A method for light-induced continuous synthesis of piperidone

Abstract

The present invention belongs to the field of pharmaceutical chemistry and fine chemical synthesis, and relates to a method for light-induced continuous synthesis of piperidones, wherein the compound represented by formula I, the compound represented by formula II, a base and an organic photocatalyst are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device provided with a light source for reaction, and the piperidone compound represented by formula III is obtained. In the present invention, indole halogen is used as an initiator, and under the induction of visible light, a free radical is formed, and then a cyclization reaction occurs with an alkene-alkyne substance. Compared with the prior art, the present invention adopts organic photocatalyst catalysis, is green and efficient, has no metal residue, and has a wide application prospect in the synthesis of pharmaceutical products.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and fine chemical synthesis, and relates to a method for light-induced continuous synthesis of piperidone. Background Art

[0002] Piperidine alkaloids include piperidone alkaloids, which are a class of alkaloids with a hexahydropiperidine ring as the parent nucleus. Currently discovered piperidine and piperidone alkaloids are widely found in animals and plants, and a large part of piperidine alkaloids have biological activity. 1 2-Piperidone is the basic unit for the synthesis of piperidines. 2 , and is also a component of many biologically active substances 3,4 Therefore, the construction of 2-piperidone compounds through organic synthesis methods has received widespread attention. Summary of the invention

[0003] The present invention mainly provides an unprecedented green and efficient synthesis method, which synthesizes piperidone compounds by light-induced enyne difunctionalization under visible light conditions.

[0004] Invention idea: Under visible light conditions, phenazine organic photocatalysts are used to induce alkyl bromide to form free radicals, and then the free radicals attack styrene to undergo cyclization to form piperidone compounds.

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

[0006] The invention discloses a method for light-induced continuous synthesis of piperidones, comprising dissolving a compound represented by formula I, a compound represented by formula II, a base and an organic photocatalyst in an organic solvent to obtain a homogeneous solution; pumping the obtained homogeneous solution into a microchannel reaction device provided with a light source for reaction to obtain a piperidone compound represented by formula III;

[0007] The compound represented by formula II has a structural formula as shown in formula II-A or formula II-B;

[0008] The piperidone compound represented by formula III has a structural formula as shown in formula III-A or formula III-B;

[0009]

[0010] The present invention includes two parallel technical solutions:

[0011] Scheme 1: The compound represented by formula I, the compound represented by formula II-A, a base and an organic photocatalyst are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device equipped with a light source for reaction to obtain a piperidone compound represented by formula III-A;

[0012] Scheme 2: The compound represented by formula I, the compound represented by formula II-B, a base and an organic photocatalyst are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device equipped with a light source for reaction to obtain a piperidinone compound represented by formula III-B.

[0013] Specifically, the compound represented by formula I is 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one, 1-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one, 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-oic acid, 2-bromo-1-(1H-indol-1-yl)-2-ethylpropane-1-one, 2-bromo-1-(1H-indol-1-yl)-2-ethylpropane-1-one, -2-methylbutane-1-one, 2-bromo-1-(1H-indol-1-yl)-3-methylbutane-1-one and 2-bromo-2-methyl-1-(3-methyl-1H-indol-1-yl)propane-1-one, preferably 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one or 2-bromo-2-methyl-1-(3-methyl-1H-indol-1-yl)propane-1-one.

[0014] The synthesis method of the compound represented by formula I is as follows: first, sodium hydride (15.0 mmol, 1.5 equiv) solvent is dissolved in ultra-dry tetrahydrofuran (100 mL), and the corresponding indole (10.0 mmol, 1.0 equiv) is slowly added under ice bath conditions, and the reaction mixture is reacted for 30 minutes; then 2-bromo-2-methylpropionyl bromide (10.0 mmol, 1.0 equiv) is slowly added dropwise to the reaction mixture, and then the reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the reaction mixture is extracted three times with 150 mL of ethyl acetate and 150 mL of water, the layers are separated, the separated organic layer is dried with anhydrous Na2SO4 and filtered, the filtrate is concentrated under reduced pressure to obtain a crude product, and the product is purified by 200-300 mesh silica gel column chromatography (eluent ratio: petroleum ether: ethyl acetate = 20:1).

