Preparation method and application of C3 position cyanoalkyl substituted quinoxalinone

Abstract

The invention belongs to the field of electrochemistry and green synthesis, and particularly relates to a preparation method and application of quinoxalinone substituted by cyanoalkyl at the C3 position. The preparation method comprises the following steps: by taking quinoxalinone and acrylonitrile as reaction raw materials, adding an electrolyte, an organic solvent and an additive, and carrying out electrolytic reaction to obtain the C3-position cyanoalkyl substituted quinoxalinone. The method for electrolytically synthesizing the C3-position cyanoalkyl substituted quinoxalinone is reported for the first time, acrylonitrile which is low in price and easy to obtain serves as an alkyl source, pre-activation of a substrate is not needed, operation is easy, cost is low, the atom utilization rate is high, participation of a chemical redox reagent is not needed, the reaction temperature is room temperature, and the method is suitable for industrial production. The C3-position cyanoalkyl substituted quinoxalinone can be efficiently and greenly synthesized; the quinoxalinone substituted by cyanoalkyl at the C3 position has good anti-cancer activity, can be used for preparing anti-cancer drugs, and has important application value.

Description

Technical Field

[0001] The invention belongs to the field of electrochemistry and green synthesis, and specifically relates to a preparation method and application of a C3-cyanoalkyl-substituted quinoxalinone. Background Art

[0002] C3 alkyl-substituted quinoxalone (quinoxaline-2(1H)-one) is an important class of drug molecules and bioactive molecular skeletons. For example, this class of molecular skeletons can be used as drug antagonists (J. Med. Chem. 2001, 44, 594–601). In addition, cyanoalkyl groups can significantly improve the physicochemical properties, pharmacodynamics and pharmacokinetic properties of drug molecules. For example, verapamil for the treatment of angina pectoris and saxagliptin for lowering blood sugar contain cyanoalkyl structures. Therefore, modifying bioactive molecules with cyano groups is one of the important means of drug development.

[0003] In view of the important uses of C3-alkyl-substituted quinoxalinones and cyanoalkyl groups in drug development, the introduction of cyanoalkyl groups into the C3 position of quinoxalinones molecules and the efficient synthesis of C3-cyanoalkyl-substituted quinoxalinones with diverse structures have important research significance and potential application value. However, the synthesis of C3-cyanoalkyl-substituted quinoxalinones is still a challenging problem, and there are no corresponding literature and patent reports. Summary of the invention

[0004] In view of the deficiencies in the prior art, the first object of the present invention is to provide a method for preparing a C3-cyanoalkyl-substituted quinoxalinone; the preparation method has the advantages of simple operation, low cost and environmental protection.

[0005] The second object of the present invention is to provide the use of the C3 cyanoalkyl substituted quinoxalinone prepared by the above method, wherein the C3 cyanoalkyl substituted quinoxalinone has good anticancer activity and can be used to prepare anticancer drugs.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing a C3-cyanoalkyl-substituted quinoxalinone, the method comprising taking a quinoxalinone (quinoxaline-2(1H)-one) shown in formula I and acrylonitrile as reaction raw materials, adding an electrolyte, an organic solvent and an additive, and conducting an electrolytic reaction to obtain a C3-cyanoalkyl-substituted quinoxalinone shown in formula II; the reaction route is as follows:

[0008]

[0009] Among them, R 1is methyl, benzyl, isopropyl, 3-methoxypropyl, 3-phenoxypropyl, 3-benzyloxypropyl, alkoxy, difluoroisopropyl, chloroalkyl, methyl propionate, methyl valerate, 3-tert-butyloxycarbonyl, dimethyl-tert-butylsiloxyethyl, diphenyl-tert-butylsiloxypropyl, allyl, 1,1-dimethylallyl, butylene, propargyl, 1-methylpropargyl, butylene, alkyl propionate or propyl aryl acetate; R 2 is hydrogen, methyl, chlorine or fluorine; R 2 The benzene ring is singly substituted or polysubstituted.

[0010] Furthermore, the structural formula of the C3-cyanoalkyl-substituted quinoxalinone is any one of the following:

[0011]

[0012] Furthermore, the molar ratio of the quinoxalinone, acrylonitrile, electrolyte and additive is 1:10:1:1: the molar volume ratio of the quinoxalinone and the organic solvent is 0.3 mmol:5 mL.

[0013] Furthermore, the electrolyte is tetraethylammonium chloride (Et 4 NCl); the additive is acetic acid (HOAc); and the organic solvent is acetonitrile.

[0014] Furthermore, the anode of the electrolysis is a graphite sheet, the cathode is a zinc sheet, and the current density is 5 mA / cm 2 ; The reaction temperature is room temperature and the reaction time is 8h.

[0015] Furthermore, after the reaction is completed, the reaction solution needs to be extracted, dried, distilled under reduced pressure and separated and purified by column chromatography.

