Imidazopyridone compound as well as photocatalytic continuous synthesis method and application thereof

Abstract

The invention discloses a method for synthesizing imidazopyridone compounds by inducing bifunctionalization of phenylacetylene through a light continuous flow scheme and application of the imidazopyridone compounds. In the reaction, N-(benzothiophene-2-ylmethyl)-2-bromo-N-cyano-2-methylpropanamide halogen is used as an initiator, free radicals are formed under light irradiation, and then the free radicals and hydrocarbon substances are subjected to a series cyclization reaction. Compared with the prior art, the compound prepared by the invention is catalyzed by an organic photocatalyst, is green, efficient and free of metal residues, has a certain bacteriostatic effect and has an application prospect in the aspect of bacteriostasis.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical synthesis, specifically relating to a method for photoinduced organocatalytic bifunctional cyclization of alkynes and its application in preparing compounds. Background Technology

[0002] Nitrogen-containing heterocycles are a very common pharmacodynamic group in drug research and are one of the important targets for small molecule drug development today. In recent years, most of the top-selling branded drugs worldwide have nitrogen-containing heterocyclic skeletons. The antibacterial, antitumor, and other physiological activities of nitrogen-containing heterocyclic compounds, as well as their important significance in basic theoretical and applied research, have made the synthesis of these compounds and the study of their chemical and biological properties a hot topic in organic chemistry and related fields. Therefore, developing a new method for the efficient synthesis of imidazopyridone compounds is of great significance. It can not only provide important synthetic intermediates for imidazopyridone derivatives, but the synthesized imidazopyridone compounds themselves can also be used for physiological activity screening.

[0003] Imidazolidine compounds are a class of nitrogen-containing fused heterocyclic compounds with wide applications in the pharmaceutical, pesticide, and dye industries. Common imidazopyridine compounds include imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-c]pyridine, and imidazo[4,5-b]pyridine, with imidazo[1,2-a]pyridine and its derivatives being the most numerous and widely used. Several marketed drugs contain imidazo[1,2-a]pyridine scaffolds, such as the clinical anti-ulcer drug soraprazine, the anxiolytic alpidem, the sedative zolpidem, and the PDE inhibitor olprinone. Imidazol[1,2-a]pyridine compounds also exhibit a variety of biological activities and can be used as insecticides, fungicides, anti-inflammatory analgesics, and antipyretics. Imidazolidine compounds have attracted widespread interest due to their specific physiological activities and structural similarities to indole, nitrogen-containing indole, and other compounds. The benzothiochrome skeleton is a very valuable and advantageous structure. The non-selective β-receptor blocker Tertatalolol and the anti-inflammatory drug Tazarotene both contain benzothiochrome groups, and their derivatives have development potential in the treatment of various diseases such as cancer, inflammation, and infection.

[0004]

[0005] This patent develops a visible-light catalytic functionalization method for imidazolium [1,2-a]pyridinones via a continuous-flow photocatalytic sequence involving alkyne / nitrile insertion / cyclization. This method is simple, efficient, and operates under mild reaction conditions with high atom economy, requiring no metals or additives. Furthermore, compared to traditional photochemical reactions, continuous-flow photochemical microreactors offer advantages such as shorter reaction times and higher yields, demonstrating significant advantages and promising applications in practical production and industrial scale-up. The imidazopyridinone compounds prepared in this invention also exhibit antibacterial activity, showing potential for antibacterial applications. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a green and efficient reaction route for the synthesis of imidazopyridone compounds by photo-induced bifunctionalization of phenylacetylene under visible light conditions, which solves the problems of low reaction efficiency and large metal residue in the prior art.

[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0008] A green and efficient reaction route for the synthesis of imidazopyridone compounds via photo-induced bifunctionalization of phenylacetylene under visible light conditions is characterized by comprising the following steps:

[0009]

[0010] Wherein, R1 is selected from any one of -H, -CH3, -F, -Cl, -Br, -I, -OCH3, -NO2;

[0011] R2 is selected from any one of -H, -CH3, -F, -Cl, -Br, -I, -OCH3, -NO2, -OH, -NH3, -Ph;

[0012] (1) Mix substrate A, substrate B, organic photocatalyst and solvent evenly to obtain a homogeneous solution; (2) Place the homogeneous solution obtained in step (1) into a reactor under blue light irradiation; (3) Collect and purify the organic matter in step (2), i.e. the target product.

