2, 3-disubstituted quinoxaline derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 2, 3-disubstituted quinoxaline derivative as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving a quinoxaline compound, aldehyde and electrolyte in a solvent, stirring for a plurality of hours under a constant current, and after the reaction is finished, carrying out post-treatment to obtain the 2, 3-disubstituted quinoxaline derivative. The method is mild in reaction condition, simple, convenient and safe to operate, and cheap and easily available in raw materials, and is an environment-friendly green synthesis method, and the quinoxaline derivative prepared by the method can be successfully applied to synthesis of potential drug molecules with antitumor activity, and provides a convenient means for bioactive molecules and drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 2,3-disubstituted quinoxaline derivative, a preparation method thereof and an application thereof. Background Art

[0002] Quinoxaline derivatives are an important class of heterocyclic compounds with benzopyrazine structures, and have a wide range of biological activities, mainly including: antiviral; antibacterial; anti-inflammatory; antimicrobials; anthelmintics, anticancer; kinase inhibitors. Quinoxaline derivatives also form the basis of many insecticides, bactericides, herbicides, and receptor antagonists. In addition, quinoxaline derivatives are also widely used in dyes, efficient electroluminescent materials, organic semiconductors, and DNA cleavage reagents. Therefore, the research on new synthesis methods of polysubstituted quinoxaline derivatives has important application value and has attracted the attention of scientific researchers in related fields.

[0003] The traditional synthesis methods of polysubstituted quinoxalines are mainly condensation reactions between ortho-disubstituted benzene compounds and synthons containing two carbons, such as the reactions of o-phenylenediamine compounds with 1,2-dicarbonyl compounds, α-hydroxy ketones, α,β-diols, α-bromo ketones, alkynes, epoxides, etc. In recent years, the synthesis of quinoxaline compounds by transition metal-catalyzed tandem reactions has attracted the attention of organic synthetic chemists. However, traditional synthetic routes often have problems such as many reaction steps, harsh reaction conditions, difficult availability of raw materials, poor regioselectivity, and the diversity of the synthesized molecular structures being restricted by reaction substrates.

[0004] The synthesis route catalyzed by transition metals solves the problems of many reaction steps and poor regioselectivity of the traditional synthesis route to a certain extent. However, due to the introduction of metals, a metal removal step is added during the post-treatment process. Therefore, based on the structural diversity of quinoxaline compounds and their wide applications in medicine, pesticides, and industry, the development of new synthesis methods has far-reaching significance. Summary of the Invention

[0005] Aiming at the problems existing in the prior art, the present invention provides a preparation method of a 2,3-disubstituted quinoxaline derivative. This method has mild reaction conditions, is simple, convenient and safe to operate, has cheap and easily available raw materials, is an environmentally friendly green synthesis method, and the quinoxaline derivative prepared by this method can be successfully applied to the synthesis of potential drug molecules with antitumor activity, providing a convenient means for bioactive molecules and drugs.

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

[0007] The preparation method of the 2,3-disubstituted quinoxaline derivatives provided by the present invention is as follows: Dissolve quinoxaline, aldehyde and electrolyte in a solvent to obtain a reaction solution, and apply an electric current to the reaction solution for an electrochemical reaction. After the reaction is completed, perform post-treatment to obtain the 2,3-disubstituted quinoxaline derivatives.

[0008] The reaction formula is as follows:

[0009]

[0010] Among them, quinoxaline includes one of the following: quinoxaline, 6-chloroquinoxaline, 6-bromoquinoxaline, 6-methylquinoxaline, 6-methoxyquinoxaline, 6,7-dichloroquinoxaline, 6,7-dibromoquinoxaline, 6,7-dimethylquinoxaline;

[0011] The aldehyde includes one of the following: phenylpropionaldehyde, isobutyraldehyde, propionaldehyde, butyraldehyde, 2-methylvaleraldehyde, 2-methylbutyraldehyde, 2-ethylhexanal, 2-ethylbutyraldehyde, cyclopropanecarbaldehyde, cyclopentanecarbaldehyde, cyclohexanecarbaldehyde, 3-cyclohexene-1-carbaldehyde.

