A method for photo-induced continuous synthesis of pyridine compounds using a microchannel reaction device

Abstract

This invention belongs to the field of chemical synthesis and process, and relates to a method for the photoinduced continuous synthesis of pyridine compounds using a microchannel reaction device. Compound I is dissolved in an organic solvent to obtain a first mixture; an organic photocatalyst is dissolved in the organic solvent to obtain a second mixture; the first mixture, the second mixture, and an alkaline aqueous solution are simultaneously pumped into a microchannel reactor equipped with a light source within the microchannel reaction device to carry out a free radical transfer reaction. After the reaction, the effluent is post-processed to obtain compounds II and III. This invention introduces substituent groups at the 2 and 4 positions of pyridine, which can improve the pharmaceutical properties and functional characteristics of the compounds, contributing to drug development and applications in other fields. The preparation method of this invention has advantages such as good regioselectivity, short reaction time, high conversion rate, few side reactions, low toxicity and pollution, low production cost, and good product quality.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis and process, and relates to a method for photo-induced continuous synthesis of pyridine compounds by using a micro-channel reaction device. BACKGROUND

[0002] Pyridine is an important organic compound, which has wide application in the fields of medicine and organic synthesis. The 2 and 4 positions in the molecular structure of pyridine are very important substitution positions for groups, and their substitutes can affect the chemical properties and biological activities of pyridine (Chemical Journal of Chinese Universities, 2019, 40(10): 2111-2120.).

[0003] Pyridine and its derivatives are widely used in drug research and development. Among them, 2-substituents and 4-substituents have important influence on the properties and biological activities of pyridine molecules. 2-substituents can usually change the acid-base properties and electron density distribution of pyridine molecules, affecting their action with receptors or enzymes. For example, 2-methylpyridine has high acidity and strong hydrogen bonding ability, and can form stable coordination structures with receptors. 2-methylpyridine is widely used in the research and development of drugs for anti-tumor, anti-inflammatory, antibacterial and analgesic aspects in the field of medicine. In addition, 2-substituted pyridine can also enhance the selectivity and activity of drugs by changing the molecular structure. For example, 2-methoxy-5-(3-methyl-1-isopropyl) pyridine is a selective COX-2 inhibitor, which is widely used in the treatment of pain and inflammation.

[0004] In contrast, 4-substituents have greater influence on the electron density and stereochemistry of pyridine molecules. 4-substituents can change the electron affinity, steric hindrance and hydrogen bonding ability of pyridine molecules, affecting their action with receptors or enzymes. For example, 4-hydroxy pyridine has strong hydrogen bonding ability and high electron density, and can form stable hydrogen bond structures with various biological macromolecules. 4-hydroxy pyridine is widely used in the research and development of drugs for antibacterial, anti-inflammatory and antioxidant aspects in the field of medicine. In addition, 4-substituents can also enhance the bioavailability and stability of drugs by changing the molecular structure. For example, 4-amino-3-fluoro-5-(3-methyl-1-isopropyl) pyridine is a broad-spectrum antibacterial drug, which can enhance the bioavailability of the drug by introducing amino substitution and fluorine atom.

[0005] The 2- and 4-positions are the reactive centers of the pyridine molecule, and have an important influence on the synthesis of pyridine and the construction of derivatives. In organic synthesis, 2- and 4-substituted pyridines are very common structural units, which can be synthesized by various reaction methods. 2-substituted pyridines can be synthesized by substitution reactions or cyclization reactions. For example, 2-bromopyridine can be obtained by N-alkylpyridine reaction. In addition, 2-substituted pyridines can also be synthesized by metal-catalyzed reactions, such as Suzuki coupling reaction and Heck reaction, etc. In the field of medicine, the synthesis of 2-substituted pyridines is of great significance, because these molecules usually have strong biological activity and selectivity.