[0016] Furthermore, ethyl acetate is used in the extraction.

[0017] The preparation method provided by the invention is based on the coupling reaction of quinoxalinone and acrylonitrile, and can prepare quinoxalinone substituted with cyanoalkyl at the C3 position efficiently and greenly without adding an external chemical redox reagent.

[0018] The application of the C3-cyanoalkyl-substituted quinoxalinone prepared by the above method, wherein the C3-cyanoalkyl-substituted quinoxalinone can be used for preparing anticancer drugs.

[0019] Furthermore, the C3-cyanoalkyl-substituted quinoxalinone can be used to prepare anti-breast cancer drugs.

[0020] Beneficial Effects

[0021] (1) The present invention uses quinoxalinone and acrylonitrile as reaction raw materials to carry out electrolytic reaction to efficiently and greenly synthesize C3-cyanoalkyl-substituted quinoxalinone. The present invention reports for the first time a preparation method for electrolytically synthesizing C3-cyanoalkyl-substituted quinoxalinone.

[0022] (2) The present invention directly uses cheap and readily available acrylonitrile as the alkyl source, and there is no need to pre-activate the substrate. Therefore, the preparation process provided by the present invention has the advantages of low cost and high atomic utilization rate. The present invention does not require the participation of chemical redox reagents, and the reaction temperature is room temperature. Therefore, the process has the significant advantages of being economical and green.

[0023] (3) The C3-cyanoalkyl-substituted quinoxalinone prepared by the present invention has good anticancer activity and can be used to prepare anticancer drugs, thus having important application value. DETAILED DESCRIPTION

[0024] The following description further describes the specific details of the present invention for a full understanding of the present invention. The terms used in the description of the present invention are only used to illustrate the advantages and features of the present invention and are not intended to limit the present invention.

[0025] Unless otherwise defined, all professional and scientific terms used in the present invention have the same meanings as those understood by those skilled in the art of the present invention. Unless otherwise specified, the drugs or reagents used in the present invention are used in accordance with the product instructions or in the conventional methods of use in the relevant field. The process of the present invention is further described based on the instructions and specific embodiments.

[0026] The route for synthesizing C3 cyanoalkyl-substituted quinoxalinone of the present invention is:

[0027]

[0028] Among them, R 1 is methyl, benzyl, isopropyl, 3-methoxypropyl, 3-phenoxypropyl, 3-benzyloxypropyl, alkoxy, difluoroisopropyl, chloroalkyl, methyl propionate, methyl valerate, 3-tert-butyloxycarbonyl, dimethyl-tert-butylsiloxyethyl, diphenyl-tert-butylsiloxypropyl, allyl, 1,1-dimethylallyl, butylene, propargyl, 1-methylpropargyl, butylene, alkyl propionate or propyl aryl acetate; R 2 is hydrogen, methyl, chlorine or fluorine; R 2 The benzene ring is singly substituted or polysubstituted.

[0029] Example 1

[0030] The raw materials N-methylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 75%.

[0031]

[0032] Example 2

[0033] The raw materials 6,7-dimethyl-N-methylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The above mixed solution was heated at 5 mA / cm at room temperature. 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 71%.

[0034]

[0035] Example 3

[0036] The raw materials 6,7-difluoro-N-methylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 64%.

[0037]

[0038] Example 4

[0039] The raw materials 6-methyl-N-methylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the above mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 74%.

[0040]

[0041] Example 5

[0042] The raw materials N-benzylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 73%.

[0043]

[0044] Example 6

[0045] The raw materials N-isopropylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 68%.

[0046]

[0047] Example 7

[0048] The raw materials N-3-methoxypropylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 63%.

[0049]

[0050] Example 8

[0051] The raw materials N-3-phenoxypropylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 61%.

[0052]

[0053] Example 9

[0054] The raw materials N-3-benzyloxypropylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 63%.

[0055]

[0056] Example 10

[0057] The raw materials N-alkoxyquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 67%.

[0058]

[0059] Embodiment 11

[0060] The raw materials N-difluoroisopropylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 59%.

[0061]

[0062] Example 12

[0063] The raw materials N-chloroalkylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 69%.

[0064]

[0065] Example 13

[0066] The raw materials N-methylpropionate quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 67%.

[0067]

[0068] Embodiment 14

[0069] The raw materials N-methylpentanoate quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 70%.

[0070]

[0071] Embodiment 15

[0072] The raw materials N-3-tert-butyloxycarbonylpropylamine protected quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the above mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 69%.

[0073]

[0074] Example 16

[0075] The raw materials N-dimethyl-tert-butylsilyloxyethyl protected quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the above mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 70%.

[0076]

[0077] Embodiment 17

[0078] The raw materials N-diphenyl-tert-butylsilyloxypropyl protected quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 64%.

