2-(cyanomethyl)benzimidate fluorine compound and preparation method and application thereof

Abstract

The present application relates to a kind of 2-(cyanomethyl) benzimidate fluorine compound and its preparation method and application. By 2-imino-3-fluoro-3-azido indane compound and silica gel are rearranged in solvent reaction;After rearrangement reaction, negative pressure filtration and rotary evaporation concentration are obtained 2-(cyanomethyl) benzimidate fluorine compound. Compared with prior art, the preparation method of the present application is mild, easy to operate, high selectivity, good atom economy, wide substrate applicability, avoids the use of high-toxic fluorinated reagent, has little impact on the environment, and the obtained 2-(cyanomethyl) benzimidate fluorine compound has obvious inhibitory activity on pepper phytophthora blight, apple rot fungus, rice curvularia and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a 2-(cyanomethyl)benzylimine fluorine compound, its preparation method and application. Background Technology

[0002] 2-(cyanomethyl)benzylimine fluoride compounds are an important class of organic synthesis intermediates. Their structures contain both highly reactive acyl fluoride and cyanomethyl groups, and they have broad application prospects in medicinal chemistry, materials science, and pesticide chemistry. As acylation reagents, the acyl fluoride group exhibits higher chemical stability and selectivity compared to traditional acyl chlorides and acid anhydrides. It can undergo acylation reactions with nucleophiles such as amines and alcohols under mild conditions, and is widely used in peptide synthesis, drug molecule modification, and functional material preparation. Meanwhile, the cyanomethyl group is a key precursor for constructing various functional groups such as heterocycles, carboxylic acids, and amides, and plays an important role in drug molecule synthesis.

[0003] Currently, the synthesis methods for 2-(cyanomethyl)benzylimine fluoride compounds mainly suffer from the following shortcomings: The reaction conditions are harsh: some routes require high temperature, high pressure or strong Lewis acid catalysis, which places high demands on equipment and has poor substrate applicability, making it difficult to introduce multiple substituents; the fluorinating reagents used (such as SF4, DAST, Deoxo-Fluor, etc.) are highly toxic, corrosive, and pose high operational risks, and are prone to side reactions, making it difficult to scale up production. Poor atom economy: Existing methods often involve multi-step reactions and protection-deprotection operations, resulting in low atom utilization and large emissions of waste, which does not conform to the concept of green chemistry. Poor selectivity of rearrangement reactions: Some methods involving ring expansion and rearrangement have problems such as poor regioselectivity, many byproducts, and difficulty in separation and purification, which make it difficult to meet the needs of industrial production.

[0004] Patent CN120904079A discloses a 2-(cyanomethyl)benzoyl fluoride compound, its preparation method, and its application. The method involves mixing a 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative as a reactant with silica gel activated at 120°C and performing a rearrangement reaction. The silica gel is placed in a muffle furnace and activated at 120°C for 2 hours. After the reaction, the mixture is filtered under negative pressure and concentrated by rotary evaporation to obtain the 2-(cyanomethyl)benzoyl fluoride compound. However, this method uses only one substitution variable for the substrate, resulting in narrow substrate applicability.

[0005] Therefore, developing a method for preparing 2-(cyanomethyl)benzylimine fluorinated compounds that is mild, easy to operate, highly atom-economical, and has broad substrate applicability is of significant industrial and academic value. Summary of the Invention

[0006] The purpose of this invention is to overcome the problems of harsh reaction conditions, poor atom economy, and narrow substrate applicability in the synthesis of existing 2-(cyanomethyl)benzylimine fluoride compounds, and to provide a 2-(cyanomethyl)benzylimine fluoride compound, its preparation method, and its application.

[0007] The objective of this invention can be achieved through the following technical solutions: This invention provides a fluorinated 2-(cyanomethyl)benzylimine compound, the general structural formula of which is shown in Formula II: ; Among them, R 1 It is one of the following: hydrogen atom, phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl; R 2 It is one of phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl.

[0008] Furthermore, R 1 When the substituted phenyl group is selected from 4-chloro-, 4-bromo-, 4-tert-butyl-, 4-methyl-, 4-trifluoromethyl-, 4-methoxy-, 5-methyl-, 5-methoxy-, and 4,5-dimethoxy-hydrogen, the substituent in the substituted phenyl group is selected from one of the following: 4-chloro-, 4-bromo-, 4-tert-butyl-, 4-methyl-, 4-trifluoromethyl-, 4-methoxy-, 5-methyl-, 5-methoxy-, and 4,5-dimethoxy-hydrogen. R 2 When the substituted phenyl group is selected from 4-chlorophenyl, 4-bromophenyl, 4-(trifluoromethyl)phenyl, 4-(tert-butylsulfinyl)phenyl, and 4-benzylamino.