[0006] The synthesis of 4-substituted pyridines is also an important topic in organic synthesis. The synthesis of 4-substituted pyridines usually adopts substitution reactions, metal-catalyzed reactions or oxidation reactions, etc. For example, 4-aminopyridine can be synthesized by amination reaction and catalytic hydrogenation reaction. 4-substituted pyridines can also be synthesized by oxidation reactions, such as Baeyer-Villiger oxidation reaction and epoxidation reaction, etc. In the field of medicine, the synthesis of 4-substituted pyridines is also of great significance, because these molecules usually have strong biological activity and drug efficacy. Therefore, it is of great significance to develop a simple and green process for synthesizing 2-substituted pyridines and 4-substituted pyridines. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a novel, green and efficient synthesis method, which can synthesize 2-substituted pyridine and 4-substituted pyridine by realizing the functionalization of non-activated remote C-H bond through radical migration of O and N center radicals under visible light conditions.

[0008] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0009] The present application discloses a method for continuous synthesis of pyridine compounds under visible light irradiation by using a micro-channel reaction device, which comprises the following steps:

[0010] (1) dissolving compound I in an organic solvent to obtain a first mixed solution; dissolving an organic photocatalyst in the organic solvent to obtain a second mixed solution;

[0011] (2) pumping the first mixed solution and the second mixed solution obtained in step (1) and an alkaline aqueous solution into a micro-channel reactor provided with a light source in the micro-channel reaction device to carry out a radical transfer reaction; after the reaction is completed, the reaction effluent is treated to obtain compound II and compound III;

[0012] The structural formulae of the compound I, the compound II and the compound III are as follows:

[0013]

[0014] In some embodiments, in step (1), the organic photocatalyst is tris(2-phenylpyridine) iridium, tris(2,2'-bipyridine) hexachloroiridate(II), 2-(2,4-difluorophenyl)-5- trifluoromethylpyridine][2-2'-bipyridine] iridium di(hexafluorophosphate), tris(2,2'- bipyridine) ruthenium dichloride, or 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)- quinolinone; the organic solvent is any one or a combination of several of chloroform, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, benzene, N,N-dimethylformamide, and N,N- dimethylaniline.

[0015] In some embodiments, preferably, in step (1), the organic photocatalyst is 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)-quinolinone or tris(2,2'-bipyridine) ruthenium dichloride, more preferably, the organic photocatalyst is 3-(diphenylphosphino)-6-methoxy-1- methyl-2(1H)-quinolinone; the organic solvent is acetonitrile or chloroform, more preferably, the organic solvent is acetonitrile.

[0016] In some embodiments, in step (1), the molar volume ratio of compound I to the organic solvent in the first mixture is 0.1-1.9 mmol: 1 mL; the molar volume ratio of the organic photocatalyst to the organic solvent in the second mixture is 1-7 mmol: 1 mL.

[0017] In some embodiments, preferably, in step (1), the molar volume ratio of compound I to the organic solvent in the first mixture is 1 mmol: 1 mL; the molar volume ratio of the organic photocatalyst to the organic solvent in the second mixture is 4 mmol: 1 mL.

[0018] In some embodiments, in step (2), the concentration of the base in the aqueous alkaline solution is 1-5 mmol / mL; the base is any one or a combination of several of potassium phosphate, potassium carbonate, sodium bicarbonate, lithium tert-butoxide, and triethylamine.

[0019] In some embodiments, preferably, in step (2), the concentration of the base in the aqueous alkaline solution is 3 mmol / mL; the base is sodium bicarbonate or triethylamine; more preferably, the base is sodium bicarbonate.

[0020] In some embodiments, in step (2), the flow rate of the first mixed solution into the microchannel reactor is 0.1-0.7 mL / min; the flow rate of the second mixed solution into the microchannel reactor is 0.3-0.9 mL / min; and the flow rate of the alkaline aqueous solution into the microchannel reactor is 0.08-0.16 mL / min.

[0021] In some embodiments, preferably, in step (2), the flow rate of the first mixed solution into the microchannel reactor is 0.3-0.5 mL / min; the flow rate of the second mixed solution into the microchannel reactor is 0.5-0.9 mL / min; and the flow rate of the alkaline aqueous solution into the microchannel reactor is 0.10-0.16 mL / min.

