A fluorine-containing pyridine nitrogen oxide derivative and preparation method thereof

Abstract

The invention discloses a fluorine-containing pyridine nitrogen oxide derivative and a synthesis method thereof. The structure of the compound of the invention is: wherein R1 is ‑CH3, ‑OCH3, ‑Br, ‑Cl or ‑COOCH3. The invention realizes a free radical reaction between pyridine nitrogen oxide and ethyl bromodifluoroacetate under visible light catalysis, thereby completing the synthesis of the fluorine-containing pyridine nitrogen oxide derivative. The difluoroalkylation reaction of the pyridine nitrogen oxide of the invention has high reactivity, easy access to substrates, and relatively low fluorine-containing reagents, and low cost; the method of the invention has the characteristics of mild reaction, simple operation, wide substrate adaptability and high yield.

Description

Technical Field

[0001] The present invention relates to a pyridine nitrogen oxide derivative and a preparation method thereof, in particular to a fluorine-containing pyridine nitrogen oxide derivative and a preparation method thereof. Background Art

[0002] As one of the activated species of pyridine, pyridine nitrogen oxide has the unique function of nitrogen-oxygen bond. It has a wide range of applications in the field of pharmaceutical development due to its change in chemical reactivity. The introduction of fluorine-containing functional groups can improve the lipophilicity, membrane permeability and antioxidant properties of the substrate, and can also improve the metabolic stability and efficacy of drug molecules. Pyridine nitrogen oxide can also be used as a catalyst in various reactions. Pyridine nitrogen oxide is used as an esterification catalyst, epoxy resin cross-linking promoter, and cephalosporin IV ring expansion catalyst. In the dye industry, pyridine nitrogen oxide can also be used as an oxidant. The difluoroalkylation reaction of pyridine has rarely been reported. The difluoroalkylation product of pyridine nitrogen oxide can be quickly and efficiently deoxygenated to obtain pyridine difluoroalkylation products, which provides a new idea for the difluoroalkylation reaction of pyridine. At the same time, this method also provides a convenient and effective way for the difluoroalkylation reaction of pyridine nitrogen oxide.

[0003] Ethyl difluorobromoacetate is easy to prepare, cheap and readily available, and is a common commercial fluorinated building block. In the past few years, photocatalysis has provided a more sustainable option for free radical-initiated reactions from the perspectives of safety, cost and availability. The current difluoroalkylation of pyridine N-oxides is still limited by low reactivity, limited substrate range and the use of expensive fluorinated reagents. Therefore, the difluoroalkylation of pyridine N-oxides remains a great challenge. So far, there has been no report on the difluoroalkylation of pyridine N-oxides under photocatalytic conditions. Summary of the invention

[0004] In order to solve the problems of the prior art, the purpose of the present invention is to overcome the shortcomings of the prior art, provide a fluorine-containing pyridine nitrogen oxide derivative and a synthesis method thereof, and provide a new compound of a pyridine nitrogen oxide derivative. The method of the present invention realizes the synthesis of a fluorine-containing pyridine nitrogen oxide derivative using ethyl bromodifluoroacetate under photocatalytic conditions, the reaction process is simple, easy to control, the product yield is good to excellent, and there is great industrial value.

[0005] In order to achieve the above invention purpose, the invention concept of the present invention is:

[0006] The present invention adopts the following reaction equation:

[0007]

[0008] Wherein: R=-CH3, -OCH3, -Br, -Cl, -COOCH3.

[0009] According to the above inventive concept, the present invention adopts the following technical solution:

[0010] A fluorine-containing pyridine nitrogen oxide derivative, the structure of the compound is:

[0011]

[0012] Wherein, R is -CH3, -OCH3, -Br, -Cl or -COOCH3.

[0013] A method for preparing the fluorine-containing pyridine nitrogen oxide derivative of the present invention comprises the following steps:

[0014] (1) Preparation of reactant mixed solution system:

[0015] Pyridine nitrogen oxide, a photocatalyst and a base are added to a round-bottom flask, and after replacing nitrogen at least three times, ethyl difluorobromoacetate is added, and finally a solvent is added to obtain a reactant mixed solution system;

[0016] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0017] At room temperature, the reactant mixed solution system is irradiated with blue light for at least 16 hours. After the reaction is completed, the solvent is removed and the fluorine-containing pyridine nitrogen oxide is obtained through purification.

