Preparation method and application of fluorine-containing acylimide derivative

Abstract

The application discloses a preparation method and application of a fluorine-containing acylimide derivative, and belongs to the technical field of organic synthesis, and comprises the following steps: taking carboxylic acid, olefin, halogen-substituted ester or halogen-substituted alkyl as raw materials, and in the presence of a photocatalyst, alkali and a solvent, a fluorine-containing acylimide derivative is obtained through reaction under visible light induction; the fluorine-containing acylimide derivative prepared by the method can be applied to preparation of antibacterial, anti-inflammatory and anticancer drugs and the like, and has very important medicinal value.

Description

Technical Field

[0001] This invention relates to a method for preparing fluorinated imide derivatives and their applications, belonging to the field of organic synthesis technology. Background Technology

[0002] Fluorinated imide derivatives are an important class of organic compounds whose molecular skeletons contain both imide functional groups (-CO-N-CO-) and fluorine substituents. They are functionalized derivatives of imide compounds modified by fluorine substitution. The combination of fluorine atoms and the imide structure gives these derivatives the advantages of both types of structures, making them irreplaceable in fields such as medicine, pesticides, and materials science.

[0003] In the field of pharmaceutical technology, it can be used for the development of fluorinated drug precursors, structural modification of peptide or amide drugs, and is also a key framework for intermediates of anticancer and anti-inflammatory drugs. In the field of pesticide technology, it belongs to the branches of agricultural active ingredient precursor development technology and high-efficiency pesticide molecular design technology. Its structure can regulate the selectivity of pesticide targets and is often used in the molecular design of insecticides and herbicides. For example, the field residual effect of fluorinated imide herbicides is more than 30% longer than that of non-fluorinated counterparts. In the field of functional materials technology, it belongs to the branches of fluorinated functional material preparation technology and material surface modification technology. It can be used as a monomer for the synthesis of fluorinated polymers to impart weather resistance and hydrophobicity to materials.

[0004] Existing methods for synthesizing fluorinated imide derivatives have several limitations: some fluorinating reagents are highly toxic and corrosive, making them difficult to operate; the synthetic routes are cumbersome, product separation and purification are difficult, and yields are low; at the same time, they have poor adaptability to substrates containing sensitive functional groups, making it difficult to meet the synthetic requirements of complex fluorinated imide derivatives, and some methods rely on noble metal catalysts, increasing synthesis costs and causing heavy metal residue problems. Cai et al. (J.Am.Chem.Soc.2025,147,18438-18444) reported a new Kharasch reaction, which utilizes various carboxylic acid-derived redox reactive esters as alkyl sources, effectively introducing highly functionalized alkyl groups and providing a general method for directly constructing α-halocarbonyl compounds from carboxylic acids. However, this system is only suitable for aliphatic carboxylic acids, has a narrow substrate range, relies on expensive reagents, and produces products with limited structures. Giri et al. (Chem. Sci. 2024, 15, 10659-10667) utilized photoredox catalysis to activate dichlorodifluoroacetic acid (CDFA) and α-halocarboxylic acids, achieving solvent-controlled bifunctionalization of olefins for the synthesis of γ-lactones, γ-lactams, and α,α-difluoro esters. However, this method is highly solvent-dependent, and the starting materials are incompatible with polycarboxylic acids, fluorinated olefins / halogenated compounds, etc., exhibiting poor compatibility with nitrogen- and oxygen-containing heterofunctional substrates, making it difficult to expand the types of product structures. The aforementioned existing methods generally suffer from substrate limitations, poor functional group tolerance, low adaptability to reaction conditions, and limited product structures. Furthermore, some methods have high reagent costs and lack industrial scale-up feasibility, severely restricting the application of fluorinated imide derivatives in pharmaceuticals, pesticides, and other fields.

[0005] Therefore, developing a mild, efficient, and widely applicable method for preparing fluorinated imide derivatives that enables the synergistic construction of multiple functional groups has significant practical value and application prospects. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the first objective of the present invention is to provide a fluorinated imide derivative.