[0015] Specifically, the compound represented by formula II-A is any one of styrene, 2-fluorostyrene, 3-fluorostyrene, 4-fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2-bromostyrene, 3-bromostyrene, 4-bromostyrene, 2-methoxystyrene, 3-methoxystyrene, 4-methoxystyrene, 2-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2-nitrostyrene, 3-nitrostyrene, 4-nitrostyrene, α-bromostyrene, n-propylene, isopropylene, 1,3-propadiene, 4-(trifluoromethyl)styrene, 4-cyanostyrene and 4-tert-butylstyrene, preferably any one of styrene, 4-fluorostyrene, 4-chlorostyrene, 4-bromostyrene, 4-methoxystyrene, 4-methylstyrene, 4-(trifluoromethyl)styrene, 4-cyanostyrene and 4-tert-butylstyrene.

[0016] Specifically, the compound represented by formula II-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-nitrophenylacetylene, Any one of 3-nitrophenylacetylene, 4-nitrophenylacetylene, 2-cyanophenylacetylene, 3-cyanophenylacetylene, 4-cyanophenylacetylene, n-propyne, 4-(trifluoromethyl)phenylacetylene and 4-ethylphenylacetylene, preferably any one of phenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-methoxyphenylacetylene, 4-methylphenylacetylene, 4-(trifluoromethyl)phenylacetylene and 4-ethylphenylacetylene.

[0017] Specifically, the base is any one or a combination of potassium phosphate, potassium carbonate, sodium bicarbonate, lithium tert-butoxide, triethylamine, 4-dimethylaminopyridine and pyridine, preferably triethylamine.

[0018] Specifically, the organic photocatalyst is 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, 5,10-bis(1-naphthyl)-5,10-dihydrophenazine, 10-phenylphenothiazine , 10-(4-methoxyphenyl)phenothiazine, 10-(1-naphthyl)phenothiazine, dinaphthylbenzene, 3,7-di(4-(1,1'-biphenyl))-(10-(1-naphthyl))-10-phenoxazine and 5,10-di(4-(nitrile)phenyl)-5,10-dihydrophenazine or a combination of several thereof, preferably 5,10-di(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine.

[0019] The synthesis method of the organic photocatalyst is described in the prior art. 5 .

[0020] Specifically, the organic solvent is any one or a combination of ethylene dichloride, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, acetonitrile, benzene, N,N-dimethylformamide and N,N-dimethylaniline, preferably ethylene dichloride.

[0021] Specifically, the molar ratio of the compound represented by formula I, the compound represented by formula II, the base and the organic photocatalyst is 1:1-3:1.1-2:0.05-0.1, preferably 1:1:1.1:0.05.

[0022] Specifically, the concentration of the compound represented by formula I in the homogeneous solution is 0.02-2 mmol / mL, preferably 0.25 mmol / mL.

[0023] Specifically, the light source is blue light with a wavelength of 420nm-430nm and a power of 10W.

[0024] Specifically, the microchannel reaction device includes an injector, a micromixer, a microchannel reactor, a receiver, and a light source; the injector, micromixer, microchannel reactor and receiver are connected in series through a pipeline; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reactor.

[0025] Specifically, the microchannel reactor is a quartz coil with a tube diameter of 0.2 to 2 mm and a retention volume of 0.25 to 8 mL, preferably 1 mL; the length of the connecting pipe between the injector and the microchannel reactor is 10 cm to 50 cm; the length of the connecting pipe between the microchannel reactor and the receiver is 10 cm to 50 cm.

[0026] Specifically, the homogeneous solution is pumped into the microchannel reaction device at a flow rate of 0.05-0.2 mL / min, preferably 0.1 mL / min; the reaction residence time is 5-40 min, preferably 10 min, and the reaction temperature is room temperature.

[0027] Beneficial effects:

[0028] (1) In the present invention, indole halogen is used as an initiator, and under the induction of visible light, free radicals are formed, and then a cyclization reaction occurs with olefins and alkynes. Compared with the prior art, the present invention uses organic photocatalysts, which is green and efficient, has no metal residue, short reaction time, no need for heating, high yield, and has broad application prospects in the synthesis of pharmaceutical products.

[0029] (2) The piperidone compounds prepared by the present invention lay a foundation for the synthesis of pharmaceutical products, making their application in the field of biomedical materials more competitive. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] 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.

