08-0.12M, preferably 0.09-0.11M, and most preferably 0.1M.

[0024] The reaction temperature is 20-30℃, preferably 23-27℃, and most preferably 25℃; the reaction time is 8-16h, preferably 10-14h, and most preferably 12h; the reaction atmosphere is an air atmosphere or an inert gas atmosphere, wherein the inert gas is either nitrogen or argon.

[0025] The application of a fluoroquinazolinone compound as an agricultural fungicide, wherein the agricultural fungicide is used to control plant pathogenic fungi, including Rhizoctonia solani, Take-all fungus of wheat, and Sheath blight fungus of wheat.

[0026] The beneficial effects of this invention are:

[0027] This invention selects readily available 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid compound 1 and oxime ether compound 2 as reactants. Using quinazolinone as the basic skeleton, it successfully splices together multiple advantageous active fragments such as trifluoromethyl, oxime ether and amide, realizing the construction of fluorinated quinazolinone compounds with multiple advantageous skeletons in one step, providing a new idea and method for the fields of medicine, green bactericides and other fields.

[0028] The eight compounds prepared in this invention all exhibited certain fungicidal activity against three common agricultural pathogenic fungi: Rhizoctonia solani, Take-all fungus, and Sheath blight fungus. The results showed that the eight newly synthesized compounds all possessed inhibitory activity against these three different pathogens. Compound 3d showed an inhibition rate of 90.7% against Take-all fungus, demonstrating promising application prospects. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 This is the 1H NMR spectrum of compound 3a;

[0031] Figure 2 This is the 13C NMR spectrum of compound 3a;

[0032] Figure 3 This is the 19F NMR spectrum of compound 3a;

[0033] Figure 4 This is the 1H NMR spectrum of compound 3b;

[0034] Figure 5 This is the 13C NMR spectrum of compound 3b;

[0035] Figure 6 This is the 19F NMR spectrum of compound 3b;

[0036] Figure 7 This is the 1H NMR spectrum of compound 3c;

[0037] Figure 8 This is the 13C NMR spectrum of compound 3c;

[0038] Figure 9 This is the 19F NMR spectrum of compound 3c;

[0039] Figure 10 This is the 1H NMR spectrum of compound 3d;

[0040] Figure 11 This is the 13C NMR spectrum of compound 3d;

[0041] Figure 12 This is the 19F NMR spectrum of compound 3d;

[0042] Figure 13 This is the 1H NMR spectrum of compound 3e;

[0043] Figure 14 This is the 13C NMR spectrum of compound 3e;

[0044] Figure 15 This is the 19F NMR spectrum of compound 3e;

[0045] Figure 16 This is the 1H NMR spectrum of compound 3f;

[0046] Figure 17 This is the 13C NMR spectrum of compound 3f;

[0047] Figure 18 This is the 19F NMR spectrum of compound 3f;

[0048] Figure 19 This is the 1H NMR spectrum of compound 3g;

[0049] Figure 20 This is the 13C NMR spectrum of compound 3g;

[0050] Figure 21 This is the 19F NMR spectrum of compound 3g;

[0051] Figure 22 This is the 1H NMR spectrum of compound 3h;

[0052] Figure 23 This is the 13C NMR spectrum of compound 3h;

[0053] Figure 24 This is the 19F NMR spectrum of compound 3h. Detailed Implementation

[0054] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] Example 1

[0056] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0057]

[0058] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3a) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product data characterization: PE:EA = 5:1, R f = 0.52, white solid, 82% yield. 1H NMR (400 MHz, Chloroform-d) δ 11.19 (s, 1H), 8.44 (d, J = 7.1Hz, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.02 – 7.97 (m,1H), 7.78 – 7.74 (m, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.38 – 7.34 (m,1H), 7.19 – 7.14 (m, 1H), 5.27 (s, 2H), 3.77 (s, 3H), 2.29 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 167.19, 165.24, 157.10, 151.64 (q, J = 37.0 Hz), 150.85, 135.53, 135.26, 129.90, 129.45, 128.88, 128.58, 124.20, 124.16,123.82, 122.08, 119.60 (q, J = 275.5 Hz), 116.23, 66.92, 62.27, 14.25. 19 F NMR(377 MHz, Chloroform-d) δ -70.63. HRMS (ESI) m / z calculated for C 20 H 18 F3N4O3[M+H] + 419.1331 found: 419.1332.

