A method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device

Abstract

The invention discloses a method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device, comprising the following steps: (1) dissolving the α,β-unsaturated ketoxime ester shown in formula I in a solvent as a reaction solution A; (2) dissolving the 2-benzoylacetanilide shown in formula II and the polyformaldehyde shown in III and an alkaline additive in a solvent as a reaction solution B; (3) pumping the reaction solution A and the reaction solution B simultaneously into a microchannel reactor with a copper tube as a reaction pipeline for reaction; (4) collecting the effluent of the microchannel reactor to obtain 2,3-disubstituted pyrrole compounds as shown in formula IV. The invention provides a method for continuously preparing 2,3-disubstituted pyrrole compounds using a microchannel reaction device, the reaction involved in the method is a homogeneous system, no noble metal catalyst needs to be added, and there is good substrate adaptability, and there is great potential in late industrial applications.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of pyrrole compounds, and in particular relates to a method for synthesizing 2,3-disubstituted pyrrole compounds by utilizing a microchannel reaction device. Background Art

[0002] Pyrrole is a common structural unit in many natural products and drugs, and has a variety of biological activities such as antifungal, antiviral, lipid-lowering and anticancer. In addition, pyrrole also plays an important role in the synthesis of agrochemicals, dyes and functional materials. Therefore, the synthesis of functionalized pyrrole has always attracted the attention of organic synthesizers and pharmacists. At present, the main methods for preparing pyrrole derivatives are: (1) a one-pot four-component tandem cyclization reaction of α-ketoaldehyde, aniline, activated alkyne and aromatic nucleophile to synthesize pentasubstituted pyrrole, see reference (J.Org.Chem.2020,85,10,6697–6708); (2) using oxime and azadienes as raw materials, pyrrole derivatives are synthesized through [3+2] spiro-annulation and aromatization reactions (Org.Chem.Front.2021,8,3776–3782); (3) copper / amine co-catalyzed regioselective [3+2] cyclization reaction of α,β-unsaturated acetyl oxime with enal to synthesize pyrrole derivatives, see reference (Org.Chem.Front.2018,5,1698-1701). Although there are many routes for preparing polysubstituted pyrroles, the existing methods have problems such as the use of precious metal catalysts, cumbersome reaction steps, long reaction time and low efficiency. In addition, the synthesis methods of 2,3-disubstituted pyrrole compounds are rarely reported. Summary of the invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for synthesizing 2,3-disubstituted pyrrole compounds 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 achieve the efficient synthesis of 2,3-disubstituted pyrrole compounds simply and efficiently without using precious metal catalysts.

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

[0005] A method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device, using α,β-unsaturated ketoxime ester compound I, 2-benzoylacetanilide II and polyformaldehyde III as reaction raw materials, adding alkaline additives, and using a microchannel reaction device to prepare 2,3-disubstituted pyrrole compounds as shown in formula IV, the reaction formula is as follows:

[0006]

[0007] Among them, R 1 , R 2 Independently selected from unsubstituted or substituted phenyl, thienyl, naphthyl and ester groups; the value of n is 8-50; the microchannel reaction device adopts a copper tube microchannel reactor.

[0008] Preferably, the substituted phenyl group is selected from phenyl groups substituted by halogen, C1 alkyl or C1 alkoxy.

[0009] More preferably, the R 1 is phenyl, 4-methoxybenzene, 4-bromobenzene, 3-methoxybenzene, 3-bromobenzene, 2-methoxybenzene, thienyl or naphthyl; 2 It is 4-methoxybenzene, 4-chlorobenzene, thienyl, phenyl or ester.

[0010] Specifically, the method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device of the present invention comprises the following steps:

[0011] (1) dissolving an α,β-unsaturated ketoxime ester compound I in an organic solvent to prepare a homogeneous solution A; dissolving 2-benzoylacetanilide II, polyformaldehyde III and an alkaline additive in an organic solvent to prepare a homogeneous solution B;

[0012] (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 simultaneously, and after mixing, they are introduced into the copper tube microchannel reactor for reaction; the copper tube microchannel reactor can replace the catalytic effect of the transition metal catalyst in the reaction process.

