CN115872993A - Method for continuously synthesizing piperidone through photoinduction - Google Patents
Method for continuously synthesizing piperidone through photoinduction Download PDFInfo
- Publication number
- CN115872993A CN115872993A CN202211527570.7A CN202211527570A CN115872993A CN 115872993 A CN115872993 A CN 115872993A CN 202211527570 A CN202211527570 A CN 202211527570A CN 115872993 A CN115872993 A CN 115872993A
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- Prior art keywords
- formula
- product iii
- bromo
- indol
- homogeneous solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 23
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 239000012456 homogeneous solution Substances 0.000 claims abstract description 53
- -1 piperidone compound Chemical class 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000005086 pumping Methods 0.000 claims abstract description 24
- 239000011941 photocatalyst Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 230000006698 induction Effects 0.000 claims abstract description 4
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- 238000005070 sampling Methods 0.000 description 1
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Abstract
The invention belongs to the field of medicinal chemistry and fine chemistry synthesis, and relates to a method for continuously synthesizing piperidone by photoinduction, which comprises the steps of dissolving a compound shown as a formula I, a compound shown as a formula II, alkali 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 the piperidone compound shown in the formula III. According to the invention, indole halogen is used as an initiator, and forms free radicals under the induction of visible light, and then generates cyclization reaction with an eneyne hydrocarbon substance. Compared with the prior art, the invention adopts the organic photocatalyst for catalysis, is green and efficient, has no metal residue, and has wide application prospect in the aspect of synthesizing medical products.
Description
Technical Field
The invention belongs to the field of medicinal chemistry and fine chemical synthesis, and relates to a method for continuously synthesizing piperidone by photoinduction.
Background
The piperidine alkaloid contains piperidone alkaloid, and is alkaloid with hexahydropiperidine ring as mother nucleus. The piperidines and piperidinones that are currently foundThe alkali is widely present in animals and plants, and most of piperidine alkaloids have biological activity 1 . 2-piperidones are basic units for synthesizing piperidines 2 Are also part of various bioactive substances 3,4 . Therefore, the construction of 2-piperidones by organic synthesis methods has received much attention.
Disclosure of Invention
The invention mainly provides an unprecedented green high-efficiency synthesis method, which synthesizes piperidone compounds by light-induced double functionalization of eneyne under the condition of visible light.
The invention idea is as follows: under the condition of visible light illumination, a phenazine organic photocatalyst is used for inducing alkyl bromide to form a free radical, and then the free radical attacks styrene to carry out cyclization to generate the piperidone compound.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention discloses a method for continuously synthesizing piperidone by photoinduction, which comprises the steps of dissolving a compound shown as a formula I, a compound shown as a formula II, alkali 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 shown in a formula III;
the structural formula of the compound shown in the formula II is shown as a formula II-A or a formula II-B;
the structural formula of the piperidone compound shown in the formula III is shown in a formula III-A or a formula III-B;
the invention comprises two parallel technical schemes:
the first scheme is as follows: dissolving a compound shown as a formula I, a compound shown as a formula II-A, alkali 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 shown in a formula III-A;
scheme II: dissolving a compound shown as a formula I, a compound shown as a formula II-B, alkali 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 the piperidone compound shown in the formula III-B.
Specifically, the compound represented by the formula I is any one of 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one, 1-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one, 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-oic acid, 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, preferably 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one or 2-bromo-2- (1H-indol-1-yl) propane-1-one.
The synthesis method of the compound shown in the formula I comprises the following steps: firstly, sodium hydride (15.0 mmol,1.5 equiv) solvent is added into super-dry tetrahydrofuran (100 mL) slowly under the ice-bath condition, and then the corresponding indole (10.0 mmol,1.0 equiv) is added for reaction for 30 minutes; 2-bromo-2-methylpropanoyl bromide (10.0 mmol,1.0 equiv) was slowly added dropwise to the reaction mixture, and then the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted three times with 150mL of ethyl acetate and 150mL of water, the layers were separated, and the separated organic layer was washed with anhydrous Na 2 SO 4 Drying and filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by using 200-300 mesh silica gel column chromatography to obtain the product (eluent ratio: petroleum ether: ethyl acetate = 20.
Specifically, the compound represented by the 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, a-bromostyrene, n-propylene, isopropene, 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.