[0007] The technical solution used in this invention is as follows:

[0008] A fluorinated imide derivative has the following structural formula:

[0009] ;

[0010] In the formula: R1 is selected from phenyl, p-tolyl, p-methoxyphenyl, phthalimide, phenoxyethyl, and cyclohexyl; R2 is selected from phenyl, p-methylphenyl, p-fluorophenyl, and benzyloxymethyl; and R3 is a halogen-substituted ester group or a halogen-substituted alkyl group.

[0011] Furthermore, the halogen-substituted ester group or halogen-substituted alkyl group is F or / and Br.

[0012] Furthermore, the fluorinated imide derivative is any one of the following compounds:

[0013] .

[0014] The second objective of this invention is to provide a simple and efficient method for preparing fluorinated imide derivatives, which utilizes a photocatalytic system to achieve a multi-component synergistic reaction, thereby solving the problems of harsh conditions, limited substrates, and low yields in existing methods.

[0015] A method for preparing a fluorinated imide derivative includes the following steps: using carboxylic acid, olefin, halogen-substituted ester group or halogen-substituted alkyl group as raw material, reacting in the presence of a photocatalyst, a base and an organic solvent under visible light induction to obtain the fluorinated imide derivative.

[0016] The reaction equations involved are shown below:

[0017] .

[0018] In the formula: R1 is selected from phenyl, p-tolyl, p-methoxyphenyl, phthalimide, phenoxyethyl, and cyclohexyl; R2 is selected from phenyl, p-methylphenyl, p-fluorophenyl, and benzyloxymethyl; and R3 is a halogen-substituted ester group or a halogen-substituted alkyl group.

[0019] Further settings include:

[0020] The organic solvent is one of 1,2-dichloroethane, dichloromethane, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, ethyl acetate, tetrahydrofuran, and acetonitrile.

[0021] The catalyst is one of the following: bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine] bis(4,4'-di-tert-butyl-2,2'-bipyridine)iridium(III) hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-methylpyridine] bis(4,4'-di-tert-butyl-2,2'-bipyridine)iridium(III) hexafluorophosphate, bis(2-phenylpyridine) bis(4,4'-di-tert-butyl-2,2'-bipyridine)iridium(III) hexafluorophosphate, tri(2-phenylpyridine)iridium(III), tri(2,2'-bipyridine)ruthenium(II) hexafluorophosphate, 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanophenyl, and eosin Y.

[0022] The amount of catalyst used, based on the amount of carboxylic acid added, is 1-10 mol% of the amount of carboxylic acid added, preferably 5.0 mol%.

[0023] The alkali is one of potassium carbonate, sodium bicarbonate, cesium carbonate, potassium hydroxide, sodium acetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-diisopropylethylamine, and triethylamine.

[0024] The visible light is preferably blue light with a wavelength of 400-450nm.

[0025] The reaction temperature is room temperature, and the reaction time is 12-36 hours.

[0026] Particularly preferred is that the catalyst is selected from tris(2-phenylpyridine)iridium(III), the base is potassium carbonate, and the organic solvent is acetonitrile, which can achieve the best yield.

[0027] A third objective of this invention is to provide an application of fluorinated imide derivatives in the preparation of antibacterial drugs. The fluorinated imide derivatives prepared by this invention have significant pharmaceutical value; relying on the optimizing effect of fluorine atoms on molecular physicochemical properties and biological activity, they can be applied to the preparation of antibacterial, anti-inflammatory, and anticancer drugs.

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] (1) This invention provides a novel method for preparing fluorinated imide derivatives, which solves the difficulties of existing processes, avoids the use of expensive fluorinating reagents, uses simple and safe chemical raw materials, and utilizes visible light to achieve rapid derivatization, thereby reducing costs.