[0012] The electrolyte is ammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate.

[0013] The solvent includes 1,2-dichloroethane, dimethyl sulfoxide; the dosage ratio of quinoxaline to the organic solvent is 0.5 - 1.0 mmol : 6 - 12 mL.

[0014] The molar ratio of quinoxaline to aldehyde is 1 : 1 - 3; the concentration of the electrolyte in the reaction solution is 0.1 M - 0.5 M.

[0015] The reaction temperature is 25°C - 80°C, the reaction time is 6 - 24 hours; the current is 5 - 15 mA.

[0016] The post-treatment process is: extraction, drying, rotary evaporation to remove the solvent, and column chromatography separation to obtain the 2,3-disubstituted quinoxaline derivatives.

[0017] In the present invention, it is preferred to place a graphite electrode (+) and a platinum electrode (-), a graphite electrode (+) and a graphite electrode (-), or a platinum electrode (+) and a platinum electrode (-) in the reaction solution before the start of the electrochemical reaction.

[0018] The obtained 2,3-disubstituted quinoxaline derivatives have the following structural formula:

[0019]

[0020] Among them, R1 is one of hydrogen, methyl, fluorine, chlorine, bromine; R2 is one of ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, triphenylpropyl.

[0021] In addition, the present invention also provides the use of the above-mentioned 2,3-disubstituted quinoxaline derivatives in the preparation of anti-tumor drugs.

[0022] The beneficial effects of the present invention are as follows:

[0023] The reaction conditions of the present invention are mild, the raw materials are cheap and easily available, the operation is simple, the yield is high, and there is no participation of metals and catalysts. It can be successfully used to synthesize potential drug molecules with anti-tumor activity, providing a convenient means for the synthesis of bioactive molecules and drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 1H NMR spectrum of the compound of Example 1;

[0025] Figure 2 13C NMR spectrum of the compound of Example 1;

[0026] Figure 3 1H NMR spectrum of the compound of Example 2;

[0027] Figure 4 13C NMR spectrum of the compound of Example 2;

[0028] Figure 5 1H NMR spectrum of the compound of Example 3;

[0029] Figure 6 13C NMR spectrum of the compound of Example 3. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] The technical solutions of the present invention will be further specifically described below through examples. These examples are for the purpose of illustrating the present invention and are not intended to limit the present invention. All other examples obtained by those of ordinary skill in the art based on the examples in this application without creative efforts shall fall within the scope of protection of this application.

[0031] The experimental methods described in the examples are all conventional methods unless otherwise specified; the reagents and materials are all commercially available unless otherwise specified.

[0032] Example 1

[0033] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0034]

[0035] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solution and perform microwave ultrasonic treatment for 5 min. Combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 68.1 mg of the product with a yield of 85%. The 1H NMR spectrum of the product is as shown in Figure 1 shown, and the 13C NMR spectrum is as shown in Figure 2 shown.

[0036] HRMS(ESI+) theoretical calculation for C 12 H 13 N2O[M+H] + : 201.1028, found: 201.1025.

[0037] Example 2

[0038] 3-Propylquinoxaline-2-carbaldehyde (Ⅲ-b)

[0039]

[0040] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), butyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solution and perform microwave ultrasonic treatment for 5 min. Combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 64.9 mg of the product with a yield of 81%. The 1H NMR spectrum of the product is as shown in Figure 3 shown, and the 13C NMR spectrum is as shown in Figure 4 shown.

[0041] HRMS(ESI+) theoretical calculation for C12 H 13 N2O[M+H] + : 201.1028, measured value: 201.1031.

[0042] Example 3

[0043] 3-Phenylquinoxaline-2-carbaldehyde (Ⅲ-c)

[0044]

[0045] Add quinoxaline (52 mg, 0.4 mmol), phenylpropanal (161 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) into a 50 mL Schlenk tube equipped with a magnetic stir bar. Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions for microwave ultrasonic treatment for 5 min, combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 81.9 mg of the product with a yield of 78%. The 1H NMR spectrum of the product is as Figure 5 shown, and the 13C NMR spectrum is as Figure 6 shown.

