A method for synthesizing pyrimidine compounds using a microchannel reaction device

Abstract

The present invention discloses a method for synthesizing pyrimidine compounds using a microchannel reaction device, wherein amidine compound I and α,β-unsaturated ketoxime ester compound II are used as reaction raw materials, and a pyrimidine compound shown in formula III is prepared using a microchannel modular reaction device under the action of a catalyst. Compared with the prior art, the present invention uses α,β-unsaturated ketoxime ester compounds and amidine compounds as substrates to prepare new pyrimidine compounds, and the method avoids multi-component reactions and uses cheap metal catalysts to quickly and efficiently synthesize products.

Description

Technical Field

[0001] The invention relates to a preparation technology of pyrimidine compounds, and in particular to a method for synthesizing pyrimidine compounds by using a microchannel reaction device. Background Art

[0002] Pyrimidine rings exist in many key molecules that constitute biological systems. Pyrimidine and its derivatives have a wide range of biological potentials. Therefore, people are committed to developing new transformation methods to construct various pyrimidine derivatives. In synthetic chemistry, the use of oxime derivatives to synthesize a variety of pyrimidine compounds has attracted widespread attention from chemists.

[0003] At present, the preparation methods of pyrimidine derivatives mainly include: (1) using the [3+1+1+1] cyclization process to condense aminoolefins, orthoesters and ammonium acetate in the presence of Lewis acid catalysts to synthesize pyrimidine derivatives, see the literature (Org. Lett. 2009, 11, 2161-2164); (2) under acidic conditions, tetrahydropyrimidone is synthesized in one step by condensation of urea / thiourea, aromatic aldehydes and ketosulfone / ketosulfonamide solutions, see the literature (Arkivoc 2014, 86-107.); (3) condensation reaction of amidine with various chalcones to generate pyrimidine, see the literature (Arkivoc 2000, 37-42.); (4) in the presence of anhydrous sodium carbonate, pyrimidine derivatives are synthesized by condensation of chalcone with guanidine / acetamidine and formamidine (see the literature Bioorg. Chem. 2018, 78, 130-140.). Although there are many routes for preparing pyrimidine, most pyrimidine synthesis routes are greatly limited in their industrial application due to toxic byproducts, the use of metal trifluorides, excess base, etc. Summary of the invention

[0004] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for synthesizing pyrimidine derivatives using a microchannel reaction device in view of the shortcomings of the prior art, so as to solve the problems of complicated reaction steps, long reaction time, low reaction efficiency, etc. in the prior art, and to simply and efficiently realize the synthesis of pyrimidine derivatives without using precious metal catalysts.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] A method for synthesizing pyrimidine compounds using a microchannel reaction device, using an amidine compound I and an α,β-unsaturated ketoxime ester compound II as reaction raw materials, and using a microchannel reaction device to prepare a pyrimidine compound shown in formula III under the action of a catalyst, the reaction formula is as follows:

[0007]

[0008] Among them, R1 , R 2 R is independently selected from any one of unsubstituted or substituted phenyl, thienyl, naphthyl or C1-C5 alkyl; 3 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.

[0009] Preferably, R 1 , R 2 R is independently selected from any one of unsubstituted or substituted phenyl, thienyl, naphthyl or C1-C5 alkyl; 3 Independently selected from any one of unsubstituted or substituted phenyl, thienyl, ester or C1-C5 alkyl.

[0010] More preferably, R 1 Any one selected from 4-chlorophenyl, 3-methoxyphenyl, 2-bromophenyl, and thienyl; said R 2 Any one selected from phenyl, 4-bromophenyl, 3-methoxyphenyl, 2-fluorophenyl or naphthyl; R 3 Any one selected from the group consisting of ethoxy, phenyl, methyl, 4-chloro, 3-methyl, 3-bromo, 2-methoxy, and thienyl.

[0011] Specifically, the method for synthesizing pyrimidine compounds using a microchannel reaction device of the present invention comprises the following steps:

[0012] (1) dissolving an amidine compound I and a catalyst in an organic solvent to prepare a homogeneous solution A; dissolving an α,β-unsaturated ketoxime ester compound II in an organic solvent to prepare a homogeneous solution B;

[0013] (2) The homogeneous solution A and the homogeneous solution B obtained in the above step (1) are respectively pumped into the micromixer of the microchannel reaction device at the same time, and after mixing, they are introduced into the microchannel reactor for reaction;

[0014] (3) Collecting the effluent from the microchannel reactor to obtain the pyrimidine compound III.

