A visible light-mediated synthesis method of 3-alkylquinoxaline-2 (1H) ketone compounds

Abstract

The present invention discloses a visible light-mediated 3-alkylquinoxaline-2 (1 H ) A method for synthesizing ketone compounds, comprising reacting the raw material 3,4-dihydro-1 H The 2-quinoxaline ketone compound and the alkyl NHPI ester compound are placed in a reaction solvent, and reacted under the action of a catalyst 4CzIPN and a base DABCO, and under the conditions of blue light irradiation and air environment to obtain the target product 3-alkylquinoxaline-2 (1 H ) ketone compounds. The present invention uses greener and cleaner visible light as energy to induce the reaction, and uses green and environmentally friendly solvent dimethyl carbonate as a reaction solvent. The raw materials are simple and easy to obtain, and the yield of the target product is high.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of quinoxalinone and its derivatives, relates to a synthesis method of 3-alkylquinoxaline-2(1H)ketone compounds, and specifically relates to a visible light-mediated synthesis method of 3-alkylquinoxaline-2(1H)ketone compounds. Background Art

[0002] The structural formula of 3-alkylquinoxaline-2(1H)one compounds is as follows: Quinoxalinone and its derivatives are an important class of nitrogen heterocyclic compounds, which are widely present in natural products, drugs and functional materials with various biological activities and have good pharmacodynamics. At the same time, quinoxalinone has multiple active sites, which can be used to modify and transform drugs. Researchers have found that derivatives synthesized with it as a structural nucleus have a variety of pharmacological activities, such as antithrombotic effects (J.Med.Chem.2004,47,16,4089-4099), antioxidant effects (J.Med.Chem.2015,58,3,1254-1267), anticancer effects (Eur.J.Med.Chem.2014,86,122-132), etc. Therefore, in-depth research on 3-alkylquinoxaline-2 (1H) ketone compounds and their derivatives will help expand the wider application of such compounds in the field of drug research, which is of great significance for the development of new therapeutic drugs.

[0003] The commonly used synthesis method at present is to use 2-hydroxyquinoxalinone as a reaction raw material to synthesize 3-alkylquinoxaline-2(1H)one compounds and their derivatives, but the reaction conditions generally use transition metal catalysis (ACS Sustainable Chemistry & Engineering, 2019, 7(16), 14153-14160), oxidants (Organic Letters, 2020, 22(15): 5984-5989) or high temperature conditions (Angewandte Chemie International Edition, 2020, 59(27): 10859-10863). At the same time, the reaction solvents used are not green and environmentally friendly solvents, and the reaction conditions are relatively harsh and not green and environmentally friendly.

[0004] In the synthetic routes that have been reported so far, the industrial synthesis of 3-alkylquinoxaline-2(1H)one compounds is restricted by factors such as the difficulty in separating and purifying the source of the starting materials, the generally high requirements for process equipment such as the reaction conditions, and the use of environmentally friendly solvents. Therefore, it is of practical significance to develop a method to construct 3-alkylquinoxaline-2(1H)one compounds by direct alkyl aromatization reaction of 3,4-dihydro-1H-2-quinoxaline compounds promoted by visible light using environmentally friendly solvents. Summary of the invention

[0005] The technical problem solved by the present invention is to provide a method for synthesizing 3-alkylquinoxaline-2(1H)one compounds mediated by visible light with simple process and low cost. The method uses 3,4-dihydro-1H-2-quinoxaline compounds and alkyl NHPI ester compounds as starting reaction raw materials, and utilizes visible light-induced reaction to obtain 3-alkylquinoxaline-2(1H)one compounds with high yield. The present invention uses greener and cleaner visible light as energy and uses green and environmentally friendly solvent anhydrous dimethyl carbonate as reaction solvent. The raw materials are simple and easy to obtain and the yield of the target product is high.