[0013] In some embodiments, in step (1), the substrate A is N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide, 2-bromo-N-cyano-2-methyl-N-(3-methylbenzothiophene-2-methylene)propionamide, or 2-bromo-N-cyano-2. Methyl-N-(4-methylbenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(5-methylbenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(6-methylbenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(7-methylbenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(5-fluorobenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(5-chlorobenzothiophene-2-methylene)propamide, 2-bromo-N-cyano-2-methyl-N-(5-chlorobenzothiophene-2-methylene)propamide, 2-bromo-N-cyano- 2-Bromo-N-Cyano-2-Methyl-N-(5-bromobenzothiophene-2-methylene)propamide, 2-Bromo-N-Cyano-2-Methyl-N-(5-iodobenzothiophene-2-methylene)propamide, 2-Bromo-N-Cyano-2-Methyl-N-(5-methoxybenzothiophene-2-methylene)propamide, 2-Bromo-N-Cyano-2-Methyl-N-(5-trifluoromethylbenzothiophene-2-methylene)propamide, 2-Bromo-N-Cyano-2-Methyl-N-(5-nitrobenzothiophene-2-methylene)propamide, 2-Bromo-N-Cyano-2-Methyl-N-(5-phenylbenzothiophene-2-methylene)propamide.

[0014] In some embodiments, in step (1), the substrate B is phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorophenylacetylene, 2-chlorophenylacetylene, 3-chlorophenylacetylene, 4-chlorophenylacetylene, 2-bromophenylacetylene, 3-bromophenylacetylene, 4-bromophenylacetylene, 2-methoxyphenylacetylene, 3-methoxyphenylacetylene, 4-methoxyphenylacetylene, 2-methylphenylacetylene, 3-methylphenylacetylene, 4-methylphenylacetylene, or β-bromophenylacetylene.

[0015] In some embodiments, in step (1), the organic catalyst is selected from one or more of 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine, 5,10-bis(4-(methoxy)phenyl)-5,10-dihydrophenazine, 5,10-diphenyl-5,10-dihydrophenazine, 5,10-bis(2-naphthyl)-5,10-dihydrophenazine or 5,10-bis(1-naphthyl)-5,10-dihydrophenazine, 3,7-bis(4-(1,1′-biphenyl))-(10-(1-naphthyl))-10-phenoxazine, and 5,10-bis(4-(cyano)phenyl)-5,10-dihydrophenazine.

[0016] In some embodiments, preferably, in step (1), the substrate A is 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine.

[0017] In some embodiments, in step (1), the solvent is selected from one or more of dichloroethane, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, acetonitrile, benzene, N,N-dimethylformamide, or N,N-dimethylaniline.

[0018] In some embodiments, preferably, in step (1), the solvent is 1,4-dioxane.

[0019] In some embodiments, in step (1), the concentration of substrate A in the homogeneous solution is 0.01 to 0.5 mmol / mL.

[0020] In some embodiments, preferably, in step (1), the concentration of substrate A in the homogeneous solution is 0.05 mmol / mL.

[0021] In some embodiments, in step (1), the concentration of substrate B in the homogeneous solution is 0.03 to 0.3 mmol / mL.

[0022] In some embodiments, preferably, in step (1), the concentration of substrate B in the homogeneous solution is 0.15 mmol / mL.

[0023] In some embodiments, in step (1), the concentration of the organic photocatalyst in the homogeneous solution is 0.001 to 0.1 mmol / mL.

[0024] In some embodiments, preferably, in step (1), the concentration of the organic photocatalyst in the homogeneous solution is 0.008 mmol / mL.

[0025] In some embodiments, in step (2), the concentration ratio of substrate A, substrate B, and organic photocatalyst in the homogeneous solution is 1:3:0.1.

[0026] In some embodiments, in step (2), the flow rate of the homogeneous solution in the microreactor is 0.04 to 0.16 mL / min.

[0027] In some embodiments, preferably, in step (2), the flow rate of the homogeneous solution in the microreactor is 0.1 mL / min.

[0028] In some embodiments, in step (2), the residence time in the reaction device is 10-40 min, the blue light wavelength is 420 nm to 430 nm, and the blue light power is 30 W.

[0029] In some embodiments, preferably, in step (2), the residence time in the reaction apparatus is 30 min.

[0030] In some embodiments, the reaction temperature in step (2) is room temperature.

[0031] In another aspect, this invention provides novel antibacterial compounds, their derivatives, their stereoisomers, racemic or non-racemic mixtures of their stereoisomers, or pharmaceutically acceptable salts or solvates thereof for the treatment or prevention of fungal infections, and for inducing programmed cell death. Experiments have demonstrated that the imidazopyridone compounds prepared using the above method exhibit antibacterial activity against certain bacteria.