[0030] (2) This invention utilizes low-cost substrates such as olefins, carboxylic acids, and fluorine-containing compounds under visible light conditions to synthesize high-value-added derivatives and achieve precise introduction of fluorine. It has the advantages of low cost, mild reaction conditions, short reaction time, and easy processing.

[0031] (3) The present invention prepares a fluorinated imide derivative, which has very important medicinal value. Relying on the optimization effect of fluorine atoms on molecular physicochemical properties and biological activity, it can be applied to the preparation of antibacterial, anti-inflammatory and anticancer drugs, and has high economic benefits.

[0032] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0033] Figure 1 The antibacterial effect of ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate prepared in Example 1 against Escherichia coli.

[0034] Figure 1 In the formula: a: DMSO solution; b: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 20 mg / mL; c: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 40 mg / mL; d: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 60 mg / mL.

[0035] Figure 2 The antibacterial effect of ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate prepared in Example 3 against Escherichia coli.

[0036] Figure 2 In the formula: a: DMSO solution; b: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate at a concentration of 20 mg / mL; c: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate at a concentration of 40 mg / mL; d: ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate at a concentration of 60 mg / mL.

[0037] Figure 3 The antibacterial effect of ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate prepared in Example 5 against Escherichia coli.

[0038] Figure 3 In the formula: a: DMSO solution; b: ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 20 mg / mL; c: ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 40 mg / mL; d: ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate at a concentration of 60 mg / mL. Detailed Implementation

[0039] The following detailed description of specific embodiments of the present invention, in conjunction with the accompanying drawings, does not limit the scope of the claims. Unless otherwise specified, the raw materials and reagents used in the embodiments are existing technology or commercially available products.

[0040] Example 1

[0041] Acetonitrile (2 mL) was added to a 4 mL clear glass vial equipped with a magnetic stir bar and a rubber stopper. Then, ethyl difluorobromoacetate (0.6 mmol, 3.0 equiv), tris(2-phenylpyridinium)iridium(III) (Ir(ppy)3, 5.0 mol%), benzoic acid (0.2 mmol, 1.0 equiv), potassium carbonate (0.6 mmol, 3.0 equiv), and styrene (0.6 mmol, 3.0 equiv) were added to the vial. The reaction mixture was purged with argon for 5–10 minutes and reacted at room temperature under a 3W blue LED lamp (420 nm, 100% power) for 24 hours. After the reaction was complete (the reaction progress was monitored by thin-layer chromatography (TLC), the solid was centrifuged, and the organic layer was concentrated. The crude product was separated by silica gel column chromatography (PE:EA=20:3 elution), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate.

[0042] The reaction equations involved are as follows:

[0043]

[0044] Product confirmation:

[0045] Name: Ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-phenylbutyrate

[0046] .

[0047] 1 H NMR (400 MHz, Chloroform-d) δ 7.59 – 7.45 (m, 5H), 7.41 (t, J =7.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 5.3 Hz, 2H), 6.11 (dd, J= 9.6, 4.6 Hz, 1H), 4.27 (qd, J = 7.2, 2.6 Hz, 2H), 3.56 (ddt, J = 20.3,15.4, 10.0 Hz, 1H), 2.99 (dtd, J = 20.2, 15.5, 4.6 Hz, 1H), 1.80 (s, 3H),1.33 (t, J = 7.2 Hz, 3H).

[0048] 13C NMR (101 MHz, Chloroform-d) δ 174.05, 173.70, 163.73 (t, J = 32.3Hz), 142.82, 138.55, 136.74, 132.95, 128.99, 128.79, 128.76, 128.52, 128.25,128.07, 125.72, 118.42 – 112.92 (m), 63.20, 53.73, 36.25 (t, J = 22.6 Hz), 28.08, 13.92.