[0018] Preferably, in the step (1), the molar ratio of the pyridine nitrogen oxide, ethyl difluorobromoacetate, photocatalyst and base is 1-2.5:2-5:0.01-0.025:2-5.

[0019] In the step (1), the structure of the pyridine nitrogen oxide is: Wherein, R is -CH3, -OCH3, -Br, -Cl or -COOCH3.

[0020] In the step (1), the structural formula of ethyl difluorobromoacetate is BrCF2CO2Et.

[0021] In the step (1), the photocatalyst is at least one of fac-Ir(ppy)3, Ir(dtbbpy)(ppy)2[PF6], and Ru(bpy)3Cl2·6H2O.

[0022] In the step (1), the base is at least one of sodium bicarbonate, cesium carbonate, sodium tert-butoxide, potassium acetate, imidazole, and triethylamine.

[0023] In the step (1), the solvent is at least one of dimethyl sulfoxide, dichloromethane, acetone, cyclohexane, anhydrous ethanol and N,N-dimethylformamide.

[0024] In the step (2), during purification, silica gel column chromatography is used for separation, and the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0025] Compared with the prior art, the present invention has the following obvious outstanding substantive features and significant advantages:

[0026] 1. The present invention synthesizes a series of fluorine-containing pyridine nitrogen oxides by a one-pot method by reacting pyridine nitrogen oxides containing different functional groups with ethyl difluorobromoacetate under photocatalysis in a solvent and adding a photocatalyst and a base;

[0027] 2. The difluoroalkylation reaction of pyridine nitrogen oxide of the present invention has high reactivity, the substrate is easy to obtain, and the fluorine-containing reagent is relatively cheap, so the cost is low;

[0028] 3. The method of the present invention has the characteristics of mild reaction, simple operation, wide substrate adaptability and high yield. DETAILED DESCRIPTION

[0029] In the following embodiment, a fluorine-containing pyridine nitrogen oxide derivative has the structure of:

[0030]

[0031] Wherein, R is -CH3, -OCH3, -Br, -Cl or -COOCH3.

[0032] The above scheme is further described below in conjunction with specific implementation examples. The preferred embodiments of the present invention are described in detail as follows:

[0033] Embodiment 1

[0034] In this embodiment, a method for preparing a fluorine-containing pyridine nitrogen oxide derivative, preparing 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methylpyridine nitrogen oxide, comprises the following steps:

[0035] (1) Preparation of reactant mixed solution system:

[0036] In a 50 ml reaction bottle, 0.42 sodium bicarbonate (0.42 g, 5 mmol), a photocatalyst (0.02 g, 0.025 mmol), and 4-methylpyridine nitrogen oxide (0.27 g, 2.5 mmol) were added in sequence. After nitrogen was replaced three times, ethyl difluorobromoacetate (1.01 g, 5 mmol) was added, and finally 25 ml of dimethyl sulfoxide solvent was added to obtain a reactant mixed solution system;

[0037] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0038] At room temperature, the reactant mixed solution system was irradiated with 30W blue light for 16 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. After purification, 0.47 grams of white solid was obtained, and the yield of fluorinated pyridine nitrogen oxide was 82%.

[0039] Experimental test analysis:

[0040] In this embodiment, 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methylpyridine nitrogen oxide has the structure of:

[0041]

[0042] Molecular formula: C 10 H 11 F2NO3

[0043] Chinese name: 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methylpyridine nitrogen oxide

[0044] English name: 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-4-methylpyridine1-oxide

[0045] Molecular weight: 231

[0046] Appearance: white solid

[0047] H NMR (500 MHz, CDCl3): δ ppm 8.07 (d, J = 6.5 Hz, 1H), 7.51 (s, 1H), 7.22 (d, J = 6.5 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0048] NMR fluorine spectrum (470 MHz, CDCl3, internal standard: C6F6): δ ppm -110.09 (s, 2F).

[0049] Carbon nuclear magnetic resonance spectrum (125 MHz, CDCl3): δppm 161.4 (t, J = 31.1 Hz), 142.1 (t, J = 29.0 Hz), 138.9, 137.8, 128.6, 124.6 (t, J = 4.9 Hz), 108.9 (t, J = 249.8 Hz), 63.3, 20.6, 13.9.

[0050] High-resolution mass spectrometry (high-resolution mass spectrometer Premier CAB088): theoretical value: 232.0780; measured value: 232.0779.