[0046] HRMS(ESI+) Theoretical calculation C 17 H 15 N2O[M+H] + : 263.1184, measured value: 263.1181.

[0047] Example 4

[0048] 3-Cyclopropylquinoxaline-2-carbaldehyde (Ⅲ-d)

[0049]

[0050] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), cyclopropanecarbaldehyde (84.1 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions and perform microwave ultrasonic treatment for 5 min. Combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 65.3 mg of the product with a yield of 82%.

[0051] HRMS(ESI+) Theoretical calculation for C 12 H 11 N2O[M+H] + : 199.0871, found: 199.0872.

[0052] Example 5

[0053] 3-Cyclohexylquinoxaline-2-carbaldehyde (Ⅲ-e)

[0054]

[0055] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), cyclohexanecarbaldehyde (134.6 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions and perform microwave ultrasonic treatment for 5 min. Combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 76.9 mg of the product with a yield of 80%.

[0056] HRMS(ESI+) Theoretical calculation for C 15 H 17 N2O[M+H] + : 241.1341, found: 241.1337.

[0057] Example 6

[0058] 3-(Pentan-2-yl)quinoxaline-2-carbaldehyde (Ⅲ-f)

[0059]

[0060] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add quinoxaline (52 mg, 0.4 mmol), 2-methylpentanal (120.2 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions and perform microwave ultrasound for 5 min, combine the reaction solution with the washing solutions after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 75.8 mg of the product, with a yield of 83%.

[0061] HRMS(ESI+) Theoretical calculation for C 14 H 17 N2O[M+H] + : 229.1341, Found: 229.1343.

[0062] Example 7

[0063] 3-(Pentan-3-yl)quinoxaline-2-carbaldehyde (Ⅲ-g)

[0064]

[0065] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add quinoxaline (52 mg, 0.4 mmol), 2-ethylbutanal (120.2 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions and perform microwave ultrasound for 5 min, combine the reaction solution with the washing solutions after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 71.2 mg of the product, with a yield of 78%.

[0066] HRMS(ESI+) Theoretical calculation for C 14 H 17 N2O[M+H] + : 229.1341, Measured value: 229.1345.

[0067] Example 8

[0068] 3-(Heptan-3-yl)quinoxaline-2-carbaldehyde (Ⅲ-h)

[0069]

[0070] Add quinoxaline (52 mg, 0.4 mmol), 2-ethylhexanal (153.9 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) into a 50 mL Schlenk tube equipped with a magnetic stir bar. Subsequently, insert a graphite electrode and a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for reaction for 8 h. After the reaction is completed, wash the electrodes three times with dichloromethane, combine the washing solutions, soak the electrodes in the washing solutions for microwave ultrasonic treatment for 5 min, combine the reaction solution with the washing solution after microwave ultrasonic treatment, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column with n-hexane / ethyl acetate to obtain 77.9 mg of the product with a yield of 76%.

[0071] HRMS(ESI+) Theoretical calculation for C 16 H 21 N2O[M+H] + : 257.1654, Measured value: 257.1653.

[0072] Example 9

[0073] 6,7-Dimethylquinoxaline (Ⅰ-b)

[0074]

[0075] 4,5-Dimethyl-1,2-phenylenediamine (100 mg, 0.925 mmol) and methanol solution (5 mL) were added to a 50 mL round-bottom flask. Glyoxal solution (40%, 134 mg, 0.11 mL, 0.925 mmol) was added to the above solution. After the addition was completed, the reaction was carried out at room temperature until the raw materials disappeared (detected by TLC). After the reaction was completed, ethyl acetate and brine were added to the reaction solution in turn, and liquid separation was carried out. The organic phase was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated ammonium chloride aqueous solution, the organic phase was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was further purified by recrystallization with ethyl acetate / petroleum ether to obtain 139 mg of the product with a yield of 95%.