[0049] 19 F NMR (376 MHz, Chloroform-d) δ -103.22 (dd, J = 20.5, 10.4 Hz), -103.93 (dd, J = 20.5, 10.4 Hz), -106.02 (dd, J = 20.5, 15.9 Hz), -106.73 (dd,J = 20.4, 15.9 Hz).

[0050] Replacement Example 1-27

[0051] To investigate the effect of different process conditions on the synthesis yield of fluorinated imide derivatives, the following experiments were conducted.

[0052] The preparation method is the same as that in Example 1, except that the types of catalysts, organic solvents, and bases used in the reaction are adjusted, and their effects on the reaction are tested, as shown in Table 1.

[0053] Table 1

[0054] .

[0055] As shown in Table 1, in the synthesis process of fluorinated imide derivatives, the highest product yield (88%) is obtained when K2CO3 is selected as the base, Ir(ppy)3 is used as the catalyst, and acetonitrile is used as the solvent.

[0056] Example 2

[0057] This embodiment describes the preparation of ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(p-tolyl)butyrate.

[0058] The preparation method was the same as in Example 1, except that p-methylstyrene (0.6 mmol) was used instead of styrene (0.6 mmol), and other conditions and procedures were the same as in Example 1. Ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(p-tolyl)butyrate was prepared with a yield of 85%.

[0059] Product characterization:

[0060] .

[0061] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.49 (m, 3H), 7.43 – 7.34 (m,4H), 7.14 – 7.10 (m, 2H), 6.07 (dd, J = 9.5, 4.7 Hz, 1H), 4.26 (qd, J = 1.32 (t, J = 7.1 Hz, 3H).

[0062] 13 C NMR (101 MHz, Chloroform-d) δ 174.05, 173.70, 163.74 (t, J = 32.6Hz), 137.77, 136.80, 135.56, 132.88, 129.16, 128.95, 128.76, 127.96, 125.67,118.66 – 112.52 (m), 63.15, 53.52, 36.31 (t, J = 22.5 Hz), 28.09, 21.09,13.90.

[0063] 19 F NMR (376 MHz, Chloroform-d) δ -103.09 (dd, J = 20.5, 10.3 Hz), -103.79 (dd, J = 20.4, 10.5 Hz), -105.88 (dd, J = 20.4, 16.0 Hz), -106.58 (dd,J = 20.4, 16.0 Hz).

[0064] Example 3

[0065] This embodiment describes the preparation of ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate.

[0066] The preparation method was the same as in Example 1, except that 0.6 mmol of p-fluorostyrene was used instead of 0.6 mmol of styrene. Other conditions and procedures were the same as in Example 1. Ethyl 4-(N-acetylbenzamido)-2,2-difluoro-4-(4-fluorophenyl)butyrate was prepared with a yield of 78%.

[0067] Product characterization:

[0068] .

[0069] 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (dq, J = 6.8, 2.8, 2.1 Hz, 3H), 7.49 (dd, J = 8.7, 5.4 Hz, 2H), 7.42 (dd, J = 8.3, 7.1 Hz, 2H), 7.01 (t, J =8.7 Hz, 2H), 6.09 (dd, J = 9.3, 4.9 Hz, 1H), 4.28 (qd, J = 7.1, 1.8 Hz, 2H), 3.52 (dddd, J = 20.2, 15.3, 10.4, 9.3 Hz, 1H), 2.96 (dtd, J = 20.4, 15.4, 4.9Hz, 1H), 1.78 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0070] 13 C NMR (101 MHz, Chloroform-d) δ 173.95, 173.58, 163.62 (t, J = 32.4Hz), 162.27 (d, J = 247.3 Hz), 136.57, 134.34 (d, J = 3.4 Hz), 133.06,130.10, 130.01, 129.02, 128.70, 117.95 – 112.76 (m), 115.32 (d, J = 21.5 Hz).36.35 (t, J = 22.6 Hz). 63.21, 53.04, 28.08, 13.87.

