A method for synthesizing 2,4,6-trisubstituted pyrimidine compounds using a microchannel reaction device

Abstract

The present invention belongs to the technical field of organic chemical synthesis, and relates to a method for synthesizing 2,4,6-trisubstituted pyrimidine compounds using a microchannel reaction device. The method uses α, β-unsaturated ketoxime ester compounds I and malononitrile as raw materials, adds a catalyst, and uses a microchannel reaction device to prepare 2,4,6-trisubstituted pyrimidine compounds III. The present invention uses α, β-unsaturated ketoxime ester compounds and malononitrile as substrates for the first time to prepare new 2,4,6-trisubstituted pyrimidine compounds. The method uses cheap ferric chloride as a catalyst, which is simple to operate and more environmentally friendly than previous synthetic routes. The microchannel reaction device used in the present invention can accelerate the reaction rate, shorten the reaction time, and realize the continuous synthesis of such compounds; and the reaction process is easy to control, can effectively improve the safety of the reaction process, and has great potential in later industrial applications.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis and relates to a method for synthesizing 2,4,6-trisubstituted pyrimidine compounds by utilizing a microchannel reaction device. Background Art

[0002] Pyrimidine compounds are widely present in natural products and have attracted much attention in the fields of medicine, pesticides, functional materials, etc. They have been widely used in the treatment and prevention of human diseases. In addition, pyrimidine compounds can be used as fungicides and herbicides in the agricultural field. Therefore, people are committed to developing new synthetic methods to construct various pyrimidine derivatives.

[0003] At present, there are mainly the following methods for preparing pyrimidine derivatives: (1) Synthesis by reaction of amidine with carbonyl group under transition metal or base catalysis, see reference (Tetrahedron Lett. 2019, 60, 1103-1107); (2) Multi-component synthesis from amidine and two different alcohols catalyzed by various metal-ligand complexes, see reference (Org. Lett. 2019, 21, 1116-1120); (3) [2+2+2] cyclization reaction of ketone or alkyne with two molecules of nitrile, see reference (Org. Lett. 2018, 20, 3399-3402); (4) One-pot condensation preparation of aldehyde, ketone and NH4OAc, see reference (Asian J. Org. Chem. 2020, 9, 242-246). However, most existing synthesis methods require strong acids or bases, noble metal-ligand complexes, and stoichiometric oxidants, which are complicated and costly, and do not conform to the development direction of green chemistry today. Therefore, it is of great significance to develop new methods for the synthesis of 2,4,6-trisubstituted pyrimidine compounds with high efficiency, low cost, and diverse structures. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing 2,4,6-trisubstituted pyrimidine compounds using a microchannel reaction device in view of the deficiencies in the prior art, so as to solve the problems existing in the prior art such as complicated reaction steps, the need for precious metal-ligand complexes, high synthesis costs, etc., and to achieve the synthesis of 2,4,6-trisubstituted pyrimidine compounds in a simple and efficient manner.

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

[0006] The invention discloses a method for synthesizing 2,4,6-trisubstituted pyrimidine compounds by using a microchannel reaction device, wherein α,β-unsaturated ketoxime ester compound I and malononitrile are used as raw materials, a catalyst is added, and the 2,4,6-trisubstituted pyrimidine compound III is prepared by using a microchannel reaction device;

[0007]

[0008] Among them, R 1 , R 2 Independently selected from unsubstituted or substituted phenyl, thienyl, naphthyl, C1-C5 alkyl, biphenyl or alkoxyacyl.

[0009] In some embodiments, the substitution is selected from halogen, C1-C5 alkyl or C1-C5 alkoxy.

[0010] In some embodiments, the R 1 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, biphenyl or thienyl, wherein R 2 It is ethoxycarbonyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-methylphenyl, 2-methoxyphenyl or 2-chlorophenyl.

[0011] In some embodiments, the catalyst is any one or a combination of aluminum chloride, ferrous chloride, ferric chloride, boron trifluoride etherate, zinc acetate and zinc trifluoromethanesulfonate, preferably ferric chloride.