[0059] Example 2

[0060] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0061]

[0062] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3b) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product data characterization: PE:EA = 5:1, R f = 0.43, white solid, 72% yield. 1 H NMR (400 MHz, Chloroform-d) δ 11.40 (s, 1H), 8.46 (d, J = 7.0Hz, 1H), 8.39 – 8.33 (m, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.99 (ddd, J = 8.5,7.0, 1.5 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 – 7.31 (m, 1H), 7.20 – 7.12 (m, 1H), 5.26 (s, 2H), 4.28 (hept, J = 6.2Hz, 1H), 2.32 (s, 3H), 1.19 (d, J = 6.4 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 167.30, 165.13, 156.49, 151.67 (q, J = 36.4 Hz), 150.85, 135.91, 135.20,129.73, 129.47, 128.86, 128.58, 124.12, 124.06, 123.91, 121.88, 119.63 (q, J= 275.3 Hz), 116.31, 76.41, 66.80, 21.70, 14.19. 19 F NMR (377 MHz, Chloroform-d) δ -70.66. HRMS (ESI) m / z calculated for C 22 H 22 F3N4O3 [M+H +447.1644 found: 447.1646.

[0063] Example 3

[0064] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0065]

[0066] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3c) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product characterization data: PE:EA = 5:1, R f = 0.45, white solid, 50% yield. 1 H NMR (400 MHz, Chloroform-d) δ 10.87 (s, 1H), 8.40 (dd, J = 17.5,7.6 Hz, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 – 7.95 (m, 1H), 7.80 – 7.72 (m,1H), 7.46 (dd, J = 7.9, 1.5 Hz, 1H), 7.41 – 7.33 (m, 1H), 7.17 (t, J = 7.6Hz, 1H), 5.26 (s, 2H), 4.65 – 4.61 (m, 1H), 4.53 – 4.50 (m, 1H), 4.32 – 4.29(m, 1H), 4.24 – 4.21 (m, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ167.24, 165.19, 156.77, 151.69 (q, J = 36.9 Hz), 150.85, 135.75, 135.23,129.81, 129.50, 128.90, 128.58, 124.14, 124.07, 123.93, 122.05, 119.62 (q, J= 275.5 Hz), 116.30, 81.25, 66.88, 28.05, 19.08, 14.15. 19 F NMR (377 MHz,Chloroform-d) δ 18.39, -70.66. HRMS (ESI) m / z calculated for C 21 H 19 F4N4O3 [M+H + 451.1393 found: 451.1395.

[0067] Example 4

[0068] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0069]

[0070] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3d) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product data characterization: PE:EA = 5:1, R f = 0.38, white solid, 71% yield. 11H NMR (400 MHz, Chloroform-d) δ 10.89 (s, 1H), 8.40 (d, J = 8.3Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 – 7.93 (m,1H), 7.71 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 – 7.32(m, 1H), 7.21 – 7.13 (m, 1H), 7.03 (dq, J = 11.0, 7.7, 7.2 Hz, 2H), 6.92 –6.84 (m, 1H), 4.99 (s, 2H), 4.95 (s, 2H), 2.39 (s, 3H). 13 13C NMR (101 MHz,Chloroform-d) δ 167.09, 165.10, 158.40, 151. $72 (q, J = 36.6 Hz), 151.46 (dd,J = 41.3, 12.1 Hz), 148.99 (dd, J = 41.7, 12.8 Hz), 135.51, 135.23, 134.52(dd, J = 5.3, 3.9 Hz), 130.16, 129.48, 128.87, 128.72, 124.26, 123.92,123.73, 123.17 (dd, J = 6.5, 3.6 Hz), 122.12, 119.61 (q, J = 275.4 Hz),117.47 (d, J = 17.3 Hz), 116.36, 116.18, 116.16, 74.78, 66.57, 14.72. 19 19F NMR(377 MHz, Chloroform-d) δ -70.56, -136.95 (d, J = 20.8 Hz), -138.52 (d, J =20.8 Hz). HRMS (ESI) m / z calculated for C 26 19 20 19F5N4O3 [M+H] + : 531.1456 found:531.1460.

