A method for preparing an azvudine intermediate using a microchannel reactor

Abstract

The present invention belongs to the field of organic synthesis, and in particular to the field of organic drug synthesis technology, and more specifically to a method for preparing an azvudine intermediate by using a microchannel reactor, wherein a new synthesis route is provided, that is, compound III is used as a raw material, reacted with alkyl bromide or alkyl iodide to obtain compound II; and then reacted with acyl fluoride using a continuous flow microchannel reactor to obtain a target product compound I, thereby realizing the application of a microchannel reactor in the preparation of an azvudine intermediate. By performing a continuous flow type reaction in a microchannel reactor, the reaction time and reaction temperature can be accurately controlled, and the problems of long reaction time, many by-products, excessively high reaction temperature, high equipment requirements, low yield and purity, etc. in each reaction step in the prior art are effectively solved.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, in particular to the technical field of organic drug synthesis, and more specifically to a method for preparing an azithromycin intermediate using a microchannel reactor. Background Art

[0002] Azvudine, also known as Azifudine, was invented by Professor Chang Junbiao and developed jointly by Henan Zhenshi Biotechnology Co., Ltd., Zhengzhou University, Henan Normal University, and Henan Academy of Sciences High-Tech Research Center. It is an HIV reverse transcriptase (RT) inhibitor and a new generation of AIDS treatment drugs that are world-leading and domestically pioneered.

[0003] In the process of synthesizing azithromycin compounds, there is an important intermediate compound, which is 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranosyl. The chemical structure of the compound is as follows:

[0004]

[0005] The method for synthesizing 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranosyl in the prior art is to use compound I as a raw material and prepare it by fluorinating the hydroxyl group at position 2. The process can be expressed as follows:

[0006]

[0007] In this process, it is inevitable to use fluorinated reagents, for example, HF or tetrabutylammonium fluoride are used in the technical solution disclosed in CN 101531695. Both fluorinated reagents are toxic, especially HF is a gas under normal pressure, which is highly toxic and corrosive.

[0008] Patent CN101555267 discloses another method for synthesizing 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranosyl, in which DAST (diethylaminosulfur trifluoride) is used as a fluorination agent to fluorinate the hydroxyl group at position 2. The fluorination agent is in liquid form and is extremely unstable. It decomposes in water and releases a large amount of highly toxic sulfur dioxide and HF gas, causing serious environmental pollution. It is very likely to explode in the event of collision or high temperature during production, storage, and transportation.

[0009] Therefore, in the synthesis of 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose, there arise problems such as high requirements for equipment, great difficulty in industrialization, easy corrosion and damage of equipment, and high production costs.

[0010] Microchannel reactors have high specific surface area and regular laminar flow characteristics. When reactants react in microchannel reactors, they can continuously participate in subsequent reactions, thereby obtaining efficient space-time yields. At the same time, compared with traditional preparation processes, microchannel reactors also have the advantages of fast mass transfer rate, short residence time, good repeatability, and easy automation control.

[0011] At present, there is no technical solution using a microchannel reactor in the existing preparation process of the azithromycin intermediate 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranosyl. Summary of the invention

[0012] The technical problem to be solved by the present invention is to provide a new preparation method of an azithromycin intermediate, thereby achieving improvements in the cost, yield, safety and environmental friendliness of the azithromycin intermediate synthesis process.

[0013] In order to solve the above technical problems, the present invention discloses a method for preparing an azvudine intermediate by a microchannel reactor, the method comprising the following steps:

[0014] (1) Compound II is mixed with a hydrocarbon solvent and stirred to form a material A;

[0015] (2) mixing acyl fluoride and hydrocarbon solvent, stirring evenly to form material B;

[0016] (3) mixing the boron trifluoride coordination compound and the hydrocarbon solvent, stirring evenly to form material C;

[0017] (4) Material A, material B and material C are respectively transported to the microchannel reactor through the feed pipes, and each feed pipe is provided with a metering pump, and the flow rate of each material is controlled by the metering pump, wherein the flow rate of material A is controlled to 7.5 ml / min, the flow rate of material B is controlled to 3 ml / min, and the flow rate of material C is controlled to 1.5 ml / min. Material A, material B and material C simultaneously enter the microchannel reactor for mixed reaction, and the mixing temperature is controlled by an external heat exchanger at a reaction temperature between -20 and 20 ° C, and the reaction residence time is controlled to 20 to 200 s;

[0018] (5) The mixture obtained after the reaction is directed into a separator filled with water, and after separation, the organic layer is taken, and further dried and distilled to obtain compound I;

[0019] Wherein compound II and compound I are as follows,

[0020]

[0021] Wherein R is methyl or ethyl.