[0012] In some embodiments, the method for synthesizing 2,4,6-trisubstituted pyrimidine compounds using a microchannel reaction device specifically comprises the following steps:

[0013] (1) dissolving an α,β-unsaturated ketoxime ester compound I and a catalyst in a solvent to obtain a homogeneous solution A; dissolving malononitrile in a solvent to obtain a homogeneous solution B;

[0014] (2) The homogeneous solution A and the homogeneous solution B obtained in step (1) are pumped into a micromixer at the same time, mixed, and pumped into a microreactor for addition reaction. After the reaction is completed, the reaction effluent is collected and post-treated to obtain a 2,4,6-trisubstituted pyrimidine compound III.

[0015] In some embodiments, in step (1), the solvent is any one or a combination of 1,2-dichloroethane, γ-valerolactone, tetrahydrofuran, cyclohexane, acetonitrile, 1,4-dioxane, ethyl acetate, toluene and water, preferably 1,4-dioxane or toluene, more preferably 1,4-dioxane.

[0016] In some embodiments, in step (1), the concentration of the α,β-unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05-0.1 mmol / mL, preferably 0.1 mmol / mL; the concentration of the catalyst in the homogeneous solution A is 0.005-0.01 mmol / mL, preferably 0.005 mmol / mL; the concentration of malononitrile in the homogeneous solution B is 0.2-0.4 mmol / mL, preferably 0.4 mmol / mL.

[0017] In some embodiments, in step (2), when the homogeneous solution A and the homogeneous solution B are pumped into the micromixer simultaneously, the molar ratio of the α,β-unsaturated ketoxime ester compound I, the catalyst, and malononitrile is 1:0.01-0.2:2-5, preferably 1:0.05:4.

[0018] Wherein, in step (2), the flow rate of the homogeneous solution A pumped into the micromixer is 0.4-1.0 mL / min, preferably 0.5 mL / min; the flow rate of the homogeneous solution B pumped into the micromixer is 0.4-1.0 mL / min, preferably 0.5 mL / min; the flow rate ratio of the homogeneous solution A to the homogeneous solution B pumped into the micromixer is 1:0.8-2, preferably 1:1.

[0019] In some embodiments, in step (2), the addition reaction has a reaction temperature of 100-130°C, preferably 110°C, a reaction residence time of 2-10 min, preferably 4 min; and a volume of the microreactor of 3-10 mL, preferably 4 mL.

[0020] In some embodiments, the microchannel reaction device includes a connecting pipe, a feed pump a, a feed pump b, a micromixer, a microreactor and a receiver; wherein the feed pump a and the feed pump b are connected in parallel through a pipe and then connected to the micromixer; the micromixer, the microreactor and the receiver are connected in series in sequence through the pipe.

[0021] Wherein, the micro mixer is a Y-shaped tube with an inner diameter of 6 mm and an outer diameter of 9 mm, and is made of polytetrafluoroethylene.

[0022] Wherein, the pipe in the microreactor is a capillary tube or a polytetrafluoroethylene tube, preferably a polytetrafluoroethylene tube; the inner diameter of the coil of the microreactor is 0.5-1 mm, preferably 0.5 mm.

[0023] Wherein, the feed pump is a syringe pump, model TYD01-01-CE.

[0024] Wherein, in step (2), the post-treatment is vacuum concentration followed by column chromatography separation and purification to obtain 2,4,6-trisubstituted pyrimidine compound III; the vacuum concentration is rotary evaporation to remove the organic solvent, and the rotary evaporation temperature is 45°C; the column chromatography separation and purification is column chromatography using an eluent with a volume ratio of petroleum ether to ethyl acetate of 10:1.

[0025] Wherein, the reaction temperature of the microreactor is controlled by an oil bath.

[0026] The 2,4,6-trisubstituted pyrimidine compound III prepared by the above preparation method has three functional sites at the 2-position, 4-position and 6-position. By combining with different types of donor units, the optical properties of pyrimidine-based luminescent molecules can be effectively regulated and improved. Luminescent materials based on pyrimidine rings have great development potential. The introduction of cyano (CN) with electron-withdrawing ability on the pyrimidine ring can obtain different CN-based acceptor units, as shown in the literature (Journal of materials chemistry C, 2017, 5(31): 7699-714). They can be used as OLED functional materials or TADF luminescent materials, as shown in the literature (Journal of materials chemistry C, 2014, 4(12): 2274-2278).