[0031] Figure 1 is the H NMR spectrum of product III-A-1;

[0032] Figure 2 is the carbon NMR spectrum of product III-A-1;

[0033] Figure 3 is the H NMR spectrum of product III-A-2;

[0034] Figure 4 is the carbon NMR spectrum of product III-A-2;

[0035] Figure 5 is the H NMR spectrum of product III-A-3;

[0036] Figure 6 is the carbon NMR spectrum of product III-A-3;

[0037] Figure 7 is the NMR fluorine spectrum of product III-A-3;

[0038] Figure 8 is the H NMR spectrum of product III-A-4;

[0039] Fig. 9 is the carbon NMR spectrum of product III-A-4;

[0040] Fig.10 is the H NMR spectrum of product III-A-5;

[0041] Fig.11 is the carbon NMR spectrum of product III-A-5;

[0042] Fig.12 is the H NMR spectrum of product III-A-6;

[0043] Fig.13 is the carbon NMR spectrum of product III-A-6;

[0044] Fig.14 is the H NMR spectrum of product III-A-7;

[0045] Fig.15 is the carbon NMR spectrum of product III-A-7;

[0046] Fig.16 is the NMR fluorine spectrum of product III-A-7;

[0047] Fig.17 is the H NMR spectrum of product III-A-8;

[0048] Fig.18 is the carbon NMR spectrum of product III-A-8;

[0049] Fig.19 is the H NMR spectrum of product III-A-9;

[0050] Fig. 20 is the carbon NMR spectrum of product III-A-9;

[0051] Fig.21 is the H NMR spectrum of product III-A-10;

[0052] Fig. 22 is the carbon NMR spectrum of product III-A-10;

[0053] Fig.23 This is the H NMR spectrum of product III-B-1;

[0054] Fig.24 is the carbon NMR spectrum of product III-B-1;

[0055] Fig.25 This is the H NMR spectrum of product III-B-2;

[0056] Fig.26 is the carbon NMR spectrum of product III-B-2;

[0057] Fig. 27 This is the H NMR spectrum of product III-B-3;

[0058] Fig.28is the carbon NMR spectrum of product III-B-3;

[0059] Fig.29 is the NMR fluorine spectrum of product III-B-3;

[0060] Fig.30 is the H NMR spectrum of product III-B-4;

[0061] Fig.31 is the carbon NMR spectrum of product III-B-4;

[0062] Fig.32 is the H NMR spectrum of product III-B-5;

[0063] Fig.33 is the carbon NMR spectrum of product III-B-5;

[0064] Fig.34 is the H NMR spectrum of product III-B-6;

[0065] Fig.35 is the carbon NMR spectrum of product III-B-6;

[0066] Fig.36 is the H NMR spectrum of product III-B-7;

[0067] Fig.37 is the carbon NMR spectrum of product III-B-7;

[0068] Fig.38 is the NMR fluorine spectrum of product III-B-7;

[0069] Fig.39 is the H NMR spectrum of product III-B-8;

[0070] Fig.40 is the carbon NMR spectrum of product III-B-8;

[0071] Fig.41 is the H NMR spectrum of product III-B-9;

[0072] Fig.42 This is the carbon NMR spectrum of product III-B-9. DETAILED DESCRIPTION

[0073] 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.

[0074] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0075] The synthesis method of the compound represented by formula I used in the present invention is as follows: firstly, sodium hydride (15.0mmol, 1.5equiv) solvent is dissolved in ultra-dry tetrahydrofuran (100mL), and the corresponding indole (10.0mmol, 1.0equiv) is slowly added under ice bath conditions, and the reaction mixture is reacted for 30 minutes; then 2-bromo-2-methylpropionyl bromide (10.0mmol, 1.0equiv) is slowly added dropwise to the reaction mixture, and then the reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the reaction mixture is extracted three times with 150mL of ethyl acetate and 150mL of water, the layers are separated, the separated organic layer is dried with anhydrous Na2SO4 and filtered, the filtrate is concentrated under reduced pressure to obtain a crude product, and the product is purified by 200-300 mesh silica gel column chromatography (eluent ratio: petroleum ether: ethyl acetate = 20:1).

[0076] The synthesis method of the organic photocatalyst used in the present invention is based on the prior art. 5 .

