A method for synthesizing pyridine compounds using a microchannel reaction device

Abstract

The invention discloses a method for synthesizing pyridine compounds using a microchannel reaction device, using α,β-unsaturated ketoxime ester compound I and cyclopropanol compound II as raw materials, and using a microchannel modular reaction device to prepare the pyridine compound shown in formula III. Compared with the prior art, the present invention uses cyclopropanol compound II as a raw material to prepare pyridine compounds containing electron-withdrawing groups that are difficult to synthesize by other methods without the action of a noble metal catalyst.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for synthesizing pyridine compounds by using a microchannel reaction device. Background Art

[0002] Pyridine and its derivatives have a wide range of physiological and pharmaceutical activities and have a wide range of application values ​​in the fields of medicine and pesticides. In addition, they can also play an important role in organic synthesis as ligands and catalysts. Therefore, their synthesis methods have attracted widespread attention from chemists and pharmacologists. In recent years, literature has reported the synthesis of pyridine compounds by cyclization of α,β-unsaturated ketoxime esters with alkenes (alkynes) and carbonyl compounds. However, these methods have the following problems: (1) the use of precious metal catalysts such as rhodium, ruthenium and iron is required; (2) the reaction selectivity is poor, the reaction rate is slow, and many side reactions lead to difficulties in separation and purification; (3) pyridine compounds containing electron-withdrawing groups are difficult to synthesize. Therefore, it is of great significance to develop new and efficient methods for the synthesis of pyridine compounds containing electron-withdrawing groups. Summary of the invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for synthesizing pyridine compounds using a microchannel reaction device in view of the shortcomings of the prior art, so as to solve the problems of poor reaction selectivity, slow reaction speed, and many side reactions in the prior art, and to simply and efficiently realize the synthesis of pyridine compounds containing electron-withdrawing groups without using precious metal catalysts.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A method for synthesizing pyridine compounds using a microchannel reaction device, using an α,β-unsaturated ketoxime ester compound I and a cyclopropanol compound II as reaction raw materials, and using a microchannel reaction device to prepare a pyridine compound shown in formula III, the reaction formula is as follows:

[0006]

[0007] Among them, R 1 , R 3 R is independently selected from any one of unsubstituted or substituted phenyl, thienyl, naphthyl or C1-C5 alkyl; 2 Independently selected from any one of unsubstituted or substituted phenyl, thienyl, ester or C1-C5 alkyl; the substituted phenyl is selected from phenyl substituted by halogen, C1-C5 alkyl or C1-C5 alkoxy.

[0008] Preferably, R 1Any one selected from 4-chlorophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methoxyphenyl, and phenyl; said R 2 Any one selected from ethoxy, phenyl, 4-methoxyphenyl, 3-methylphenyl, 2-chlorophenyl or thienyl; R 3 Any one selected from phenyl, 4-bromophenyl, 3-methylphenyl, 2-chlorophenyl, thienyl and naphthyl.

[0009] Furthermore, the present invention also provides a method for synthesizing pyridine compounds using the above-mentioned microchannel reaction device, which specifically comprises the following steps:

[0010] (1) dissolving an α,β-unsaturated ketoxime ester compound I in an organic solvent to prepare a homogeneous solution A; dissolving a cyclopropanol compound II, a ligand, a base, and an oxidant in an organic solvent to prepare a homogeneous solution B;

[0011] (2) The homogeneous solution A and the homogeneous solution B obtained in the above step (1) are simultaneously pumped into the micromixer of the microchannel reaction device, and after mixing, are passed into the microchannel reactor for reaction;

[0012] (3) Collecting the effluent from the microchannel reactor and separating and purifying it to obtain the pyridine compound III.

[0013] Specifically, in step (1), the organic solvent is any one of toluene, 1,2-dichloroethane, tetrahydrofuran, cyclohexane, acetonitrile, 1,4-dioxane, ethyl acetate, dichloromethane, chlorobenzene, trifluorotoluene, or a combination of two or more thereof, preferably toluene.