[0071] 19F NMR (376 MHz, Chloroform-d) δ -103.42 (dd, J = 20.4, 10.5 Hz), -104.13 (dd, J = 20.5, 10.5 Hz), -105.99 (dd, J = 20.4, 15.4 Hz), -106.69 (dd,J = 20.5, 15.4 Hz), -113.82.

[0072] Example 4

[0073] This embodiment describes the preparation of ethyl 4-(N-acetylbenzamido)-5-benzyloxy-2,2-difluorovalerate.

[0074] The preparation method is the same as in Example 1, except that allyl benzyl ether (0.6 mmol) is used instead of styrene (0.6 mmol), and other conditions and procedures are the same as in Example 1. Ethyl 4-(N-acetylbenzamido)-5-benzyloxy-2,2-difluorovalerate is prepared with a yield of 90%.

[0075] Product confirmation:

[0076] .

[0077] 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (dd, J = 8.3, 1.4 Hz, 2H), 7.57– 7.52 (m, 1H), 7.41 (dd, J = 8.3, 7.1 Hz, 2H), 7.31 – 7.26 (m, 2H), 7.25 –7.22 (m, 1H), 7.20 – 7.16 (m, 2H), 5.07 (d, J = 1.1 Hz, 2H), 3.93 (dddd, J =17.9, 10.8, 7.2, 3.6 Hz, 2H), 3.68 (qd, J = 9.5, 6.6 Hz, 2H), 3.16 (dq, J =11.2, 6.1 Hz, 1H), 2.64 – 2.42 (m, 2H), 2.28 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

[0078] 13C NMR (101 MHz, Chloroform-d) δ 173.99, 173.58, 164.28 – 163.41 (m), 140.34, 134.56, 132.64, 128.66, 128.64, 128.47, 128.08, 127.21, 115.74 (dd, J = 251.9, 249.2 Hz), 74.74, 73.26, 62.69, 39.84 (dd, J = 5.6, 2.7 Hz), 36.94 (t, J = 23.3 Hz), 25.51, 13.72.

[0079] 19 F NMR (376 MHz, Chloroform-d) δ -100.87 (t, J = 14.1 Hz), -101.56 (t, J = 14.1 Hz), -105.98 (t, J = 18.1 Hz), -106.67 (t, J = 18.2 Hz).

[0080] Example 5

[0081] This embodiment describes the preparation of ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate.

[0082] The preparation method is the same as in Example 1, except that p-methylbenzoic acid (0.2 mmol) is used instead of benzoic acid (0.2 mmol). Other conditions and procedures are the same as in Example 1. Ethyl 4-(N-acetyl-4-methylbenzamido)-2,2-difluoro-4-phenylbutyrate was prepared with a yield of 90%.

[0083] Product confirmation:

[0084] .

[0085] 1H NMR (400 MHz, Chloroform-d) δ 7.47 (t, J = 7.6 Hz, 4H), 7.37 (d, J= 4.3 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.10 (dd,J = 9.4, 4.8 Hz, 1H), 4.25 (qd, J = 7.2, 2.7 Hz, 2H), 3.53 (ddt, J = 20.0,15.2, 9.9 Hz, 1H), 3.00 (dtd, J = 20.5, 15.7, 4.9 Hz, 1H), 2.38 (s, 3H), 1.80 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0086] 13 C NMR (101 MHz, Chloroform-d) δ 174.05, 173.55, 163.73 (t, J = 32.5Hz), 144.01, 142.82, 138.57, 133.90, 129.65, 129.00, 128.77, 128.47, 128.22,128.10, 128.01, 125.70, 118.76 – 110.31 (m), 63.15, 53.66, 36.36 (t, J = 22.7Hz), 27.96, 21.65, 13.90.

[0087] 19 F NMR (376 MHz, Chloroform-d) δ -103.00 (dd, J = 20.1, 9.9 Hz), -103.71 (dd, J = 20.0, 9.8 Hz), -105.82 (dd, J = 18.6, 8.6 Hz), -106.52 (dd, J= 18.5, 8.6 Hz).