[0015] Specifically, in step (1), the organic solvent is any one or a mixture of two or more of 1,2-dichloroethane, tetrahydrofuran, cyclohexane, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, toluene or water; preferably 1,2-dichloroethane.

[0016] The catalyst is any one of ferrous chloride, ferric chloride, boron trifluoride etherate, ferric sulfate, ferrous bromide, cuprous iodide, cuprous acetate, ferric trifluoromethanesulfonate or scandium trifluoromethanesulfonate, or a mixture of two or more thereof, preferably ferrous chloride.

[0017] Preferably, in step (1), the concentration of the amidine compound I in the homogeneous solution A is 0.05 mmol / L to 0.1 mmol / L; the concentration of the catalyst in the homogeneous solution A is 0.005 mmol / L to 0.01 mmol / L; and the concentration of the α,β-unsaturated ketoxime ester compound II in the homogeneous solution B is 0.05 mmol / L to 0.1 mmol / L.

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

[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 mixed solution obtained after mixing in the micromixer is 0.1-1.5 mL / min (preferably 0.5 mL / min); the reaction temperature in the microchannel reactor is 100-140° C. (preferably 130° C.), and the reaction residence time is 4-20 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 capillary or a polytetrafluoroethylene tube, preferably a polytetrafluoroethylene tube; the reaction volume of the microchannel reactor is 2mL to 8mL, and the inner diameter of the coil of the reactor is 0.5mm to 1mm; preferably, the reaction volume of the microchannel reactor is 4mL, and the inner diameter of the coil of the reactor is 0.5mm.

[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 pyrimidine 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 as substrates to prepare new pyrimidine derivatives. This method avoids multi-step reactions or multi-component reactions to improve atom utilization, can use cheap metal catalysts and low-toxic solvents, and has greener reaction conditions and is environmentally friendly.

[0025] (2) The microchannel reaction device used in the present invention can accelerate the reaction rate, shorten the reaction time, realize the continuous synthesis of such compounds, and has stable product quality. The reaction process is easy to control and can effectively improve the mass transfer and heat transfer effect of the reaction, improve the safety of the reaction process, and reduce the amount of wastewater discharged, thus having good industrial application prospects. 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 8 It 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 As shown (taking Example 1 as an example), amidine compound I and α,β-unsaturated ketoxime ester compound II are used as reaction raw materials, and a pyrimidine compound shown in formula III is prepared using a microchannel modular reaction device under the action of a catalyst. The reaction formula is as follows:

[0046]

[0047] Follow these steps:

[0048] (1) dissolving an amidine compound I and a catalyst in an organic solvent to prepare a homogeneous solution A; dissolving an α,β-unsaturated ketoxime ester compound II 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;

[0049] (2) injecting the mixture into the micro-mixer of the micro-channel reaction device in a certain proportion through a syringe pump for mixing, and then passing the mixture into the micro-channel reactor for reaction;

[0050] (3) The reaction temperature of the microchannel reactor is controlled by an oil bath;

[0051] (4) The reaction liquid was collected and quenched with water, and the target product was separated by column chromatography and the yield was obtained (unless otherwise specified, the column chromatography used 200-300 mesh silica gel produced by Shandong Qingdao Kangyexin Pharmaceutical Silica Gel Desiccant Co., Ltd.), and the column chromatography was performed using a developing solvent with a ratio of petroleum ether to ethyl acetate of 30:1.

[0052] Example 1

[0053] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 92%.

[0054] The NMR image of product 1 is shown in Figure 2 : 1 H NMR (400MHz, Chloroform-d) δ8.68–8.64(m,2H),8.33–8.27(m,3H),7.59–7.51(m,6H),4.55(q,J=7.1Hz,2H),1.51(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ166.1,165.3,165.0,156.5,137.2,136.4,131.5 ,131.2,129.1,128.7,128.6,127.5,114.0,62.5,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 19 H 16 O2N2[M+H] + 305.1285, found 305.1299.