[0022] Further preferably, the compound II is prepared by chemical reaction of compound III, potassium hydroxide and alkyl bromide or alkyl iodide in the presence of an organic solvent, and the potassium hydroxide is solid potassium hydroxide;

[0023] The compound III is as follows:

[0024]

[0025] More preferably, the boron trifluoride coordination compound is a boron trifluoride tetrahydrofuran coordination compound.

[0026] More preferably, the molar ratio of the compound II to the boron trifluoride tetrahydrofuran coordination compound is 1:0.1-0.3.

[0027] More preferably, the hydrocarbon solvent is one of n-hexane, cyclohexane, n-heptane, cycloheptane and methylcyclopentane.

[0028] More preferably, the acyl fluoride is acetyl fluoride or propionyl fluoride.

[0029] More preferably, the molar ratio of the compound II to the acyl fluoride is 1:1-2.

[0030] Further preferably, the reaction temperature includes but is not limited to -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C or 20°C. In a preferred embodiment, the reaction temperature is -10°C.

[0031] Further preferably, the reaction residence time includes but is not limited to 20s, 30s, 40s, 50s, 60s, 70s, 80s, 90s, 100s, 110s, 120s, 130s, 140s, 150s, 160s, 170s, 180s, 190s or 200s. In a preferred embodiment, the reaction time is 120s.

[0032] More preferably, the alkyl bromide or alkyl iodide is ethyl bromide or methyl iodide.

[0033] More preferably, the molar ratio of the compound III, alkyl bromide or alkyl iodide, and potassium hydroxide is 1-3:1:1-1.5.

[0034] More preferably, the organic solvent is one of dichloromethane, tetrahydrofuran or toluene.

[0035] Further preferably, the reaction temperature is 40-100°C, including but not limited to 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C or 100°C. In a preferred embodiment, the reaction temperature is 80°C.

[0036] Further preferably, the reaction time is 4 to 12 h, including but not limited to 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h. In a preferred embodiment, the reaction time is 7 h.

[0037] The present invention provides a new synthesis route, that is, compound III is used as a raw material, reacted with alkyl bromide or alkyl iodide to obtain compound II; and then reacted with acyl fluoride using a continuous flow microchannel reactor to obtain the target product compound I, thereby realizing the application of the microchannel reactor in the preparation of the intermediate of azithromycin. The continuous flow type reaction is carried out by the microchannel reactor, the materials staying in the microchannel reactor are few, the various reaction materials are fully mixed, the reaction time is short, the reaction time and reaction temperature can be accurately controlled, and local overheating or prolonged reaction time can be avoided to cause the generation of a large number of by-products, thereby effectively solving the problems of long reaction time, many by-products, too high reaction temperature, high equipment requirements, low yield and purity, etc. in each reaction step in the prior art. The present invention accurately controls the material reaction procedure through flow rate, temperature, and reaction time, greatly shortens the reaction time, has high safety, low cost, simple post-processing, and the yield and purity of the product compound I are high, which is particularly suitable for industrial large-scale production. DETAILED DESCRIPTION

[0038] In order to better understand the present invention, the present invention is further described below in conjunction with specific embodiments.

[0039] Unless otherwise specified, the reagents used in the examples of the present invention are common commercially available products.

[0040] Example 1

[0041] (a) Synthesis of Compound II:

[0042] Compound III (50 g, 108 mmol), flake potassium hydroxide (3.65 g, 65 mmol) and 100 ml of dichloromethane were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Ethyl bromide (5.88 g, 54 mmol) was then added, and the mixture was stirred at 80° C. for 7 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 25.38 g of compound II, with a yield of 95.8% and a purity of 99.6%.

[0043] (b) Synthesis of Compound I:

[0044] (1) Preparation of material A solution: Compound II (25 g, 51 mmol) was added to n-hexane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for standby use.

[0045] (2) Preparation of material B solution: Add acetyl fluoride (4.7 g, 76.5 mmol) into n-hexane, dilute to 20 ml, stir evenly, place in raw material tank B (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0046] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (1.4 g, 10.2 mmol) to n-hexane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0047] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 7.5 ml / min, the flow rate of the raw material tank B to 3 ml / min, and the flow rate of the raw material tank C to 1.5 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to -10 ° C, and keep the reaction time in the channel for 120 s. After the reaction is completed, the mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 24.14 g of compound I, with a yield of 96.5% and a purity of 99.7%.

[0048] Example 2

[0049] (a) Synthesis of Compound II:

[0050] Compound III (50 g, 108 mmol), flake potassium hydroxide (6.06 g, 108 mmol) and 100 ml of tetrahydrofuran were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Ethyl bromide (11.77 g, 108 mmol) was then added, and the mixture was stirred at 40° C. for 12 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 48.95 g of compound II, with a yield of 92.4% and a purity of 99.3%.