[0076] 1 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 2H), 7.84 (s, 2H), 2.50 (s, 6H).

[0077] 3-Isopropyl-6,7-dimethylquinoxaline-2-carbaldehyde (Ⅲ-i)

[0078]

[0079] Compound 6,7-dimethylquinoxaline (63.3 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) were added to a 50 mL Schlenk tube equipped with a magnetic stir bar. Subsequently, a graphite electrode and a platinum electrode were inserted into the reaction solution, the current was adjusted to a constant current of 10 mA, and the temperature was raised to 70 °C for reaction for 8 h. After the reaction was completed, the electrodes were washed three times with dichloromethane, the washing solutions were combined, and the electrodes were immersed in the washing solutions for microwave ultrasonic treatment for 5 min. The reaction solution was combined with the washing solution after microwave ultrasonic treatment, washed with water, and liquid separation was carried out. The organic phase was retained, washed once with saturated brine and then dried over anhydrous sodium sulfate. The dried organic phase was distilled under reduced pressure at 45 °C to distill out the solvent. The crude product was purified on a silica gel column with n-hexane / ethyl acetate to obtain 76.7 mg of the product with a yield of 84%.

[0080] HRMS (ESI+) Theoretical calculation for C 14 H 17 N2O [M + H] + : 229.1341, found: 229.1335.

[0081] Example 10

[0082] 6,7-Dichloroquinoxaline (Ⅰ-c)

[0083]

[0084] In a 50 mL round-bottom flask, 4,5-dichloro-1,2-phenylenediamine (164 mg, 0.925 mmol) and methanol solution (5 mL) were added. To the above solution, glyoxal solution (40%, 134 mg, 0.11 mL, 0.925 mmol) was added. After the addition was complete, the reaction was carried out at room temperature until the raw materials disappeared (detected by TLC). After the reaction was completed, ethyl acetate and brine were added to the reaction solution in turn. The layers were separated, and the organic phase was extracted with ethyl acetate three times. The combined organic phases were washed twice with saturated ammonium chloride aqueous solution, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was further purified by recrystallization from ethyl acetate / petroleum ether to obtain 167.5 mg of the product, with a yield of 91%.

[0085] 1 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 2H), 8.45 (s, 2H).

[0086] 3-Isopropyl-6,7-dichloroquinoxaline-2-carbaldehyde (Ⅲ-j)

[0087]

[0088] In a 50 mL Schlenk tube equipped with a magnetic stir bar, 6,7-dichloroquinoxaline (79.6 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) were added. Subsequently, a graphite electrode and a platinum electrode were inserted into the reaction solution, the current was adjusted to a constant current of 10 mA, and the temperature was raised to 70 °C for reaction for 8 h. After the reaction was completed, the electrodes were washed three times with dichloromethane, the washing solutions were combined, and the electrodes were immersed in the washing solutions for microwave ultrasound for 5 min. The reaction solution was combined with the washing solution after microwave ultrasound, washed with water, the layers were separated, the organic phase was retained, washed once with saturated brine and then dried over anhydrous sodium sulfate. The dried organic phase was distilled under reduced pressure at 45 °C to distill off the solvent. The crude product was purified on a silica gel column with n-hexane / ethyl acetate to obtain 87.2 mg of the product, with a yield of 81%.

[0089] HRMS (ESI+) Theoretical calculation for C 12 H 11 Cl2N2O [M+H] + : 269.0248, Found: 269.0245.

[0090] Example 11

[0091] 6,7-Dibromoquinoxaline (Ⅰ-d)

[0092]

[0093] In a 50 mL round-bottom flask, 4,5-dibromo-1,2-phenylenediamine (246 mg, 0.925 mmol) and methanol solution (5 mL) were added. To the above solution, glyoxal solution (40%, 134 mg, 0.11 mL, 0.925 mmol) was added. After the addition was complete, the reaction was carried out at room temperature until the raw materials disappeared (detected by TLC). After the reaction was completed, ethyl acetate and brine were successively added to the reaction solution. Liquid separation was performed, and the organic phase was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated aqueous ammonium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was further purified by recrystallization from ethyl acetate / petroleum ether to obtain 237.1 mg of the product, with a yield of 89%.