[0013] (3) Collect the effluent from the microchannel reactor to obtain 2,3-disubstituted pyrrole compound IV.

[0014] In step (1), the organic solvent is any one or a combination of two or more of N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 1,4-dioxane, and ethyl acetate, preferably N,N-dimethylacetamide.

[0015] The alkaline additive is any one of triethylenediamine, triethylamine, tetramethylethylenediamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium bisulfite and potassium phosphate, or a combination of two or more thereof, preferably triethylenediamine; the alkaline additive plays a catalytic role during the reaction.

[0016] In step (1), the concentration of the α,β-unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05-0.2 mmol / mL, preferably 0.15 mol / L; the concentration of the 2-benzoylacetanilide II in the homogeneous solution B is 0.05-0.2 mmol / mL, preferably 0.1 mol / L; the concentration of the paraformaldehyde III in the homogeneous solution B is 0.1-0.4 mmol / mL, preferably 0.3 mol / L; the concentration of the alkaline additive in the homogeneous solution B is 0.01-0.1 mmol / mL, preferably 0.06 mol / L.

[0017] In step (2), the molar ratio of the α,β-unsaturated ketoxime ester compound I, 2-benzoylacetanilide II, paraformaldehyde III and the alkaline additive in the homogeneous solutions A and B pumped into the micromixer is (1-2):1:(1-5):(0.1-1), preferably 1.5:1:3:0.6.

[0018] In step (2), the volume ratio of homogeneous solution A to homogeneous solution B is (0.8-2):1, preferably 1:1. The pumping flow rates of homogeneous solution A and homogeneous solution B are 0.1-1.0 mL / min, preferably 0.2 mL / min.

[0019] In step (2), the reaction temperature in the copper tube microchannel reactor is 110-140° C., preferably 130° C.; the reaction residence time is 4-40 min, preferably 10 min;

[0020] The pipeline in the microchannel reactor is an activated copper tube; the reaction volume of the microchannel reactor is 2-6 mL, and the inner diameter of the pipeline of the reactor is 0.5-1.5 mm; most preferably, the reaction volume of the microchannel reactor is 4 mL, and the inner diameter of the pipeline of the reactor is 1 mm.

[0021] In step (3), vacuum concentration is used as rotary evaporation to remove the organic solvent, and the rotary evaporation temperature is 45° C.; separation and purification includes column chromatography using a developing solvent with a ratio of petroleum ether to ethyl acetate of 10:1.

[0022] Furthermore, the 2,3-disubstituted pyrrole compounds prepared by the above method are also within the protection scope of the present invention.

[0023] Microchannel reactor technology has gradually become a research hotspot in the field of international fine chemical technology. A microchannel reactor is a three-dimensional structural element that can be used for chemical reactions and is manufactured with a fixed matrix using special micromachining technology. Microchannel reactors usually contain very small channel sizes (equivalent diameter less than 500 μm) and channel diversity, and fluids flow, mix, and react in these channels. Therefore, this micro-structured chemical equipment has a very large specific surface area (surface area / volume). The resulting advantage is great mass transfer and heat transfer efficiency, which can achieve precise control of the reaction temperature and instantaneous mixing of the reaction materials in precise proportions. These are the keys to improving yield, selectivity, and product quality. In addition, the process in the microfluidic field reaction system is safer, energy-saving, and environmentally friendly.

[0024] Beneficial effects:

[0025] (1) The present invention is the first to continuously prepare 2,3-disubstituted pyrrole compounds using α,β-unsaturated ketoxime ester compounds as substrates. The method only requires adding alkaline additives to the reaction system and using a copper tube microchannel reactor.

[0026] (2) The system designed by the present invention contains no solid insoluble matter, which will not cause the problem of microfluidic field pipeline blockage. It is easy to operate, highly safe, has a fast apparent reaction rate and high product selectivity.