[0014] In step (1), the ligand is any one of bipyridine and phenanthroline or a combination of two thereof, preferably 2,2'-bipyridine.

[0015] In step (1), the base is any one of DABCO (triethylenediamine), DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), TBD (1,5,7-triazabicyclo [4.4.0] dec-5-ene), DMAP (4-dimethylaminopyridine), DIPEA (N,N-diisopropylethylamine), Et3N (triethylamine), TMEDA (tetramethylethylenediamine) or a combination of two or more thereof, preferably DABCO (triethylenediamine).

[0016] In step (1), the oxidant is any one of TEMPO (2,2,6,6-tetramethylpiperidinyl oxide), 4-AcO-TEMPO (4-acetoxy-2,2,6,6-tetramethyl-1-piperidinyl oxide), 4-MeO-TEMPO (4-methoxy-2,2,6,6-tetramethyl-1-piperidinyl oxide), 4-OH-TEMPO (4-hydroxy-2,2,6,6-tetramethylpiperidinyl oxide), 4-NHAc-TEMPO (4-acetylamino-2,2,6,6-tetramethylpiperidinyl oxide), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), BQ (1,4-benzoquinone), TBHP (tert-butyl hydroperoxide), DTBP (di-tert-butyl peroxide), or a combination of two or more thereof, preferably TEMPO (2,2,6,6-tetramethylpiperidinyl oxide).

[0017] Preferably, in step (1), the concentration of the α,β-unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05-0.2 mol / L, preferably 0.1 mol / L; the concentration of the cyclopropanol compound II in the homogeneous solution B is 0.1-0.4 mol / L, preferably 0.2 mol / L; the concentration of the ligand in the homogeneous solution B is 0.005-0.02 mol / L, preferably 0.01 mol / L; the concentration of the base in the homogeneous solution B is 0.02-0.2 mol / L, preferably 0.06 mol / L; the concentration of the oxidant in the homogeneous solution B is 0.1-0.4 mol / L, preferably 0.2 mol / L.

[0018] In step (2), the molar ratio of the α,β-unsaturated ketoxime ester compound I, the cyclopropanol compound II, the ligand, the base and the oxidant in the homogeneous solution A and the homogeneous solution B pumped into the micromixer is 1:(1-2):(0.1-0.5):(0.2-1):(1-3), preferably 1:2:0.1:0.6:2.

[0019] In step (2), the pumping speeds of homogeneous solution A and homogeneous solution B are controlled so that the volume ratio of homogeneous solution A to homogeneous solution B is (0.8-2):1, preferably 1:1.

[0020] In step (2), the flow rate of the homogeneous solution is 0.1 to 1.5 mL / min, preferably 0.25 mL / min; the reaction temperature in the microchannel reactor is 100 to 130° C., preferably 120° C.; and the reaction residence time is 4 to 20 min, preferably 8 min.

[0021] In the present invention, the microchannel reaction device comprises a feed pump, a micromixer and a microchannel reactor, the feed pump is simultaneously connected to the front end of the micromixer in parallel, the rear end of the micromixer is connected to the microchannel reactor, and the connecting pipeline is a copper tube; the volume of the microchannel reactor is 2 to 8 mL, and the inner diameter of the coil of the reactor is 0.5 to 1 mm; preferably, the volume of the microchannel reactor is 4 mL, and the inner diameter of the coil of the reactor is 1 mm.

[0022] Specifically, in step (3), the effluent is separated into an organic phase, and the organic solvent is removed by rotary evaporation to obtain a crude product, and the crude product is separated and purified to obtain a pure product of pyridine compound III. Preferably, the rotary evaporation temperature is 45° C., and the separation and purification is performed by column chromatography using a developing solvent having a ratio of petroleum ether to ethyl acetate of 30:1.