[0088] Example 6

[0089] This embodiment describes the preparation of ethyl 4-(N-acetyl-4-methoxybenzamido)-2,2-difluoro-4-phenylbutyrate.

[0090] The preparation method was the same as in Example 1, except that p-methoxybenzoic acid (0.2 mmol) was used instead of benzoic acid (0.2 mmol). Other conditions and procedures were the same as in Example 1. Ethyl 4-(N-acetyl-4-methoxybenzoamide)-2,2-difluoro-4-phenylbutyrate was prepared with a yield of 87%.

[0091] Product confirmation:

[0092] .

[0093] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.52 (m, 2H), 7.49 – 7.45 (m,2H), 7.34 – 7.28 (m, 2H), 7.26 – 7.21 (m, 1H), 6.90 – 6.86 (m, 2H), 6.08 (dd,J = 9.2, 5.0 Hz, 1H), 4.25 (qd,J = 7.2, 2.7 Hz, 2H), 3.84 (s, 3H), 3.58 –3.43 (m, 1H), 3.00 (dtd, J = 20.4, 15.6, 5.0 Hz, 1H), 1.82 (s, 3H), 1.32 (t,J = 7.1 Hz, 3H).

[0094] 13 C NMR (101 MHz, Chloroform-d) δ 173.57, 173.23, 163.64, 138.57,131.34, 128.85, 128.46, 128.14, 128.01, 114.26, 63.13, 55.58, 53.67, 36.49,27.73, 13.90.

[0095] 19 F NMR (376 MHz, Chloroform-d) δ -103.08 (dd, J = 20.6, 11.0 Hz), -103.79 (dd, J = 20.1, 10.7 Hz), -105.78 – -106.13 (m), -106.66 (t, J = 18.2Hz).

[0096] Example 7

[0097] This embodiment describes the preparation of ethyl 4-[N-(2-phthalimide acetyl)acetamido]-2,2-difluoro-4-phenylbutyrate.

[0098] The preparation method is the same as in Example 1, except that phthaloylglycine (0.2 mmol) is used instead of benzoic acid (0.2 mmol), and other conditions and procedures are the same as in Example 1. Ethyl 4-[N-(2-phthalimide acetyl)acetamido]-2,2-difluoro-4-phenylbutyrate was prepared with a yield of 75%.

[0099] Product confirmation:

[0100] .

[0101] 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.39 – 7.34 (m, 2H), 7.29 (d, J = 7.3 Hz, 3H), 5.57 (dd, J = 8.1, 4.5 Hz, 1H), 4.89 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.34– 2.99 (m, 2H), 2.47 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0102] 13 C NMR (101 MHz, Chloroform-d) δ 173.77, 170.27, 167.70, 163.54,137.61, 134.09, 132.19, 128.93, 127.96, 126.48, 126.03, 123.66, 123.55,116.65 (d, J = 253.1 Hz), 77.28, 63.55, 54.27, 44.42, 36.60 (t, J = 22.2 Hz), 25.57, 13.91.

[0103] 19 F NMR (376 MHz, Chloroform-d) δ -104.17, -104.88, -105.37, -106.07.

[0104] Example 8

[0105] This embodiment describes the preparation of ethyl 2,2-difluoro-4-[N-(2-phenoxyacetyl)acetamido]-4-phenylbutyrate.

[0106] The preparation method is the same as in Example 1, except that phenoxyacetic acid (0.2 mmol) is used instead of benzoic acid (0.2 mmol), and other conditions and procedures are the same as in Example 1. Ethyl 2,2-difluoro-4-[N-(2-phenoxyacetyl)acetamido]-4-phenylbutyrate is prepared with a yield of 89%.

[0107] Product confirmation:

[0108] .