[0009] Preferably, the 2-(cyanomethyl)benzylimine fluoride compound is selected from one of the following:

[0010] Secondly, the present invention provides a method for preparing 2-(cyanomethyl)benzylimine fluorine compounds, comprising the following steps: 2-Imin-3-fluoro-3-azidoindane compounds and silica gel were rearranged in a solvent; After the rearrangement reaction was completed, the mixture was filtered under negative pressure and concentrated by rotary evaporation to obtain 2-(cyanomethyl)benzylimine fluorine compounds. The general structural formula of the 2-imino-3-fluoro-3-azido-indane compound is shown in Formula I: ; Among them, R 1 It is one of the following: hydrogen atom, phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl; R 2 It is one of phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl.

[0011] Preferably, the mass-to-volume ratio of the 2-imino-3-fluoro-3-azido-indane compound, silica gel, and solvent is 1 g:(10~20) g:(10~20) ml.

[0012] Preferably, the silica gel is selected from one of the following: 100-200 mesh, 200-300 mesh, or 300-400 mesh. Before use, it is activated at 120°C for 2-4 hours.

[0013] Preferably, the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, or 1,4-dioxane.

[0014] Preferably, the rearrangement reaction temperature is 15~25℃ and the rearrangement reaction time is 3~4h.

[0015] Thirdly, the present invention provides the application of 2-(cyanomethyl)benzylimine fluoride compounds in the preparation of antibacterial drugs.

[0016] Preferably, the pathogenic bacteria targeted by the antibacterial drug are selected from one or more of the following: apple rot fungus, rapeseed sclerotium rot fungus, tomato gray mold fungus, rice sheath blight fungus, viridans fungus, wheat scab fungus, rice curvularia fungus, pepper phytophthora fungus, apple anthracnose fungus, or tomato early blight fungus.

[0017] Compared to patent CN120904079A, this invention introduces a dual-substitution variable into the substrate, simultaneously adapting to both ketones and imines as raw materials, thus broadening the compatibility range of substrate functional groups and achieving efficient conversion of complex substituted substrates such as heterocycles, trifluoromethyl, sulfonyl, and benzylamine. In addition, this invention is compatible with various solvent systems such as dichloromethane, chloroform, hexafluoroisopropanol (HFIP), and 1,2-dichloroethane (DCE), and adds antibacterial activity testing to the organic synthesis, thus completing the evaluation of biological activity.

[0018] Compared with the prior art, the present invention has the following beneficial effects: 1) This invention uses a dichloromethane and silica gel system for a one-step rearrangement reaction, which is well compatible with various functionalized 2-imino-3-fluoro-3-azidoindenmenium compounds and can generate 2-(cyanomethyl)benzylimine fluorine compounds in good yield.

[0019] 2) The preparation method of the present invention adopts a rearrangement reaction, which is mild, simple to operate, highly selective (directly generating 2-(cyanomethyl)benzylimine fluoride compounds), has good atom economy (most of the raw material atoms are incorporated into the target product, with few by-products), and has wide substrate applicability. It overcomes the problems of harsh reaction conditions, poor atom economy, narrow substrate applicability, and the use of highly toxic fluorinating reagents in the preparation of existing 2-(cyanomethyl)benzylimine fluoride compounds. It is green and environmentally friendly, and can achieve good reaction yield.

[0020] 3) The 2-(cyanomethyl)benzylimine fluoride compounds of this invention possess potential biological activity, with the molecule containing an aromatic ring, an ortho-cyanomethyl group, and an imine fluoride active structure. The imine fluoride group has strong electrophilic activity and can interact with nucleophilic sites such as amino and thiol groups of enzyme proteins in pathogenic microorganisms, interfering with the physiological functions of key fungal enzymes. The presence of both cyanomethyl and imine fluoride pharmacodynamic groups at the ortho-position of the benzene ring creates a synergistic effect, which is beneficial for enhancing the inhibitory ability against plant pathogenic fungi. This demonstrates significant inhibitory effects against *Phytophthora capsici*, *Phytophthora macrantha*, and *Curvularia oryzae*, and the inhibitory effect of 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride (compound 3) on *Phytophthora capsici* is significantly better than that of the commercially available control drug tebuconazole. Attached Figure Description

[0021] Figure 1 The above is the 1H NMR spectrum of 2-(cyanomethyl)-N-phenylbenzylimine fluoride from Example 1 of this invention.