[0027] Beneficial effects:

[0028] (1) The present invention is the first to use α,β-unsaturated ketoxime ester compounds and malononitrile as substrates to prepare new 2,4,6-trisubstituted pyrimidine compounds. This method uses cheap ferric chloride as a catalyst and is simpler to operate and more environmentally friendly than previous synthetic routes.

[0029] (2) The microchannel reaction device used in the present invention can accelerate the reaction rate, shorten the reaction time, and realize the continuous synthesis of such compounds; and the reaction process is easy to control, which can effectively improve the safety of the reaction process and has great potential for later industrial applications.

[0030] (3) The 2,4,6-trisubstituted pyrimidine compound III prepared by the method of the present invention can be used as a standard. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] 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.

[0032] Figure 1 It is a schematic diagram of the process flow of the microchannel reaction device of the present invention;

[0033] Figure 2is the NMR image of the compound in Example 1 of the present invention;

[0034] Figure 3 is the NMR image of the compound in Example 2 of the present invention;

[0035] Figure 4 is the NMR image of the compound in Example 3 of the present invention;

[0036] Figure 5 is the NMR image of the compound of Example 4 of the present invention;

[0037] Figure 6 is the NMR image of the compound in Example 5 of the present invention;

[0038] Figure 7 is the NMR image of the compound of Example 6 of the present invention;

[0039] Figure 8 is the NMR image of the compound of Example 7 of the present invention;

[0040] Fig. 9 is the NMR image of the compound of Example 8 of the present invention;

[0041] Fig.10 is the NMR image of the compound in Example 9 of the present invention;

[0042] Fig.11 is the NMR image of the compound in Example 10 of the present invention;

[0043] Fig.12 is the NMR image of the compound in Example 11 of the present invention;

[0044] Fig.13 is the NMR image of the compound in Example 12 of the present invention;

[0045] Fig.14 is the NMR image of the compound in Example 13 of the present invention;

[0046] Fig.15 is the NMR image of the compound in Example 14 of the present invention;

[0047] Fig.16 is the NMR image of the compound in Example 15 of the present invention;

[0048] Fig.17 is the NMR image of the compound in Example 16 of the present invention;

[0049] Fig.18 is the NMR image of the compound in Example 17 of the present invention;

[0050] Fig.19 This is the NMR image of the compound of Example 18 of the present invention. DETAILED DESCRIPTION

[0051] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0052] Figure 1 The present invention is a schematic flow diagram of a microchannel reaction device, which includes a connecting pipeline, a feed pump a, a feed pump b, a micro mixer, a micro reactor and a receiver; wherein the feed pump a and the feed pump b are connected in parallel through a pipeline and then connected to the micro mixer; the micro mixer, the micro reactor and the receiver are sequentially connected in series through the pipeline.

[0053] Wherein, homogeneous solution A and homogeneous solution B prepared in proportion are added to feed pump a and feed pump b respectively.

[0054] The micromixer is a Y-shaped tube with an inner diameter of 6 mm and an outer diameter of 9 mm, and is made of polytetrafluoroethylene.

[0055] The pipe in the microreactor is a polytetrafluoroethylene tube; the inner diameter of the coil of the microreactor is 0.5 mm.

[0056] Among them, the feed pump is a syringe pump, model TYD01-01-CE.

[0057] The reaction temperature of the microreactor is controlled by an oil bath.

[0058] Among them, after the reaction is completed, the receiver collects the outflowing reaction liquid, and the outflowing reaction liquid is vacuum concentrated and then separated and purified by column chromatography to obtain the target product and the yield; the vacuum concentration is to remove the organic solvent by rotary evaporation, and the rotary evaporation temperature is 45°C; the column chromatography separation and purification is to use an eluent with a volume ratio of petroleum ether to ethyl acetate of 10:1 for column chromatography (unless otherwise specified, the column chromatography uses 200-300 mesh silica gel produced by Shandong Qingdao Kangyexin Pharmaceutical Silica Gel Desiccant Co., Ltd.).

[0059] Example 1

[0060] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0061] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) are pumped into the micro mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after mixing in a Y-type mixer, enter the microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor is 0.5 mm, and the volume of the polytetrafluoroethylene tube is 4 mL) to react at 110° C. for 4 minutes. After the reaction is completed, the organic phase is discharged from the microreactor, and vacuum concentration is performed to obtain a crude product, which is separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 90%.