[0109] 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (d, J = 4.3 Hz, 1H), 7.34 –7.30 (m, 4H), 7.23 – 7.19 (m, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.80 – 6.75 (m,2H), 5.57 (dd, J = 9.1, 4.3 Hz, 1H), 5.07 – 4.93 (m, 2H), 4.28 (q, J = 7.2Hz, 2H), 3.40 (dddd, J = 21.8, 15.6, 12.9, 9.1 Hz, 1H), 3.03 (dddd, J = 22.2,16.0, 12.7, 4.3 Hz, 1H), 2.48 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0110] 13 C NMR (101 MHz, Chloroform-d) δ 173.84, 172.53, 157.73, 137.82,129.50, 128.80, 128.06, 126.64, 125.70, 121.50, 114.62, 70.20, 63.50, 54.22,35.71, 25.63, 13.90.

[0111] 19 F NMR (376 MHz, Chloroform-d) δ -104.50, -105.22, -105.70, -106.41.

[0112] Example 9

[0113] This embodiment describes the preparation of N-acetyl-N-(3,3-dibromo-3-fluoro-1-phenylpropyl)benzamide.

[0114] The preparation method was the same as in Example 1, except that tribromofluoromethane (0.6 mmol) was used instead of ethyl difluorobromoacetate (0.6 mmol). Other conditions and procedures were the same as in Example 1. N-acetyl-N-(3,3-dibromo-3-fluoro-1-phenylpropyl)benzamide was prepared with a yield of 85%.

[0115] Product confirmation:

[0116] .

[0117] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.49 (m, 5H), 7.40 (dd, J =8.7, 6.7 Hz, 2H), 7.36 – 7.31 (m, 2H), 7.30 – 7.24 (m, 1H), 6.24 (dd, J =8.6, 3.9 Hz, 1H), 4.30 (ddd, J = 15.8, 12.5, 8.6 Hz, 1H), 3.57 (ddd, J =24.0, 15.8, 4.0 Hz, 1H), 1.80 (s, 3H).

[0118] 13 C NMR (101 MHz, Chloroform-d) δ 174.01, 173.73, 138.28, 136.62,133.04, 129.02, 128.86, 128.78, 128.64, 128.18, 125.84, 94.33 (d, J = 319.8Hz), 57.96, 54.38 (d, J = 18.4 Hz), 28.28.

[0119] 19 F NMR (376 MHz, Chloroform-d) δ -47.83.

[0120] Example 10

[0121] This embodiment describes the preparation of ethyl 4-(N-acetylcyclohexanecarbamate)-2,2-difluoro-4-phenylbutyrate.

[0122] The preparation method was the same as in Example 1, except that cyclohexanoic acid (0.2 mmol) was used instead of benzoic acid (0.2 mmol), and other conditions and procedures were the same as in Example 1. Ethyl 4-(N-acetylcyclohexanecarbamate)-2,2-difluoro-4-phenylbutyrate was prepared with a yield of 67%.

[0123] Product confirmation:

[0124] .

[0125] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.27 (m, 5H), 5.68 (dd, J =8.5, 4.8 Hz, 1H), 4.30 – 4.24 (m, 2H), 3.31 – 3.13 (m, 1H), 3.13 – 2.96 (m,1H), 2.73 (tt, J = 11.2, 3.1 Hz, 1H), 2.37 (s, 3H), 1.78 – 1.57 (m, 10H),1.33 (t, J = 7.2 Hz, 3H).

[0126] 13 C NMR (101 MHz, Chloroform-d) δ 181.23, 173.94,163.63, 138.73,129.49, 128.78, 128.61, 127.80, 126.88, 115.44, 63.31, 52.82, 46.49, 36.68,29.71, 29.19, 26.45, 25.66, 13.89.

[0127] 19 F NMR (376 MHz, Chloroform-d) δ -105.42, -105.66.

[0128] Application Examples:

[0129] This embodiment mainly examines the antibacterial properties of fluorinated imide derivatives.