[0022] Figure 2 This is the carbon NMR spectrum of 2-(cyanomethyl)-N-phenylbenzylimine fluoride from Example 1 of the present invention.

[0023] Figure 3 The NMR fluorine spectrum of 2-(cyanomethyl)-N-phenylbenzylimine fluoride in Example 1 of this invention is shown. Detailed Implementation

[0024] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0025] Unless otherwise specified, the reagents, methods, instruments, and equipment used in this invention are conventional in the art. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0026] The silica gel is activated silica gel that has been baked at 120℃ for 2 hours to remove moisture, and its specifications are selected from 100-200 mesh, 200-300 mesh, and 300-400 mesh.

[0027] The general reaction formulas for the preparation of the raw material 2-imino-3-fluoro-3-azido-indane compounds in Examples 1-8 are as follows: Where R 1 It is one of the following: hydrogen atom, phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl; R 2 It is one of phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl.

[0028] Taking the azide-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, a starting material for synthesizing compound 1, as an example: Concentrated sulfuric acid (53 μL, 1.00 mmol) was added to a methanol (5.0 mL) solution of 1-indanone (1.3206 g, 10.0 mmol) and Selectfluor (4.2511 g, 12.0 mmol). The mixture was stirred at 50°C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, and the solvent was removed under reduced pressure. Diethyl ether was added, and the mixture was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The crude product was purified by rapid column chromatography to give 2-fluoro-1-indanone.

[0029] Triethylamine (1.5168 g, 15.0 mmol) was added to a dichloromethane solution of 2-fluoro-1-indanone (1.5005 g, 10.0 mmol) at 0°C, followed by the slow dropwise addition of trimethylsilyl trifluoromethanesulfonate (2.6671 g, 12.0 mmol). After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. N-bromosuccinimide (1.9578 g, 11.0 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate solution, extracted with dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give 2-bromo-2-fluoro-1-indanone.

[0030] In a dry reaction flask, the substrate 2-bromo-2-fluoro-1-indanone (2.2796 g, 10.0 mmol) and 10 mL of CPME solvent were added and stirred to dissolve. Aniline (1.1167 g, 12.0 mmol) was added, followed by Ti(OEt)4 (2.7373 g, 12.0 mmol). The system was purged with nitrogen three times to prevent moisture absorption. The reaction was monitored by TLC, and heating was stopped when the reactants were consumed. After the system cooled to room temperature, the reaction mixture was slowly poured into a saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate, and all organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target imine product 2-bromo-2-fluoro-N-phenyl-2,3-dihydro-1H-indan-1-imine. Add 0.1521 g (0.5000 mmol) of 2-bromo-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine and 5 mL of dimethyl sulfoxide to a 10 mL reaction tube. While stirring at room temperature, add 0.0390 g (0.6000 mmol) of sodium azide. React at room temperature for 3–4 hours, monitoring the reaction progress using a thin-layer chromatography plate. The reaction is complete when the starting material spot disappears. Quench the reaction mixture with water, separate the layers, and distill under reduced pressure to obtain 2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine.

[0031] The general formulas for the reaction equations used in the preparation of the following Examples 1-8 in this invention are as follows: Specific implementation methods are described in the following examples. All products in the following examples underwent proton nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1 HNMR, carbon spectroscopy (HNMR), 13 C NMR, fluorine spectrum ( 19 Structural characterization using F NMR.

[0032] Example 1 Preparation of compound 1: 2-(cyanomethyl)-N-phenylbenzylimine fluoride.

[0033] The chemical structural formula of the raw material, azide-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, is as follows: In a 10 mL reaction tube, add 0.0373 g (0.1401 mmol) of the starting material 2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, 0.660 g of 200-300 mesh silica gel, and 0.6 mL of dichloromethane. Incubate the reaction tube at room temperature (25 ± 2 °C) and stir for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 2-(cyanomethyl)-N-phenylbenzylimine fluoride, with a yield of 93.4% and a purity of 99.5%.