[0062] The NMR image of product 1 is shown in Figure 2 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, Chloroform-d) δ7.99(dd,J=6.6,2.9Hz,2H),7.67(s,1H),7.52–7.44(m,3H),5.55(s,2H),4.48(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.6,160.7,160.6,142.2,137.3,130.8,129.0,127.5,116.1,111.0,87.9,62.9,14.2ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 14 N3O2[M+H] + 268.1081, found 268.1119.

[0063] Comparative Example 1

[0064] 0.2mmol (2E, 4E)-4-(acetoxyimino)-4-phenylbut-2-enoic acid ethyl ester (52mg), 0.02mmol ferric chloride (3mg) and 0.8mmol malononitrile (53mg) were dissolved in 2mL 1,4-dioxane and reacted in a reaction bottle at 110°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 10:1 to obtain the target product 1 with a yield of 76%.

[0065] Comparative Example 2: No catalyst involved in the reaction

[0066] (1) 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) was dissolved in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; 4 mmol of malononitrile (0.264 g) was dissolved in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0067] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were simultaneously pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.5 mL / min, respectively, and after being mixed in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, which was vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the yield of the target product 1 was 0%.

[0068] Comparative Example 3

[0069] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.1 mmol of zinc chloride (0.0136 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0070] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 46%.

[0071] Example 2

[0072] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(methylphenyl)-2-butenoate (0.275 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0073] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was obtained by discharging the microreactor, and vacuum concentration was performed to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 2, with a yield of 88%.

[0074] The NMR spectrum of product 2 is shown in Figure 3 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=8.2Hz,2H),7.66(s,1H),7.27(d,J=8.1H z,2H),5.50(s,2H),4.48(q,J=7.1Hz,2H),2.41(s,3H),1.46(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.6,160.6,160.5,142.0,141.2,134.4,129.7,127.4,116.2,110.6,87.4,62.8,29.8,21.5,14.1ppm; HRMS (ESI-TOF): m / zcalcd for C 16 H 16 N3O2[M+H] + 282.1237, found 282.1274.

[0075] Example 3

[0076] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(4-bromophenyl)but-2-enoate (0.340 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0077] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 3, with a yield of 83%.

[0078] The NMR spectrum of product 3 is shown in Figure 4 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.5Hz,2H),7.71(d,J=8.5Hz,2H),7.56(s,1H),7.23(s,2H),4.39(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, DMSO-d6) δ163.5,161.2,158.2,142.9,136.0,132.0,129.3,124.5,115.7,108.4,86.5,62.5,14.0ppm; HRMS (ESI-TOF): m / zcalcd for C 15 H 13 BrN3O2[M+H] + 346.0186, found 346.0228.

[0079] Example 4

[0080] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-([1,1'-biphenyl]-4-yl)-2-butenoate (0.337 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0081] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was obtained by discharging the microreactor, which was vacuum concentrated to obtain a crude product, and separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 4, with a yield of 78%.

[0082] The NMR spectrum of product 4 is shown in Figure 5 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.71(d,J=7.5Hz,2H),7.58(s,1H),7 .46(t,J=7.6Hz,2H),7.38(d,J=7.3Hz,1H),7.20(s,2H),4.37(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)ppm; 13 CNMR(100MHz,DMSO-d6)δ163.5,161.2,158.8,142.6,142.1,139.1,135.7,129.0,1 28.0,127.8,127.0,126.8,115.6,108.2,85.9,62.3,13.9ppm; HRMS(ESI-TOF):m / z calcd for C 21 H 18 N3O2[M+H] + 344.1394, found 344.1372.

[0083] Example 5

[0084] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(3-methoxyphenyl)but-2-enoate (0.291 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0085] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 5, with a yield of 87%.

[0086] The NMR spectrum of product 5 is shown in Figure 6 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.55(d,J=7.6Hz,2H),7.37(t,J=8.1Hz,1H),7. 05–6.96(m,1H),5.56(s,2H),4.47(q,J=7.1Hz,2H),3.87(s,3H),1.45(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ163.5,160.6,160.3,160.1,142.1,138.6,129.9,1 19.9,116.5,116.1,112.8,111.0,88.0,62.9,55.5,14.1ppm; HRMS(ESI-TOF):m / z calcd for C 16 H 16 N3O3[M+H] + 298.1186, found 298.1254.