[0032] According to some embodiments of the present invention, the fungi include Staphylococcus aureus and Escherichia coli.

[0033] The reaction formula of this invention is as follows:

[0034]

[0035] Wherein, R1 is selected from any one of -H, -CH3, -F, -Cl, -Br, -I, -OCH3, -NO2;

[0036] R2 is selected from any one of -H, -CH3, -F, -Cl, -Br, -I, -OCH3, -NO2, -OH, -NH3, -Ph;

[0037] Beneficial effects:

[0038] This invention uses N-(benzothiophene-2-ylmethyl)-2-bromo-N-cyano-2-methylpropionamide halogens as initiators to form free radicals under light irradiation, which then undergo cyclization reactions with alkynes. Compared with existing technologies, this invention's method is simple and efficient, with mild reaction conditions, high atom economy, no need for metals or additives, no metal residues in the product, short reaction time, no need for heating, and high yield. It also provides a class of promising antibacterial candidate compounds. Furthermore, continuous flow photochemical microreactors, compared with traditional photochemical reactions, have advantages such as short reaction time and high yield, offering significant advantages and promising application prospects in practical production and industrial scale-up. Attached Figure Description

[0039] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0040] Figure 1The image shows the 1H NMR spectrum of compound 6,6-dimethyl-8-phenyl-2-(3-phenyl-4H-thiochromene-4-yl)imidazo[1,2-a]pyridine-5(6H)-one (3a) in the embodiments of the present invention.

[0041] Figure 2 The image shows the 13C NMR spectrum of compound 6,6-dimethyl-8-phenyl-2-(3-phenyl-4H-thiochromene-4-yl)imidazo[1,2-a]pyridine-5(6H)-one (3a) in the embodiments of the present invention.

[0042] Figure 3 The 1H NMR spectrum of compound 6,6-dimethyl-8-(p-tolyl)-2-[3-(p-tolyl)-4H-thiochrome-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3b) in the embodiments of the present invention is shown.

[0043] Figure 4 The 13C NMR spectrum of compound 6,6-dimethyl-8-(p-tolyl)-2-[3-(p-tolyl)-4H-thiochrome-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3b) in the embodiments of the present invention is shown.

[0044] Figure 5 The image shows the 1H NMR spectrum of compound 6,6-dimethyl-8-(p-fluoro)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3c) in the embodiments of the present invention.

[0045] Figure 6 The 13C NMR spectrum of compound 6,6-dimethyl-8-(p-fluoro)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3c) in the embodiments of the present invention is shown.

[0046] Figure 7 The 19F NMR spectrum of compound 6,6-dimethyl-8-(p-fluoro)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3c) in the embodiments of the present invention is shown.

[0047] Figure 8 The image shows the 1H NMR spectrum of compound 6,6-dimethyl-8-(p-chloro)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridinone (3d) in the embodiments of the present invention.

[0048] Figure 9The 13C NMR spectrum of compound 6,6-dimethyl-8-(p-chloro)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3d) in the embodiments of the present invention is shown.

[0049] Figure 10 The image shows the 1H NMR spectrum of compound 6,6-dimethyl-8-(p-bromo)-2-[3-(p-tolyl)-4H-thiochromene-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3e) from the embodiments of the present invention.

[0050] Figure 11 The image shows the 13C NMR spectrum of compound 6,6-dimethyl-8-(p-bromo)-2-[3-(p-tolyl)-4H-thiochromen-4-yl]-5(6H)-imidazo[1,2-a]pyridinone (3e) in the embodiments of the present invention.

[0051] Figure 12 The 13C NMR spectrum of compound 6,6-dimethyl-8-(p-methoxy)-2-[3-(p-tolyl)-4H-thiochrome-4-yl]-5(H)-imidazo[1,2-a]pyridone (3e) in the embodiments of the present invention is shown.

[0052] Figure 13 The image shows the 13C NMR spectrum of compound 6,6-dimethyl-8-(p-methoxy)-2-[3-(p-tolyl)-4H-thiochrome-4-yl]-5(6H)-imidazo[1,2-a]pyridone (3e) in the embodiments of the present invention.

[0053] Figure 14 This is a schematic diagram of the microchannel reaction device used in an embodiment of the present invention. Detailed Implementation Plan

[0054] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0055] 1. A schematic diagram of the microchannel reaction device used in the embodiments of the present invention is shown below. Figure 13 As shown, the microchannel reactor includes a connecting pipe, a feed pump, a microreactor (quartz coil), an LED light source, and a receiver; wherein, the feed pump is connected to the feed inlet of the microreactor through the connecting pipe; the discharge outlet of the microreactor is connected to the receiver through the connecting pipe; wherein, the microchannel reactor is a quartz coil; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reactor.