[0055] Example 2

[0056] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 0.8 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 5 min. The organic phase was obtained by discharging 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 with a yield of 86%.

[0057] Example 3

[0058] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 120°C for 8 min. The organic phase was obtained by discharging 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 with a yield of 90%.

[0059] Example 4

[0060] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 8 mL) and reacted at 130°C for 16 min. The organic phase was obtained by discharging 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 with a yield of 88%.

[0061] Example 5

[0062] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 1 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. The organic phase was obtained by discharging 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 with a yield of 87%.

[0063] Comparative Example 1

[0064] 0.2mmol (0.039g) of N-phenylbenzamidine, 0.4mmol (0.104g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester and 0.02mmol (2.5mg) of ferrous chloride were dissolved in 2mL of 1,2-dichloroethane and reacted in a reaction bottle at 130°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 72%.

[0065] Example 6

[0066] 1 mmol (0.230 g) of 4-chloro-N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 2 with a yield of 96%.

[0067] The NMR image of product 2 is shown in Figure 3 : 1 H NMR (400MHz, Chloroform-d) δ8.62–8.58(m,2H),8.30–8.26(m,3H),7.59–7.55(m,3H),7.51–7.47(m,2H),4.55(q,J=7.1Hz,2H),1.51(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.4,164.9,164.8,156.7,137.9,137.0,134.8,13 1.3,129.4,128.7,128.7,128.7,113.8,62.6,14.3ppm; HRMS(ESI-TOF):m / zcalcd for C 19 H 15 O2ClN2[M+H] + 339.0895, found 339.0944.

[0068] Example 7

[0069] 1 mmol (0.226 g) of 3-methoxy-N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 3 with a yield of 93%.

[0070] The NMR image of product 3 is shown in Figure 4 : 1 H NMR(400MHz,Chloroform-d)δ8.31–8.25(m,4H),8.22–8.20(m,1H),7.57–7.56(m,3H),7.45(t, J=8.0Hz,1H),7.09–7.06(m,1H),4.55(q,J=7.1Hz,2H),3.95(s,3H),1.51(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ166.0,165.0,164.9,159.9,156.4,138.7,136.3 131.6,129.6,129.1,127.5,121.3,117.2,114.1,113.7,62.5,55.5,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 20 H 18 O3N2[M+H] + 335.139, found 335.1405.

[0071] Example 8

[0072] 1 mmol (0.274 g) of 2-bromo-N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 4 with a yield of 89%.

[0073] The NMR image of product 4 is shown in Figure 5 : 1 H NMR(400MHz,Chloroform-d)δ8.38(s,1H),8.30–8.27(m,2H),7.90(dd,J=7.7,1.7Hz,1H),7.74–7.72(m,1H),7. 55–7.53(m,3H),7.46–7.42(m,1H),7.32(td,J=7.7,1.8Hz,1H),4.55(q,J=7.1Hz,2H),1.48(t,J=7.1Hz,3H)ppm; 13 CNMR(100MHz,Chloroform-d)δ166.8,166.0,164.6 156.3,139.2,136.1,134.0,132.2,131.8,130.8,129.2,127.7 127.5,122.2,114.4,62.7,14.3ppm; HRMS(ESI-TOF):m / zcalcd for C 19 H 15 O2BrN2[M+H] + 383.039, found 383.0417.

[0074] Example 9

[0075] 1 mmol (0.202 g) of N-phenylthiophene-2-carboximidamide and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.522 g) of (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 5 with a yield of 86%.

[0076] The NMR of product 5 is shown in Figure 6 : 1 H NMR(400MHz,Chloroform-d)δ8.50(dd,J=3.1,1.2Hz,1H),8.28–8.23(m,2H),8.21(s,1H),8.07(dd,J= 5.0,1.3Hz,1H),7.57–7.53(m,3H),7.41–7.39(m,1H),4.53(q,J=7.1Hz,2H),1.50(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ166.1,164.9,162.4,156.4,141.3,136.3,131.5,129.1,127.9,127.4,126.0,113.6,62.5ppm; HRMS (ESI-TOF): m / z calcd for C 17 H 14 O2N2S[M+H] + 311.0849, found 311.0860.