[0087] Example 6

[0088] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(3-chlorophenyl)-2-butenoate (0.296 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0089] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, which was vacuum concentrated to obtain a crude product, and separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 6, with a yield of 84%.

[0090] The NMR spectrum of product 6 is shown in Figure 7 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.91–7.83(m,1H),7.65(s,1H),7. 48–7.35(m,2H),5.53(s,2H),4.49(q,J=7.1Hz,2H),1.47(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.4,160.6,158.9,142.4,138.9,135.2,130.7,130.2,127.7,125.5,115.9,110.9,88.6,63.0,14.2ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 13 ClN3O2[M+H] + 302.0691, found 302.0717.

[0091] Example 7

[0092] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(3-nitrophenyl)-2-butenoate (0.306 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0093] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 7, with a yield of 69%.

[0094] The NMR spectrum of product 7 is shown in Figure 8 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.89–8.82(m,1H),8.50(d,J=7.9Hz,1H),8.33(dd,J=8.1,1.9Hz,1H),7 .79(t,J=8.0Hz,1H),7.66(s,1H),7.36(s,2H),4.40(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H)ppm; 13 CNMR(100MHz,DMSO-d6)δ163.3,161.1,156.7,148.3,143.2,138.3,133.4,130.5,124.9,121.6,115.3,108.5,87.2,62.4,13.8ppm; HRMS(ESI-TOF):m / z calcd for C 15 H 13 N4O4[M+H] + 313.0931, found 313.0975.

[0095] Example 8

[0096] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(2-methoxyphenyl)but-2-enoate (0.291 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0097] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 8, with a yield of 87%.

[0098] The NMR spectrum of product 8 is shown in Fig. 9 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.74(dd,J=7.7,1.6Hz,1H),7.45–7.38(m,1H),7.06(t,J=7.5 Hz,1H),7.00(d,J=8.3Hz,1H),5.54(s,2H),4.46(q,J=7.1Hz,2H),3.88(s,3H),1.44(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ163.8,160.5,159.7,157.5,141.1,131.6,131.0,1 27.0,121.1,116.2,115.8,111.7,87.3,62.6,55.7,14.1ppm; HRMS(ESI-TOF):m / z calcd for C 16 H 16 N3O3[M+H] + 298.1186, found 298.1231.

[0099] Example 9

[0100] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(2-chlorophenyl)but-2-enoate (0.296 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0101] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, which was vacuum concentrated to obtain a crude product, and separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 9, with a yield of 72%.

[0102] The NMR spectrum of product 9 is shown in Fig.10 , the specific NMR number average and mass spectrum data are: 1 H NMR(400MHz,Chloroform-d)δ7.56(s,1H),7.54–7.50(m,1H),7.50–7.46(m,1H), 7.41–7.34(m,2H),5.62(s,2H),4.47(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.3,160.6,160.5,141.6,137.5,132.2,131.1,130.8,130.5,127.2,115.8,115.2,88.6,62.9,14.1ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 13 ClN3O2[M+H] + 302.0691, found 302.0738.

[0103] Example 10

[0104] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(naphthalen-2-yl)but-2-enoate (0.311 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0105] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro mixer of the microchannel reaction device at a flow volume ratio of 1:1, and the flow rate was 0.5 mL / min. After mixing in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 10, with a yield of 76%.

[0106] The NMR spectrum of product 10 is shown in Fig.11 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz, DMSO-d6)δ8.64(s,1H),8.18(dd,J=8.6,1.6Hz,1H),8.05–7.98(m,2H),7.95–7.91(m, 1H),7.69(s,1H),7.58–7.52(m,2H),7.23(s,2H),4.39(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)ppm; 13 C NMR(100MHz,DMSO-d6)δ163.6,161.2,159.2,142.7,134.2,133.8,132.8,128.9,128.4,1 27.6,127.5,127.2,126.7,124.2,115.7,108.6,85.9,62.3,13.9ppm; HRMS(ESI-TOF):m / z calcd for C 19 H 16 N3O2[M+H] + 318.1237, found 318.2985.