[0056] The diameter of the connecting pipe is 3mm.

[0057] The feed pump mentioned is model number Ref TYD01.

[0058] The flow tube diameter of the microreactor is 1 mm.

[0059] 2. The 2-bromo-N-cyano-2-methylpropionamide compounds 1, phenylacetylene compounds (2a-2e), and imidazopyridone compounds (3a-3e) shown in Compound 1 used in the embodiments of the present invention are shown in Tables 1, 2, and 3, respectively.

[0060] Table 1 Reactants: 2-bromo-N-cyano-2-methylpropionamide compounds

[0061]

[0062] Table 2: Phenylacetylene compounds

[0063]

[0064] Table 3: Imidazolidinediones

[0065]

[0066] Example 1: Synthesis of compound 3a

[0067] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (14.1 mg, 0.03 mmol, 0.1 equivalent), phenylacetylene (98.7 μL, 0.9 mmol, 3.0 equivalent), N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide (101.4 mg, 0.3 mmol, 1.0 equivalent) and Et3N (45.9 μL, 0.33 mmol, 1.1 equivalent) were dissolved in 1,4-dioxane (6 mL) to obtain a homogeneous solution. The homogeneous solution was pumped into a microchannel reactor at a flow rate of 0.1 mL / min. The microchannel reactor was irradiated with a blue light lamp (30 W, 220 V, LED, wavelength 420 nm-430 nm) for 30 min, and the eluent was collected in a sample flask. The filtrate was concentrated under reduced pressure, and the residue was separated chromatographically on silica gel using a 5:1 eluent of petroleum ether and ethyl acetate to obtain the desired product 3a. The conversion rate was 88%, and Ms = 461.1683 g / mol.

[0068] The 1H NMR spectrum of compound 3a is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1HNMR (400MHz, DMSO-d6) 67.81-7.68 (m, 4H), 7.57 (dd, J=6.8, 2.1Hz, 1H), 7.44-7.36 (m, 6H), 7 .33-7.26(m, 3H), 7.22(s, 1H), 7.07(s, 1H), 6.49(s, 1H), 5.46(s, 1H), 1.38(d, J=5.3Hz, 6H). 13 C NMR (101MHz, DMSO-d6) δ173.42, 146.56, 144.32, 139.73, 139.70, 135.13, 134.02, 133.64, 130.85, 130.64, 128.96, 128.80 , 128.70, 128.51, 127.81, 127.53, 127.38, 126.43, 126.35, 125.43, 118.58, 109.66, 43.86, 43.40, 26.34, 26.15.HRMS (ESI) calcd forC30H24N2OS[M+H]: 461.1682; found: 461.1685.

[0069] Example 2: Reacting by changing the concentration of compound 1

[0070] The preparation method was the same as in Example 1, except that the concentration of compound 1 was replaced with 0.01 mmol / mL, and product 3a was finally prepared with a yield of 62%.

[0071] Example 3: Reacting by changing the concentration of compound 1

[0072] The preparation method was the same as in Example 1, except that the concentration of compound 1 was replaced with 0.02 mmol / mL, and product 3a was finally prepared with a yield of 71%.

[0073] Example 4: Reacting by changing the concentration of compound 1

[0074] The preparation method was the same as in Example 1, except that the concentration of compound 1 was replaced with 0.04 mmol / mL, and product 3a was finally prepared with a yield of 84%.

[0075] Example 5: Reacting by changing the concentration of compound 1

[0076] The preparation method was the same as in Example 1, except that the concentration of compound 1 was replaced with 0.08 mmol / mL, and product 3a was finally prepared with a yield of 79%.

[0077] Example 6: Reacting by changing the concentration of compound 2a

[0078] The preparation method was the same as in Example 1, except that the concentration of compound 2a was replaced with 0.03 mmol / mL, and product 3a was finally prepared with a yield of 58%.

[0079] Example 7: Reacting by changing the concentration of compound 2a

[0080] The preparation method was the same as in Example 1, except that the concentration of compound 2a was replaced with 0.06 mmol / mL, and product 3a was finally prepared with a yield of 64%.

[0081] Example 8: Reacting by changing the concentration of compound 2a

[0082] The preparation method was the same as in Example 1, except that the concentration of compound 2a was replaced with 0.09 mmol / mL, and product 3a was finally prepared with a yield of 75%.