[0077] Example 1

[0078] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), styrene (115.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in dichloroethane (DCE, 4 mL) as a solvent and mixed to obtain a homogeneous solution. The homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-1 with a conversion rate of 93% and Ms = 289.1469 g / mol. Figure 1 is the H NMR spectrum of product Ⅲ-A-1, Figure 2 This is the carbon NMR spectrum of product III-A-1.

[0079] Example 2

[0080] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-methylstyrene (131.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-2 with a conversion rate of 89% and Ms = 303.1623 g / mol. Figure 3 is the H NMR spectrum of product Ⅲ-A-2, Figure 4 This is the carbon NMR spectrum of product III-A-2.

[0081] Example 3

[0082] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-fluorostyrene (119.3 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-3 with a conversion rate of 77% and Ms = 307.1376 g / mol. Figure 5 is the H NMR spectrum of product Ⅲ-A-3, Figure 6 is the carbon NMR spectrum of product Ⅲ-A-3, Figure 7 This is the NMR fluorine spectrum of product III-A-3.

[0083] Example 4

[0084] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-chlorostyrene (120.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-4 with a conversion rate of 70% and Ms = 323.1077 g / mol. Figure 8 is the H NMR spectrum of product Ⅲ-A-4, Fig. 9 This is the carbon NMR spectrum of product III-A-4.

[0085] Example 5

[0086] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-bromostyrene (130.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-5 with a conversion rate of 68% and Ms = 367.0573 g / mol. Fig.10 is the H NMR spectrum of product Ⅲ-A-5, Fig.11 This is the carbon NMR spectrum of product III-A-5.

[0087] Example 6

[0088] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-methoxystyrene (133.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9, μL 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-6 with a conversion of 51% and Ms = 320.1652 g / mol. Fig.12 is the H NMR spectrum of product Ⅲ-A-6, Fig.13 This is the carbon NMR spectrum of product III-A-6.

[0089] Example 7

[0090] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-(trifluoromethyl)styrene (147.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9, μL 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-7 with a conversion rate of 62% and Ms = 357.1348 g / mol. Fig.14 is the H NMR spectrum of product Ⅲ-A-7, Fig.15 is the carbon NMR spectrum of product Ⅲ-A-7, Fig.16 This is the NMR fluorine spectrum of product III-A-7.

[0091] Example 8

[0092] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-cyanostyrene (120.2 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-8 with a conversion rate of 76% and Ms = 314.1424 g / mol. Fig.17 is the H NMR spectrum of product Ⅲ-A-8, Fig.18 This is the carbon NMR spectrum of product III-A-8.

[0093] Example 9

[0094] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-tert-butylstyrene (183.2 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-9 with a conversion rate of 82% and Ms = 345.2096 g / mol. Fig.19 is the H NMR spectrum of product Ⅲ-A-9, Fig. 20 This is the carbon NMR spectrum of product III-A-9.

[0095] Example 10

[0096] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), styrene (115.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-2-methyl-1-(3-methyl-1H-indol-1-yl)propan-1-one (279.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-A-10 with a conversion rate of 90% and Ms = 303.1623 g / mol. Fig.21 is the H NMR spectrum of product Ⅲ-A-10, Fig. 22 This is the carbon NMR spectrum of product III-A-10.

[0097] Embodiment 11

[0098] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), phenylacetylene (109.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-1 with a conversion rate of 93% and Ms = 287.1319 g / mol. Fig.23 is the H NMR spectrum of product Ⅲ-B-1, Fig.24 This is the carbon NMR spectrum of product III-B-1.

[0099] Example 12

[0100] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-methylphenylacetylene (126.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-2 with a conversion of 89% and Ms = 301.1467 g / mol. Fig.25 is the H NMR spectrum of product Ⅲ-B-2, Fig.26 This is the carbon NMR spectrum of product III-B-2.

[0101] Example 13

[0102] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-fluorophenylacetylene (114.6 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-3 with a conversion rate of 77% and Ms = 305.1216 g / mol. Fig. 27 is the H NMR spectrum of product Ⅲ-B-3, Fig.28 is the carbon NMR spectrum of product Ⅲ-B-3, Fig.29 This is the NMR fluorine spectrum of product III-B-3.