[0107] Embodiment 11

[0108] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-(thiophen-2-yl)but-2-enoate (0.267 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0109] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro mixer of the microchannel reaction device at a flow volume ratio of 1:1, and the flow rate was 0.5 mL / min. After mixing in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 11, with a yield of 75%.

[0110] The NMR spectrum of product 11 is shown in Fig.12 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz,Chloroform-d)δ7.72–7.66(m,1H),7.56(s,1H),7.52–7.46(m,1H),7.12 (dd,J=4.9,3.9Hz,1H),5.47(s,2H),4.48(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.4,160.5,155.4,142.9,141.9,130.5,128.6,127.8,116.1,109.5,87.1,62.9,14.2ppm; HRMS (ESI-TOF): m / z calcd for C 13 H 12 N3O2S[M+H] + 274.0645, found 274.2769.

[0111] Example 12

[0112] (1) Dissolve 1 mmol (1E,2E)-1,3-diphenylprop-2-en-1-one O-acetyl oxime (0.265 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0113] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 12, with a yield of 75%.

[0114] The NMR spectrum of product 12 is shown in Fig.13 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, Chloroform-d) δ8.00 (dd, J=7.3, 2.3Hz, 2H), 7.64 (dd, J=7.5, 2.0Hz, 2H), 7.55–7.46 (m, 6H), 7.21 (s, 1H), 5.39 (s, 2H) ppm; 13 C NMR (100MHz, Chloroform-d) δ160.4,160.0,155.3,138.1,137.1,130.3,129.9,129.1,128.9,128.3,127.5,117.3,111.3,88.4ppm; HRMS (ESI-TOF): m / z calcd for C 18 H 14 N3[M+H] + 272.1182, found 272.1229.

[0115] Example 13

[0116] (1) Dissolve 1 mmol (1E,2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one O-acetyl oxime (0.295 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0117] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 13, with a yield of 73%.

[0118] The NMR spectrum of product 13 is shown in Fig.14 , the specific NMR data and mass spectrometry data are: 1 H NMR(400MHz, DMSO-d6)δ8.08(d,J=8.8Hz,2H),7.66–7.60(m,2H),7.51(d,J= 6.0Hz,3H),7.18(s,1H),7.00(d,J=8.8Hz,2H),6.92(s,2H),3.78(s,3H)ppm; 13 C NMR (100MHz, DMSO-d6) δ161.0,160.8,158.3,154.7,137.2,129.9,129.5,128.9,128.7,128.3,117.3,114.0,108.5,85.7,55.3ppm; HRMS (ESI-TOF): m / z calcd for C 19 H 16 N3O[M+H] + 302.1288, found 302.1355.

[0119] Embodiment 14

[0120] (1) Dissolve 1 mmol (1E,2E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one O-acetyl oxime (0.300 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0121] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 14, with a yield of 75%.

[0122] The NMR spectrum of product 14 is shown in Fig.15 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, Chloroform-d) δ7.99 (dd, J=6.5, 3.1Hz, 2H), 7.57 (d, J=8.5Hz, 2H), 7.54–7.45 (m, 5H), 7.16 (s, 1H), 5.42 (s, 2H) ppm; 13 C NMR (100MHz, Chloroform-d) δ160.4,160.2,153.9,137.9,136.2,135.4,130.5,129.6,129.4,129.0,127.5,117.1,111.1,88.1ppm; HRMS (ESI-TOF): m / z calcd for C 18 H 13 ClN3[M+H] + 306.0793, found 306.0852.

[0123] Embodiment 15

[0124] (1) Dissolve 1 mmol (1E,2E)-1-phenyl-3-(m-tolyl)prop-2-en-1-one O-acetyl oxime (0.279 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0125] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, which was vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 15, with a yield of 62%.

[0126] The NMR spectrum of product 15 is shown in Fig.16 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.17–8.01(m,2H),7.49–7.35(m,6H),7.30(d,J=7.0Hz,1H),7.22(s,1H),6.97(s,2H),2.36(s,3H)ppm; 13 C NMR(100MHz,DMSO-d6)δ160.9,158.6,155.0,138.1,137.6,137.0,130.2,130.1,12 8.9,128.7,128.6,127.3,125.4,117.1,109.2,86.6,21.0ppm; HRMS(ESI-TOF):m / z calcd for C 19 H 16 N3[M+H] + 286.1339, found 286.1339.