[0083] Example 9: Reacting by changing the concentration of compound 2a

[0084] The preparation method was the same as in Example 1, except that the concentration of compound 2a was replaced with 0.12 mmol / mL, and product 3a was finally prepared with a yield of 82%.

[0085] Example 10: Reactions were carried out by changing the concentration of compound 2a.

[0086] The preparation method was the same as in Example 1, except that the concentration of compound 2a was replaced with 0.18 mmol / mL, and product 3a was finally prepared with a yield of 77%.

[0087] Example 11: Reacting by changing the concentration of the catalyst

[0088] The preparation method was the same as in Example 1, except that the catalyst concentration was replaced with 0.001 mmol / mL, and product 3a was finally obtained with a yield of 68%.

[0089] Example 12: Reaction with varying catalyst concentration

[0090] The preparation method was the same as in Example 1, except that the catalyst concentration was replaced with 0.002 mmol / mL, and product 3a was finally obtained with a yield of 70%.

[0091] Example 13: Reaction with varying catalyst concentration

[0092] The preparation method was the same as in Example 1, except that the catalyst concentration was replaced with 0.004 mmol / mL, and product 3a was finally obtained with a yield of 79%.

[0093] Example 14: Reaction with varying catalyst concentration

[0094] The preparation method was the same as in Example 1, except that the catalyst concentration was replaced with 0.01 mmol / mL, and product 3a was finally obtained with a yield of 86%.

[0095] Example 15: Reaction by changing the flow rate of the syringe pump

[0096] The preparation method was the same as in Example 1, except that the flow rate of the syringe pump was replaced with 0.04 mmol / mL, and the final product 3a was obtained with a yield of 49%.

[0097] Example 16: Reaction by changing the flow rate of the syringe pump

[0098] The preparation method was the same as in Example 1, except that the flow rate of the syringe pump was replaced with 0.08 mmol / mL, and the final product 3a was obtained with a yield of 70%.

[0099] Example 17: Reaction by changing the flow rate of the syringe pump

[0100] The preparation method was the same as in Example 1, except that the flow rate of the syringe pump was replaced with 0.12 mmol / mL, and the final product 3a was obtained with a yield of 87%.

[0101] Example 18: Reaction by changing the flow rate of the syringe pump

[0102] The preparation method was the same as in Example 1, except that the flow rate of the syringe pump was replaced with 0.16 mmol / mL, and the final product 3a was obtained with a yield of 72%.

[0103] Example 18: Reacting by changing the wavelength of the blue light lamp

[0104] The preparation method is the same as in Example 1, except that the wavelength of the blue light lamp is replaced with 395nm-405nm, and the final product 3a is obtained with a yield of 55%.

[0105] Example 18: Reacting by changing the wavelength of the blue light lamp

[0106] The preparation method is the same as in Example 1, except that the wavelength of the blue light lamp is replaced with 450nm-460nm, and the final product 3a is obtained with a yield of 72%.

[0107] Example 19: Reacting by changing the retention time

[0108] The preparation method was the same as in Example 1, except that the retention time was changed from 30 min to 10 min, and the final product 3a was obtained with a conversion rate of 41%.

[0109] Example 20: Reacting by changing the retention time

[0110] The preparation method was the same as in Example 1, except that the retention time was changed from 30 min to 20 min, and the final product 3a was obtained with a conversion rate of 79%.

[0111] Example 21: Reacting by changing the retention time

[0112] The preparation method was the same as in Example 1, except that the retention time was changed from 30 min to 40 min, and the final product 3a was obtained with a conversion rate of 84%.

[0113] Example 22: Reaction was carried out in a microchannel with a diameter of 1.5 mm.

[0114] The preparation method is the same as in Example 1, except that the 1 mm quartz coil is replaced with a 1.5 mm quartz coil, and the final product 3a is obtained with a conversion rate of 79%.

[0115] Example 23: Synthesis of compound 3b

[0116] The preparation method was the same as in Example 1, except that compound 2a was replaced with p-methylphenylacetylene (2b), and the final product 3b was obtained with a conversion rate of 85% and Ms = 489.1995 g / mol.

[0117] The 1H NMR spectrum of compound 3b is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1 HNMR (400MHz, DMSO-d6) δ7.66 (d, J=8.1Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.40 (dd, J=7.3, 1.8Hz, 1H), 7.28 (td, J=6.6, 1 .8Hz, 2H), 7.25-7.15(m, 6H), 7.08(s, 1H), 6.44(s, 1H), 5.42(s, 1H), 2.36(s, 3H), 2.31(s, 3H), 1.36(d, J=5.1Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ173.47, 146.64, 144.33, 138.96, 138.06, 137.17, 136.91, 134.06, 133.48, 132.24, 130.86, 130.66, 129.56, 1 29.08, 128.64, 127.47, 127.30, 126.32, 126.23, 125.23, 117.41, 109.57, 43.86, 43.32, 26.35, 26.20, 21.26, 21.14.HRMS(ESI)calcd for C32H28N2OS[M+H]: 489.1995; found: 489.1992.