[0034] Characterization data of the product 2-(cyanomethyl)-N-phenylbenzylimine fluoride (spectral data as follows) Figure 1 , 2 (As shown in Figure 3) 1H NMR spectrum ( 1 H NMR): 1 H NMR (400 MHz, DMSO-) d 6) δ 7.99 (d, J = 7.8 Hz,1H), 7.75 - 7.65 (m, 2H), 7.59 (td, J = 7.3, 6.9, 2.0 Hz, 1H), 7.49 - 7.40(m, 2H), 7.33 - 7.21 (m, 3H), 4.42 (s, 2H). Carbon spectrum (CMR) 13 C NMR): 13 C NMR (101 MHz, DMSO- d 6) δ 147.70, 144.30, 142.19,142.06, 132.84, 132.06, 132.02, 131.19, 131.16, 130.09, 130.04, 129.01,128.66, 126.97, 125.73, 122.85, 118.79, 22.99. Fluorine spectrum ( 19 F NMR): 19 F NMR (376 MHz, DMSO- d 6) δ -33.82. The chemical structure of (cyanomethyl)-N-phenylbenzylimine fluoride is shown below: Example 2 Preparation of compound 1: 2-(cyanomethyl)-N-phenylbenzylimine fluoride.

[0035] The chemical structural formula of the raw material, azide-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, is as follows: In a 10 mL reaction tube, add 0.050 g (0.1879 mmol) of the starting material 2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, 0.752 g of 200-300 mesh silica gel, and 0.7 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 2-(cyanomethyl)-N-phenylbenzylimine fluoride, with a yield of 93.1% and a purity of 99.4%.

[0036] Characterization data of product 2-(cyanomethyl)-N-phenylbenzylimine fluoride: 1H NMR spectrum ( 1 H NMR): 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (d, J = 7.8 Hz,1H), 7.75 - 7.65 (m, 2H), 7.59 (td, J = 7.3, 6.9, 2.0 Hz, 1H), 7.49 - 7.40(m, 2H), 7.33 - 7.21 (m, 3H), 4.42 (s, 2H). Carbon spectrum (CMR) 13 C NMR): 13 C NMR (101 MHz, DMSO- d6) δ 147.70, 144.30, 142.19,142.06, 132.84, 132.06, 132.02, 131.19, 131.16, 130.09, 130.04, 129.01,128.66, 126.97, 125.73, 122.85, 118.79, 22.99. Fluorine spectrum ( 19 F NMR): 19 F NMR (376 MHz, DMSO- d 6) δ -33.82. The chemical structure of (cyanomethyl)-N-phenylbenzylimine fluoride is shown below: Example 3 Preparation of compound 2: N-(4-chlorophenyl)-2-(cyanomethyl)benzylimine fluoride.

[0037] The chemical structural formula of the raw material 2-azido-N-(4-chlorophenyl)-2-fluoro-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.050 g (0.1667 mmol) of the starting material 2-azido-N-(4-chlorophenyl)-2-fluoro-2,3-dihydro-1H-inden-1-imine, 0.752 g of 200-300 mesh silica gel, and 0.7 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product N-(4-chlorophenyl)-2-(cyanomethyl)benzylimine fluoride, with a yield of 90.1% and a purity of 98.4%.

[0038] Characterization data of the product N-(4-chlorophenyl)-2-(cyanomethyl)benzylimine fluoride: 1H NMR spectrum ( 1 H NMR): 1 H NMR (400 MHz, DMSO- d 6) δ 7.97 (d, J= 7.8 Hz,1H), 7.75 - 7.63 (m, 2H), 7.57 (td, J = 7.3, 2.0 Hz, 1H), 7.52 - 7.45 (m,2H), 7.31 (d, J = 8.4 Hz, 2H), 4.41 (s, 2H). Carbon spectrum (CMR) 13 C NMR): 13 C NMR (101 MHz, DMSO-d6) δ 148.57, 145.16, 141.23,141.09, 133.17, 132.35, 132.30, 131.36, 131.33, 130.35, 130.31, 130.21,129.18, 128.83, 126.93, 126.52, 124.98, 118.95, 23.21. Fluorine spectrum ( 19 F NMR): 19 F NMR (376 MHz, DMSO- d 6) δ -33.40. The chemical structure of (4-chlorophenyl)-2-(cyanomethyl)benzylimine fluoride is shown below: Example 4 Preparation of compound 3: 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride.

[0039] The chemical structural formula of the raw material 2-azido-2-fluoro-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.1000 g (0.2993 mmol) of 2-azido-2-fluoro-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-imine, 1.20 g of 200-300 mesh silica gel, and 1.1 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride with a yield of 92.8% and a purity of 99.1%.