[0077] Example 10

[0078] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.678 g) of (2E,4E)-4-(acetoxyimino)-4-(4-bromophenyl)but-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 6 with a yield of 94%.

[0079] The NMR of product 6 is shown in Figure 7 : 1 H NMR(400MHz,Chloroform-d)δ8.64–8.62(m,2H),8.25(s,1H),8.20–8.16(m,2H),7. 72–7.68(m,2H),7.55–7.51(m,3H),4.55(q,J=7.2Hz,2H),1.51(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.4,164.9,164.8 156.7,137.0,135.3,132.3,131.33,128.9,128.7,128.7,126.3,113.7,62.6,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 19 H 15 O2BrN2[M+H] + 382.0342, found 382.0395.

[0080] Embodiment 11

[0081] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.668 g) of (2E,4E)-4-(acetoxyimino)-4-(3-methoxyphenyl)but-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 7 with a yield of 91%.

[0082] The NMR of product 7 is shown in Figure 8 : 1 H NMR(400MHz,Chloroform-d)δ8.67–8.62(m,2H),8.26(s,1H),7.90–7.86(m,1H),7.84(d,J=6.8Hz,1H),7.55–7.50(m, 3H),7.47(t,J=8.0Hz,1H),7.11(dd,J=8.1,2.7Hz,1H),4.55(q,J=7.1Hz,2H),3.94(s,3H),1.51(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.9,165.2,164.9,160.3,156.5,137.9,137.2,131.2,13 0.1,128.7,128.6,119.9,117.2,114.2,112.8,62.6,55.5,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 20 H 18 O3N2[M+H] + 335.1398, found 335.1411.

[0083] Example 12

[0084] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.644 g) of (2E,4E)-4-(acetoxyimino)-4-(2-fluorophenyl)but-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 8 with a yield of 85%.

[0085] The NMR of product 8 is shown in Fig. 9 : 1 H NMR(400MHz,Chloroform-d)δ8.64–8.62(m,2H),8.41–8.36(m,2H),7.53–7.50(m,4H), 7.39–7.34(m,1H),7.26–7.20(m,1H),4.54(q,J=7.2Hz,2H),1.50(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.2,164.8,162.5(d,J=8.8Hz),161.7(d,J=254.5Hz),156.4,137.1,132.9(d,J=8.8Hz),131.2,131.0(d,J=2 .8Hz), 128.6, 128.6, 124.8 (d, J = 3.6Hz), 124.7 (d, J = 10.1Hz), 118.2 (d, J = 12.4Hz), 116.7 (d, J = 22.6Hz), 62.1, 14.3ppm; HRMS (ESI-TOF): m / z calcd for C 19 H 15 O2FN2[M+H] + 323.1198, found 323.1204.

[0086] Example 13

[0087] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.622 g) of (2E,4E)-4-(acetoxyimino)-4-(naphthalene-2-yl)but-2-enoic acid ethyl ester was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 9 with a yield of 88%.

[0088] The NMR image of product 9 is shown in Fig.10 : 1 H NMR(400MHz,Chloroform-d)δ8.81(s,1H),8.72–8.67(m,2H),8.44–8.40(m,2H),8.07–8.00( m,2H),7.94–7.90(m,1H),7.62–7.53(m,5H),4.58(q,J=7.1Hz,2H),1.53(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ166.2,165.3,165.0,156.5,136.5,135.0,134.6,133.3,131.6,129.4 ,129.2,129.1,128.3,127.8,127.5,127.3,126.3,125.4,114.1,62.6,14.3ppm; HRMS(ESI-TOF):m / z calcd forC 23 H 18 O2N2[M+H] + 355.1441, found 355.1471.

[0089] Embodiment 14

[0090] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.530 g) of (1E,2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 10 with a yield of 95%.

[0091] The NMR image of product 10 is shown in Fig.11 : 1 H NMR (400MHz, Chloroform-d) δ8.76–8.73(m,2H),8.33–8.29(m,4H),8.03(s,1H),7.60–7.52(m,8H)ppm; 13 C NMR (100MHz, Chloroform-d) δ164.8,164.6,138.2,137.6,130.8,130.7,129.0,128.5,128.5,127.3,110.3ppm; HRMS (ESI-TOF): m / z calcd for C 22 H 16 N2[M+H] + 309.1386, found 309.1442.