[0027] (3) The present invention does not require the use of expensive transition metal catalysts, which reduces the reaction cost and solves the environmental pollution problem caused by post-processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] 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.

[0029] Figure 1 The present invention is a schematic diagram of a process for synthesizing 2,3-disubstituted pyrrole compounds by using a microchannel reaction device.

[0030] Figure 2 is the NMR image of the compound in Example 1.

[0031] Figure 3 This is the NMR image of the compound in Example 2.

[0032] Figure 4 is the NMR image of the compound of Example 3.

[0033] Figure 5 This is the NMR image of the compound of Example 4.

[0034] Figure 6 This is the NMR image of the compound of Example 5.

[0035] Figure 7 This is the NMR image of the compound of Example 6.

[0036] Figure 8 This is the NMR image of the compound of Example 7.

[0037] Fig. 9 This is the NMR image of the compound of Example 8.

[0038] Fig.10 This is the NMR image of the compound of Example 9.

[0039] Fig.11 is the NMR image of the compound of Example 10.

[0040] Fig.12 is the NMR image of the compound of Example 11.

[0041] Fig.13 This is the NMR image of the compound of Example 12. DETAILED DESCRIPTION

[0042] The present invention can be better understood with reference to the following examples.

[0043] use Figure 1 The device diagram is as follows: (1) homogeneous solution A and homogeneous solution B prepared in proportion are added to injection pump a and injection pump b respectively; (2) the homogeneous solution A and B are injected into the micro-mixer of the microchannel reaction device in a certain proportion by the injection pump for mixing, and then the mixture is sent to the copper tube microchannel reactor for reaction; (3) the reaction temperature of the copper tube microchannel reactor is controlled by an oil bath; (4) the effluent reaction liquid is collected, quenched by adding water, and separated by column chromatography to obtain the target product and the yield (unless otherwise specified, the column chromatography uses 200-300 mesh silica gel produced by Shandong Qingdao Kangyexin Pharmaceutical Silica Gel Desiccant Co., Ltd.).

[0044] The pipes in the microchannel reactor are activated copper pipes. The activation method is as follows: first flush the pipes with 40 mL of dilute sulfuric acid solution. Then, flush the pipes with 20 mL of distilled water, and then draw 40 mL of trifluoroethanol to flush the pipes. Finally, purge and dry them under nitrogen atmosphere for 20 minutes.

[0045] Example 1-1

[0046] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained from the discharge of the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 90%. The NMR spectrum is shown in Figure 2 : 1 H NMR(400MHz,Chloroform-d)δ7.70–7.68(m,2H),7.42–7.37(m,3H),5.69–5.62(m,3H),4.09(q,J= 7.2Hz,2H),2.75(dd,J=15.9,2.7Hz,1H),2.50(dd,J=16.0,7.9Hz,1H),1.18(t,J=7.2Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.4,168.9,131.5,130.7,129.0,128.1,95.7,80.5,61.1,38.6,14.3ppm; HRMS (ESI-TOF): m / z calcd for C 14 H 16 NO2[M+H] + 230.1176, found 230.1186.

[0047] Comparative Example 1

[0048] 0.3mmol (0.0783g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester, 0.2mmol (0.0478g) 2-benzoylacetanilide, 0.04mmol (2.5mg) copper powder, 0.6mmol (0.018g) paraformaldehyde and 0.12mmol (0.0134g) triethylenediamine were dissolved in 2mL N,N-dimethylacetamide and reacted in a reaction bottle at 130°C for 10h. After the reaction, water (10mL) was added thereto, and then extracted with ethyl acetate (10mL×3), the organic layer was washed with saturated NaCl solution (10mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, and the yield was 55%.

[0049] Example 1-2

[0050] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL dimethyl sulfoxide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL dimethyl sulfoxide, 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 0.2mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 80%.