[0040] Characterization data of the product 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride: 1 H NMR (400 MHz, DMSO- d 6) δ 7.98 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.3Hz, 2H), 7.74 - 7.65 (m, 2H), 7.58 (td, J = 7.3, 6.7, 2.1 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 4.43 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 146.09, 145.95, 133.23, 131.16, 131.13,130.30, 130.26, 128.63, 126.40, 126.24, 126.20, 126.17, 126.13, 126.04,126.00, 125.72, 125.60, 122.92, 118.68, 22.97. 19 F NMR (376 MHz, DMSO- d 6) δ -32.47, -60.74. The chemical structure of 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride is shown below: Example 5 Preparation of compound 3: 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride.

[0041] The chemical structural formula of the raw material 2-azido-2-fluoro-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.1300 g (0.3889 mmol) of the starting material 2-azido-2-fluoro-N-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-imine, 1.7 g of 200-300 mesh silica gel, and 1.6 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride with a yield of 92.3% and a purity of 99.0%.

[0042] Characterization data of the product 2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride: 1 H NMR (400 MHz, DMSO- d 6) δ 7.98 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.3Hz, 2H), 7.74 - 7.65 (m, 2H), 7.58 (td, J = 7.3, 6.7, 2.1 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 4.43 (s, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 146.09, 145.95, 133.23, 131.16, 131.13,130.30, 130.26, 128.63, 126.40, 126.24, 126.20, 126.17, 126.13, 126.04,126.00, 125.72, 125.60, 122.92, 118.68, 22.97. 19 F NMR (376 MHz, DMSO- d 6) δ -32.47, -60.74. The chemical structural formula of (cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride is shown below: Example 6 Preparation of compound 4: 5-chloro-2-(cyanomethyl)-N-phenylbenzylimine fluoride.

[0043] The chemical structural formula of the raw material 6-chloro-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.1000 g (0.3325 mmol) of the starting material 6-chloro-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, 1.3 g of 200-300 mesh silica gel, and 1.2 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 5-chloro-2-(cyanomethyl)-N-phenylbenzylimine fluoride, with a yield of 88.6% and a purity of 97.8%.

[0044] Characterization data of the product 5-chloro-2-(cyanomethyl)-N-phenylbenzylimine fluoride: 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (d, J = 2.3 Hz, 1H), 7.78 (d, J= 2.3Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.36 - 7.22 (m, 3H), 4.41 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 141.81, 141.69, 133.17, 132.49, 130.99,129.61, 129.57, 129.03, 126.06, 123.01, 118.45, 22.47. 19 F NMR (376 MHz, DMSO- d 6) δ -33.39. The chemical structure of 5-chloro-2-(cyanomethyl)-N-phenylbenzylimine fluoride is shown below: Example 7 Preparation of compound 5: 5-bromo-2-(cyanomethyl)-N-phenylbenzylimine fluoride.

[0045] The chemical structural formula of the raw material 6-bromo-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.1000 g (0.2897 mmol) of the starting material 6-bromo-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, 1.2 g of 200-300 mesh silica gel, and 1.1 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 5-bromo-2-(cyanomethyl)-N-phenylbenzylimine fluoride, with a yield of 89.3% and a purity of 96.7%.

[0046] Characterization data of the product 5-bromo-2-(cyanomethyl)-N-phenylbenzylimine fluoride: 1 H NMR (400 MHz, DMSO-d 6) δ 8.10 (d, J = 2.2 Hz, 1H), 7.91 (dd, J =8.3, 2.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.33 - 7.22(m, 3H), 4.39 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 146.40, 142.97, 141.81, 141.69, 135.42,133.11, 133.08, 132.41, 132.36, 131.38, 131.34, 129.02, 123.01, 121.37,118.37, 22.54. 19 F NMR (376 MHz, DMSO- d 6) δ -33.37. The chemical structure of bromo-2-(cyanomethyl)-N-phenylbenzylimine fluoride is shown below: Example 8 Preparation of compound 6: 5-(methoxy)-2-(cyanomethyl)-N-phenylbenzylimine fluoride.