[0103] Embodiment 14

[0104] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-chlorophenylacetylene (118.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using a 10:1 ratio of petroleum ether to ethyl acetate to give the desired product III-B-4. Conversion rate 70%, Ms = 321.0947 g / mol. Fig.30 is the H NMR spectrum of product Ⅲ-B-4, Fig.31 This is the carbon NMR spectrum of product III-B-4.

[0105] Embodiment 15

[0106] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-bromophenylacetylene (120.6 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-5 with a conversion of 68% and Ms = 365.0415 g / mol. Fig.32 is the H NMR spectrum of product Ⅲ-B-5, Fig.33 This is the carbon NMR spectrum of product III-B-5.

[0107] Example 16

[0108] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-methoxyphenylacetylene (129.7 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using a 10:1 ratio of petroleum ether to ethyl acetate to give the desired product III-B-6. Conversion rate 51%, Ms = 317.1416 g / mol. Fig.34 is the H NMR spectrum of product Ⅲ-B-6, Fig.35 This is the carbon NMR spectrum of product III-B-6.

[0109] Embodiment 17

[0110] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-(trifluoromethyl)phenylacetylene (139.9 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-7 with a conversion of 62% and Ms = 355.1184 g / mol. Fig.36 is the H NMR spectrum of product Ⅲ-B-7, Fig.37 is the carbon NMR spectrum of product Ⅲ-B-7, Fig.38 This is the NMR fluorine spectrum of product III-B-7.

[0111] Embodiment 18

[0112] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), 4-ethylphenylacetylene (141.5 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate 10:1 to obtain the desired product III-B-8 with a conversion of 82% and Ms = 315.1623 g / mol. Fig.39 is the H NMR spectrum of product Ⅲ-B-8, Fig.40 This is the carbon NMR spectrum of product III-B-8.

[0113] Embodiment 19

[0114] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), phenylacetylene (109.8 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-2-methyl-1-(3-methyl-1H-indol-1-yl)propan-1-one (279.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using a 10:1 ratio of petroleum ether to ethyl acetate to give the desired product III-B-9. Conversion rate 90%, Ms = 301.1463 g / mol. Fig.41 is the H NMR spectrum of product Ⅲ-B-9, Fig.42 This is the carbon NMR spectrum of product III-B-9.

[0115] Embodiment 20

[0116] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), styrene (115.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed. The mixture was placed in a reaction tube irradiated with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm) for 4 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel using an eluent of petroleum ether and ethyl acetate in a ratio of 10:1 to obtain the desired product III-A-1 with a conversion rate of 83% and Ms = 289.1469 g / mol.

[0117] Embodiment 21

[0118] At room temperature, 5,10-bis(4-(trifluoromethyl)phenyl)-5,10-dihydrophenazine (23.5 mg, 50.0 μmol, 5% equivalent), styrene (115.0 μL, 1.0 mmol, 1.0 equivalent), 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one (265.0 mg, 1.0 mmol, 1.0 equivalent) and Et3N (152.9 μL, 1.1 mmol, 1.1 equivalent) were dissolved in solvent DCE (4 mL) and mixed to obtain a homogeneous solution. The above homogeneous solution was pumped into a microchannel reactor, and the pump flow rate was controlled to be 0.1 mL / min. In a microchannel reactor without irradiation with a blue light lamp (10 W, 220 V, LED, wavelength 420 nm to 430 nm), the retention time was 10 min, and the reaction effluent was collected in a sample flask. The desired product III-A-1 was not obtained and the conversion rate was 0.

[0119] The present invention provides a method and idea for the photoinduced continuous synthesis of piperidone. There are many methods and approaches to realize 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 realized by existing technologies.

[0120] References:

[0121] 1.M.Amat,C.Escolano,NRLor,O.Lozano,A.Gomez-Esque,R.Griera andJ.Bosch,Archivoc,2005,DOI:10.3998 / file.5550190.0006.912,115-123.

[0122] 2. I. Baussanne, C. Travers and J. Royer, Tetrahedron Asymmetry, 1998, 9, 797-804.

[0123] 3.P.Jadav,R.Bahekar,SRShah,D.Patel,A.Joharapurkar,M.Jain,KVVMSairam and PKSingh,Bioorganic&Medicinal Chemistry Letters,2014,24,1918-1922.