[0023] Beneficial effects:

[0024] (1) The present invention is the first to use α,β-unsaturated ketoxime ester compounds and cyclopropanol compounds as substrates to prepare pyridine compounds containing electron-withdrawing groups that are difficult to synthesize by other methods without the action of precious metal catalysts.

[0025] (2) The microchannel reaction device used in the present invention can accelerate the reaction rate, improve the safety of the reaction process, and realize the continuous synthesis of pyridine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0027] Figure 1 It is a schematic diagram of the process of the microchannel reaction device of the present invention.

[0028] Figure 2 It is the NMR image of the compound of Example 1 of the present invention.

[0029] Figure 3 It is the NMR image of the compound of Example 6 of the present invention.

[0030] Figure 4 It is the NMR image of the compound of Example 7 of the present invention.

[0031] Figure 5 It is the NMR image of the compound of Example 8 of the present invention.

[0032] Figure 6 It is the NMR image of the compound of Example 9 of the present invention.

[0033] Figure 7 It is the NMR image of the compound in Example 10 of the present invention.

[0034] Figure 8It is the NMR image of the compound of Example 11 of the present invention.

[0035] Fig. 9 This is the NMR image of the compound of Example 12 of the present invention.

[0036] Fig.10 This is the NMR image of the compound of Example 13 of the present invention.

[0037] Fig.11 This is the NMR image of the compound of Example 14 of the present invention.

[0038] Fig.12 This is the NMR image of the compound of Example 15 of the present invention.

[0039] Fig.13 This is the NMR image of the compound of Example 16 of the present invention.

[0040] Fig.14 This is the NMR image of the compound of Example 17 of the present invention.

[0041] Fig.15 This is the NMR image of the compound of Example 18 of the present invention.

[0042] Fig.16 This is the NMR image of the compound of Example 19 of the present invention.

[0043] Fig.17 This is the NMR image of the compound in Example 20 of the present invention. DETAILED DESCRIPTION

[0044] The present invention can be better understood with reference to the following examples.

[0045] The microchannel modular reaction device used in the present invention is as follows Figure 1 The microchannel reaction device includes a feed pump, a micromixer and a microchannel reactor. The feed pump is connected to the front end of the micromixer in parallel, and the rear end of the micromixer is connected to the microchannel reactor. The connecting pipe is a copper pipe. The volume of the microchannel reactor is 4 mL, and the inner diameter of the coil of the reactor is 1 mm.

[0046] The present invention uses α,β-unsaturated ketoxime ester compound I and cyclopropanol compound II as raw materials and uses a microchannel modular reaction device to prepare a pyridine compound shown in formula III. The reaction formula is as follows:

[0047]

[0048] Follow these steps:

[0049] (1) dissolving an α,β-unsaturated ketoxime ester compound I in an organic solvent to prepare a homogeneous solution A; dissolving a cyclopropanol compound II ligand, a base, and an oxidant in an organic solvent to prepare a homogeneous solution B; adding the homogeneous solution A to a syringe pump a, and adding the homogeneous solution B to a syringe pump b;

[0050] (2) injecting the mixture into a micro mixer according to a certain ratio through a syringe pump for mixing, and then passing the mixture into a microchannel reactor for reaction;

[0051] (3) The reaction temperature of the microchannel reactor is controlled by an oil bath;

[0052] (4) Collect the effluent reaction liquid, concentrate in vacuo to obtain a crude product, separate the target product by column chromatography and obtain the yield (unless otherwise specified, the column chromatography uses 200-300 mesh silica gel produced by Shandong Qingdao Kangyexin Pharmaceutical Silica Gel Desiccant Co., Ltd.), and use a developing solvent with a ratio of petroleum ether to ethyl acetate of 30:1 for column chromatography.