[0047] The chemical structural formula of the raw material 6-(methoxy)-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine is as follows: In a 10 mL reaction tube, add 0.1200 g (0.4053 mmol) of 6-(methoxy)-2-azido-2-fluoro-N-phenyl-2,3-dihydro-1H-inden-1-imine, 1.6 g of 200-300 mesh silica gel, and 1.5 mL of dichloromethane. Stir the reaction tube at room temperature for 3-4 h to allow for rearrangement. Monitor the reaction progress using a thin-layer chromatography plate (developing solvent: petroleum ether / ethyl acetate = 10:1 v / v; silica gel plate GF254; UV 254 nm). The reaction is considered complete when the starting material spot (Rf≈0.7) disappears and the target product spot (Rf≈0.6) appears stably. After the reaction is complete, obtain the reaction mixture; transfer the reaction mixture to a Buchner funnel lined with filter paper and filter under vacuum. The filter cake was washed several times with a small amount of ethyl acetate, and the resulting filtrate was concentrated by rotary evaporation under reduced pressure to obtain the product 5-(methoxy)-2-(cyanomethyl)-N-phenylbenzylimine fluoride, with a yield of 84.8% and a purity of 96.8%.

[0048] Characterization data of the product 5-(methoxy)-2-(cyanomethyl)-N-phenylbenzylimine fluoride: 1 H NMR (400 MHz, DMSO- d 6) δ 7.57 (d, J = 8.5 Hz, 1H), 7.50 - 7.39 (m,3H), 7.31 - 7.20 (m, 4H), 4.30 (s, 2H), 3.84 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 159.10, 142.31, 142.19, 132.85, 132.81,129.20, 128.82, 128.20, 127.78, 125.98, 123.91, 123.07, 119.22, 118.30,115.58, 115.54, 55.80, 22.36. 19 F NMR (376 MHz, DMSO- d 6) δ -33.72. The chemical structure of (methoxy)-2-(cyanomethyl)-N-phenylbenzylimine fluoride is shown below: Example 9: In vitro activity test against plant pathogenic fungi Test strains: A total of 10 strains were tested, including apple rot pathogens ( The waltz of evil ), rapeseed sclerotium pathogen ( Sclerotinia sclerotiorum ), tomato gray mold ( Botrytis cinerea Rice sheath blight pathogen ( Rhizoctonia solani ), Trichoderma viride ( Trichoderma virens ), wheat scab ( Fusarium grasses Rice curvularia ( ) Curvularia lunate ), Phytophthora capsici ( Phytophthora capsicum Apple anthracnose bacteria ( Colletotrichum gloeosporioides ), tomato early blight pathogen ( Alternaria nightshade The above-mentioned test strains are all common strains that can be obtained through commercial channels.

[0049] Positive control drug used in the test: Tebuconazole.

[0050] Other items: glucose, agar powder, cutting board, knife, gauze, potatoes, absorbent cotton, sealing film, marker, etc.

[0051] Methods for determining antibacterial activity: The growth rate method, also known as the inhibition zone method or agar plate method, is described in "Research Methods for Plant Chemical Protection" edited by Mu Liyi. It involves mixing different concentrations of pesticide solutions with melted culture medium to create a toxic medium. Pathogens are then inoculated onto the surface of the medium, and the toxicity of the pesticide is determined by the rate of pathogen growth, expressed as the size of the colony diameter over a specific time period.

[0052] Aseptic culture of potato dextrose agar (PDA) was prepared by the following method: 200g of peeled and diced potatoes were added to 1000mL of distilled water and boiled for 30 minutes. The mixture was filtered through four layers of gauze, and the filtrate was poured into a clean saucepan. An appropriate amount of water was added, followed by 20g of glucose and 18g of agar powder. The mixture was heated and stirred constantly with a glass rod until completely dissolved. After complete dissolution, the volume was adjusted to 1000mL with distilled water. Finally, the volume was dispensed into 300mL Erlenmeyer flasks according to the calculated volume.

[0053] First, a dimethyl sulfoxide (DMSO) solution containing the test compounds (compounds 2, 3, and 6) was added to a sterile petri dish containing approximately 10 mL of potato dextrose agar (PDA). Then, mycelial cakes with a diameter of 6 mm were excised from the fungal colonies and placed in the center of the PDA petri dish at 28°C for 3–7 days. Three antifungal tests were performed for each compound. Additionally, pure DMSO and tebuconazole were used as negative and positive controls, respectively. The inhibition rate (I) of the test compounds was calculated according to the following formula: I = (CT) / (C - 0.6) × 100% In this formula, C represents the average hyphal diameter of the negative control, and T represents the average hyphal diameter of the PDA treated with the compound.