[0118] Example 24: Synthesis of compound 3c

[0119] The preparation method was the same as in Example 1, except that compound 2a was replaced with p-fluorophenylacetylene (2c), and the final product 3c was obtained with a conversion rate of 78% and Ms = 497.1496 g / mol.

[0120] The 1H NMR spectrum of compound 3c is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1 HNMR (400MHz, DMSO-d6) δ7.81 (dd, J=8.7, 5.7Hz, 2H), 7.76 (dd, J=8.8, 5.5Hz, 2H), 7.58-7.53 (m, 1H), 7.43 (dd, J =7.3, 1.9Hz, 1H), 7.32-7.20 (m, 6H), 7.18 (s, 1H), 7.03 (s, 1H), 6.51 (s, 1H), 5.44 (s, 1H), 1.38 (d, J = 5.3Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ173.36, 158.20 (d, J=627.5Hz), 157.76 (d, J=623.6Hz), 146.51, 144.23, 139.70, 136.35, 133.84, 132.60, 130.82 (d, J=8.0Hz), 130.62, 128.53 (d, J=7.9H z), 127.59, 127.42, 126.34, 124.33, 118.58, 115.82, 115.61, 115.46, 115.25, 109.74, 43 .86, 43.45, 26.32, 26.12.19FNMR(376MHz, DMSO-d6)δ-113.71, -115.08.HRMS(ESI)calcd for C30H22N2OSF2[M+H]: 497.1494; found: 497.1497.

[0121] Example 25: Synthesis of compound 3d

[0122] The preparation method was the same as in Example 1, except that compound 2a was replaced with p-chlorophenylacetylene (2d), and the final product 3d was obtained with a conversion rate of 69% and Ms = 529.0837 g / mol.

[0123] The 1H NMR spectrum of compound 3d is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1 HNMR (400MHz, Chloroform-d) δ7.60-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.39 (dd, J=6.9, 2.0Hz, 1H), 7.34-7. 28 (m, 3H), 7.26-7.19 (m, 4H), 7.11 (s, 1H), 6.84 (s, 1H), 6.09 (s, 1H), 5.25 (s, 1H), 1.37 (d, J=11.8Hz, 6H). 13C NMR (101MHz, Chloroform-d) δ171.77, 145.12, 142.88, 137.43, 137.15, 133.53, 132.48, 132.30, 132.19, 131.95, 129.56, 129.03 ,128.83,127.57,127.41,126.58,126.07,126.00,125.17,124.86,117.58,109.46,43.78,42.33,25.53,25.40.HRMS(ESI)calcd for C30H22N2OSCl2[M+H]: 529.0903; found: 529.0908.

[0124] Example 26: Synthesis of compound 3e

[0125] The preparation method was the same as in Example 1, except that compound 2a was replaced with p-bromophenylacetylene (2e), and the final product 3e was obtained with a conversion rate of 53% and Ms = 616.9895 g / mol.

[0126] The 1H NMR spectrum of compound 3e is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1 HNMR (400MHz, Chloroform-d) δ7.53-7.36 (m, 9H), 7.30 (dd, J=7.4, 1.7Hz, 1H), 7.21 (dd, J=7.0, 5.3Hz, 1H), 7.17 (dd , J=7.3, 1.7Hz, 1H), 7.11 (d, J=1.1Hz, 1H), 6.85 (d, J=1.1Hz, 1H), 6.09 (s, 1H), 5.24 (s, 1H), 1.37 (d, J=11.9Hz, 6H). 13 C NMR (101MHz, Chloroform-d) δ171.75, 142.91, 137.86, 137.18, 132.65, 132.45, 132.36, 131.94, 130.54, 130.38, 129.50, 129.13, 129.04, 126.86, 126.08, 126.02, 125.17, 124.92, 121.76, 120.46, 117.66, 109.45, 43.69, 42.34, 25.50, 25.38.HRMS(ESI))calcd for C30H22N2OSBr2[M+H]: 616.9892; found: 616.9895.

[0127] Example 27: Synthesis of compound 3f

[0128] The preparation method was the same as in Example 1, except that compound 2a was replaced with p-methoxyphenylacetylene (2f), and the final product 3f was obtained with a conversion rate of 64% and Ms = 521.1898 g / mol.