[0053] Example 1

[0054] 1mmol (0.261g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DABCO and 2mmol (0.312g) of TEMPO were dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 90%. Figure 2 : 1 H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.27(s,1H),8.11(d,J=7.7Hz,2H),7.82(d,J=7.1H z,2H),7.63–7.58(m,1H),7.55–7.45(m,5H),4.13(q,J=7.1Hz,2H),1.08(t,J=7.2Hz,3H)ppm; 13C NMR(100MHz,Chloroform-d)δ194.8,165.1,159.6,149.2,138.4,137.7,137.1,133.7,13 2.9,130.2,129.5,129.1,128.8,127.2,119.6,62.4,13.5ppm; HRMS(ESI-TOF):m / zcalcd for C 21 H 18 O3N[M+H] + 332.1281, found 332.1301.

[0055] Example 2

[0056] 1mmol (0.261g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DABCO and 2mmol (0.312g) of TEMPO were dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 8min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 84%.

[0057] Example 3

[0058] 1mmol (0.261g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10mL of acetonitrile, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DABCO and 2mmol (0.312g) of TEMPO were dissolved in 10mL of acetonitrile, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 80%.

[0059] Example 4

[0060] 1mmol (0.261g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DBU and 2mmol (0.312g) of TEMPO were dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 75%.

[0061] Example 5

[0062] 1mmol (0.261g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DABCO and 2mmol (0.312g) of 4-OH-TEMPO were dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained by discharging the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 82%.

[0063] Comparative Example 1

[0064] 0.2mmol (52.2mg) (2E, 4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester, 0.4mmol (53.6mg) 1-phenyl-1-cyclopropanol, 0.03mmol (2mg) copper powder, 0.04mmol (6.2mg) 2,2′-bipyridine, 0.12mmol (13.4mg) DABCO and 0.4mmol (62.4mg) TEMPO were dissolved in 2mL toluene and reacted in a reaction bottle at 120°C for 12h. The crude product was concentrated in vacuo and separated by column chromatography with a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 1 with a yield of 65%.

[0065] Example 6

[0066] 1mmol (0.339g) of (2E,4E)-4-(acetoxyimino)-4-(4-bromophenyl)but-2-enoic acid ethyl ester was dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) of 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) of 2,2′-bipyridine, 0.6mmol (0.067g) of DABCO and 2mmol (0.312g) of TEMPO were dissolved in 10mL of toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 2 with a yield of 93%. Figure 3 : 1 H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.24(s,1H),8.01–7.97(m,2H),7.82–7.78(m,2H),7.67– 7.63(m,2H),7.62–7.58(m,1H),7.50–7.45(m,2H),4.12(q,J=7.2Hz,2H),1.06(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ194.6,164.9,158.3,149.2,138.5,137.0,136.6,133.7 ,133.3,132.2,129.4,128.8,128.7,124.9,119.3,62.5,13.5ppm; HRMS(ESI-TOF):m / z calcd for C 21 H 17 O3BrN[M+H] + 410.0386, found 410.0396.

[0067] Example 7

[0068] 1mmol (0.291g) (2E, 4E)-4-(acetoxyimino)-4-(3-methoxyphenyl) but-2-enoic acid ethyl ester was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 3 with a yield of 86%. Figure 4 : 1 H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.24(s,1H),7.80(d,J=7.2Hz,2H),7.69(s,1H),7.64(d,J=7.8Hz,1H),7.59–7 .53(m,1H),7.47–7.36(m,3H),7.00(dd,J=8.3,2.7Hz,1H),4.10(q,J=7.1Hz,2H),3.87(s,3H),1.04(t,J=7.2Hz,3H)ppm; 13 CNMR(100MHz,Chloroform-d)δ194.7,165.1,160.3,159.2,149.1,139.1,138.4,137.1,133.6,1 33.0,130.0,129.4,128.8,119.7,119.6,116.2,112.3,62.3,55.4,13.5ppm; HRMS(ESI-TOF):m / z calcd for C 22 H 20 O4N[M+H] + 362.1387, found 362.1402.