[0071] Example 5

[0072] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0073]

[0074] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3e) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product characterization data: PE:EA = 8:1, R f = 0.41, white solid, 78% yield. 1 H NMR (400 MHz, Chloroform-d) δ 10.92 (s, 1H), 8.37 (dd, J = 8.3,1.3 Hz, 1H), 8.30 (dd, J = 8.3, 1.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.95(ddd, 7.23 – 7.18 (m, 1H), 7.10– 7.04 (m, 1H), 5.15 (s, 2H), 4.85 (s, 2H), 2.46 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 166.96, 165.28, 158.20, 151.34 (q), 150.79, 136.95, 135.48,135.12, 132.72, 130.10, 129.52, 129.32, 128.85, 128.73, 128.28, 127.57,124.24 (d, J = 10.0 Hz), 123.61, 122.40, 122.09, 119.63 (q, J = 275.5 Hz),116.22, 75.41, 66.52, 14.83.19 F NMR (377 MHz, Chloroform-d) δ -70.49. HRMS(ESI) m / z calculated for C 26 H 21 BrF3N4O3 [M+H] + : 573.0749 found: 573.0752.

[0075] Example 6

[0076] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0077]

[0078] The specific steps included: Compound 1a (0.5 mmol), compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3f) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product data characterization: PE:EA = 5:1, R f = 0.45, white solid, 70% yield. 1H NMR (400 MHz, Chloroform-d) δ 11.43 (s, 1H), 8.46 (d, J = 7.0 Hz,1H), 8.38 (d, J = 6.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.99 (ddd, J = 8.5,7.0, 1.5 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H),7.40 – 7.31 (m, 1H), 7.20 – 7.12 (m, 1H), 5.25 (s, 2H), 4.08 (p, J = 6.2 Hz,1H), 2.33 (s, 3H), 1.66 – 1.60 (m, 1H), 1.49 (ddd, J = 13.7, 7.5, 6.2 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 167.29, 165.09, 156.51, 151.66 (q, J = 37.0 Hz), 150.83, 135.96, 135.19, 129.70, 129.56, 129.47, 128.84, 128.56, 124.04, 123.92,121.86, 119.62 (q, J = 275.8 Hz), 116.31, 81.38, 66.75, 28.45, 19.26, 14.09,9.55. 19 F NMR (377 MHz, Chloroform-d) δ -70.65. HRMS (ESI) m / z calculated forC 23 H 24 F3N4O 33 [M+H]: 461.1801 found: 461.1805.

[0079] Example 7

[0080] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0081]

[0082] The specific steps included: Compound 1a (0.5 mmol), Compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product (3 g) was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product characterization data: PE:EA = 5:1, R f = 0.41, Melting range: 168.4-169.8 ℃, white solid, 61% yield. 1 H NMR (400 MHz, Chloroform-d) δ 10.94 (s, 1H),8.44 (dd, J = 8.3, 1.3 Hz, 1H), 8.40 – 8.34 (m, 1H), 8.16 (d, J = 8.4 Hz,1H), 8.01 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.80 – 7.71 (m, 1H), 7.53 (dd, J =8.0, 1.6 Hz, 1H), 7.44 – 7.35 (m, 1H), 7.35 – 7.27 (m, 2H), 7.28 – 7.17 (m,4H), 5.19 (s, 2H), 4.73 (s, 2H), 2.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 167.06, 165.23, 157.72, 151.50 (q, J = 36.6 Hz), 150.69, 137.80, 135.57,135.06, 129.89, 129.33, 128.71, 128.66, 128.60, 127.94, 126.92, 124.04,123.79, 121.99, 119.64 (q, J = 275.3 Hz), 116.22, 75.75, 66.20, 14.58. 19 F NMR(377 MHz, Chloroform-d) δ -70.48. HRMS (ESI) m / z calculated for C 26 H 22 F3N4O3[M+H]+ Found: 495.1644; Found: 495.1648.