[0051] Embodiment 2

[0052] This embodiment is basically the same as the first embodiment, except that:

[0053] In this embodiment, a method for preparing a fluorine-containing pyridine nitrogen oxide derivative, preparing 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methoxypyridine nitrogen oxide, comprises the following steps:

[0054] (1) Preparation of reactant mixed solution system:

[0055] In a 50 ml reaction bottle, sodium bicarbonate (0.42 g, 5 mmol), photocatalyst (0.02 g, 0.025 mmol), 4-methoxypyridine nitrogen oxide (0.31 g, 2.5 mmol) were added in sequence, nitrogen was replaced three times, difluoroethyl bromide (1.01 g, 5 mmol) was added, and finally 25 ml of dimethyl sulfoxide solvent was added to obtain a reactant mixed solution system;

[0056] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0057] At room temperature, the reactant mixed solution system was irradiated with 30W blue light for 16 hours. After the reaction, it was cooled to room temperature, the solvent was removed, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. After purification, 0.43 grams of white solid was obtained, and the yield of fluorinated pyridine nitrogen oxide was 70%.

[0058] Experimental test analysis:

[0059] In this embodiment, 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methylpyridine nitrogen oxide has the structure of:

[0060]

[0061] Molecular formula: C 10 H 11 F2NO4

[0062] Chinese name: 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methoxypyridine N-oxide

[0063] English name: 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-4-methoxypyridine1-oxide

[0064] Molecular weight: 247

[0065] Appearance: white solid

[0066] H NMR (500 MHz, CDCl3): δ ppm 8.10 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H), 6.95 (dd, J = 7.3, 3.5 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0067] Fluorine nuclear magnetic resonance spectrum (470 MHz, CDCl3, internal standard: C6F6): δ ppm -110.00 (s, 2F).

[0068] Carbon nuclear magnetic resonance spectrum (125 MHz, CDCl3): δppm 161.2 (t, J = 30.9 Hz), 157.7, 143.5 (t, J = 29.3 Hz), 140.3, 114.1, 109.4 (t, J = 5.3 Hz), 108.7 (t, J = 250.7 Hz), 63.3, 56.5, 13.9.

[0069] High-resolution mass spectrometry (high-resolution mass spectrometer Premier CAB088): theoretical value: 248.0729; measured value: 248.0728.

[0070] Embodiment 3

[0071] This embodiment is basically the same as the above embodiment, with the following features:

[0072] In this embodiment, a method for preparing a fluorine-containing pyridine nitrogen oxide derivative, preparing 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-bromopyridine nitrogen oxide, has the following steps:

[0073] (1) Preparation of reactant mixed solution system:

[0074] In a 50 ml reaction bottle, sodium bicarbonate (0.42 g, 5 mmol), photocatalyst (0.02 g, 0.025 mmol), 4-bromopyridine nitrogen oxide (0.44 g, 2.5 mmol) were added in sequence, nitrogen was replaced three times, difluoroethyl bromide (1.01 g, 5 mmol) was added, and finally 25 ml of dimethyl sulfoxide solvent was added to obtain a reactant mixed solution system;

[0075] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0076] At room temperature, the reactant mixed solution system was irradiated with 30W blue light for 16 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. After purification, 0.44 grams of brown solid was obtained, and the yield of fluorinated pyridine nitrogen oxide was 59%.

[0077] Experimental test analysis:

[0078] In this embodiment, 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-bromopyridine nitrogen oxide has the structure of:

[0079]

[0080] Molecular formula: C9H8BrF2NO3

[0081] Chinese name: 4-bromo-2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)pyridine nitrogen oxide

[0082] English name: 4-bromo-2-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyridine1-oxide

[0083] Molecular weight: 295

[0084] Appearance: brown solid

[0085] H NMR (500 MHz, CDCl3): δ ppm 8.05 (d, J = 6.5 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.55 (dd, J = 6.5, 2.5 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0086] NMR fluorine spectrum (470 MHz, CDCl3, internal standard: C6F6): δ ppm -110.26 (s, 2F).

[0087] Carbon nuclear magnetic resonance spectrum (125 MHz, CDCl3): δppm 160.8 (t, J = 30.6 Hz), 143.8 (t, J = 29.5 Hz), 140.4, 131.1, 127.4 (t, J = 6.3 Hz), 118.9.108.4 (t, J = 252.0 Hz), 63.5, 13.8.