[0069] Example 8

[0070] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 4 with a yield of 89%. Figure 5 : 1 H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.10(dd,J=8.3,1.5Hz,2H),7.82(s,1H) ,7.68(d,J=6.7Hz,2H),7.50–7.36(m,4H),7.33–7.29(m,2H),7.28–7.18(m,5H)ppm; 13 CNMR(100MHz,Chloroform-d)δ196.6,159.0,149.8,149.7,138.5,138.0,137.1,133.4,132 .7,129.9,129.8,129.0,128.8,128.7,128.7,128.4,127.3,121.0ppm; HRMS(ESI-TOF):m / z calcd for C 24 H 18 ON[M+H] + 336.1383, found 336.1396.

[0071] Comparative Example 2

[0072] 0.2mmol (53mg) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetyl oxime, 0.4mmol (53.6mg) 1-phenyl-1-cyclopropanol, 0.03mmol (2mg) copper powder, 0.04mmol (6.2mg) 2,2′-bipyridine, 0.12mmol (13.4mg) DABCO and 0.4mmol (62.4mg) TEMPO were dissolved in 2mL toluene and reacted in a reaction bottle at 120°C for 12h. The crude product was concentrated in vacuo and separated by column chromatography with a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 4 with a yield of 68%.

[0073] Example 9

[0074] 1mmol (0.295g) (1E, 2E) -1- (2-methoxyphenyl) -3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 5 with a yield of 85%. Figure 6 : 1 H NMR(400MHz,Chloroform-d)δ8.82(s,1H),8.02(s,1H),7.92(dd,J=7.7,1.8Hz,1H),7.72(d,J=6.9Hz,2 H),7.45–7.38(m,2H),7.35–7.21(m,7H),7.12(t,J=7.3Hz,1H),7.03(d,J=8.3Hz,1H),3.88(s,3H)ppm; 13C NMR(100MHz,Chloroform-d)δ196.9,157.8,157.2,149.3,148.5,138.2,137.1,133.3,132.2,131.4,13 0.7,129.9,128.8,128.6,128.6,128.4,128.2,125.6,121.2,111.5,55.7ppm; HRMS(ESI-TOF):m / zcalcd for C 25 H 20 O2N[M+H] + 366.1489, found 366.1513.

[0075] Example 10

[0076] 1mmol (0.299g) (1E, 2E)-1-(3-chlorophenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 6 with a yield of 89%. Figure 7 : 1 H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.13(s,1H),7.98(td,J=4.4,1.7Hz,1 H),7.81(s,1H),7.68(d,J=7.1Hz,2H),7.46–7.39(m,3H),7.34–7.22(m,7H)ppm; 13C NMR(100MHz,Chloroform-d)δ196.4,157.4,150.0,149.7,140.3,137.7,137.0,135.1,133.5,133.2, 130.2,129.9,129.7,128.9,128.8,128.6,128.4,127.4,125.3,121.1ppm; HRMS(ESI-TOF):m / zcalcd for C 24 H 17 OClN[M+H] + 370.0993, found 370.1012.

[0077] Embodiment 11

[0078] 1mmol (0.299g) (1E, 2E)-1-(4-chlorophenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 7 with a yield of 96%. Figure 8 : 1 H NMR (400MHz, Chloroform-d) δ8.79(s,1H),8.08–8.04(m,2H),7.81(s,1H),7.71–7.66(m,2H),7.50–7.41(m,3H),7.34–7.24(m,7H)ppm; 13 C NMR(100MHz,Chloroform-d)δ196.4,157.7,150.0,149.7,137.8,137.0,136.9,136.0,133 .4,132.9,129.9,129.2,128.9,128.7,128.6,128.5,128.4,120.8ppm; HRMS(ESI-TOF):m / z calcdfor C 24 H17 OClN[M+H] + 370.0993, found 370.1013.