[0006] The present invention adopts the following technical scheme to solve the above technical problems. A visible light-mediated synthesis method of 3-alkylquinoxaline-2(1H)ketone compounds is characterized by the specific steps of: adding reaction raw materials 3,4-dihydro-1H-2-quinoxaline compounds and alkyl NHPI ester compounds, catalyst 4CzIPN, base DABCO and reaction solvent anhydrous dimethyl carbonate (DMC) into a reaction container in sequence, and using blue light to induce reaction to obtain the target product 3-alkylquinoxaline-2(1H)ketone compounds; wherein the structure of the 3,4-dihydro-1H-2-quinoxaline compounds is shown in formula A, the structure of the alkyl NHPI ester compounds is shown in formula B, and the structure of the 3-alkylquinoxaline-2(1H)ketone compounds is shown in formula C:

[0007]

[0008] R in Formula A and Formula C 1 is H, Cl, Br, F, methyl, methoxy or methyl ester, and R in formula B and formula C 2 C 1-6 Straight chain or branched alkyl, substituted C 1-6 Straight or branched alkyl, C 3-6 Cycloalkyl or heterocycloalkyl, wherein the substitution C 1-6 The substituent in the straight chain or branched alkyl group is C 3-6 Cycloalkyl, phenyl, ester or phenol.

[0009] Further defined, the compound corresponding to formula C is:

[0010]

[0011]

[0012] It is further defined that the molar ratio of the 3,4-dihydro-1H-2-quinoxalinone compound, the alkyl NHPI ester compound, the catalyst and the base is 1:1-3:0.01-0.1:1-3.

[0013] It is further defined that the light source of the blue light is a blue LED lamp with a wavelength of 450-460nm and a power of 5-10W.

[0014] It is further defined that the reaction temperature of the reaction process is 25-40° C., and the reaction time is 6-24 hours.

[0015] It is further specified that after the reaction is completed, a saturated NaCl solution is added to the reaction solution to quench the reaction, and then extracted three times with ethyl acetate. After the organic phases are combined, they are dried over anhydrous sodium sulfate and separated by column chromatography to obtain the target compound 3-alkylquinoxaline-2(1H)one compound.

[0016] The visible light-mediated synthesis method of 3-alkylquinoxaline-2(1H)ketone compounds of the present invention is characterized in that the synthesis route is:

[0017]

[0018] R 1 is H, Cl, Br, F, methyl, methoxy or methyl ester, R 2 C 1-6 Straight chain or branched alkyl, substituted C 1-6 Straight or branched alkyl, C 3-6 Cycloalkyl or heterocycloalkyl, wherein the substitution C 1-6 The substituent in the straight chain or branched alkyl group is C 3-6 Cycloalkyl, phenyl, ester or phenol.

[0019] Compared with the prior art, the present invention has the following advantages and beneficial effects: the present invention does not require the use of transition metal catalysts, nor does it require the addition of oxidants, uses green and environmentally friendly solvent dimethyl carbonate as a reaction solvent, uses photosensitizer 4CzIPN as a catalyst under visible light mediation, and reacts at 25 to 40°C to synthesize the target product. The method is simple and safe to operate, the reaction conditions are mild, the raw materials are cheap and easy to obtain, and the light source of the method is visible light, which is green and pollution-free, the catalyst is relatively friendly to the environment, and the solvent is a green and environmentally friendly solvent. In addition, the yield of the target product synthesized by the present invention is high, it has good functional group tolerance and substrate application range, and the method can be used for the later modification of drugs, and is expected to be used in drug research and development. DETAILED DESCRIPTION

[0020] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0021] Example 1

[0022] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL glass reaction tube equipped with a magnetic rod, and the mixture was stirred at room temperature for 12h under irradiation with a blue LED lamp having a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 41.1mg of the target product was obtained by column chromatography. The target product was a white solid, and the yield of the target product was 90% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0023]

[0024] The above white solid was subjected to nuclear magnetic spectrum analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.29(s,1H),7.70(d,J=8.4Hz,1H),7.46(t,J=7.8Hz,1H),7.27- 7.25(m,2H),3.19-3.15(m,1H),1.87-1.70(m,5H),1.48-1.33(m,4H),1.27-1.20(m,1H). 13 C NMR(150MHz,DMSO-d6)δ164.9,154.2,131.7,131.5,129.4,128.2,123.1,115.2,39.5,30.1,25.9,25.8.HRMSCalcd for C 14 H 17 N2O[M+H] + :m / z 229.1335,Found:229.1334.