[0094] 1 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 8.44 (s, 2H).

[0095] 3-Isopropyl-6,7-dibromoquinoxaline-2-carbaldehyde (Ⅲ-k)

[0096]

[0097] In a 50 mL Schlenk tube equipped with a magnetic stir bar, compound 6,7-dibromoquinoxaline (115.2 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) were added. Subsequently, a graphite electrode and a platinum electrode were inserted into the reaction solution, the current was adjusted to a constant current of 10 mA, and the temperature was raised to 70 °C for reaction for 8 h. After the reaction was completed, the electrodes were washed three times with dichloromethane, the washing solutions were combined, and the electrodes were immersed in the washing solutions for microwave ultrasound for 5 min. The reaction solution was combined with the washing solution after microwave ultrasound, washed with water, and liquid separation was performed. The organic phase was retained, washed once with saturated brine, dried over anhydrous sodium sulfate, and the dried organic phase was distilled under reduced pressure at 45 °C to distill off the solvent. The crude product was purified on a silica gel column with n-hexane / ethyl acetate to obtain 111.7 mg of the product, with a yield of 78%.

[0098] HRMS (ESI+) Theoretical calculation for C 12 H 11 Br2N2O [M+H] + : 356.9238, found: 356.9234.

[0099] Example 12

[0100] 6,7-Difluoroquinoxaline (Ⅰ-e)

[0101]

[0102] 4,5-Difluoro-1,2-phenylenediamine (133 mg, 0.925 mmol) and methanol solution (5 mL) were added to a 50 mL round-bottom flask. Glyoxal solution (40%, 134 mg, 0.11 mL, 0.925 mmol) was added to the above solution. After the addition was completed, the reaction was carried out at room temperature until the raw materials disappeared (detected by TLC). After the reaction was completed, ethyl acetate and brine were added to the reaction solution in turn. The mixture was separated by liquid-liquid extraction. The organic phase was extracted with ethyl acetate three times. The combined organic phases were washed twice with saturated ammonium chloride aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was further purified by recrystallization from ethyl acetate / petroleum ether to obtain 90.7 mg of the product, with a yield of 59%.

[0103] 1 1H NMR (500 MHz, CDCl3) δ 8.84 (s, 2H), 7.87 (t, J = 9.3 Hz, 2H).

[0104] 3-Isopropyl-6,7-difluoroquinoxaline-2-carbaldehyde (Ⅲ-l)

[0105]

[0106] Compound 6,7-difluoroquinoxaline (66.5 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL) were added to a 50 mL Schlenk tube equipped with a magnetic stir bar. Subsequently, a graphite electrode and a platinum electrode were inserted into the reaction solution, and the current was adjusted to a constant current of 10 mA. The temperature was raised to 70 °C and the reaction was carried out for 8 h. After the reaction was completed, the electrodes were washed three times with dichloromethane. The washing solutions were combined, and the electrodes were immersed in the washing solutions and sonicated by microwave for 5 min. The reaction solution was combined with the washing solution after microwave sonication, washed with water, and separated by liquid-liquid extraction. The organic phase was retained, washed once with saturated brine, and then dried over anhydrous sodium sulfate. The dried organic phase was distilled under reduced pressure at 45 °C to remove the solvent. The crude product was purified on a silica gel column with n-hexane / ethyl acetate to obtain 64.3 mg of the product, with a yield of 68%.

[0107] HRMS (ESI+) Theoretical calculation for C 12 H 11 F2N2O [M + H] + : 237.0839, Found: 237.0833.

[0108] Example 13

[0109] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0110]

[0111] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a graphite electrode into the reaction solution, adjust the current to a constant current of 10 mA, heat to 70 °C and react for 8 h. After the reaction is completed, wash the electrode three times with dichloromethane, combine the washing solutions, soak the electrode in the washing solution and perform microwave ultrasound for 5 min. Combine the reaction solution with the washing solution after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 58.5 mg of the product with a yield of 73%.