[0124] 4. Kosugi T., DRMitchell, A. Fujino, M. Imai, M. Kambe, S. Kobayashi, H. Makino, Y. Matsueda, Y. Oue, K. Komatsu, K. Imaizumi, Y. Sakai, S. Sugiura, O. Takenouchi, G. Unok i,Y.Yamakoshi,V.Cunliffe,J.Frearson,R.Gordon,CJHarris,H.Kalloo-Hosein,J.Le,G.Patel,DJSimpson,B.Sherborne,PSThomas,N.Suzuki,M.Takimoto-Kamimura andK.-i.Kataoka,Journal of MedicinalChemistry,2012,55,10312-10313.

[0125] 5. JCTeriot, CHLim, H. Yang, MDRyan, CBMusgrave and GMMiyake, Science, 2016, 352, 1082-1086.

Claims

1. A method for light-induced continuous synthesis of piperidone, characterized in that: The compound represented by formula I, the compound represented by formula II, a base and an organic photocatalyst are dissolved in an organic solvent to obtain a homogeneous solution; the obtained homogeneous solution is pumped into a microchannel reaction device equipped with a light source for reaction to obtain a piperidone compound represented by formula III; The compound represented by formula II has a structural formula as shown in formula II-A or formula II-B; The piperidone compound represented by formula III has a structural formula as shown in formula III-A or formula III-B; The compound represented by formula I is any one of 2-bromo-1-(1H-indol-1-yl)-2-methylpropane-1-one, 2-bromo-1-(1H-indol-1-yl)-2-ethylpropane-1-one, 2-bromo-1-(1H-indol-1-yl)-2-methylbutane-1-one, 2-bromo-1-(1H-indol-1-yl)-3-methylbutane-1-one and 2-bromo-2-methyl-1-(3-methyl-1H-indol-1-yl)propane-1-one; The compound represented by formula II-A is any one of styrene, 2-fluorostyrene, 3-fluorostyrene, 4-fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2-bromostyrene, 3-bromostyrene, 4-bromostyrene, 2-methoxystyrene, 3-methoxystyrene, 4-methoxystyrene, 2-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2-nitrostyrene, 3-nitrostyrene, 4-nitrostyrene, α-bromostyrene, 4-(trifluoromethyl)styrene, 4-cyanostyrene and 4-tert-butylstyrene; The compound represented by formula II-B is any one of 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-nitrophenylacetylene, 3-nitrophenylacetylene, 4-nitrophenylacetylene, 2-cyanophenylacetylene, 3-cyanophenylacetylene, 4-cyanophenylacetylene, 4-(trifluoromethyl)phenylacetylene and 4-ethylphenylacetylene; The base is any one or a combination of potassium phosphate, potassium carbonate, sodium bicarbonate, lithium tert-butoxide, triethylamine, 4-dimethylaminopyridine and pyridine; The organic photocatalyst is any one or a combination 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, 5,10-bis(1-naphthyl)-5,10-dihydrophenazine and 5,10-bis(4-(nitrile)phenyl)-5,10-dihydrophenazine; The organic solvent is any one or a combination of ethylene dichloride, 1,4-dioxane, acetonitrile and N,N-dimethylformamide; The light source is blue light with a wavelength of 420nm-430nm and a power of 10W.

2. The method according to claim 1, characterized in that The molar ratio of the compound represented by formula I, the compound represented by formula II, the base and the organic photocatalyst is 1:1-3:1.1-2:0.05-0.

1.

3. The method according to claim 1, characterized in that The concentration of the compound represented by formula I in the homogeneous solution is 0.02-2 mmol / mL.

4. The method according to claim 1, characterized in that: The microchannel reaction device comprises an injector, a micromixer, a microchannel reactor, a receiver and a light source; the injector, the micromixer, the microchannel reactor and the receiver are connected in series through a pipeline; the light source is located outside the microchannel reactor, and its illumination range covers the microchannel reactor.

5. The method according to claim 4, characterized in that The microchannel reactor is a quartz coil with a diameter of 0.2-2 mm and a retention volume of 0.25-8 mL; the length of the connecting pipe between the injector and the microchannel reactor is 10-50 cm; the length of the connecting pipe between the microchannel reactor and the receiver is 10-50 cm.

6. The method according to claim 1, characterized in that The flow rate of the homogeneous solution pumped into the microchannel reaction device is 0.05-0.2 mL / min; the reaction residence time is 5-40 min, and the reaction temperature is room temperature.

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