[0079] Example 12

[0080] 1mmol (0.299g) (1E, 2E) -3- (2-chlorophenyl) -1-phenylpropyl -2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 8 with a yield of 85%. Fig. 9 : 1 H NMR(400MHz,Chloroform-d)δ8.89(s,1H),8.10(d,J=6.5Hz,2H),7.81(s,1H),7.75(d,J=7.2Hz,2H) ,7.54–7.45(m,4H),7.39–7.33(m,2H),7.32–7.28(m,1H),7.28–7.25(m,1H),7.25–7.19(m,2H)ppm; 13 C NMR(100MHz,Chloroform-d)δ195.3,159.0,150.3,147.8,138.3,137.0,136.9,133.2,132.5, 132.0,131.0,130.0,129.8,129.8,129.0,128.3,127.4,126.9,122.4ppm; HRMS(ESI-TOF):m / z calcd for C 24 H 17 OClN[M+H] + 370.0993, found 370.1009.

[0081] Example 13

[0082] 1mmol (0.299g) (1E, 2E) -3- (4-chlorophenyl) -1-phenylpropyl -2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 9 with a yield of 93%. Fig.10 : 1 H NMR(400MHz,Chloroform-d)δ8.82(s,1H),8.14–8.09(m,2H),7.82(s,1H),7.7 4(d,J=6.9Hz,2H),7.56–7.48(m,4H),7.39–7.33(m,2H),7.31–7.24(m,4H)ppm; 13 C NMR(100MHz,Chloroform-d)δ196.3,159.2,149.8,148.7,138.3,137.0,136.4,135.1, 133.7,132.4,129.9,129.9,129.0,129.0,128.6,127.3,120.9ppm; HRMS(ESI-TOF):m / z calcd for C 24 H 17 OClN[M+H] + 370.0993, found 370.1013.

[0083] Embodiment 14

[0084] 1mmol (0.295g) (1E, 2E) -3- (4-methoxyphenyl) -1-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 10 with a yield of 92%. Fig.11 : 1 H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.10–8.05(m,2H),7.78(s,1H),7.72–7. 68(m,2H),7.4–7.42(m,1H),7.35–7.22(m,7H),7.05–7.00(m,2H),3.87(s,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ196.7,161.2,158.7,149.8,149.8,138.2,137.2,133.3, 131.9,131.0,129.9,128.7,128.6,128.4,120.2,114.3,55.4ppm; HRMS(ESI-TOF):m / z calcd for C 25 H 20 O2N[M+H] + 366.1489, found 366.1505.

[0085] Embodiment 15

[0086] 1mmol (0.271g) (1E, 2E)-1-phenyl-3-thienylpropyl-2-ene-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.268g) 1-phenyl-1-cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 11 with a yield of 86%. Fig.12 : 1 H NMR(400MHz,Chloroform-d)δ8.74(s,1H),8.12–8.08(m,2H),7.91(s,1H),7.78(d,J=7.0Hz,2H),7.56–7 .45(m,4H),7.38–7.32(m,2H),7.29(d,J=5.1Hz,1H),7.11(dd,J=3.7,1.2Hz,1H),6.91–6.88(m,1H)ppm; 13 C NMR(100MHz,Chloroform-d)δ196.6,159.0,149.4,141.5,139.0,138.3,136.8,133.7,132 .0,129.9,129.8,129.0,129.0,128.6,128.2,128.2,127.3,120.2ppm; HRMS(ESI-TOF):m / z calcd for C 22 H 16 ONS[M+H] + 342.0947, found 342.0975.

[0087] Example 16

[0088] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.296g) 1-(2-methylphenyl) cyclopropane-1-ol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 12 with a yield of 88%. Fig.13 : 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.12–8.07(m,2H),7.77(s,1H),7.51–7. 43(m,3H),7.29–7.17(m,7H),7.09–7.05(m,1H),7.02–6.97(m,1H),2.47(s,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ198.4,159.1,150.4,150.2,139.2,138.4,138.3,137.4,133.9,131.8,131.6,131.0 129.8,129.0,128.6,128.5,128.4,127.3,125.2,121.2,21.0ppm; HRMS(ESI-TOF):m / z calcd for C 25 H 20 ON[M+H] + 350.1539, found 350.1556.