[0127] Example 16

[0128] (1) Dissolve 1 mmol (1E,2E)-3-(2-methoxyphenyl)-1-phenylprop-2-en-1-one O-acetyl oxime (0.295 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0129] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 16, with a yield of 77%.

[0130] The NMR spectrum of product 16 is shown in Fig.17 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.04–8.00(m,2H),7.45–7.39(m,4H),7.28(dd,J=7.5,1.6H z,1H),7.12(d,J=13.2Hz,2H),7.03(t,J=7.4Hz,1H),6.86(s,2H),3.74(s,3H)ppm; 13 C NMR(100MHz,DMSO-d6)δ160.1,158.3,156.0,152.9,137.7,130.9,130.1,130.0,12 8.7,127.2,126.1,120.7,116.8,111.8,110.3,89.2,55.5ppm; HRMS(ESI-TOF):m / z calcd for C 19 H 16 N3O[M+H] + 302.1288, found 302.1354.

[0131] Embodiment 17

[0132] (1) Dissolve 1 mmol (1E,2E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one O-acetyl oxime (0.300 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0133] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 17, with a yield of 70%.

[0134] The NMR spectrum of product 17 is shown in Fig.18 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, DMSO-d6) δ8.01(dd,J=6.6,3.1Hz,2H),7.55(d,J=7.2Hz,1H),7.46–7.36(m,6H),7.11(s,1H),7.01(s,2H)ppm; 13 C NMR(100MHz,DMSO-d6)δ160.2,158.6,153.1,137.3,136.2,131.3,130.9,130.7 ,130.3,129.8,128.8,127.6,127.3,116.2,109.8,88.5ppm; HRMS(ESI-TOF):m / z calcd for C 18 H 13 ClN3[M+H] + 306.0793, found 306.0849.

[0135] Embodiment 18

[0136] (1) Dissolve 1 mmol (1E,2E)-3-phenyl-1-(thiophen-2-yl)prop-2-en-1-one O-acetyl oxime (0.271 g) and 0.05 mmol ferric chloride (0.0081 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol malononitrile (0.264 g) in 10 mL 1,4-dioxane to obtain a homogeneous solution B.

[0137] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were simultaneously pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.5 mL / min, respectively, and after being mixed in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 18, with a yield of 70%.

[0138] The NMR spectrum of product 18 is shown in Fig.19 , the specific NMR data and mass spectrometry data are: 1 H NMR (400MHz, Chloroform-d) δ7.66(d,J=3.5Hz,1H),7.64–7.59(m,2H),7.51–7.55(m,3H),7.48(d,J=5.0Hz,1H),7.16–7.08(m,2H),5.36(s,2H)ppm; 13 C NMR (100MHz, Chloroform-d) δ160.2,155.1,154.6,143.6,136.8,130.0,129.7,129.0,128.4,128.2,127.0,117.2,109.6,87.8ppm; HRMS (ESI-TOF): m / z calcd for C 16 H 12 N3S[M+H] + 278.0746, found 278.0806.

[0139] Embodiment 19

[0140] This example is the same as Example 1, except that the reaction temperature is replaced from 110°C to 130°C.

[0141] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0142] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 130° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, which was vacuum concentrated to obtain a crude product, and separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 82%.

[0143] Embodiment 20

[0144] This example is the same as Example 1, except that the solvent 1,4-dioxane is replaced by toluene.

[0145] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of toluene to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of toluene to obtain a homogeneous solution B.

[0146] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 0.5 mL / min, and after being mixed in a Y-type mixer, they were introduced into a microreactor (the inner diameter of the polytetrafluoroethylene tube of the microreactor was 0.5 mm, and the volume of the polytetrafluoroethylene tube was 4 mL) for reaction at 110° C. for 4 min. After the reaction was completed, the organic phase was obtained by discharging the microreactor, and vacuum concentration was performed to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 75%.

[0147] Embodiment 21

[0148] This example is the same as Example 1, except that the flow rate of the homogeneous solution A and the homogeneous solution B is changed from 0.5 mL / min to 1 mL / min.