Specifically, the compound represented by the formula ii-B is any one of phenylacetylene, 2-fluoroacetylene, 3-fluoroacetylene, 4-fluoroacetylene, 2-chloroacetylene, 3-chloroacetylene, 4-chloroacetylene, 2-bromophenylacetylene, 3-bromobhenylacetylene, 4-bromobhenylacetylene, 2-methoxyphenylacetylene, 3-methoxyphenylacetylene, 4-methoxyphenylacetylene, 2-methylphenylacetylene, 3-methylphenylacetylene, 4-methylphenylacetylene, 2-nitrophenylacetylene, 3-nitrophenylacetylene, 4-nitrophenylacetylene, 2-cyanophenylacetylene, 3-cyanophenylacetylene, 4-cyanophenylacetylene, n-propyne, 4- (trifluoromethyl) phenylacetylene and 4-ethylphenylacetylene, and is preferably any one of phenylacetylene, 4-fluoroacetylene, 4-chlorobenzene acetylene, 4-bromophenylacetylene, 4-methoxyphenylacetylene, 4-methylphenylacetylene, 4- (trifluoromethyl) phenylacetylene and 4-ethylphenylacetylene.
Specifically, the base is any one or a combination of potassium phosphate, potassium carbonate, sodium bicarbonate, lithium tert-butoxide, triethylamine, 4-dimethylaminopyridine and pyridine, and triethylamine is preferred.
Specifically, the organic photocatalyst is any one or a combination of several kinds 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, 10-phenylphenazine, 10- (4-methoxyphenyl) phenothiazine, 10- (1-naphthyl) phenothiazine, perylene, 3, 7-bis (4- (1, 1' -biphenyl)) - (10- (1-naphthyl)) -10-phenoxazine, and 5, 10-bis (4- (nitrile) phenyl) -5, 10-dihydrophenazine, and preferably 5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine.
Wherein, the synthesis method of the organic photocatalyst refers to the prior art 5 。
Specifically, the organic solvent is any one or a combination of several of dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, acetonitrile, benzene, N-dimethylformamide and N, N-dimethylaniline, and preferably dichloroethane.
Specifically, the molar ratio of the compound shown in the formula I to the compound shown in the formula II to the alkali to the organic photocatalyst is 1:1 to 3: 1.1-2: 0.05 to 0.1, preferably 1:1:1.1:0.05.
specifically, the concentration of the compound shown in the formula I in the homogeneous solution is 0.02-2 mmol/mL, and preferably 0.25mmol/mL.
Specifically, the light source is blue light, the wavelength is 420 nm-430 nm, and the power is 10W.
Specifically, the microchannel reaction device comprises a sample injector, a micromixer, a microchannel reactor, a receiver and a light source; the sample injector, the micro mixer, the micro-channel reactor and the receiver are connected in series through pipelines; the light source is positioned outside the microchannel reactor, and the illumination range of the light source covers the microchannel reactor.
Specifically, the microchannel reactor is a quartz coil, the pipe diameter is 0.2-2 mm, and the retention volume is 0.25-8 mL, preferably 1mL; the length of a connecting pipeline between the sample injector and the micro-channel reactor is 10 cm-50 cm; the length of the connecting pipeline between the microchannel reactor and the receiver is 10 cm-50 cm.
Specifically, the flow rate of the homogeneous solution pumped into the microchannel reaction device is 0.05-0.2 mL/min, preferably 0.1mL/min; the reaction has the reaction residence time of 5-40 min, preferably 10min, and the reaction temperature is room temperature.
Has the advantages that:
(1) According to the invention, indole halogen is used as an initiator, and forms free radicals under the induction of visible light, and then the free radicals and eneyne hydrocarbon substances undergo cyclization reaction. Compared with the prior art, the method adopts the organic photocatalyst for catalysis, is green and efficient, has no metal residue, short reaction time, no need of heating, high yield and wide application prospect in the aspect of synthesizing medical products. .