[0083] Example 8

[0084] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0085]

[0086] The specific steps included: Compound 1a (0.5 mmol), Compound 2a (1.0 mmol) (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.25 mmol), and dichloromethane (5.0 mL) were added to a 25 mL round-bottom flask under air atmosphere and reacted overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the target product was obtained by silica gel column chromatography (3 h). All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product data characterization: PE:EA = 5:1, R f = 0.39, white solid, 54% yield. 1 H NMR (400 MHz, Chloroform-d) δ 10.85 (s, 1H), 8.38 (dd, J = 8.3, 1.3Hz, 1H), 8.33 (dd, J = 8.2, 1.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.96 (ddd,J = 8.5, 7.0, 1.4 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.48 (dd,J = 7.9, 1.6 Hz,1H), 7.40 – 7.31 (m, 1H), 7.24 – 7.21 (m, 2H), 7.16 (td, J = 8.2, 1.7 Hz, 3H), 5.06 (s, 2H), 4.76 (s, 2H), 2.40 (s, 3H). 13C NMR (101 MHz, Chloroform-d)δ 167.14, 165.17, 158.16, 151.56 (q, J = 37.0 Hz), 150.80, 136.19, 135.59,135.16, 133.95, 130.11, 129.42, 128.91, 128.83, 128.68, 128.62, 124.16,123.94, 123.86, 122.05, 119.65 (q, J = 275.6.0 Hz), 116.25, 75.19, 66.36,14.70. 19 F NMR (377 MHz, Chloroform-d) δ -70.48. HRMS (ESI) m / z calculated forC 26 H 21 ClF3N4O3 [M+H] + : 529.1254 found: 529.1256.

[0087] Example 9

[0088] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0089]

[0090] The specific steps included: Under a nitrogen atmosphere, compound 1 (0.45 mmol), compound 2d (0.855 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.675 mmol, 1.5 equivalents), 4-dimethylaminopyridine (DMAP, 0.2025 mmol, 0.45 equivalents), dichloromethane (2.5 mL), and toluene (5.0 mL) were added to a 25 mL round-bottom flask and reacted at 24 °C for 11 h. After the reaction was complete, the solvent was removed under reduced pressure, and the target product 3d was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product characterization: white solid, 67% yield, 1H NMR, 13C NMR, 19F NMR, and HRMS data were the same as in Example 4.

[0091] Example 10

[0092] A method for preparing fluoroquinazolinone compounds, the reaction formula is as follows:

[0093]

[0094] The specific steps included: Under an argon atmosphere, compound 1 (0.55 mmol), compound 2d (1.155 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.21 mmol, 2.2 equivalents), 4-dimethylaminopyridine (DMAP, 0.33 mmol, 0.6 equivalents), dichloromethane (1.25 mL), and acetonitrile (3.75 mL) (volume ratio 1:3) were added to a 25 mL round-bottom flask. The reaction was carried out at 26 °C for 13 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3d was obtained by silica gel column chromatography. All eluents were prepared by a 15:1 ratio of petroleum ether and ethyl acetate. Product characterization: white solid, 69% yield, 1H NMR, 13C NMR, 19F NMR, and HRMS data were the same as in Example 4.