[0149] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 4 mmol of malononitrile (0.264 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0150] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 1 mL / min, and after being mixed in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 86%.

[0151] Embodiment 22

[0152] This example is the same as Example 1, except that the flow rate of the homogeneous solution A and the homogeneous solution B is changed from 0.5 mL / min to 1 mL / min, and 4 mmol of malononitrile is changed to 2 mmol of malononitrile.

[0153] (1) Dissolve 1 mmol of ethyl (2E,4E)-4-(acetoxyimino)-4-phenylbut-2-enoate (0.261 g) and 0.05 mmol of ferric chloride (0.0081 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution A; dissolve 2 mmol of malononitrile (0.132 g) in 10 mL of 1,4-dioxane to obtain a homogeneous solution B.

[0154] (2) Then the homogeneous solution A and the homogeneous solution B obtained in step (1) were pumped into the micro-mixer of the microchannel reaction device at a flow volume ratio of 1:1, respectively, at a flow rate of 1 mL / min, and after being mixed in a Y-type mixer, they entered the microreactor (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 110° C. for 4 min. After the reaction was completed, the organic phase was discharged from the microreactor, and vacuum concentrated to obtain a crude product, which was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the target product 1, with a yield of 72%.

[0155] Table 1 2,4,6-trisubstituted pyrimidine compounds prepared in the examples of the present invention

[0156]

[0157]

[0158] The present invention provides a method and idea for synthesizing 2,4,6-trisubstituted 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 2,4,6-trisubstituted pyrimidine compounds using a microchannel reaction device, characterized in that: Using α,β-unsaturated ketoxime ester compound I and malononitrile as raw materials, adding a catalyst, and using a microchannel reaction device to prepare 2,4,6-trisubstituted pyrimidine compound III; Among them, R 1 , R 2 independently selected from unsubstituted or substituted phenyl, thienyl, naphthyl, C1-C5 alkyl, biphenyl or alkoxyacyl; The substitution is selected from substitution by halogen, C1-C5 alkyl or C1-C5 alkoxy; The catalyst is ferric chloride.

2. The method according to claim 1, characterized in that The R 1 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, biphenyl or thienyl, wherein R 2 It is ethoxycarbonyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-methylphenyl, 2-methoxyphenyl or 2-chlorophenyl.

3. The method according to claim 1, characterized in that The specific steps include: (1) dissolving an α,β-unsaturated ketoxime ester compound I and a catalyst in a solvent to obtain a homogeneous solution A; dissolving malononitrile in a solvent to obtain a homogeneous solution B; (2) The homogeneous solution A and the homogeneous solution B obtained in step (1) are pumped into a micromixer at the same time, mixed, and pumped into a microreactor for addition reaction. After the reaction is completed, the reaction effluent is collected and post-treated to obtain a 2,4,6-trisubstituted pyrimidine compound III.

4. The method according to claim 3, characterized in that: In step (1), the solvent is any one or a combination of 1,2-dichloroethane, γ-valerolactone, tetrahydrofuran, cyclohexane, acetonitrile, 1,4-dioxane, ethyl acetate, toluene and water.

5. The method according to claim 3, characterized in that: In step (1), the concentration of the α,β-unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05-0.1 mmol / mL; the concentration of the catalyst in the homogeneous solution A is 0.005-0.01 mmol / mL; and the concentration of malononitrile in the homogeneous solution B is 0.2-0.4 mmol / mL.

6. The method according to claim 3, characterized in that: In step (2), when the homogeneous solution A and the homogeneous solution B are pumped into the micromixer respectively and simultaneously, the molar ratio of the α,β-unsaturated ketoxime ester compound I, the catalyst, and malononitrile is 1:0.01-0.2:2-5.

7. The method according to claim 3, characterized in that In step (2), the addition reaction has a reaction temperature of 100 to 130° C. and a reaction residence time of 2 to 10 min; and the volume of the microreactor is 3 to 10 mL.

8. The method according to claim 1, characterized in that The microchannel reaction device comprises a connecting pipeline, a feed pump a, a feed pump b, a micro mixer, a micro reactor and a receiver; wherein the feed pump a and the feed pump b are connected in parallel through a pipeline and then connected to the micro mixer; the micro mixer, the micro reactor and the receiver are connected in series in sequence through the pipeline.

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