(2) The piperidone compound prepared by the method lays a foundation for synthesizing a medical product, so that the piperidone compound has higher competitiveness in the field of biomedical materials.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a NMR chart of a product III-A-1;
FIG. 2 is a NMR carbon spectrum of the product III-A-1;
FIG. 3 is a NMR chart of the product III-A-2;
FIG. 4 is a NMR carbon spectrum of the product III-A-2;
FIG. 5 is a NMR chart of the product III-A-3;
FIG. 6 is a NMR carbon spectrum of the product III-A-3;
FIG. 7 is a NMR fluorine spectrum of the product III-A-3;
FIG. 8 is a NMR chart of the product III-A-4;
FIG. 9 is a NMR carbon spectrum of product III-A-4;
FIG. 10 is a NMR chart of the product III-A-5;
FIG. 11 is a NMR carbon spectrum of product III-A-5;
FIG. 12 is a NMR chart of the product III-A-6;
FIG. 13 is a NMR carbon spectrum of product III-A-6;
FIG. 14 is a NMR chart of the product III-A-7;
FIG. 15 is a NMR carbon spectrum of product III-A-7;
FIG. 16 is a NMR fluorine spectrum of the product III-A-7;
FIG. 17 is a NMR chart of product III-A-8;
FIG. 18 is a NMR carbon spectrum of product III-A-8;
FIG. 19 is a NMR chart of product III-A-9;
FIG. 20 is a NMR carbon spectrum of product III-A-9;
FIG. 21 is a NMR chart of product III-A-10;
FIG. 22 is a NMR carbon spectrum of product III-A-10;
FIG. 23 is a NMR chart of the product III-B-1;
FIG. 24 is a NMR carbon spectrum of product III-B-1;
FIG. 25 is a NMR chart of the product III-B-2;
FIG. 26 is a NMR carbon spectrum of product III-B-2;
FIG. 27 is a NMR chart of product III-B-3;
FIG. 28 is a NMR carbon spectrum of product III-B-3;
FIG. 29 is a NMR fluorine spectrum of a product III-B-3;
FIG. 30 is a NMR chart of product III-B-4;
FIG. 31 is a NMR carbon spectrum of product III-B-4;
FIG. 32 is a NMR chart of product III-B-5;
FIG. 33 is a NMR carbon spectrum of product III-B-5;
FIG. 34 is a NMR chart of product III-B-6;
FIG. 35 is a NMR carbon spectrum of product III-B-6;
FIG. 36 is a NMR chart of product III-B-7;
FIG. 37 is a NMR carbon spectrum of product III-B-7;
FIG. 38 is a NMR fluorine spectrum of product III-B-7;
FIG. 39 is a NMR chart of product III-B-8;
FIG. 40 is a NMR carbon spectrum of product III-B-8;
FIG. 41 is a NMR chart of product III-B-9;
FIG. 42 is a NMR carbon spectrum of product III-B-9.
Detailed Description
The invention will be better understood from the following examples. However, it is easily understood by those skilled in the art that the descriptions of the embodiments are only for illustrating the present invention and should not be construed as limiting the present invention as detailed in the claims.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The synthesis method of the compound shown in the formula I used in the invention comprises the following steps: firstly, sodium hydride (15.0 mmol,1.5 equiv) solvent is added into super-dry tetrahydrofuran (100 mL) slowly under the ice-bath condition, and then the corresponding indole (10.0 mmol,1.0 equiv) is added for reaction for 30 minutes; 2-bromo-2-methylpropanoyl bromide (10.0 mmol,1.0 equiv) was slowly added dropwise to the reaction mixture, and then the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted three times with 150mL of ethyl acetate and 150mL of water, the layers were separated, and the separated organic layer was washed with anhydrous Na 2 SO 4 Drying and filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by using 200-300-mesh silica gel column chromatography to obtain a product (eluent ratio: petroleum ether: ethyl acetate = 20).
Wherein, the synthesis method of the organic photocatalyst used in the invention refers to the prior art 5 。
Example 1
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), styrene (115.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et were added at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in dichloroethane (DCE, 4 mL) as a solvent, mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the solution in the microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-a-1 with 93% conversion, ms =289.1469g/mol. FIG. 1 shows the nucleus of the product III-A-1A magnetic resonance hydrogen spectrum, and a nuclear magnetic resonance carbon spectrum of the product III-A-1 shown in figure 2.
Example 2
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-methylstyrene (131.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-a-2 with 89% conversion, ms =303.1623g/mol. FIG. 3 is a NMR hydrogen spectrum of the product III-A-2, and FIG. 4 is a NMR carbon spectrum of the product III-A-2.
Example 3
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-fluorostyrene (119.3. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-a-3 with 77% conversion, ms =307.1376g/mol. FIG. 5 is a NMR hydrogen spectrum of the product III-A-3, FIG. 6 is a NMR carbon spectrum of the product III-A-3, and FIG. 7 is a NMR fluorine spectrum of the product III-A-3.
Example 4
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-chlorostyrene (120.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-a-4 with 70% conversion, ms =323.1077g/mol. FIG. 8 is a NMR hydrogen spectrum of the product III-A-4, and FIG. 9 is a NMR carbon spectrum of the product III-A-4.