[0025] Example 2

[0026] 6-methyl-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 37.3mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 77% based on the molar amount of 6-methyl-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0027]

[0028] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),7.51(s,1H),7.29-7.27(m,1H),7.15(d,J= 8.4Hz,1H),3.17-3.11(m,1H),2.35(s,3H),1.85-1.68(m,5H),1.47-1.14(m,5H). 13 C NMR(100MHz,DMSO-d6)δ164.8,154.2,132.5,131.7,130.6,129.3,128.0,115.0,30.2,25.9,25.9,20.5.HRMS Calcd forC 15 H 19 N2O[M+H] + :m / z 243.1492,Found:243.1493.

[0029] Example 3

[0030] 7-methyl-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 36.3mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 75% based on the molar amount of 7-methyl-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0031]

[0032] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),7.58(d,J=8Hz,1H),7.08-7.04(m,2H),3.17-3.11(m,1H),2.37(s,3H),1.86-1.69(m,5H),1.48-1.21(m,5H). 13 HRMS Calcd for C 15 H 19 N2O[M+H] + :m / z 243.1492,Found:243.1491.

[0033] Example 4

[0034] 6-methoxy-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 43.9mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 85% based on the molar amount of 6-methoxy-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0035]

[0036] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.21 (s, 1H), 7.21-7.18 (m, 2H), 7.11 (d, J = 8.4Hz, 1H), 3.80 (s, 3H), 3.19-3. 15(m,1H),1.82(dd,J=30.6,12Hz,4H),1.71(d,J=12.6Hz,1H),1.47-1.33(m,4H),1.25-1.91(m,1H). 13 HRMS Calcd for C 15 H 19 N2O[M+H] + :m / z 259.1441,Found:259.1437.

[0037] Example 5

[0038] 7-Fluoro-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 43.8mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 89% based on the molar amount of 7-fluoro-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0039]

[0040] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.37(s,1H),7.42(t,J=6Hz,1H),7.10(t,J=8.4Hz,1H),6.99(d,J=9Hz,1H),3.13 (t,J=11.4Hz,1H),1.82(dd,J=32.4,12Hz,4H),1.70(d,J=12Hz,1H),1.46-1.33(m,4H),1.26-1.16(m,1H). 13 C NMR(150MHz,DMSO-d6)δ163.9,162.6,161.0,154.1,132.9(d,J=12Hz),130.4( d,J=10.5Hz),128.7,110.9(d,J=22.5Hz),101.0(d,J=27Hz),30.0,25.8,25.7. 19 F NMR(564MHz,DMSO-d6)δ-110.5.HRMS Calcd for C 14 H 16 N2O[M+H] + :m / z 247.1241,Found:247.1241.

[0041] Example 6

[0042] 6-fluoro-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 38.4mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 80% based on the molar amount of 6-fluoro-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0043]

[0044] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),7.53-7.50(m,1H),7.40-7.36(m,1H),7. 29-7.26(m,1H),3.16(t,J=10.4Hz,1H),1.87-1.69(m,5H),1.47-1.21(m,5H). 13 C NMR(100MHz,DMSO-d6)δ166.40,158.93,156.56,153.96,153.89,132.0(d,J=11 Hz), 117.3 (d, J = 24Hz), 116.5 (d, J = 9Hz), 113.4 (d, J = 22Hz), 30.0, 25.81, 25.8. 19 F NMR(376MHz,DMSO-d6)δ-119.6.HRMS Calcd forC 14 H 16 N2O[M+H] + :m / z 241.1241,Found:241.1239.