[0089] Embodiment 17

[0090] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.336g) 1-(3-chlorophenyl) cyclopropane-1-ol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 13 with a yield of 90%. Fig.14 : 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.12(d,J=7.2Hz,2H),7.86(s,1H),7.63(s ,1H),7.56–7.47(m,4H),7.40–7.36(m,1H),7.34–7.26(m,5H),7.25–7.19(m,1H)ppm; 13 C NMR(100MHz,Chloroform-d)δ195.3,159.5,149.9,149.9,138.6,138.3,137.8,134.6,133.1,132 .0,129.9,129.7,129.0,129.0,128.8,128.6,127.9,127.3,121.0ppm; HRMS(ESI-TOF):m / zcalcd for C 24 H 17 OClN[M+H] + 370.0993,found370.1011.

[0091] Embodiment 18

[0092] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.328g) 1-(4-methoxyphenyl) cyclopropane-1-ol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 14 with a yield of 94%. Fig.15 : 1 H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.10–8.05(m,2H),7.78(s,1H),7.72–7. 68(m,2H),7.46–7.42(m,1H),7.3–7.22(m,7H),7.05–7.00(m,2H),3.87(s,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ196.7,161.2,158.7,149.8,149.8,138.2,137.2,133.3, 131.9,131.0,129.9,128.7,128.6,128.4,120.2,114.3,55.4ppm; HRMS(ESI-TOF):m / z calcd for C 25 H 20 O2N[M+H] + 366.1489, found 366.1508.

[0093] Embodiment 19

[0094] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.368g) 1-(naphthalen-1-yl) cyclopropanol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the microreactor copper tube was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 15 with a yield of 90%. Fig.16 : 1 H NMR(400MHz,Chloroform-d)δ8.95(s,1H),8.68(d,J=8.6Hz,1H),8.11(d,J=7.0Hz,2H),7.82–7.77(m,2H ),7.75(d,J=8.1Hz,1H),7.59–7.53(m,1H),7.52–7.43(m,5H),7.28–7.19(m,3H),7.07–7.00(m,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ198.0,159.3,150.7,150.6,138.4,138.2,135.2,134.2,133.7,133.5,131.1, 130.9,129.9,129.0,128.4,128.4,128.3,128.2,127.4,126.5,125.8,124.0,121.3ppm; HRMS(ESI-TOF):m / z calcd for C 28 H 20 ON[M+H] + 386.1539, found 386.1582.

[0095] Embodiment 20

[0096] 1mmol (0.265g) (1E, 2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution A; 2mmol (0.280g) 1-(thiophen-2-yl)cyclopropane-1-ol, 0.1mmol (0.016g) 2,2′-bipyridine, 0.6mmol (0.067g) DABCO and 2mmol (0.312g) TEMPO were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.25mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 8min. The organic phase was obtained from the microreactor, and the crude product was obtained by vacuum concentration. The crude product was separated by column chromatography using a developing solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to obtain the target product 16 with a yield of 87%. Fig.17 : 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.10(dd,J=8.2,1.6Hz,2H),7.85(s,1H),7.75(dd,J=2.9,1.3Hz,1H ),7.55–7.47(m,3H),7.43(dd,J=5.1,1.2Hz,1H),7.40–7.36(m,2H),7.35–7.30(m,3H),7.23–7.20(m,1H)ppm; 13 C NMR(100MHz,Chloroform-d)δ189.8,159.1,149.4,149.3,142.3,138.5,138.0,135.3,133 .3,129.8,129.0,128.8,128.8,128.6,127.6,127.3,126.5,121.2ppm; HRMS(ESI-TOF):m / z calcdfor C 22 H 16 ONS[M+H] + 342.0947, found 342.0966.

[0097] Table 1 shows the structural formula and yield of the pyridine products obtained in the above examples.