[0079]

[0080] Embodiment 18

[0081] The raw materials N-allylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. The mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 68%.

[0082]

[0083] Embodiment 19

[0084] The raw materials N-1,1-dimethylallyl-protected quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the above mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 70%.

[0085]

[0086] Embodiment 20

[0087] The raw materials N-butylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 71%.

[0088]

[0089] Embodiment 21

[0090] The raw materials N-propargylquinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 71%.

[0091]

[0092] Embodiment 22

[0093] The raw materials N-1-methylpropargyl protected quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the above mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 72%.

[0094]

[0095] Embodiment 23

[0096] The raw materials N-acetyl butyl quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 73%.

[0097]

[0098] Embodiment 24

[0099] The raw materials N-alkyl propionate quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 64%.

[0100]

[0101] Embodiment 25

[0102] The raw materials N-alkyl propionate quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 65%.

[0103]

[0104] Embodiment 26

[0105] The raw materials N-arylacetate propyl quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 61%.

[0106]

[0107] Embodiment 27

[0108] The raw materials N-arylacetate propyl quinoxalinone (0.3 mmol), acrylonitrile (3 mmol), acetonitrile (5 mL), tetraethylammonium chloride (0.3 mmol) and HOAc (0.3 mmol) were added to the electrolytic cell. Then, a graphite sheet and a zinc sheet were inserted into the electrolytic cell as the anode and cathode, respectively. At room temperature, the mixed solution was heated at 5 mA / cm 2 The solution was then transferred to a separatory funnel, 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3), dried, and the solvent was removed by vacuum distillation. Finally, the target product was separated and purified by column chromatography, and the structural formula is shown below. Yield: 62%.

[0109]

[0110] Performance Testing:

[0111] In order to determine the anticancer properties of the C3 cyanoalkyl-substituted quinoxalinone synthesized in the present invention, we selected MCF-7 cells (human breast cancer cells) as the research object and tested the IC 50 The results show that the IC values ​​of the C3 cyanoalkyl-substituted quinoxalone synthesized in Examples 16, 18, 25 and 27 are 50 The values ​​were 83μM, 94μM, 77μM and 82μM respectively. The IC value of Vincristine, a widely used drug, is 50 The value is about 51 μM. From the above data, it can be found that the C3 cyanoalkyl-substituted quinoxalinone synthesized by the present invention has potential medicinal value.

Claims

1. A method for preparing a C3-cyanoalkyl-substituted quinoxalinone, characterized in that: The preparation method is to use quinoxalinone and acrylonitrile as reaction raw materials shown in formula I, add electrolyte, organic solvent and additives, and perform electrolytic reaction to obtain C3 cyanoalkyl substituted quinoxalinone shown in formula II; the reaction route is as follows: Among them, R 1 is methyl, benzyl, isopropyl, 3-methoxypropyl, 3-phenoxypropyl, 3-benzyloxypropyl, alkoxy, difluoroisopropyl, chloroalkyl, methyl propionate, methyl valerate, 3-tert-butyloxycarbonyl, dimethyl-tert-butylsilyloxyethyl, diphenyl-tert-butylsilyloxypropyl, allyl, 1,1-dimethylallyl, butylene, propargyl, 1-methylpropargyl, butylene, alkyl propionate or propyl aryl acetate; R 2 is hydrogen, methyl, chlorine or fluorine; R 2 The benzene ring is singly substituted or polysubstituted.

2. The preparation method according to claim 1, characterized in that: The structural formula of the C3 cyanoalkyl-substituted quinoxalinone is any one of the following:

3. The preparation method according to claim 1, characterized in that: The molar ratio of the quinoxalinone, acrylonitrile, electrolyte and additive is 1:10:1:1: the molar volume ratio of the quinoxalinone and the organic solvent is 0.3 mmol:5 mL.

4. The preparation method according to claim 1, characterized in that: The electrolyte is tetraethylammonium chloride; the additive is acetic acid; and the organic solvent is acetonitrile.

5. The preparation method according to claim 1, characterized in that: The anode of the electrolysis is a graphite sheet, the cathode is a zinc sheet, and the current density is 5 mA / cm 2 ; The reaction temperature is room temperature and the reaction time is 8h.

6. The preparation method according to claim 1, characterized in that: After the reaction is completed, the reaction solution needs to be extracted, dried, distilled under reduced pressure and separated and purified by column chromatography.

7. The preparation method according to claim 6, characterized in that: The extraction used ethyl acetate.

8. Use of a C3-cyanoalkyl-substituted quinoxalinone prepared by the method according to any one of claims 1 to 7, characterized in that: The C3-cyanoalkyl-substituted quinoxalinone can be used for preparing anticancer drugs.

9. The use according to claim 8, characterized in that: The C3-cyanoalkyl-substituted quinoxalinone can be used for preparing anti-breast cancer drugs.

Images