[0088] High-resolution mass spectrometry (high-resolution mass spectrometer Premier CAB088): theoretical value: 295.9729; measured value: 295.9725.

[0089] Embodiment 4

[0090] This embodiment is basically the same as the above embodiment, with the following features:

[0091] In this embodiment, a method for preparing a fluorine-containing pyridine nitrogen oxide derivative, preparing 4-chloro-2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)pyridine nitrogen oxide, has the following steps:

[0092] (1) Preparation of reactant mixed solution system:

[0093] In a 500 ml reaction bottle, sodium bicarbonate (4.20 g, 50 mmol), photocatalyst (0.16 g, 0.25 mmol), 4-chloropyridine nitrogen oxide (3.24 g, 25 mmol) were added in sequence, nitrogen was replaced three times, difluoroethyl bromide (10.15 g, 50 mmol) was added, and finally 250 ml of dimethyl sulfoxide solvent was added to obtain a reactant mixed solution system;

[0094] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0095] At room temperature, the reactant mixed solution system was irradiated with 30W blue light for 16 hours. After the reaction, it was cooled to room temperature, the solvent was removed, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. After purification, 4.58 grams of brown solid was obtained, and the yield of fluorinated pyridine nitrogen oxide was 65%.

[0096] Experimental test analysis:

[0097] In this embodiment, 4-chloro-2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)pyridine nitrogen oxide has the structure of:

[0098]

[0099] Molecular formula: C9H8ClF2NO3

[0100] Chinese name: 4-chloro-2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)pyridine nitrogen oxide

[0101] English name: 4-chloro-2-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyridine1-oxide

[0102] Molecular weight: 251

[0103] Appearance: brown solid

[0104] H NMR (500 MHz, CDCl3): δ ppm 8.13 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 2.9 Hz, 1H), 7.41 (dd, J = 7.0, 2.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0105] NMR fluorine spectrum (471MHz,CDCl3):δppm-110.31(s,CF2).

[0106] Carbon NMR (126 MHz, CDCl3): δppm 160.8 (t, J = 31.5 Hz), 143.8 (t, J = 30.2 Hz), 140.3, 132.1, 128.2, 124.6 (t, J = 5.0 Hz), 108.4 (t, J = 252.0 Hz), 63.5, 13.8.

[0107] High-resolution mass spectrometry (high-resolution mass spectrometer Premier CAB088): theoretical value: 252.0234; measured value: 252.0235.

[0108] Embodiment 5

[0109] This embodiment is basically the same as the above embodiment, with the following features:

[0110] In this embodiment, a method for preparing a fluorine-containing pyridine nitrogen oxide derivative, preparing 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-carboxylic acid methyl ester pyridine nitrogen oxide, has the following steps:

[0111] (1) Preparation of reactant mixed solution system:

[0112] In a 50 ml reaction bottle, sodium bicarbonate (0.42 g, 5 mmol), photocatalyst (0.02 g, 0.025 mmol), 4-methyl pyridine formate nitrogen oxide (0.38 g, 2.5 mmol) were added in sequence, nitrogen was replaced three times, and then difluoroethyl bromoacetate (1.01 g, 5 mmol) was added, and finally 25 ml of dimethyl sulfoxide solvent was added to obtain a reactant mixed solution system;

[0113] (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives:

[0114] At room temperature, the reactant mixed solution system was irradiated with 30W blue light for 16 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and the mixture was separated by silica gel column chromatography. The eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. After purification, 0.26 grams of white solid was obtained, and the yield of fluorinated pyridine nitrogen oxide was 38%.

[0115] Experimental test analysis:

[0116] In this embodiment, 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-methylformate pyridine nitrogen oxide has the structure of:

[0117]

[0118] Molecular formula: C 11 H 11 F2NO5

[0119] Chinese name: 2-(2-methoxy-1,1-difluoro-2-ethoxycarbonyl)-4-carboxylic acid methyl ester pyridine nitrogen oxide

[0120] English name: 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-4-(methoxycarbonyl)pyridine1-oxide

[0121] Molecular weight: 275

[0122] Appearance: white solid

[0123] H NMR (500 MHz, CDCl3): (CDCl3, 500 MHz): δ ppm 8.31 (d, J = 2.0 Hz, 1H), 8.23 ​​(d, J = 6.7 Hz, 1H), 8.02 (dd, J = 6.7, 2.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0124] NMR fluorine spectrum (470 MHz, CDCl3, internal standard: C6F6): δ ppm -110.20 (s, 2F).