[0051] Examples 1-3

[0052] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL acetonitrile, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL toluene, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into the microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing solvent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 72%.

[0053] Examples 1-4

[0054] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0732g) 4-methylaminopyridine were dissolved in 10mL N,N-dimethylacetamide, 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 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 82%.

[0055] Examples 1-5

[0056] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0606g) triethylamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 78%.

[0057] Examples 1-6

[0058] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0732g) 4-methylaminopyridine were dissolved in 10mL N,N-dimethylacetamide, 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 0.4mL / min respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 5min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 80%.

[0059] Examples 1-7

[0060] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0732g) 4-methylaminopyridine were dissolved in 10mL N,N-dimethylacetamide, 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 0.1mL / min, respectively. After mixing in a Y-type mixer, they entered the microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 20min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 83%.

[0061] Examples 1-8

[0062] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.4mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 8mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing solvent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 85%.

[0063] Examples 1-9

[0064] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1.5mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 76%.

[0065] Examples 1-10

[0066] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 120°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing agent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 83%.

[0067] Embodiment 1-11

[0068] 1.5mmol (0.3915g) (2E, 4E)-4-(acetoxyimino)-4-phenyl-2-butenoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 0.2mL / min, respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 140°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL×3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a developing solvent of petroleum ether and ethyl acetate in a ratio of 10:1, and the target product was obtained as shown in Table 1, with a yield of 85%.

[0069] Example 2

[0070] 1.5mmol (0.4635g) of (2E, 4E)-4-(acetoxyimino)-4-(4-methoxyphenyl)but-2-enoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained from the discharge of the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing solvent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 93%. The NMR spectrum is shown in Figure 3 : 1H NMR(400MHz,Chloroform-d)δ7.71(d,J=8.9Hz,2H),6.94(d,J=8.9Hz,2H),5.72–5.64(m,3H),4.16(q, J=7.1Hz,2H),3.84(s,3H),2.79(dd,J=15.9,2.6Hz,1H),2.54(dd,J=15.9,8.1Hz,1H),1.24(s,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.4,168.1,162.0,129.7,123.1,114.3,95.3,80.3,61.0,55.4,38.6,14.1ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 18 NO3[M+H] + 260.1281, found 260.1292.

[0071] Example 3

[0072] 1.5mmol (0.5085g) of (2E, 4E)-4-(acetoxyimino)-4-(4-bromophenyl)but-2-enoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 80%. The NMR spectrum is shown in Figure 4 : 1H NMR(400MHz,Chloroform-d)δ7.62(q,J=8.6Hz,4H),5.75–5.62(m,3H),4.16(q,J=7.1Hz, 2H), 2.78 (dd, J=15.9, 3.0Hz, 1H), 2.57 (dd, J=16.0, 7.8Hz, 1H), 1.25 (t, J=7.1Hz, 3H) ppm; 13 C NMR(100MHz,Chloroform-d)δ170.2,168.1,132.3,129.5,126.1,95.6,80.5,61.2,38.4,14.2ppm; HRMS(ESI-TOF):m / z calcd for C 14 H 15 BrNO2[M+H] + 308.0281, found 308.0288.

[0073] Example 4

[0074] 1.5mmol (0.4635g) (2E, 4E)-4-(acetoxyimino)-4-(3-methoxyphenyl) but-2-enoic acid ethyl ester was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 80%. The NMR spectrum is shown in Figure 5 : 1H NMR(400MHz,Chloroform-d)δ7.36(d,J=15.9Hz,2H),7.24(s,1H),7.04(d,J=10.4Hz,1H),5.76–5.66(m,3H),4 .17(q,J=7.2Hz,2H),3.86(s,3H),2.83(dd,J=15.9,2.9Hz,1H),2.57(dd,J=15.9,8.0Hz,1H),1.25(s,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.4,169.0,160.1,132.0,130.0,120.5,117.9,112.7,95.6,80.7,61.1,55.6,38.6,14.3ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 18 NO3[M+H] + 260.1281, found 260.1291.