[0098] Table 1

[0099]

[0100]

[0101] The present invention provides a method for synthesizing pyridine compounds using a microchannel reaction device. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for synthesizing pyridine compounds using a microchannel reaction device, characterized in that: Using α,β-unsaturated ketoxime ester compound I and cyclopropanol compound II as raw materials, a pyridine compound shown in formula III is prepared using a microchannel reaction device, and the reaction formula is as follows: ； Among them, R 1 , R 3 R is independently selected from any one of unsubstituted or substituted phenyl, thienyl, naphthyl or C1-C5 alkyl; 2 Independently selected from any one of unsubstituted or substituted phenyl, thienyl, ester or C1-C5 alkyl; the substituted phenyl is selected from phenyl substituted by halogen, C1-C5 alkyl or C1-C5 alkoxy; The specific steps include: (1) dissolving an α,β-unsaturated ketoxime ester compound I in an organic solvent to prepare a homogeneous solution A; dissolving a cyclopropanol compound II, a ligand, a base, and an oxidant in an organic solvent to prepare a homogeneous solution B; (2) The homogeneous solution A and the homogeneous solution B obtained in the above step (1) are simultaneously pumped into the micromixer of the microchannel reaction device, and after mixing, they are passed into the microchannel reactor for reaction; (3) collecting the effluent from the microchannel reactor and separating and purifying it to obtain the pyridine compound III; In step (1), the ligand is any one of bipyridine and phenanthroline or a combination of two; The base is any one of triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and tetramethylethylenediamine, or a combination of two or more thereof; The oxidant is any one of 2,2,6,6-tetramethylpiperidinyloxy, 4-acetoxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy free radical, 4-acetylamino-2,2,6,6-tetramethylpiperidinyloxy free radical, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,4-benzoquinone, tert-butyl hydroperoxide, and di-tert-butyl peroxide, or a combination of two or more thereof.

2. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: R 1 Any one selected from 4-chlorophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-chlorophenyl, 2-methoxyphenyl, and phenyl; said R 2 Any one selected from ethoxy, phenyl, 4-methoxyphenyl, 3-methylphenyl, 2-chlorophenyl or thienyl; R 3 Any one selected from phenyl, 4-bromophenyl, 3-methylphenyl, 2-chlorophenyl, thienyl and naphthyl.

3. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (1), the organic solvent is any one of toluene, 1,2-dichloroethane, tetrahydrofuran, cyclohexane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, chlorobenzene, trifluorotoluene, or a mixture of two or more thereof.

4. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (1), the concentration of the α,β-unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05-0.2 mol / L; the concentration of the cyclopropanol compound II in the homogeneous solution B is 0.1-0.4 mol / L; the concentration of the ligand in the homogeneous solution B is 0.005-0.02 mol / L; the concentration of the base in the homogeneous solution B is 0.02-0.2 mol / L; and the concentration of the oxidant in the homogeneous solution B is 0.1-0.4 mol / L.

5. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (2), the molar ratio of the α,β-unsaturated ketoxime ester compound I, the cyclopropanol compound II, the ligand, the base, and the oxidant in the homogeneous solution A and the homogeneous solution B pumped into the micromixer is 1:(1-2):(0.1-0.5):(0.2-1):(1-3).

6. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (2), the pumping speeds of homogeneous solution A and homogeneous solution B are controlled so that the volume ratio of homogeneous solution A to homogeneous solution B is (0.8-2):

1.

7. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (2), the flow rate of the mixed solution obtained after mixing in the micro mixer is 0.1-1.5 mL / min; the reaction temperature in the microchannel reactor is 100-130 o C, the reaction residence time is 4~20 min.

8. The method for synthesizing pyridine compounds using a microchannel reaction device according to claim 1, characterized in that: In step (3), the organic phase is separated from the effluent, and the organic solvent is removed by rotary evaporation to obtain a crude product, which is then separated and purified to obtain a pure product of pyridine compound III.

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