[0129] The 1H NMR spectrum of compound 3e is shown below. Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 The specific NMR data are as shown: 1 HNMR (400MHz, DMSO-d6) δ7.73 (d, J=8.8Hz, 2H), 7.66-7.62 (m, 2H), 7.57-7.53 (m, 1H), 7.41 (dd, J=7.4, 1.8Hz, 2H), 7.34-7.23 (m, 3H ), 7.06 (d, J=13.6Hz, 2H), 6.96 (dd, J=11.8, 8.8Hz, 4H), 6.41 (s, 1H), 5.41 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 1.36 (d, J=5.6Hz, 6H). 13 CNMR (101MHz, DMSO-d6) δ173.52, 159.76, 159.22, 146.76, 144.36, 138.18, 134.01, 133.30, 132.36, 130.96, 130.63, 130.00, 127.6 6, 127.45, 127.40, 127.26, 126.31, 124.80, 116.13, 114.36, 113.90, 109.51, 55.66, 44.00, 43.30, 26.43, 26.26.HRMS(ESI))calcd forC32H28N2O3S[M+H]: 521.1893; found: 521.1891.

[0130] Antibacterial test:

[0131] This invention tested novel antibacterial compounds, compounds 3a to 3f, as shown in Table 3. Their in vitro inhibitory activity against two types of bacteria was investigated using a two-fold dilution method. The results are shown in Table 4.

[0132] Test strains: Staphylococcus aureus and Escherichia coli. (All bacteria were purchased from the Dermatology Hospital of the Chinese Academy of Medical Sciences, Nanjing, Jiangsu Province, China)

[0133] Preparation of bacterial culture: Transfer the fully developed test strain to 5 mL of sterile physiological saline, crush it, sonicate it, shake it thoroughly to remove lumps of insoluble matter, mix it well, and use it as the original bacterial culture. When testing, adjust its concentration to 106 cells / mL before use.

[0134] Experimental Method: The test compound was dissolved in an appropriate amount of dimethyl sulfoxide, then diluted with sterile distilled water, and added to sterilized Luria Bertani medium. The sample concentrations were 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.125 mg / mL. After inoculation with the test bacteria, the mixture was incubated in a constant temperature oven for 2-7 days. The highest dilution concentration in which no bacteria grew was taken as the minimum inhibitory concentration (MIC).

[0135] The experimental results (Table 4) show that the novel antibacterial compounds have varying degrees of inhibitory activity against bacteria.

[0136] Table 4: Inhibitory activity (MIC, mg / mL) of imidazopyridone compounds against bacteria

[0137]

[0138] This invention fully demonstrates that it not only provides a novel synthetic route, but also yields an antibacterial compound with promising applications through this route.

[0139] Comparative Example 1: The reaction was carried out using a conventional reaction flask.

[0140] At room temperature and under nitrogen protection, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (14.1 mg, 0.03 mmol, 0.1 equivalent), phenylacetylene (98.7 μL, 0.9 mmol, 3.0 equivalent), N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide (101.4 mg, 0.3 mmol, 1.0 equivalent), Et3N (45.9 μL, 0.33 mmol, 1.1 equivalent), and solvent 1,4-dioxane (6 mL) were added to a 10 mL reaction tube. The reaction tube was stirred under a blue light lamp (30 W, 220 V, LED, wavelength 420 nm-430 nm) for 6 h. The filtrate was concentrated under reduced pressure, and the residue was separated by chromatography on silica gel using a 5:1 eluent of petroleum ether and ethyl acetate to obtain the desired product 3a. Conversion rate 49%, Ms = 461.1683 g / mol.

[0141] Comparative Example 2: Reactions without the application of a light source

[0142] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (14.1 mg, 0.03 mmol, 0.1 equivalent), phenylacetylene (98.7 μL, 0.9 mmol, 3.0 equivalent), N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide (101.4 mg, 0.3 mmol, 1.0 equivalent), and Et3N (45.9 μL, 0.33 mmol, 1.1 equivalent) were dissolved in 1,4-dioxane (6 mL) to obtain a homogeneous solution. This homogeneous solution was pumped into a microchannel reactor at a flow rate of 0.1 mL / min. The solution was retained for 30 min in a light-protected microchannel reactor, and the eluent was collected in a sample flask. The results showed that product 3a could not be obtained, proving that a light source is a necessary condition for the reaction.