[0112] Example 14

[0113] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0114]

[0115] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, heat to 70 °C and react for 8 h. After the reaction is completed, wash the electrode three times with dichloromethane, combine the washing solutions, soak the electrode in the washing solution and perform microwave ultrasound for 5 min. Combine the reaction solution with the washing solution after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 52.1 mg of the product with a yield of 65%.

[0116] Example 15

[0117] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0118]

[0119] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium hexafluorophosphate (193.7 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and heat to 70 °C for 8 h. After the reaction is completed, wash the electrode three times with dichloromethane, combine the washing solutions, soak the electrode in the washing solutions and perform microwave ultrasound for 5 min. Combine the reaction solution with the washing solution after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 60.1 mg of the product with a yield of 75%.

[0120] Example 16

[0121] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0122]

[0123] In a 50 mL Schlenk tube equipped with a magnetic stir bar, add the compound quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a platinum electrode into the reaction solution, adjust the current to a constant current of 5 mA, and heat to 70 °C for 24 h. After the reaction is completed, wash the electrode three times with dichloromethane, combine the washing solutions, soak the electrode in the washing solutions and perform microwave ultrasound for 5 min. Combine the reaction solution with the washing solution after microwave ultrasound, wash with water, separate the layers, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 38.4 mg of the product with a yield of 48%.

[0124] Example 17

[0125] 3-Isopropylquinoxaline-2-carbaldehyde (Ⅲ-a)

[0126]

[0127] Into a 50 mL Schlenk tube equipped with a magnetic stir bar, add quinoxaline (52 mg, 0.4 mmol), isobutyraldehyde (86.5 mg, 1.2 mmol), tetrabutylammonium tetrafluoroborate (164.6 mg, 0.5 mmol) and 1,2-dichloroethane (5 mL). Subsequently, insert a platinum electrode into the reaction solution, adjust the current to a constant current of 10 mA, and react at room temperature for 24 h. After the reaction is completed, wash with water, separate the liquid, combine the washing liquids, soak the electrode in the washing liquid and perform microwave ultrasound for 5 min. Combine the reaction solution with the washing liquid after microwave ultrasound, extract three times successively with dichloromethane and water, retain the organic phase, wash the organic phase once with saturated brine and then dry it with anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure at 45 °C to distill off the solvent. Purify the crude product on a silica gel column using n-hexane / ethyl acetate to obtain 68.9 mg of the product, with a yield of 86%.

[0128] Example 18

[0129] The anti-tumor activity (IC 50 ) of the target compound was detected by the MTT method. The specific operation of the MTT method is as follows: Culture target cells (human prostate cancer cells PC-3, lung cancer cells A549, cervical cancer cells Hela, and human liver cancer cells HepG2). Take the cells in the logarithmic growth phase and prepare a cell suspension of about 90,000 cells per milliliter. The culture medium used is RPMI1640 culture medium. Inoculate the cell suspension into a 96-well plate, 100 μL per well, and then culture in an incubator for 24 h - 48 h. The culture environment is 37 °C and 5% carbon dioxide is passed. This process needs to be observed frequently. When the cell density is about 70%, the drug (quinoxaline derivative) can be added. Add the quinoxaline derivative, with 4 replicate wells. The concentration of the compound to be tested is between 10 -6 and 10 -4 M. A control group needs to be set up. The blank control group does not add the drug. The drug addition process should be as fast as possible. After adding, place it in the incubator and culture for 48 hours. After the time, remove the culture medium in each well and wash it once with 1640 culture medium. Immediately stain with MTT (20 μL of 5 mg / mL), and the staining time is 4 hours. Aspirate the liquid in each well and add 100 μL of chromatographically pure DMSO to each well. After adding, shake on an oscillator for 10 minutes. Finally, use an enzyme-linked immunosorbent assay (ELISA) reader to detect the OD value of each well in the 96-well plate, and the detection wavelength is 490 nm. The result calculation is completed by SPSS software, and the half-lethal dose (IC 50 ) of each compound against the selected tumor cells can be obtained.