[0054] Experimental results: Under the condition of a concentration of 20 mg / L, different compounds of the present invention have broad-spectrum inhibitory activities against a variety of plant pathogenic fungi. Among them, compound 3 has an inhibition rate of 68.3% against Phytophthora capsici, while compound 2 has an inhibition rate of more than 50% against Pseudomonas aeruginosa, Pseudomonas sclerotiorum, Curvularia oryzae, and Phytophthora capsici, showing inhibitory effects against a variety of pathogens. In addition, the inhibitory effect of compound 3 against Phytophthora capsici is significantly better than that of tebuconazole (Table 1).

[0055] Table 1. Inhibition rates of different compounds against pathogens Compound 2 [N-(4-chlorophenyl)-2-(cyanomethyl)benzylimine fluoride] in the table was prepared in Example 3; Compound 3 [2-(cyanomethyl)-N-(4-(trifluoromethyl)phenyl)benzylimine fluoride] was prepared in Example 4 or 5; Compound 6 [5-(methoxy)-2-(cyanomethyl)-N-phenylbenzylimine fluoride] was prepared in Example 8.

[0056] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A 2-(cyanomethyl)benzylimine fluorine compound, characterized in that, Its general structural formula is shown in Formula II: ； Among them, R 1 It is one of the following: hydrogen atom, phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl; R 2 It is one of phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl.

2. The 2-(cyanomethyl)benzylimine fluoride compound according to claim 1, characterized in that, R 1 When the substituted phenyl group is selected from 4-chloro-, 4-bromo-, 4-tert-butyl-, 4-methyl-, 4-trifluoromethyl-, 4-methoxy-, 5-methyl-, 5-methoxy-, or 4,5-dimethoxy-hydrogen; R 2 When the substituted phenyl group is selected from 4-chlorophenyl, 4-bromophenyl, 4-(trifluoromethyl)phenyl, 4-(tert-butylsulfinyl)phenyl or 4-benzylamino.

3. The 2-(cyanomethyl)benzylimine fluoride compound according to claim 1, characterized in that, The 2-(cyanomethyl)benzylimine fluoride compound is selected from one of the following: , , , , or .

4. A method for preparing a 2-(cyanomethyl)benzylimine fluoride compound as described in any one of claims 1-3, characterized in that, Includes the following steps: 2-Imin-3-fluoro-3-azidoindane compounds and silica gel were rearranged in a solvent; After the rearrangement reaction was completed, the mixture was filtered under negative pressure and concentrated by rotary evaporation to obtain 2-(cyanomethyl)benzylimine fluorine compounds. The general structural formula of the 2-imino-3-fluoro-3-azido-indane compound is shown in Formula I: ； Among them, R 1 It is one of the following: hydrogen atom, phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl; R 2 It is one of phenyl, fused ring, alkyl, heterocyclic, aromatic heterocyclic or substituted phenyl.

5. The method for preparing 2-(cyanomethyl)benzylimine fluorine compounds according to claim 4, characterized in that, The mass-to-volume ratio of the 2-imino-3-fluoro-3-azido-indane compound, silica gel, and solvent is 1 g:(10~20) g:(10~20) ml.

6. The method for preparing 2-(cyanomethyl)benzylimine fluorine compounds according to claim 4, characterized in that, The silica gel is selected from one of the following specifications: 100-200 mesh, 200-300 mesh, or 300-400 mesh.

7. The method for preparing 2-(cyanomethyl)benzylimine fluorine compounds according to claim 4, characterized in that, The solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, dimethyl ether, methanol, ethanol, isopropanol, acetonitrile, propionitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, or 1,4-dioxane.

8. The method for preparing 2-(cyanomethyl)benzylimine fluorine compounds according to claim 4, characterized in that, The rearrangement reaction temperature is 15~25℃, and the rearrangement reaction time is 3~4h.

9. The use of a 2-(cyanomethyl)benzylimine fluoride compound according to any one of claims 1-3 in the preparation of antibacterial drugs.

10. The application according to claim 9, characterized in that, The pathogens targeted by the antibacterial drug are selected from one or more of the following: apple rot fungus, rapeseed sclerotium rot fungus, tomato gray mold fungus, rice sheath blight fungus, viridans fungus, wheat scab fungus, rice curvularia fungus, pepper phytophthora fungus, apple anthracnose fungus, or tomato early blight fungus.

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