[0045] Example 7

[0046] 7-bromo-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10ml reaction tube equipped with a magnetic electron, and stirred at room temperature for 12h under irradiation with a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 39.8mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 65% based on the molar amount of 7-bromo-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0047]

[0048] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.29(s,1H),7.69(d,J=7.8Hz,1H),7.45(t,J=7.8Hz,1H),7.27- 7.24(m,2H),3.18-3.14(m,1H),1.86-1.69(m,5H),1.47-1.32(m,4H),1.25-1.19(m,1H). 13 C NMR(150MHz,DMSO-d6)δ165.3,154.7,132.1,131.9,129.8,128.6,123.5,115.6,39.9,30.5,26.3,26.2.HRMSCalcd for C 14 H 16 N2O[M+H] + :m / z 307.0441,Found:307.0439.

[0049] Example 8

[0050] 7-chloro-3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under irradiation with a blue LED lamp having a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 25.2mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 48% based on the molar amount of 7-chloro-3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0051]

[0052] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.30 (s, 1H), 7.70 (d, J = 6.6Hz, 1H), 7.47-7.45 (m, 1H), 7.26 (d,J=4.8Hz,2H),3.20-3.14(m,J=19.3Hz,1H),1.87-1.71(m,5H),1.48-1.23(m,5H). 13 C NMR(150MHz,DMSO-d6)δ164.8,154.2,131.7,131.5,129.4,128.2,123.0,115.1,40.1,30.1,25.84,25.8.HRMSCalcd for C 14 H 16 ClN2O[M+H] + :m / z 263.0951,Found:263.0936.

[0053] Example 9

[0054] 2-Oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (0.2mmol), 1,3-dioxoisoindole-2-cyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron, and stirred at room temperature for 12h under irradiation with a blue LED lamp with a wavelength of 455nm. After the reaction, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and the target product 52.6mg was obtained by column chromatography. The target product was a white solid. The yield of the target product was 92% based on the molar amount of 2-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester as 100%. The structural formula of the target product is as follows:

[0055]

[0056] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.59(s,1H),8.19(s,1H),7.99(d,J=8.4Hz,1H),7.32(d,J=8 .4Hz,1H),3.17-3.13(m,1H),1.88-1.70(m,5H),1.47-1.33(m,4H),1.26-1.21(m,1H). 13 HRMS Calcd for C 20 H 23 N2O[M+H] + :m / z 287.1390,Found:287.1341.

[0057] Example 10

[0058] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-cyclopropanecarboxylate, DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron, and the mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid of 24.2mg. The yield of the target product was 65% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0059]

[0060] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),7.59(d,J=8.0Hz,1H),7.44-7.40(m,1H),7.26-7.21(m,2H),2.71-2.65(m,1H),1.07-1.05(m,4H). 13 C NMR(100MHz,DMSO-d6)δ162.3,154.8,131.7,131.0,128.8,127.6,123.1,115.2,11.6,11.0.HRMS Calcd for C 11 H 11 N2O[M+H] + :m / z 187.0866,Found:187.0821.

[0061] Embodiment 11

[0062] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-tetrahydropyran carboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol), and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 22.1mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 48% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0063]

[0064] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR(600MHz,DMSO-d6)δ12.35(s,1H),7.73(d,J=7.8Hz,1H),7.48(t,J=7.2Hz,1H), 7.29-7.26(m,2H),3.96(dd,J=11.4,3Hz,2H),3.49-3.45(m,2H),1.80-1.69(m,4H). 13 C NMR(150MHz,DMSO-d6)δ163.2,154.2,131.6,131.57,129.6,128.3,123.1,115.2,67.0,37.0,29.8.HRMS Calcd forC 13 H 14 N2NaO[M+Na] + :m / z 253.0953,Found:253.0914.