[0022] In some embodiments, in step (2), when the first mixed solution, the second mixed solution and the alkaline aqueous solution are simultaneously pumped into the microchannel reactor, the molar ratio of Compound I in the first mixed solution to the organic photocatalyst in the second mixed solution to the base in the alkaline aqueous solution is 1:6-8:0.6-1.6, preferably 1:6-8:0.6-1.2, and more preferably 1:8:1.2.

[0023] In some embodiments, in step (2), the light source arranged around the microchannel reactor is blue light with a wavelength of 420-430 nm and a power of 10 W.

[0024] In some embodiments, in step (2), the pipe of the microchannel reactor is a quartz coil with a pipe diameter of 0.5-1.5 mm and a retention volume of 6-15 mL; and the radical transfer reaction is carried out at room temperature.

[0025] In some embodiments, preferably, in step (2), the pipe of the microchannel reactor is a quartz coil with a pipe diameter of 1.0 mm and a retention volume of 10-15 mL.

[0026] In some embodiments, the microchannel reactor device comprises a connecting pipe, a first feed pump, a second feed pump, a third feed pump, a micro-mixer, a microchannel reactor, a light source and a receiver; the first feed pump, the second feed pump and the third feed pump are connected in parallel to the micro-mixer through the pipe; the micro-mixer, the microchannel reactor and the receiver are connected in series through the pipe; and the light source is located outside the microchannel reactor and covers the microchannel reactor with its light range.

[0027] In some embodiments, the diameter of the connecting pipe is 1 mm.

[0028] In some embodiments, the model of the feed pump is TYD01 of Leifer.

[0029] The micro-mixer is a cross-junction micro-mixer.

[0030] The pipe diameter of the micro-channel reactor is preferably 1 mm.

[0031] After the reaction, the reaction effluent is post-treated, specifically, the reaction liquid is concentrated under vacuum, and column chromatography is used for separation and purification; the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1.

[0032] The 2-substituted pyridine product and the 4-substituted pyridine product prepared by the preparation method have wide application in medicine. They can be used as raw materials for anti-tumor, anti-viral, anti-inflammatory and anti-bacterial drugs, have various pharmacological effects, and can be used for treating various diseases. For example, famous drugs such as imatinib, lopinavir, terbinafine and clarithromycin are prepared from 4-substituted pyridine compounds. Research and synthesis of these compounds are of great significance for discovering new drugs, improving medical treatment and promoting human health.

[0033] Advantages:

[0034] (1) The 2-substituted pyridine prepared by the preparation method can enhance the stability and solubility of the compound, improve the pharmacokinetic properties thereof, and also can adjust the lipophilicity and acid-base property of the compound, thereby affecting the efficacy and selectivity thereof. The 4-substituted pyridine can enhance the stereochemical diversity of the compound, broaden the structural space of the compound, and also can improve the electronic properties of the compound, thereby adjusting the optical and electronic properties thereof. Introduction of a substituent group at the 2-position and the 4-position of pyridine can improve the drug properties and functional characteristics of the compound, and is helpful for drug research and development and application in other fields.

[0035] (2) The preparation method has good regioselectivity, short reaction time, high conversion rate, few side reactions, low toxicity and pollution, low production cost, good product quality and the like.

[0036] (3) The preparation method uses a micro-channel reaction device, the intermolecular diffusion distance is short during the reaction, the specific surface area of the micro-channel is large, the miniaturization of the size strengthens the heat transfer and mass transfer process of the equipment, the micro-reaction channel is usually simpler and easier to operate, and human errors in the production process are reduced. The use of the micro-reaction channel can reduce the waste of chemical drugs, improve the speed and efficiency of the reaction, and is helpful for reducing the production cost. BRIEF DESCRIPTION OF DRAWINGS

[0037] The above and / or other aspects of the present application will become apparent and more readily appreciated from the following description, taken in conjunction with the accompanying drawings, in which:

[0038] Figure 1Synthetic route schematic diagram of the micro-channel reaction device used in the present application.

[0039] Figure 2 Reaction equation diagram for synthesizing pyridine compounds in the present application; wherein PC is a photocatalyst.

[0040] Figure 3 H NMR spectrum of compound 2-cyclopentylpyridine (compound II) in the embodiment of the present application. 1 H NMR spectrum.