[0092] Comparative Example 2

[0093] 0.2mmol (0.039g) of N-phenylbenzamidine, 0.4mmol (0.123g) of (1E,2E)-1,3-diphenylpropyl-2-allyl-1-one o-acetyl oxime and 0.02mmol (0.0025g) of ferrous chloride were dissolved in 2mL of 1,2-dichloroethane and reacted in a reaction bottle at 130°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 10 with a yield of 74%.

[0094] Embodiment 15

[0095] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.598 g) of (1E,2E)-1-(4-chlorophenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 11 with a yield of 98%.

[0096] The NMR of product 11 is shown in Fig.12 : 1 H NMR (400MHz, Chloroform-d) δ8.73–8.68(m,2H),8.31–8.24(m,4H),7.99(s,1H),7.58–7.51(m,8H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.0,164.6,163.6,138.0,137.4,137.0,136.0,130 .9,130.8,129.2,129.0,128.6,128.5,128.5,127.3,110.0ppm; HRMS(ESI-TOF):m / z calcd for C 22 H 15 ClN2[M+H] + 343.0997, found 343.1042.

[0097] Example 16

[0098] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.558 g) of (1E,2E)-1-(3-methylphenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 12 with a yield of 86%.

[0099] The NMR image of product 12 is shown in Fig.13 : 1 H NMR(400MHz,Chloroform-d)δ8.78–8.74(m,2H),8.33–8.29(m,2H),8.13–8.06(m,2H), 8.00(s,1H),7.61–7.52(m,6H),7.49–7.43(m,1H),7.38–7.34(m,1H),2.53(s,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ165.0,164.7,164.5,138.7,138.3,137.6,137.6,131.6,130.8, 130.7,129.0,128.9,128.6,128.5,128.0,127.3,124.5,110.4,21.7ppm; HRMS(ESI-TOF):m / z calcd for C 23 H 18 N2[M+H] + 323.1543, found 323.1565.

[0100] Embodiment 17

[0101] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.686 g) of (1E,2E)-1-(3-bromophenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 13 with a yield of 86%.

[0102] The NMR of product 13 is shown in Fig.14 : 1 H NMR(400MHz,Chloroform-d)δ8.72–8.67(m,2H),8.43–8.41(m,1H),8.31–8.25(m,2H),8. 21–8.16(m,1H),7.95(s,1H),7.67–7.64(m,1H),7.57–7.51(m,6H),7.43–7.39(m,1H)ppm; 13 C NMR(100MHz,Chloroform-d)δ166.1,165.3,165.0,156.5,137.2,136.4,131.5 ,131.2,129.1,128.7,128.6,127.5,114.0,62.5,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 22 H 15 BrN2[M+H] + 387.0491, found 387.0561.

[0103] Embodiment 18

[0104] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.590 g) of (1E,2E)-1-(2-methoxyphenyl)-3-phenylpropyl-2-ene-1-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 14 with a yield of 85%.

[0105] The NMR of product 14 is shown in Fig.15 : 1 H NMR(400MHz,Chloroform-d)δ8.79–8.73(m,2H),8.34–8.27(m,4H),7.61–7.53( m,6H),7.52–7.47(m,1H),7.23–7.18(m,1H),7.10–7.06(m,1H),3.96(s,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ164.3,163.7,163.5,158.2,138.5,138.0,131.6,131.4,130.6 130.5,128.9,128.5,128.4,127.5,127.0,121.3,115.5,111.7,55.8ppm; HRMS(ESI-TOF):m / z calcd for C 23 H 18 N2O[M+H] + 339.1492, found 339.1504.

[0106] Embodiment 19

[0107] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.406 g) of (2Z,3E)-4-phenylbutanedione o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 a flow rate of 0.5 mL / min, respectively, and after mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. The organic phase was obtained from the discharge of the microreactor, and the crude product was obtained by vacuum concentration. The target product 15 was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 30:1, and the yield was 85%.