[0065] Example 12

[0066] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1-(tert-butyl)-4-(1,3-dioxoisoindoline)piperidine-1,4-dicarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and stirred at room temperature for 12h under irradiation with a blue LED light of 455nm. After the reaction, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and separated by column chromatography to obtain 55.3mg of the target product, which was a white solid. The yield of the target product was 84% ​​based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%.

[0067] The structural formula of the target product is as follows:

[0068]

[0069] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),7.71(d,J=7.6Hz,1H),7.48(t,J=6.8Hz,1H),7.29-7.22(m,2H),4 .07(d,J=9.2Hz,2H),2.87(s,2H),1.85(d,J=12.0Hz,2H),1.55-1.49(m,2H),1.41(s,9H),1.22(s,1H). 13 HRMS Calcd for C 18 H 24 N3O3[M+H] + :m / z330.1812,Found:330.1816.

[0070] Embodiment 13

[0071] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-isobutylcarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 25.6mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 68% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0072]

[0073] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.29(s,1H),7.71(d,J=8.4Hz,1H),7.46(t,J=7.8Hz,1H),7.28-7.25(m,2H),3.49-3.42(m,1H),1.21(d,J=6.6Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ165.6,154.2,131.6,131.5,129.4,128.2,123.0,115.2,29.9,20.0.HRMS Calcd for C 11 H 14 N2O[M+H] + :m / z 189.1022,Found:189.1005.

[0074] Embodiment 14

[0075] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-neopentylcarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and stirred at room temperature for 12h under irradiation with a blue LED light of 455nm. After the reaction, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was 33.1mg of a white solid. The yield of the target product was 82% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0076]

[0077] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.21 (s, 1H), 7.70 (d, J = 5.6Hz, 1H), 7.47 (s, 1H), 7.27-7.26 (m, 2H), 1.41 (s, 9H). 13 C NMR(100MHz,DMSO-d6)δ165.8,153.7,132.0,131.0,129.6,128.5,122.9,114.8,38.8,27.6.HRMS Calcd for C 12 H 16 N2O[M+H] + :m / z 203.1179,Found:203.1183.

[0078] Embodiment 15

[0079] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-methylcyclohexanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and the mixture was stirred at room temperature for 12h under irradiation with a blue LED lamp having a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 28.1mg of the target product was obtained by column chromatography. The target product was a white solid, and the yield of the target product was 58% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0080]

[0081] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.19 (s, 1H), 7.71 (d, J = 8Hz, 1H), 7.47 (t, J = 7.6Hz ,1H),7.28-7.24(m,2H),2.43-2.41(m,2H),1.57-1.40(m,8H),1.35(s,3H). 13 HRMS Calcd for C 15 H 19 N2O[M+H] + :m / z 243.1492,Found:243.1487.

[0082] Example 16

[0083] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-phenylcyclopropanecarboxylate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and the mixture was stirred at room temperature for 12h under irradiation with a blue LED lamp having a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 39.3mg of the target product was obtained by column chromatography. The target product was a white solid, and the yield of the target product was 75% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0084]

[0085] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1H NMR (600MHz, DMSO-d6) δ12.25(s,1H),7.77(d,J=8.4Hz,1H),7.49(t,J=7.8Hz,1H),7.29-7 .28(m,2H),7.23(d,J=3.6Hz,4H),7.15-7.14(m,1H),1.45-1.38(m,2H),1.28-1.23(m,2H). 13 HRMS Calcd for C 17 H 14 N2NaO[M+Na] + :m / z 285.1004,Found:285.0994.

[0086] Embodiment 17

[0087] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-phenylpropionate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and stirred at room temperature for 12h under irradiation with a blue LED light of 455nm. After the reaction, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 34.5mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 69% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0088]

[0089] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR(600MHz,DMSO-d6)δ12.30(s,1H),7.80(d,J=7.8Hz,1H),7.49(t,J=7.8Hz,1H), 7.30-7.25(m,6H),7.18-7.16(m,1H),4.70(q,J=6.6Hz,1H),1.55(d,J=6.6Hz,3H). 13HRMS Calcd for C 16 H 15 N2O[M+H] + :m / z 251.1179,Found:251.1182.