[0125] Carbon NMR (125 MHz, CDCl3): δppm 163.3, 160.9 (t, J = 31.0 Hz), 143.3 (t, J = 30.0 Hz), 139.9, 127.9, 126.6, 124.7 (t, J = 5.2 Hz), 108.7 (t, J = 250.5 Hz), 63.5, 53.1, 13.8.

[0126] High-resolution mass spectrometry (high-resolution mass spectrometer Premier CAB088): theoretical value: 276.0679; measured value: 276.0677.

[0127] Application test analysis of the use of the compounds synthesized in the above embodiments of the present invention:

[0128] The fluorinated pyridine nitrogen oxide derivatives of the above embodiment have the unique function of nitrogen-oxygen bonds. The introduction of fluorinated functional groups can improve the lipophilicity, membrane permeability and antioxidant properties of the substrate, and can also improve the metabolic stability and efficacy of drug molecules. It can also be used as an esterification catalyst, an epoxy resin cross-linking promoter, a cephalomycin IV ring expansion catalyst, etc., and can quickly complete the reaction with an ideal yield to achieve the synthesis of the target product. In the dye industry, the fluorinated pyridine nitrogen oxide derivatives of the above embodiment can also be used as an oxidant. The fluorinated pyridine nitrogen oxide derivatives of the above embodiment can achieve the difluoroalkylation reaction of pyridine, and the difluoroalkylation product of pyridine nitrogen oxide can be quickly and efficiently deoxygenated to obtain pyridine difluoroalkylation products with a yield of nearly 100% within 2 hours. The reaction is safer and more convenient. This is a new method for achieving difluoroalkyl modification of pyridine. The above embodiment of the present invention realizes the free radical reaction of pyridine nitrogen oxide and ethyl bromodifluoroacetate under visible light catalysis, and completes the synthesis of fluorinated pyridine nitrogen oxide derivatives. The difluoroalkylation reaction of pyridine nitrogen oxide in the above embodiment of the present invention has high activity, the substrate is easy to obtain, and the fluorine-containing reagent is relatively cheap, and the cost is low; the method in the above embodiment of the present invention has the characteristics of mild reaction, simple operation, wide substrate adaptability and high yield.

[0129] The embodiments of the present invention are described above, but the present invention is not limited to the above embodiments. Various changes can be made according to the purpose of the invention. Any changes, modifications, substitutions, combinations or simplifications made according to the spirit and principle of the technical solution of the present invention should be equivalent replacement methods. As long as they meet the purpose of the invention and do not deviate from the technical principles and inventive concepts of the present invention, they belong to the protection scope of the present invention.

Claims

1. A method for preparing a fluorine-containing pyridine nitrogen oxide derivative, characterized in that: The steps are as follows: (1) Preparation of reactant mixed solution system: Pyridine nitrogen oxide, a photocatalyst and a base are added to a round-bottom flask, and after the nitrogen is replaced at least 3 times, ethyl difluorobromoacetate is added, and finally a solvent is added to obtain a reactant mixed solution system; the structure of the pyridine nitrogen oxide is: Wherein, R is -CH3, -OCH3, -Br, -Cl or -COOCH3; the photocatalyst is fac-Ir(ppy)3; the base is at least one of sodium bicarbonate, imidazole and triethylamine; the solvent is at least one of dimethyl sulfoxide, acetone, anhydrous ethanol and N,N-dimethylformamide; the structural formula of ethyl difluorobromoacetate is BrCF2CO2Et; (2) Preparation of fluorine-containing pyridine nitrogen oxide derivatives: At room temperature, the reactant mixed solution system is irradiated with blue light for at least 16 hours. After the reaction is completed, the solvent is removed and purified to obtain a fluorine-containing pyridine nitrogen oxide derivative, the compound structure of which is: Wherein, R is -CH3, -OCH3, -Br, -Cl or -COOCH3.

2. The method for preparing the fluorine-containing pyridine nitrogen oxide derivative according to claim 1, characterized in that: In the step (1), the molar ratio of the pyridine nitrogen oxide, ethyl difluorobromoacetate, photocatalyst and base is 1-2.5:2-5:0.01-0.025:2-5.

3. The method for preparing the fluorine-containing pyridine nitrogen oxide derivative according to claim 1, characterized in that: In the step (2), during purification, silica gel column chromatography is used for separation, and the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1.

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