[0075] Example 5

[0076] 1.5mmol (0.5085g) of (2E, 4E)-4-(acetoxyimino)-4-(3-bromophenyl)but-2-enoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained from the discharge of the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing solvent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 76%. The NMR spectrum is shown in Figure 6 : 1H NMR (400MHz, Chloroform-d) δ7.94 (s, 1H), 7.66–7.61 (m, 2H), 7.33 (t, J = 7.9Hz, 1H), 5.77–5.61 (m, 3H), 4. 16(q,J=7.2Hz,2H),2.79(dd,J=15.9,3.2Hz,1H),2.57(dd,J=15.9,7.9Hz,1H),1.26(d,J=7.1Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.2,167.8,134.5,132.7,131.0,130.6,126.6,123.3,95.7,80.5,61.3,38.4,14.3ppm; HRMS (ESI-TOF): m / z calcd for C 14 H 15 BrNO2[M+H] + 308.0281, found 308.0293.

[0077] Example 6

[0078] 1.5mmol (0.4635g) of (2E, 4E)-4-(acetoxyimino)-4-(2-methoxyphenyl)but-2-enoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, and water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3). The organic layer was washed with a saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 75%. The NMR spectrum is shown in Figure 7 : 1H NMR(400MHz,Chloroform-d)δ7.87(dd,J=7.7,1.6Hz,1H),7.46–7.39(m,1H),7.02(t,J=7.3Hz,1H),6.93(d,J=8.4Hz,1H),5.7 4–5.89(m,3H),4.09(s,2H),3.85(s,3H),2.70(dd,J=16.4,3.6Hz,1H),2.44(dd,J=15.8,7.8Hz,1H),1.22(t,J=7.2Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.8,169.1,157.7,132.6,130.9,121.3,120.4,111.4,94.4,82.5,60.8,55.5,38.0,14.2ppm; HRMS (ESI-TOF): m / z calcd for C 15 H 18 NO3[M+H] + 260.1281, found 260.1291.

[0079] Example 7

[0080] 1.5mmol (0.4005g) of (2E, 4E)-4-(acetoxyimino)-4-(thiophene-2-yl)-2-butenoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 80%. The NMR spectrum is shown in Figure 8 : 1H NMR(400MHz,Chloroform-d)δ7.53(d,J=5.1Hz,1H),7.35(d,J=3.6Hz,1H),7.11(dd,J=5.0,3.8Hz,1H),5.67(d,J=3.8Hz,2H), 5.59–5.55(m,1H),4.18(q,J=7.1Hz,2H),2.91(dd,J=16.0,3.1Hz,1H),2.66(dd,J=16.0,8.4Hz,1H),1.26(t,J=7.2Hz,3H)ppm; 13 C NMR (100MHz, Chloroform-d) δ170.1,163.1,134.5,130.4,129.7,127.8,95.0,80.7,61.0,38.8,14.1ppm; HRMS (ESI-TOF): m / z calcd for C 14 H 14 NO2S[M+H] + 236.0740, found 236.0732.

[0081] Example 8

[0082] 1.5mmol (0.4665g) of (2E, 4E)-4-(acetoxyimino)-4-(2-naphthyl)but-2-enoic acid ethyl ester was dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) of 2-benzoylacetanilide, 3mmol (0.090g) of paraformaldehyde and 0.6mmol (0.0672g) of triethylenediamine were dissolved in 10mL of N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained from the discharge of the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 85%. The NMR spectrum is shown in Fig. 9 : 1H NMR(400MHz,Chloroform-d)δ8.10(s,1H),7.98(d,J=10.3Hz,1H),7.93–7.86(m,3H),7.59–7.53(m,3H),5.86–5.74(m ,3H),4.18(q,J=7.1,1.2Hz,2H),2.91(dd,J=16.0,3.0Hz,1H),2.64(dd,J=16.0,8.4Hz,1H),1.25(t,J=7.2Hz,3H)ppm; 13 C NMR(100MHz,Chloroform-d)δ170.5,168.9,134.7,132.9,129.0,128.9,128.6,128. 1,128.0,127.9,127.0,124.6,95.7,80.6,61.2,38.7,14.3ppm; HRMS(ESI-TOF):m / z calcd for C 18 H 18 NO2[M+H] + 280.1332, found 280.1342.