[0041] Figure 4 C NMR spectrum of compound 2-cyclopentylpyridine (compound II) in the embodiment of the present application. 13 C NMR spectrum.

[0042] Figure 5 H NMR spectrum of compound 4-cyclopentylpyridine (compound III) in the embodiment of the present application. 1 H NMR spectrum.

[0043] Figure 6 C NMR spectrum of compound 4-cyclopentylpyridine (compound III) in the embodiment of the present application. 13 C NMR spectrum.

[0044] Figure 7 Position placement relationship diagram of the light source and the micro-channel reactor. DETAILED DESCRIPTION

[0045] In the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0046] Figure 1 Synthetic route schematic diagram of the micro-channel reaction device used in the present application, the micro-channel reaction device comprises a connecting pipeline, a first feed pump, a second feed pump, a third feed pump, a micro-mixer, a micro-channel reactor, a light source and a receiver; the first feed pump, the second feed pump and the third feed pump are connected in parallel to the micro-mixer through the pipeline; the micro-mixer, the micro-channel reactor and the receiver are connected in series through the pipeline; the light source is located outside the micro-channel reactor, and the light range of the light source covers the micro-channel reactor; the specific position placement relationship of the light source and the micro-channel reactor is shown in Figure 7 .

[0047] The diameter of the connecting pipeline is 1 mm, and the length is 15 cm.

[0048] The model of the feed pump is LEVER TYD01.

[0049] The micro-mixer is a cross-junction micro-mixer.

[0050] The pipeline of the micro-channel reactor is a quartz coil pipe, and the pipeline diameter is 1mm.

[0051] After the reaction is completed, the reaction effluent is post-treated, specifically: the reaction liquid is concentrated under vacuum, and column chromatography is used for separation and purification; the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1.

[0052] The reaction equation for synthesizing the pyridine compound is shown in the following formula (I). Figure 2

[0053] The compound I used in the embodiment of the application is 1-(cyclopentylmethoxy)pyridine-1-oxonium-4-tosylate, CAS: 2417390-63-5, which can be purchased or prepared according to the following method.

[0054] Preparation of 1-(cyclopentylmethoxy)pyridine-1-oxonium-4-tosylate:

[0055]

[0056] 2.0mmol pyridine N-oxide is dissolved in 2mL MeCN, then 2.2mmol cyclopentylmethyl tosylate is added to the system, and the reaction mixture is stirred at 80℃ for 24 hours, and the reaction is monitored by TLC during the reaction; after the reaction is completed, the reaction liquid is concentrated under vacuum to obtain a concentrate, and the concentrate is recrystallized twice from a DCM (2mL) and Et2O (60mL) solution at-20℃ to obtain 1-(cyclopentylmethoxy)pyridine-1-oxonium-4-tosylate.

[0057] Example 1

[0058] (1) 1mmol 1-(cyclopentylmethoxy)pyridine-1-oxonium-4-tosylate is dissolved in 1mL acetonitrile to obtain a first mixed solution; 2mmol 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)-quinolinone is dissolved in 0.5mL acetonitrile to obtain a second mixed solution.

[0059] ​(2) 3 mmol of sodium bicarbonate was dissolved in 1 mL of deionized water to obtain a sodium bicarbonate aqueous solution; the first mixed solution, the second mixed solution and the sodium bicarbonate aqueous solution obtained in step (1) were simultaneously pumped into a micro-mixer in a micro-channel reaction device for mixing, and then were continuously pumped into a micro-channel reactor provided with a light source (10 mL) for free radical transfer reaction under irradiation of blue light (wavelength: 420-430 nm, power: 10 W) at room temperature; wherein the pumping flow rate of the first mixed solution was 0.3 mL / min, the pumping flow rate of the second mixed solution was 0.6 mL / min, and the pumping flow rate of the sodium bicarbonate aqueous solution was 0.12 mL / min; after the reaction was completed, the reaction solution was determined by HPLC, and the yield of compound II was 66.3%, and the yield of compound III was 22.0%; the reaction solution was collected and vacuum concentrated to obtain a crude product, which was separated by column chromatography (V 乙酸乙酯 :V 石油醚 = 1:5) to obtain the target products, compound II and compound III.