[0051] (b) Synthesis of Compound I:

[0052] (1) Preparation of material A solution: Compound II (25 g, 51 mmol) was added to cyclohexane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for standby use.

[0053] (2) Preparation of material B solution: Add acetyl fluoride (3.2 g, 51 mmol) into cyclohexane, dilute to 20 ml, stir evenly, place in raw material tank B (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0054] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (2.1 g, 15.3 mmol) to cyclohexane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0055] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 5 ml / min, the flow rate of the raw material tank B to 2 ml / min, and the flow rate of the raw material tank C to 1 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to -20°C, and keep the reaction time in the channel for 20 seconds. The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 23.11 of compound I, with a yield of 92.4% and a purity of 99.5%.

[0056] Example 3

[0057] (a) Synthesis of Compound II:

[0058] Compound III (50 g, 108 mmol), flake potassium hydroxide (3.03 g, 54 mmol) and 100 ml of toluene were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Methyl iodide (5.11 g, 36 mmol) was then added, and the mixture was stirred at 100° C. for 4 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 15.49 g of compound II, with a yield of 90.3% and a purity of 99.2%.

[0059] (b) Synthesis of Compound I:

[0060] (1) Preparation of material A solution: Compound II (24.3 g, 51 mmol) was added to n-heptane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected with nitrogen for standby use.

[0061] (2) Preparation of material B solution: Propionyl fluoride (7.8 g, 102 mmol) was added to n-heptane, diluted to 20 ml, stirred evenly, and placed in raw material tank B (the bottom of the raw material tank was connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected by nitrogen for use.

[0062] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (0.7 g, 5.1 mmol) to n-heptane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0063] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 10 ml / min, the flow rate of the raw material tank B to 4 ml / min, and the flow rate of the raw material tank C to 2 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to 20°C, and keep the reaction time in the channel for 200s. The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 22.31g of compound I, with a yield of 91.8% and a purity of 99.4%.

[0064] Comparative Example 1

[0065] Synthesis of compound II:

[0066] Compound III (100 g, 216 mmol), flake potassium hydroxide (3.65 g, 65 mmol) and 100 ml of dichloromethane were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Ethyl bromide (5.88 g, 54 mmol) was then added, and the mixture was stirred at 80° C. for 7 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 22.7 g of compound II, with a yield of 85.7% and a purity of 94.5%.

[0067] Comparative Example 2

[0068] Synthesis of compound II:

[0069] Compound III (50 g, 108 mmol), flake potassium hydroxide (6.06 g, 108 mmol) and 100 ml of dichloromethane were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Ethyl bromide (5.88 g, 54 mmol) was then added, and the mixture was stirred at 80° C. for 7 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 23.18 g of compound II, with a yield of 87.5% and a purity of 96.2%.

[0070] Comparative Example 3

[0071] Synthesis of compound II:

[0072] Compound III (50 g, 108 mmol), flake potassium hydroxide (3.65 g, 65 mmol) and 100 ml of dichloromethane were added to the reaction vessel, and the mixture was stirred at 80° C. for 3 h. Ethyl bromide (5.88 g, 54 mmol) was then added, and the mixture was stirred at 20° C. for 7 h. After the reaction was completed, the mixture was cooled to room temperature (about 25° C.), filtered, and the organic phase was separated and dried by distillation to obtain 21.53 g of compound II, with a yield of 81.3% and a purity of 92.5%.

[0073] Comparative Example 4

[0074] Synthesis of Compound I:

[0075] (1) Preparation of material A solution: Compound II (25 g, 51 mmol) prepared in step (a) of Example 1 was added to n-hexane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected by nitrogen for standby use.

[0076] (2) Preparation of material B solution: Add acetyl fluoride (1.6 g, 25.5 mmol) into n-hexane, dilute to 20 ml, stir evenly, place in raw material tank B (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0077] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (1.4 g, 10.2 mmol) to n-hexane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0078] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 7.5 ml / min, the flow rate of the raw material tank B to 3 ml / min, and the flow rate of the raw material tank C to 1.5 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to -10 ° C, and keep the reaction time in the channel for 120 s. The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 17.86 g of compound I, with a yield of 71.4% and a purity of 94.7%.

[0079] Comparative Example 5

[0080] Synthesis of Compound I:

[0081] (1) Preparation of material A solution: Compound II (25 g, 51 mmol) prepared in step (a) of Example 1 was added to n-hexane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected by nitrogen for standby use.

[0082] (2) Preparation of material B solution: Add acetyl fluoride (4.7 g, 76.5 mmol) into n-hexane, dilute to 20 ml, stir evenly, place in raw material tank B (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0083] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (0.36 g, 2.55 mmol) to n-hexane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0084] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 7.5 ml / min, the flow rate of the raw material tank B to 3 ml / min, and the flow rate of the raw material tank C to 1.5 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to -10 ° C, and keep the reaction time in the channel for 120 s. The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 19.66 g of compound I, with a yield of 78.6% and a purity of 96.2%.