[0083] Example 9

[0084] 1.5mmol (0.3975g) (1E, 2E)-1,3-diphenylprop-2-en-1-one O-acetyl oxime was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 84%. The NMR spectrum is shown in Fig.10 : 1H NMR (400MHz, Chloroform-d) δ7.57–7.54(m,2H),7.44–7.43(m,8H),5.51(s,1H),5.42(d,J=2.5Hz,2H),5.38(s,1H),5.16(s,1H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.8,138.1,138.0,137.9,129.4,128.6,128.5,128.5,128.3,127.7,121.9,79.8,77.3ppm; HRMS (ESI-TOF): m / z calcd forC 17 H 16 N[M+H] + 234.1277, found 234.1289.

[0085] Example 10

[0086] 1.5mmol (0.4425g) (1E, 2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one O-acetoxime was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 86%. The NMR spectrum is shown in Fig.11 : 1 H NMR (400MHz, Chloroform-d) δ7.52 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 4.3 Hz, 5H), 6.93 (d, J = 8. 8Hz,2H),5.53(s,1H),5.40(d,J=2.6Hz,2H),5.36(s,1H),5.14(s,1H),3.84(s,3H)ppm; 13C NMR (100MHz, Chloroform-d) δ163.2,160.8,138.3,138.2,130.7,130.2,128.7,128.5,127.7,121.7,113.7,80.0,77.4,55.5ppm; HRMS (ESI-TOF): m / z calcd for C 18 H 18 NO[M+H] + 264.1383, found 264.1389.

[0087] Embodiment 11

[0088] 1.5mmol (0.4485g) (1E, 2E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one O-acetoxime was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm, and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing agent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 86%. The NMR spectrum is shown in Fig.12 : 1 H NMR (400MHz, Chloroform-d) δ7.55–7.52(m,2H),7.43–7.35(m,7H),5.51(s,1H),5.42(d,J=1.7Hz,2H),5.35(s,1H),5.12(s,1H)ppm; 13 C NMR (100MHz, Chloroform-d) δ164.2,138.5,138.3,137.1,134.9,130.1,129.6,129.4,129.1,128.9,122.6,80.5,77.2ppm; HRMS (ESI-TOF): m / z calcd forC 17 H 15ClN[M+H] + 268.0888, found 268.0893.

[0089] Example 12

[0090] 1.5mmol (0.4065g) (1E, 2E)-1-phenyl-3-(thiophen-2-yl) prop-2-en-1-one O-acetyl oxime was dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution A; 1mmol (0.2390g) 2-benzoylacetanilide, 3mmol (0.090g) paraformaldehyde and 0.6mmol (0.0672g) triethylenediamine were dissolved in 10mL N,N-dimethylacetamide, and the resulting mixed solution was recorded as solution B. Then, solution A and solution B were pumped into a microchannel reaction device at a flow volume ratio of 1:1, with flow rates of 0.2mL / min respectively. After mixing in a Y-type mixer, they entered a microchannel reactor (the inner diameter of the copper tube of the microreactor was 1mm and the volume of the copper tube was 4mL) and reacted at 130°C for 10min. The organic phase was obtained by discharging the microreactor, water (40 mL) was added thereto, and then extracted with ethyl acetate (40 mL × 3), the organic layer was washed with saturated NaCl solution (30 mL), dried by adding anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The target product was separated by column chromatography with a developing solvent ratio of petroleum ether to ethyl acetate of 10:1, as shown in Table 1, with a yield of 78%. The NMR spectrum is shown in Fig.13 : 1 H NMR(400MHz,Chloroform-d)δ7.56(dd,J=6.5,3.1Hz,2H),7.44–7.43(m,3H),7.36(dd,J=5.0,1.2Hz,1H),7. 08(d,J=3.5Hz,1H),7.03(d,J=8.6Hz,1H),5.72(s,1H),5.58(s,1H),5.43(d,J=12.6Hz,2H),5.37(s,1H)ppm; 13 C NMR (100MHz, Chloroform-d) δ163.1,141.3,138.1,136.6,129.6,128.6,128.4,126.9,126.6,126.5,122.0,78.4,73.1ppm; HRMS (ESI-TOF): m / z calcd forC 15 H 14 NS[M+H] + 240.0841, found 240.0832.