[0130] The antibacterial properties of the fluorinated imide derivatives prepared in Examples 1, 3, and 5 were evaluated using the following methods:

[0131] (1) Preparation of antibacterial agent samples

[0132] Accurately weigh appropriate amounts of the products prepared in Examples 1, 3, and 5, and prepare sample solutions with concentrations of 20 mg / mL, 40 mg / mL, and 60 mg / mL respectively using DMSO as the solvent. Test their inhibitory effects on Escherichia coli.

[0133] (2) Preparation of bacterial suspension

[0134] Take a strain of Escherichia coli and place it in a test tube. Add 5 mL of culture medium to the test tube and incubate it in a constant temperature and humidity incubator at 37°C for 6-8 hours. Then, use an inoculation loop to streak the bacterial solution evenly on nutrient broth agar medium. Incubate the medium in a constant temperature incubator for 12-20 hours to obtain a single colony of Escherichia coli. Pick a single Escherichia coli colony with a pipette tip and place it in 5 mL of LB medium. Incubate at 37°C for 8-10 hours to obtain a bacterial solution with OD=1.

[0135] (3) Antibacterial zone test

[0136] After turning on the ultra-clean hood for 30 minutes, perform aseptic operations. Soak blank drug sensitivity test strips in the aforementioned sample solution for 5 minutes. Take 40 μL of the test bacterial solution and spread it evenly on nutrient broth agar medium. Then, attach the drug sensitivity test strips soaked in the drug solution to the medium. Incubate the medium in a 37°C incubator overnight and then observe the size of the inhibition zone.

[0137] The results of the antibacterial performance test are shown in Table 2. Figures 1-3 As shown:

[0138] Table 2. Results of the inhibition zone experiment

[0139] .

[0140] As shown in Table 2, Figures 1-3 As shown, Examples 1, 3, and 5 all exhibited certain antibacterial effects against Escherichia coli, and the antibacterial effect was further enhanced with increasing concentration.

[0141] Summarize:

[0142] This invention uses olefins as bridging units to achieve a three-component imide derivatization reaction with fluorine-containing compounds and carboxylic acids under the action of base and induced by visible light. The reaction conditions are mild, the raw materials are inexpensive and readily available, the operation process is simple, and the reaction has broad applicability. It can effectively replace the synthesis of traditional complex fluorine-containing imide derivatives without the need for complex substrate design. At the same time, since the imide-based compound has high pharmacological activity, it has strong practicality.

[0143] It is understood that the above detailed description of the present invention is for illustrative purposes only and is not intended to limit the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention to achieve the same technical effects; as long as the usage requirements are met, they are all within the protection scope of the present invention.

Claims

1. A fluorinated imide derivative, characterized in that, The structure is as follows: 。 2. A method for preparing the fluorinated imide derivative of claim 1, characterized in that, The process includes the following steps: using carboxylic acid, olefin, and ethyl difluorobromoacetate as raw materials, and reacting them under visible light in the presence of a photocatalyst, a base, and an organic solvent to obtain fluorinated imide derivatives; The organic solvent is acetonitrile; the catalyst is Ir(ppy)3; and the base is potassium carbonate. The structural formula of the carboxylic acid is as follows: ; The structural formula of the olefin is as follows: ; The structural formula of the fluorinated imide derivative is as follows: ; In the formula: the substituents R1, R2, and R3 are the same as those in claim 1.

3. The method for preparing a fluorinated imide derivative according to claim 2, characterized in that: The amount of catalyst used, based on the amount of carboxylic acid added, is 1-10 mol of the amount of carboxylic acid added.

4. The method for preparing a fluorinated imide derivative according to claim 2, characterized in that: The reaction was carried out at room temperature for 12-36 hours.

5. The method for preparing a fluorinated imide derivative according to claim 2, characterized in that: The visible light is blue light with a wavelength of 400-450nm.

6. The use of the fluorinated imide derivative of claim 1 in the preparation of a drug for inhibiting Escherichia coli.

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