[0143] This invention provides a photocatalytic continuous synthesis method for imidazopyridone compounds and its application. Many methods and approaches exist to achieve this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A photocatalytic, green, and efficient reaction route for imidazopyridone compounds and its application, comprising the following steps: (1) Dissolve 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine, N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide, phenylacetylene and Et3N in a solvent to obtain a homogeneous solution. (2) The above homogeneous solution was pumped into a microchannel reactor irradiated with violet light, and the reaction was carried out under light irradiation. The product was then collected. (3) Dilute the compound with culture medium, add it to bacterial culture, and observe the lowest drug concentration at which no bacteria grows visible to the naked eye.

2. The preparation method according to claim 1, characterized in that, The organic catalyst described in step (1) is selected from one or more of 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine, 5,10-bis(4-(methoxy)phenyl)-5,10-dihydrophenazine, 5,10-diphenyl-5,10-dihydrophenazine, 5,10-bis(2-naphthyl)-5,10-dihydrophenazine, or 5,10-bis(1-naphthyl)-5,10-dihydrophenazine, 10-phenylphenthiazine, 10-(4-methoxyphenyl)phenthiazine, 10-(1-naphthyl)phenthiazine, dinaphthylbenzene, 3,7-bis(4-(1,1′-biphenyl))-(10-(1-naphthyl))-10-phenoxazine, and 5,10-bis(4-(cyano)phenyl)-5,10-dihydrophenazine.

3. The preparation method according to claim 1, characterized in that, In step (1), the solvent is selected from one or more of dichloroethane, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, acetonitrile, benzene, N,N-dimethylformamide or N,N-dimethylaniline.

4. The preparation method according to claim 1, characterized in that, In step (1), substrate A is N-(benzothiophene-2-methylene)-2-bromo-N-cyano-2-methylpropionamide, 2-bromo-N-cyano-2-methyl-N-(3-methylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(4-methylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-methylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(6-methylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(7-methylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-fluorobenzothiophene-2-methylene)propionamide, etc. Propionamide, 2-bromo-N-cyano-2-methyl-N-(5-chlorobenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-bromobenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-iodobenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-methoxybenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-trifluoromethylbenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-nitrobenzothiophene-2-methylene)propionamide, 2-bromo-N-cyano-2-methyl-N-(5-phenylbenzothiophene-2-methylene)propionamide.

5. The preparation method according to claim 1, characterized in that, In step (1), the substrate B is phenylacetylene, 2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorophenylacetylene, 2-chlorophenylacetylene, 3-chlorophenylacetylene, 4-chlorophenylacetylene, 2-bromophenylacetylene, 3-bromophenylacetylene, 4-bromophenylacetylene, 2-methoxyphenylacetylene, 3-methoxyphenylacetylene, 4-methoxyphenylacetylene, 2-methylphenylacetylene, 3-methylphenylacetylene, 4-methylphenylacetylene, 2-hydroxyphenylacetylene, 3-hydroxyphenylacetylene, 4-hydroxyphenylacetylene, or β-bromophenylacetylene.

6. The method for continuous photocatalytic preparation of imidazopyridone compounds according to claim 1, characterized in that, In step (1), the concentration of substrate A in the homogeneous solution is 0.01–0.5 mmol / mL; the concentration of substrate B is 0.03–0.3 mmol / mL; and the concentration of the organic photocatalyst is 0.001–0.01 mmol / mL.

7. The method for continuous photocatalytic preparation of imidazopyridone compounds according to claim 1, characterized in that, In step (2), the flow rate of the homogeneous solution in the microchannel reaction device is 0.04-0.16 mL / min, the reaction residence time is 10-40 min, and the reaction temperature is room temperature.

8. The method for continuous photocatalytic preparation of imidazopyridone compounds according to claim 1, characterized in that, In step (2), the wavelength of the blue light is 420nm~430nm and the power of the blue light is 9-30W.

9. The method for continuous photocatalytic preparation of imidazopyridone compounds according to claim 1, characterized in that, In step (2), the microchannel reaction device includes a sample injector, a micromixer, a microchannel reactor, a receiver, and a light source; the sample injector, micromixer, microchannel reactor, and receiver are connected in series via pipes; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reactor; the microchannel reactor uses a quartz coil with a retention volume of 1-3.5 ml and a tube diameter of 0.8-1.5 mm; the length of the connecting tube between the sample injector and the microchannel reactor is 10 cm-50 cm, and the length of the connecting tube between the microchannel reactor and the receiver is 10 cm-50 cm.

10. The application of the imidazopyridone compound according to claim 1, characterized in that, In step (3), the microbial culture device includes a cell culture dish, a constant temperature incubator, and the bacteria are selected from one or more of Staphylococcus aureus and Escherichia coli.

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