Example 5
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-bromostyrene (130.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et were added at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-a-5 with a conversion of 68% and Ms =367.0573g/mol. FIG. 10 is a NMR chart of the product III-A-5, and FIG. 11 is a NMR chart of the product III-A-5.
Example 6
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5 mg, 50.0. Mu. Mol,5% equiv.), 4-methoxystyrene (133.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methyl-phenazinePropane-1-one (265.0mg, 1.0mmol,1.0 equiv.) and Et 3 Dissolving N (152.9, mu L of 1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-a-6 with 51% conversion, ms =320.1652g/mol. FIG. 12 is a NMR hydrogen spectrum of the product III-A-6, and FIG. 13 is a NMR carbon spectrum of the product III-A-6.
Example 7
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4- (trifluoromethyl) styrene (147.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et at room temperature 3 Dissolving N (152.9, mu L of 1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-a-7 with a conversion of 62% and Ms =357.1348g/mol. FIG. 14 is a NMR hydrogen spectrum of the product III-A-7, FIG. 15 is a NMR carbon spectrum of the product III-A-7, and FIG. 16 is a NMR fluorine spectrum of the product III-A-7.
Example 8
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-cyanostyrene (120.2. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0mg, 1.0mmol,1.0 equiv.) and Et at room temperature 3 N (152.9. Mu.L, 1.1mmol,1.1 equiv.) was dissolved in DCE (4 mL) as a solvent and mixed,obtaining a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in the microchannel reactor irradiated by a blue light lamp (10W, 220V, LED, wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-a-8 with 76% conversion, ms =314.1424g/mol. FIG. 17 shows the NMR spectrum of the product III-A-8, and FIG. 18 shows the NMR spectrum of the product III-A-8.
Example 9
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-t-butylstyrene (183.2. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-a-9 with 82% conversion, ms =345.2096g/mol. FIG. 19 is a NMR hydrogen spectrum of the product III-A-9, and FIG. 20 is a NMR carbon spectrum of the product III-A-9.
Example 10
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), styrene (115.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-2-methyl-1- (3-methyl-1H-indol-1-yl) propan-1-one (279.0 mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol,1.1 equivalent) in solvent DCE (4 mL) and mixing to obtain homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, and performing microchannel reaction irradiated by a blue light lamp (10W, 220V, LED, wavelength of 420 nm-430 nm)In the vessel, the retention time was 10min, and the reaction effluent was collected with a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-a-10 with 90% conversion, ms =303.1623g/mol. FIG. 21 is a NMR hydrogen spectrum of the product III-A-10, and FIG. 22 is a NMR carbon spectrum of the product III-A-10.
Example 11
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), phenylacetylene (109.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et were added at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-B-1 with 93% conversion, ms =287.1319g/mol. FIG. 23 is a NMR chart of the product III-B-1, and FIG. 24 is a NMR chart of the product III-B-1.
Example 12
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-methylphenylacetylene (126.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 for the chromatographic separation with an eluent of (1),the desired product iii-B-2 was obtained with 89% conversion, ms =301.1467g/mol. FIG. 25 is a NMR hydrogen spectrum of the product III-B-2, and FIG. 26 is a NMR carbon spectrum of the product III-B-2.
Example 13
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5 mg, 50.0. Mu. Mol,5% equiv.), 4-fluoroacetylene (114.6. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et3N (152.9. Mu.L, 1.1mmol,1.1 equiv.) were dissolved in a solvent DCE (4 mL) at room temperature and mixed to give a homogeneous solution, which was pumped into a microchannel reactor with the pump flow rate controlled at 0.1mL/min, in a microchannel reactor irradiated with a blue lamp (10W, 220V, LED, wavelength 420nm to 430 nm), with a retention time of 10min, and the reaction effluent was collected by sampling. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-B-3 with 77% conversion, ms =305.1216g/mol. FIG. 27 is a NMR hydrogen spectrum of a product III-B-3, FIG. 28 is a NMR carbon spectrum of the product III-B-3, and FIG. 29 is a NMR fluorine spectrum of the product III-B-3.
Example 14
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-chlorophenylacetylene (118.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product III-B-4. Conversion 70%, ms =321.0947g/mol. FIG. 30 shows a NMR chart of the product III-B-4, and FIG. 31 shows a NMR chart of the product III-B-4And (4) a spectrogram.