[0095] bactericidal activity test

[0096] Dissolve 16.6 mg of the synthesized drugs from Examples 1-8 above in 0.66 mL of DMSO, then add an aqueous solution containing 1% Tween 80 to prepare a 0.5 mg / mL solution of the original drug. Under aseptic conditions, pipette appropriate amounts of each test drug into conical flasks, shake thoroughly, and then pour equal amounts into three 9 cm diameter petri dishes to prepare 0.5 mg / mL drug-containing plates. A blank control without the drug was included in the above experiments, and each treatment was repeated three times. Under aseptic conditions, use a 6.5 mm diameter punch to cut mycelial cakes along the edge of the cultured pathogen. Inoculate the mycelial cakes into the center of the drug-containing plate with the mycelial side facing up. Cover the plate and incubate at 25°C. When the diameter of the control colonies exceeds 6 cm, measure the colony diameter using the cross-sectional method and take the average value. Calculate the inhibition rate at the end of the incubation period.

[0097] The calculation formula is: Antibacterial rate I = (D0 - Dt) / D0 × 100%

[0098] Table 1. In vitro fungicidal activity of the target compound against three plant pathogenic fungi at 0.5 mg / mL.

[0099]

[0100] All values ​​are the mean of three replicates.

[0101] “±”All experimental results are expressed as “mean ± standarddeviation”.

[0102] The test results are shown in Table 1. All eight compounds showed certain bactericidal activity against Rhizoctonia solani, Take-all fungus, and Sheath blight fungus. The overall antibacterial effect against Take-all fungus was better than that against Rhizoctonia solani and Sheath blight fungus. Among them, compound 3d achieved a bactericidal rate of 90.7% against Take-all fungus, showing good application prospects.

[0103] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A fluoroquinazolinone compound, characterized in that, The structural formula of the fluoroquinazolinone compound is shown below: In the formula R 1 =Me, i-Pr, 2-fluoroethyl, 3,4-F-PhCH2, 2-Br-PhCH2, s-Bu, PhCH2 or 4-Cl-PhCH2.

2. The method for preparing the fluoroquinazolinone compound according to claim 1, characterized in that, Includes the following steps: A reaction solution was prepared by mixing 2-((2-(trifluoromethyl)quinazoline-4-yl)oxy)acetic acid, oxime ethers, a condensing agent, a catalyst, and a solvent, and the fluorinated quinazoline ketone compound was obtained by reaction. The reaction formula is as follows: ， In the formula R 1 =Me, i-Pr, 2-fluoroethyl, 3,4-F-PhCH2, 2-Br-PhCH2, s-Bu, PhCH2 or 4-Cl-PhCH2.

3. The method for preparing fluoroquinazolinone compounds according to claim 2, characterized in that, The solvent is dichloromethane, or a mixture of dichloromethane and an auxiliary solvent; the auxiliary solvent is any one or more of ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, toluene, and chlorobenzene; the volume ratio of dichloromethane to the auxiliary solvent is 1:(1-4).

4. The method for preparing the fluoroquinazolinone compound according to claim 3, characterized in that, The condensing agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide.

5. The method for preparing the fluoroquinazolinone compound according to claim 4, characterized in that, The catalyst is any one or more of 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate.

6. The method for preparing the fluoroquinazolinone compound according to claim 5, characterized in that, The amount of the condensing agent is 1-3 equivalents of 2-((2-(trifluoromethyl)quinazoline-4-yl)oxy)acetic acid; the amount of the catalyst is 0.3-0.7 equivalents of 2-((2-(trifluoromethyl)quinazoline-4-yl)oxy)acetic acid.

7. The method for preparing the fluoroquinazolinone compound according to claim 6, characterized in that, The molar ratio of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid to oxime ether compounds is 1:(1.5-2.5).

8. The method for preparing the fluoroquinazolinone compound according to claim 7, characterized in that, The concentration of 2-((2-(trifluoromethyl)quinazolin-4-yl)oxy)acetic acid in the reaction solution is 0.08-0.12M.

9. The method for preparing the fluoroquinazolinone compound according to claim 8, characterized in that, The reaction temperature is 20-30℃, the reaction time is 8-16h, and the reaction atmosphere is an air atmosphere or an inert gas atmosphere; the inert gas is either nitrogen or argon.

10. The application of the fluoroquinazolinone compound of claim 1 as an agricultural fungicide, characterized in that, The agricultural fungicide is used to control plant pathogenic fungi.

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