[0060] The nuclear magnetic data of compound II: the nuclear magnetic hydrogen spectrum of compound II is as shown in Figure 3 , and the nuclear magnetic carbon spectrum is as shown in Figure 4 ; the specific nuclear magnetic data is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.45-8.35 (m, 1H), 7.40 (td, J = 7.7, 1.9 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.91 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 3.04 (p, J = 8.1 Hz, 1H), 2.00-1.90 (m, 2H), 1.73-1.63 (m, 4H), 1.60-1.52 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 165.46, 148.96, 135.94, 121.51, 120.71, 47.82, 33.36, 25.69.

[0061] The nuclear magnetic data of compound III: the nuclear magnetic hydrogen spectrum of compound III is as shown in Figure 5 , and the nuclear magnetic carbon spectrum is as shown in Figure 6 ; the specific nuclear magnetic data is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.50-8.30 (m, 2H), 7.09-6.87 (m, 2H), 2.87 (ddd, J = 17.1, 9.4, 7.6 Hz, 1H), 2.04-1.92 (m, 2H), 1.77-1.66 (m, 2H), 1.64-1.57 (m, 2H), 1.53-1.44 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 155.56, 149.48, 122.58, 45.06, 33.86, 25.46.

[0062] Example 2

[0063] The same operation as Example 1, the only difference is that the first mixed solution pump flow rate is 0.5 mL / min, the second mixed solution pump speed is 0.8 mL / min, the base solution pump speed is 0.14 mL / min, the first microreactor volume is 12 mL. After the reaction, the reaction liquid is determined by HPLC, the yield of compound II is 44.6%, and the yield of compound III is 29.8%.

[0064] Example 3

[0065] The same operation as Example 1, the only difference is that the first mixed solution pump flow rate is 0.5 mL / min, the second mixed solution pump speed is 0.8 mL / min, the base solution pump speed is 0.14 mL / min, the first microreactor volume is 15 mL. After the reaction, the reaction liquid is determined by HPLC, the yield of compound II is 51.44%, and the yield of compound III is 25.6%.

[0066] Example 4

[0067] The same operation as Example 1, the only difference is that the first mixed solution pump flow rate is 0.5 mL / min, the second mixed solution pump speed is 0.8 mL / min, the base solution pump speed is 0.1 mL / min, the first microreactor volume is 12 mL. After the reaction, the reaction liquid is determined by HPLC, the yield of compound II is 54.32%, and the yield of compound III is 28.64%.

[0068] Example 5

[0069] The same operation as Example 1, the only difference is that the first mixed solution pump flow rate is 0.5 mL / min, the second mixed solution pump speed is 0.8 mL / min, the base solution pump speed is 0.16 mL / min, the first microreactor volume is 15 mL. After the reaction, the reaction liquid is determined by HPLC, the yield of compound II is 44.39%, and the yield of compound III is 29.3%.

[0070] Example 6

[0071] The same operation as Example 1, the only difference is that the photo catalyst 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)-quinolinone is replaced by tris(2,2'-bipyridine) ruthenium dichloride, and after the reaction, the reaction liquid is determined by HPLC, the yield of compound II is 40.87%, and the yield of compound III is 39.09%.

[0072] Example 7

[0073] The operation is the same as Example 1, the difference is that the solvent acetonitrile is replaced by chloroform, after the reaction, the reaction solution is determined by HPLC, the yield of compound II is 49.36%, and the yield of compound III is 26.78%.

[0074] Example 8

[0075] The operation is the same as Example 1, the difference is that sodium bicarbonate is replaced by triethylamine, after the reaction, the reaction solution is determined by HPLC, the yield of compound II is 33.25%, and the yield of compound III is 39.0%.