Example 15
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-bromophenylacetylene (120.6. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0mg, 1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-B-5 with a conversion of 68% and Ms =365.0415g/mol. FIG. 32 shows a NMR chart of the product III-B-5, and FIG. 33 shows a NMR chart of the product III-B-5.
Example 16
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-methoxyphenylacetylene (129.7. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0mg, 1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL) for mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the flow rate of the pump to be 0.1mL/min, keeping the solution in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and wavelength of 420-430 nm) for 10min, and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product III-B-6. Conversion 51%, ms =317.1416g/mol. FIG. 34 is a NMR chart of the product III-B-6, and FIG. 35 is a NMR chart of the product III-B-6.
Example 17
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5 mg, 50.0. Mu. Mol,5% w/w) was added at room temperatureAmount), 4- (trifluoromethyl) phenylacetylene (139.9. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product iii-B-7 with a conversion of 62%, ms =355.1184g/mol. FIG. 36 is a NMR hydrogen spectrum of the product III-B-7, FIG. 37 is a NMR carbon spectrum of the product III-B-7, and FIG. 38 is a NMR fluorine spectrum of the product III-B-7.
Example 18
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), 4-ethylphenylacetylene (141.5. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0mg, 1.0mmol,1.0 equiv.) and Et at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to yield the desired product iii-B-8 with 82% conversion, ms =315.1623g/mol. FIG. 39 is a NMR hydrogen spectrum of the product III-B-8, and FIG. 40 is a NMR carbon spectrum of the product III-B-8.
Example 19
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), phenylacetylene (109.8. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-2-methyl-1- (3-methyl-1H-indol-1-yl) propan-1-one (279.0 mg,1.0mmol,1.0 equiv.) at room temperature0 eq) and Et 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor irradiated by a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether with ethyl acetate 10:1 to give the desired product III-B-9. Conversion 90%, ms =301.1463g/mol. FIG. 41 is a NMR hydrogen spectrum of the product III-B-9, and FIG. 42 is a NMR carbon spectrum of the product III-B-9.
Example 20
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), styrene (115.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et were added at room temperature 3 N (152.9. Mu.L, 1.1mmol,1.1 equiv.) was dissolved in solvent DCE (4 mL) and mixed, and the mixture was reacted for 4 hours in a reaction tube irradiated with a blue light lamp (10W, 220V, LED, wavelength 420 nm-430 nm). After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified on silica gel using petroleum ether and ethyl acetate 10:1 to yield the desired product iii-a-1 with 83% conversion, ms =289.1469g/mol.
Example 21
5, 10-bis (4- (trifluoromethyl) phenyl) -5, 10-dihydrophenazine (23.5mg, 50.0. Mu. Mol,5% equiv.), styrene (115.0. Mu.L, 1.0mmol,1.0 equiv.), 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one (265.0 mg,1.0mmol,1.0 equiv.), and Et were added at room temperature 3 Dissolving N (152.9 mu L,1.1mmol and 1.1 equivalent) in a solvent DCE (4 mL), mixing to obtain a homogeneous solution, pumping the homogeneous solution into a microchannel reactor, controlling the pump flow rate to be 0.1mL/min, keeping the time for 10min in a microchannel reactor without the irradiation of a blue light lamp (10W, 220V, LED and the wavelength of 420 nm-430 nm), and collecting reaction effluent by using a sample receiving flask. The desired product III-A-1 was not obtained with a conversion of 0.
The present invention provides a method and a concept for continuously synthesizing piperidone by light induction, and a plurality of methods and ways for implementing the technical scheme, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, a plurality of modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention. All the components not specified in this embodiment can be implemented by the prior art.
Reference:
1.M.Amat,C.Escolano,N.R.Llor,O.Lozano,A.Gomez-Esque,R.Griera and J.Bosch,Arkivoc,2005,DOI:10.3998/ark.5550190.0006.912,115-123.
2.I.Baussanne,C.Travers and J.Royer,Tetrahedron-Asymmetry,1998,9,797-804.
3.P.Jadav,R.Bahekar,S.R.Shah,D.Patel,A.Joharapurkar,M.Jain,K.V.V.M.Sairam and P.K.Singh,Bioorganic&Medicinal Chemistry Letters,2014,24,1918-1922.
4.T.Kosugi,D.R.Mitchell,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.Unoki,Y.Yamakoshi,V.Cunliffe,J.Frearson,R.Gordon,C.J.Harris,H.Kalloo-Hosein,J.Le,G.Patel,D.J.Simpson,B.Sherborne,P.S.Thomas,N.Suzuki,M.Takimoto-Kamimura and K.-i.Kataoka,Journal of MedicinalChemistry,2012,55,10312-10313.