[0091] Table 1 Containing compounds of the present invention

[0092]

[0093]

[0094] The present invention provides a method for synthesizing 2,3-disubstituted pyrrole 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 2,3-disubstituted pyrrole compounds using a microchannel reaction device, characterized in that: by α, β -Unsaturated ketoxime ester compound I, 2-benzoylacetanilide II and polyformaldehyde III are used as reaction raw materials, and alkaline additives are added to prepare 2,3-disubstituted pyrrole compounds as shown in formula IV using a microchannel reaction device. The reaction formula is as follows: ； Among them, R 1 , R 2 Independently selected from unsubstituted or substituted phenyl, thienyl, naphthyl and ester groups; the value of n is 8-50; the microchannel reaction device adopts a copper tube microchannel reactor; The alkaline additive is any one or a combination of two or more of triethylenediamine, triethylamine, tetramethylethylenediamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium bisulfite and potassium phosphate; The specific steps are as follows: (1) α,β - unsaturated ketoxime ester compound I is dissolved in an organic solvent to prepare a homogeneous solution A; 2-benzoylacetanilide II, polyformaldehyde III and an alkaline additive are dissolved 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 copper tube microchannel reactor for reaction after mixing; (3) collecting the effluent from the microchannel reactor to obtain 2,3-disubstituted pyrrole compound IV; In step (2), the homogeneous solutions A and B are pumped into the micromixer. α,β - The molar ratio of the unsaturated ketoxime ester compound I, 2-benzoylacetanilide II, paraformaldehyde III and the alkaline additive is (1-2):1:(1-5):(0.1-1); In step (2), the reaction temperature in the copper tube microchannel reactor is 110-140 o C, reaction residence time is 4~40min; The substituted phenyl group is selected from phenyl groups substituted by halogen, C1 alkyl or C1 alkoxy.

2. The method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device according to claim 1, characterized in that: The R 1 is 4-methoxybenzene, 4-bromobenzene, 3-methoxybenzene, 3-bromobenzene, 2-methoxybenzene, thienyl or naphthyl; 2 It is 4-methoxybenzene, 4-chlorobenzene, thienyl, phenyl or ester.

3. The method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device according to claim 1, characterized in that: In step (1), the organic solvent is any one of N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dichloroethane, toluene, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 1,4-dioxane, and ethyl acetate, or a combination of two or more thereof.

4. The method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device according to claim 1, characterized in that: In step (1), the α,β -The concentration of the unsaturated ketoxime ester compound I in the homogeneous solution A is 0.05~0.2 mmol / mL; the concentration of the 2-benzoylacetanilide II in the homogeneous solution B is 0.05~0.2 mmol / mL, the concentration of the paraformaldehyde III in the homogeneous solution B is 0.1~0.4 mmol / mL, and the concentration of the alkaline additive in the homogeneous solution B is 0.01~0.1 mmol / mL.

5. The method for synthesizing 2,3-disubstituted pyrrole compounds using a microchannel reaction device according to claim 1, characterized in that: In step (2), the volume ratio of homogeneous solution A to homogeneous solution B is (0.8-2):1, and the pumping flow rates of homogeneous solution A and homogeneous solution B are 0.1-1.0 mL / min, respectively.

Images