[0076] Reaction in a conventional reaction bottle

[0077] The reaction is carried out in a 50 mL round-bottom flask, 4.3 g of 1-(cyclopentylmethoxy) pyridine-1-oxonium-4-tosylate (0.01 mol), 0.76 g of 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)-quinolinone (0.02 mol) is dissolved in 15 mL of acetonitrile, 2.52 g of sodium bicarbonate (0.03 mol) is dissolved in 10 mL of deionized water and added to the reaction system, and the reaction is carried out under irradiation of blue light (wavelength of 420 nm-430 nm, power of 10 W) at room temperature for 24 h. After the reaction, the reaction solution is filtered, the filter cake is washed with acetonitrile, the solvent is removed by reduced pressure distillation, and the compound II and compound III are separated by silica gel column chromatography (V 乙酸乙酯 :V 石油醚 1):5) with a yield of 29.45% for compound II and 18.98% for compound III.

[0078] Reaction under light-free conditions

[0079] The operation is the same as Example 1, the difference is that the reaction is carried out in the dark without light, and the generation of compound II and compound III is not monitored.

[0080] Reaction without light catalyst

[0081] The operation is the same as Example 1, the difference is that no organic photocatalyst is added, and the generation of compound II and compound III is not monitored.

[0082] The application provides a method for continuously synthesizing pyridine compounds by light induction by using a micro-channel reaction device, and the method has many specific implementation methods and approaches, and the above description is only a preferred embodiment of the application, and it should be pointed out that, for ordinary skilled in the art, some improvements and refinements can be made without departing from the principle of the application, and the improvements and refinements should also be regarded as the protection scope of the application. The components not explicitly described in the embodiment can be realized by using the prior art.

Claims

1. A method for the continuous photoinduced synthesis of pyridine compounds using a microchannel reactor, characterized by, The method comprises the following steps: (1) dissolving compound I in an organic solvent to obtain a first mixture; dissolving an organic photocatalyst in the organic solvent to obtain a second mixture; (2) pumping the first mixture, the second mixture and an alkaline aqueous solution obtained in step (1) into a micro-channel reactor provided with a light source to perform a free radical transfer reaction, and then treating the reaction effluent to obtain compound II and compound III; The structural formulae of the compounds I, II and III are shown as follows: In step (1), the organic photocatalyst is tris(2,2'-bipyridyl)ruthenium dichloride or 3-(diphenylphosphino)-6-methoxy-1-methyl-2(1H)-quinolinone; In step (2), the concentration of the base in the alkaline aqueous solution is 1-5 mmol / mL; and the base is sodium bicarbonate or triethylamine; In step (2), when the first mixture, the second mixture and the alkaline aqueous solution are pumped into the micro-channel reaction device, the molar ratio of compound I in the first mixture to the organic photocatalyst in the second mixture and the base in the alkaline aqueous solution is 1:6-8:0.6-1.6; In step (2), the light source arranged around the micro-channel reactor is blue light with a wavelength of 420-430 nm and a power of 10 W.

2. The method of claim 1, wherein, In step (1), the organic solvent is any one or a combination of several of trichloromethane, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, benzene, N,N-dimethylformamide and N,N-dimethylaniline.

3. The method of claim 1, wherein, In step (1), the molar volume ratio of compound I to the organic solvent in the first mixture is 0.1-1.9 mmol:1 mL; and the molar volume ratio of the organic photocatalyst to the organic solvent in the second mixture is 1-7 mmol:1 mL.

4. The method of claim 1, wherein, In step (2), the flow rate of the first mixture pumped into the micro-channel reaction device is 0.1-0.7 mL / min; the flow rate of the second mixture pumped into the micro-channel reaction device is 0.3-0.9 mL / min; and the flow rate of the alkaline aqueous solution pumped into the micro-channel reaction device is 0.08-0.16 mL / min.

5. The method of claim 1, wherein, In step (2), the pipeline of the micro-channel reactor is a quartz coil with a pipe diameter of 0.5-1.5 mm and a retention volume of 6-15 mL; and the free radical transfer reaction is performed at room temperature.

6. The method of claim 1, wherein, The micro-channel reaction device comprises a connecting pipeline, a first feeding pump, a second feeding pump, a third feeding pump, a micro-mixer, a micro-channel reactor, a light source and a receiver; the first feeding pump, the second feeding pump and the third feeding pump are connected in parallel to the micro-mixer through a pipeline; the micro-mixer, the micro-channel reactor and the receiver are connected in series through a pipeline; and the light source is located outside the micro-channel reactor and covers the micro-channel reactor in the illumination range.

Images