[0130] The inhibitory effect of the 2,3-disubstituted quinoxaline derivatives prepared in Examples 1-6 on tumor cell proliferation was detected. The MTT method was used to determine the in vitro inhibitory effect of the compounds on human prostate cancer cells PC-3, human lung cancer cells A549, cervical cancer cells Hela and human liver cancer cells HepG2, and the half inhibitory concentration (IC 50 ), the results are shown in Table 1.

[0131] Table 1 In vitro inhibitory activity of 2,3-disubstituted quinoxaline derivatives against different tumor cells

[0132]

[0133] Through experiments, it was found that the synthesized 2,3-disubstituted quinoxaline derivatives have the function of inhibiting tumor cells, and the parent core structure can be further optimized to obtain a molecular structure with better activity. This can reflect that the designed 2,3-disubstituted quinoxaline derivatives have inhibitory functions in anti-tumor cells and have certain application prospects.

[0134] Finally, it should be noted that the above are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims

1. A 2,3-disubstituted quinoxaline derivative, characterized in that, The structural formula of the quinoxaline derivative is shown as follows: Among them, R1 is one of hydrogen, methyl, fluorine, chlorine, and bromine; R2 is one of ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, and triphenylpropyl.

2. A method for preparing a 2,3-disubstituted quinoxaline derivative according to claim 1, characterized in that, The preparation method is as follows: Dissolve quinoxaline, aldehyde, and electrolyte in a solvent to obtain a reaction solution, and then apply an electric current to the reaction solution for an electrochemical reaction. After the reaction is completed, perform post-treatment to obtain a 2,3-disubstituted quinoxaline derivative.

3. The preparation method of the 2,3-disubstituted quinoxaline derivative according to claim 2, characterized in that, The quinoxaline is: quinoxaline, 6-chloroquinoxaline, 6-bromoquinoxaline, 6-methylquinoxaline, 6-methoxyquinoxaline, 6,7-dichloroquinoxaline, 6,7-dibromoquinoxaline, 6,7-dimethylquinoxaline.

4. The preparation method of the 2,3-disubstituted quinoxaline derivatives according to claim 2, characterized in that, The aldehyde is: phenylpropionaldehyde, isobutyraldehyde, propionaldehyde, butyraldehyde, 2-methylvaleraldehyde, 2-methylbutyraldehyde, 2-ethylhexanal, 2-ethylbutyraldehyde, cyclopropanecarbaldehyde, cyclopentanecarbaldehyde, cyclohexanecarbaldehyde, 3-cyclohexene-1-carbaldehyde.

5. The preparation method of the 2,3-disubstituted quinoxaline derivatives according to claim 2, characterized in that, The electrolyte is: ammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, and the solvent includes 1,2-dichloroethane and dimethyl sulfoxide.

6. The preparation method of the 2,3-disubstituted quinoxaline derivative according to claim 2, characterized in that, The molar ratio of the quinoxaline to the aldehyde is: 1:1 - 3; the concentration of the electrolyte in the reaction solution is: 0.1 M - 0.5 M.

7. The preparation method of the 2,3-disubstituted quinoxaline derivative according to claim 2, characterized in that, The reaction temperature is: 25 - 80 °C, and the reaction time is: 6 - 24 hours.

8. The preparation method of the 2,3-disubstituted quinoxaline derivative according to claim 2, characterized in that, The current is: 5 - 15 mA, and the molar volume ratio of quinoxaline to the organic solvent is: 0.5 - 1.0 mmol: 6 - 12 mL.

9. The preparation method of the 2,3-disubstituted quinoxaline derivatives according to claim 2, characterized in that, The post-treatment process is: extraction, drying, rotary evaporation to remove the solvent, and column chromatography separation to obtain a 2,3-disubstituted quinoxaline derivative.

10. Use of a 2,3-disubstituted quinoxaline derivative according to claim 1, characterized in that, The 2,3-disubstituted quinoxaline derivative is used to prepare a drug for inhibiting tumors.

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