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Claims (13)
1. a method for continuously synthesizing piperidone by light induction is characterized in that a compound shown as a formula I, a compound shown as a formula II, alkali and an organic photocatalyst are dissolved 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 shown as a formula III;
the structural formula of the compound shown in the formula II is shown as a formula II-A or a formula II-B;
the structural formula of the piperidone compound shown in the formula III is shown in a formula III-A or a formula III-B;
2. the method according to claim 1, wherein the compound represented by formula i is any one of 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one, 1-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-one, 2-bromo-1- (1H-indol-1-yl) -2-methylpropan-1-oic acid, 2-bromo-1- (1H-indol-1-yl) -2-ethylpan-n-1-one, 2-bromo-1- (1H-indol-1-yl) -2-methylbutan-1-one, 2-bromo-1- (1H-indol-1-yl) -3-methylbutan-1-one, and 2-bromo-2-methyl-1- (3-methyl-1H-indol-1-yl) propan-1-one.
3. The method according to claim 1, wherein the compound represented by formula II-A is any one of styrene, 2-fluorostyrene, 3-fluorostyrene, 4-fluorostyrene, 2-bromostyrene, 3-bromostyrene, 4-bromostyrene, 2-methoxystyrene, 3-methoxystyrene, 4-methoxystyrene, 2-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2-nitrostyrene, 3-nitrostyrene, 4-nitrostyrene, a-bromostyrene, n-propylene, i-propylene, 1, 3-propadiene, 4- (trifluoromethyl) styrene, 4-cyanostyrene and 4-t-butylstyrene.
4. The method according to claim 1, wherein the compound represented by formula II-B is any one of phenylacetylene, 2-fluoroacetylene, 3-fluoroacetylene, 4-fluoroacetylene, 2-chloroacetylene, 3-chloroacetylene, 4-chloroacetylene, 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, n-propyne, 4- (trifluoromethyl) phenylacetylene and 4-ethylphenylacetylene.
5. The method according to claim 1, wherein the base is any one or a combination of potassium phosphate, potassium carbonate, sodium bicarbonate, lithium tert-butoxide, triethylamine, 4-dimethylaminopyridine and pyridine.
6. The method of claim 1, wherein the organic photocatalyst is any 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, 5, 10-bis (1-naphthyl) -5, 10-dihydrophenazine, 10-phenylphenazine, 10- (4-methoxyphenyl) phenothiazine, 10- (1-naphthyl) phenothiazine, perylene, 3, 7-bis (4- (1, 1' -biphenyl)) - (10- (1-naphthyl)) -10-phenoxazine, and 5, 10-bis (4- (nitrile) phenyl) -5, 10-dihydrophenazine.
7. The method according to claim 1, wherein the organic solvent is any one or more of dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, ethylene glycol dimethyl ether, acetonitrile, benzene, N-dimethylformamide and N, N-dimethylaniline.
8. The method of claim 1, wherein the molar ratio of the compound of formula i, the compound of formula ii, the base, and the organic photocatalyst is 1:1 to 3: 1.1-2: 0.05 to 0.1.
9. The method of claim 1, wherein the concentration of the compound of formula i in the homogeneous solution is 0.02 to 2mmol/mL.
10. The method of claim 1, wherein the light source is blue light having a wavelength of 420nm to 430nm and a power of 10W.
11. The method of claim 1, wherein the microchannel reactor comprises an injector, a micromixer, a microchannel reactor, a receiver, a light source; the sample injector, the micro mixer, the micro channel reactor and the receiver are connected in series through pipelines; the light source is positioned at the outer side of the micro-channel reactor, and the illumination range of the light source covers the micro-channel reactor.
12. The method of claim 11, wherein the microchannel reactor is a quartz coil, the tube diameter is 0.2-2 mm, and the retention volume is 0.25-8 mL; the length of a connecting pipeline between the sample injector and the microchannel reactor is 10 cm-50 cm; the length of the connecting pipeline between the microchannel reactor and the receiver is 10 cm-50 cm.
13. The method of claim 1, wherein the flow rate of the homogeneous solution pumped into the microchannel reactor device is 0.05 to 0.2mL/min; the reaction is carried out, the reaction residence time is 5-40 min, and the reaction temperature is room temperature.
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