[0085] Comparative Example 6

[0086] Synthesis of Compound I:

[0087] (1) Preparation of material A solution: Compound II (25 g, 51 mmol) prepared in step (a) of Example 1 was added to n-hexane, diluted to 50 ml, stirred evenly, and placed in a raw material tank A (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve) and protected by nitrogen for standby use.

[0088] (2) Preparation of material B solution: Add acetyl fluoride (4.7 g, 76.5 mmol) into n-hexane, dilute to 20 ml, stir evenly, place in raw material tank B (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0089] (3) Preparation of material C solution: Add boron trifluoride tetrahydrofuran coordination compound (1.4 g, 10.2 mmol) to n-hexane, dilute to 10 ml, stir evenly, place in raw material tank C (the bottom of the raw material tank is connected to the corresponding feed pipe of the microchannel reactor through a valve), and protect with nitrogen for use.

[0090] (4) Open the valve at the bottom of the raw material tank, and use the feed pump to deliver the material A solution in the raw material tank A, the material B solution in the raw material tank B, and the material C solution in the raw material tank C. Set the flow rate of the raw material tank A to 7.5 ml / min, the flow rate of the raw material tank B to 3 ml / min, and the flow rate of the raw material tank C to 1.5 ml / min through the metering pump, then preheat the material A solution, the material B solution, and the material C solution, set the temperature of the heat exchanger to 30°C, and keep the reaction time in the channel for 120 seconds. The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken and further dried with anhydrous sodium sulfate, and then distilled to obtain 21.44 g of compound I, with a yield of 85.7% and a purity of 96.4%.

[0091] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an azvudine intermediate using a microchannel reactor, characterized in that: The method comprises the following steps: (1) Compound II is mixed with a hydrocarbon solvent and stirred to form a material A; (2) mixing the acyl fluoride and the hydrocarbon solvent, stirring evenly to form material B; (3) mixing the boron trifluoride coordination compound and the hydrocarbon solvent, stirring evenly to form material C; (4) Material A, material B and material C are respectively transported to the microchannel reactor through feed pipes, and each feed pipe is provided with a metering pump, and the flow rate of each material is controlled by the metering pump, wherein the flow rate of material A is controlled to 7.5 ml / min, the flow rate of material B is controlled to 3 ml / min, and the flow rate of material C is controlled to 1.5 ml / min. Material A, material B and material C simultaneously enter the microchannel reactor for mixed reaction, and the mixing temperature is controlled by an external heat exchanger at a reaction temperature between -20 and 20 ° C, and the reaction residence time is controlled to 20 to 200 s; (5) The mixture obtained after the reaction is directed into a separator filled with water. After separation, the organic layer is taken, and further dried and distilled to obtain compound I; Wherein compound II and compound I are as follows, 、 ； Wherein R is methyl or ethyl.

2. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The compound II is prepared by chemical reaction of compound III, potassium hydroxide and alkyl bromide or alkyl iodide in the presence of an organic solvent, and the potassium hydroxide is solid potassium hydroxide; Wherein compound III is as follows: 。 3. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The boron trifluoride coordination compound is a boron trifluoride tetrahydrofuran coordination compound.

4. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 3, characterized in that: The molar ratio of the compound II to the boron trifluoride tetrahydrofuran coordination compound is 1:0.1-0.

3.

5. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The hydrocarbon solvent is one of n-hexane, cyclohexane, n-heptane, cycloheptane and methylcyclopentane.

6. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The acyl fluoride is acetyl fluoride or propionyl fluoride.

7. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The molar ratio of the compound II to the acyl fluoride is 1:1-2.

8. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The reaction temperature was -10°C.

9. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 1, characterized in that: The reaction time is 120s.

10. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 2, characterized in that: The alkyl bromide or alkyl iodide is ethyl bromide or methyl iodide.

11. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 2, characterized in that: The molar ratio of the compound III, alkyl bromide or alkyl iodide, and potassium hydroxide is 1-3:1:1-1.

5.

12. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 2, characterized in that: The organic solvent is one of dichloromethane, tetrahydrofuran or toluene.

13. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 2, characterized in that: The reaction temperature is 40~100℃.

14. The method for preparing an azvudine intermediate using a microchannel reactor according to claim 13, characterized in that: The reaction temperature was 80°C.

15. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 2, characterized in that: The reaction time is 4~12h.

16. The method for preparing an azvudine intermediate by a microchannel reactor according to claim 15, characterized in that: The reaction time is 7h.

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