[0108] The NMR of product 15 is shown in Fig.16 : 1 H NMR (400MHz, Chloroform-d) δ8.63–8.60(m,2H),8.25–8.20(m,2H),7.55–7.49(m,6H),7.47(s,1H),2.66(s,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ167.8,164.3,163.7,138.1,137.3,130.7,130.5,128.8,128.5,128.4,127.2,114.0,24.6ppm; HRMS (ESI-TOF): m / z calcd for C 17 H 14 N2[M+H] + 247.1230, found 247.1238.

[0109] Embodiment 20

[0110] 1 mmol (0.196 g) of N-phenylbenzamidine and 0.05 mmol (6.25 mg) of ferrous chloride were dissolved in 10 mL of 1,2-dichloroethane, and the resulting mixed solution was recorded as solution A; 2 mmol (0.542 g) of (1E,2E)-3-phenyl-1-thiophenepropyl-2-ene-one o-acetoxime was dissolved in 10 mL of 1,2-dichloroethane, 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 0.5 mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) and reacted at 130°C for 8 min. 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 16 with a yield of 92%.

[0111] The NMR of product 16 is shown in Fig.17 : 1 H NMR (400MHz, Chloroform-d) δ8.70–8.65(m,2H),8.29–8.24(m,2H),7.93(d,J=3.7Hz,1H),7.86(s,1H),7.59–7.50(m,7H),7.23–7.19(m,1H)ppm; 13 C NMR(100MHz,Chloroform-d)δ164.6,164.5,159.7,143.4,137.8,137.4,130.9, 130.8,129.8,128.9,128.5,128.3,127.3,127.1,108.5ppm; HRMS(ESI-TOF):m / z calcdfor C 20 H 14 N2S[M+H] + 315.095, found 315.1038.

[0112] Table 1 shows the structural formula and yield of the pyrimidine products obtained in the above examples.

[0113] Table 1

[0114]

[0115]

[0116] The present invention provides a method and method for synthesizing pyrimidine compounds using a microchannel reaction device. There are many methods and approaches 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 pyrimidine compounds using a microchannel reaction device, characterized in that: Using amidine compound I and α,β-unsaturated ketoxime ester compound II as reaction raw materials, a pyrimidine compound III is prepared by using a microchannel reaction device under the action of a catalyst and a solvent. The reaction formula is as follows: ； Among them, R 1 Any one selected from 4-chlorophenyl, 3-methoxyphenyl, 2-bromophenyl, and thienyl; said R 2 Any one selected from phenyl, 4-bromophenyl, 3-methoxyphenyl, 2-fluorophenyl or naphthyl; R 3 Any one selected from ethoxy, phenyl, methyl, 4-chloro, 3-methyl, 3-bromo, 2-methoxy, and thienyl; The catalyst is ferrous chloride; The reaction temperature in the microchannel reaction device is 100~140℃.

2. The method for synthesizing pyrimidine compounds using a microchannel reaction device according to claim 1, characterized in that: The specific steps include: (1) dissolving an amidine compound I and a catalyst in an organic solvent to prepare a homogeneous solution A; dissolving an α,β-unsaturated ketoxime ester compound II 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 pumped into the micromixer of the microchannel reaction device respectively and then introduced into the microchannel reactor for reaction after mixing; (3) Collect the effluent from the microchannel reactor to obtain pyrimidine compound III.

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

4. The method for synthesizing pyrimidine compounds using a microchannel reaction device according to claim 2, characterized in that: In step (1), the concentration of the amidine compound I in the homogeneous solution A is 0.05 mmol / L to 0.1 mmol / L; the concentration of the catalyst in the homogeneous solution A is 0.005 mmol / L to 0.01 mmol / L; and the concentration of the α,β-unsaturated ketoxime ester compound II in the homogeneous solution B is 0.05 mol / L to 0.1 mmol / L.

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

6. The method for synthesizing pyrimidine compounds using a microchannel reaction device according to claim 2, 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 pyrimidine compounds using a microchannel reaction device according to claim 2, characterized in that: In step (2), the flow rate of the mixed solution obtained after mixing in the micromixer is 0.1-1.5 mL / min; and the reaction residence time in the microchannel reaction device is 4-20 min.

8. The method for synthesizing pyrimidine compounds using a microchannel reaction device according to claim 2, 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 pyrimidine compound III.

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