[0090] Embodiment 18

[0091] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-hexanoate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 33.7mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 78% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0092]

[0093] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.28(s,1H),7.70(d,J=7.8Hz,1H),7.46(t,J=7.2Hz,1H) ,7.27-7.22(m,2H),2.76(t,J=6.6Hz,2H),1.69(s,2H),1.33(s,4H),0.87(s,3H). 13 HRMS Calcdfor C 13 H 16 N2NaO[M+Na] + :m / z 239.1160,Found:239.1145.

[0094] Embodiment 19

[0095] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-phenylbutyrate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and the mixture was stirred at room temperature for 12h under irradiation with a blue LED light of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 48.8mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 92% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0096]

[0097] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.29(s,1H),7.71(d,J=7.8Hz,1H),7.46(t,J=7.2Hz,1H),7.29-7.23 (m,6H),7.17(t,J=6.6Hz,1H),2.79(t,J=7.2Hz,2H),2.69(t,J=7.2Hz,2H),2.03-1.98(m,2H). 13 HRMS Calcd for C 17 H 17 N2O[M+H] + :m / z 265.1335,Found:265.1330.

[0098] Embodiment 20

[0099] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-oxopentanoate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 33.3mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 70% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0100]

[0101] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),7.67(d,J=7.8Hz,1H),7.46(t,J=7.2H z,1H),7.28-7.24(m,2H),2.99-2.97(m,2H),2.91-2.89(m,2H),2.19(s,3H). 13 HRMS Calcd for C 12 H 13 N2O[M+H] + :m / z 239.0765,Found:239.0791.

[0102] Embodiment 21

[0103] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dioxoisoindole-2-pentanedioic acid methyl ester (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic rod, and the mixture was stirred at room temperature for 12h under irradiation with a blue LED lamp having a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 36.4mg of the target product was obtained by column chromatography. The target product was a white solid, and the yield of the target product was 74% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0104]

[0105] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),7.71(d,J=8.0Hz,1H),7.47(t,J=7.2Hz,1H),7.28- 7.24(m,2H),3.56(s,3H),2.80(t,J=7.2Hz,2H),2.43(t,J=7.2Hz,2H),2.01-1.84(m,2H). 13 HRMS Calcd for C 13 H 14 N2NaO[M+Na] + :m / z 269.0902,Found:269.0890.

[0106] Embodiment 22

[0107] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1-(1,3-dioxoisoindole)-7-methylheptanedioic acid methyl ester (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron. The mixture was stirred at room temperature for 12h under the irradiation of a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. 45.5mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 83% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. The structural formula of the target product is as follows:

[0108]

[0109] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (600MHz, DMSO-d6) δ12.28(s,1H),7.68(d,J=21Hz,1H),7.46(d,J=4.2Hz,1H),7.31-7 .22(m,2H),3.57(s,3H),2.76(s,2H),2.31(s,2H),1.69(s,2H),1.57(s,2H),1.36(s,2H). 13 HRMS Calcd for C 15 H 18 N2NaO[M+Na] + :m / z 297.1215,Found:297.1210.

[0110] Embodiment 23

[0111] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 3-(5-(2,5-dimethylphenoxy)-2-methylpentyl)quinoxaline-2(1H)-one (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron, and stirred at room temperature for 12h under irradiation with a blue LED lamp with a wavelength of 455nm. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 40.2mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 54% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. This example is a late modification of the small molecule drug gemfibrozil. The structural formula of the target product is as follows:

[0112]

[0113] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),7.71(d,J=7.6Hz,1H),7.47(t,J=7.2Hz,1H),7.28-7.24(m,2H),6 .94(d,J=7.2Hz,1H),6.62-6.57(m,2H),3.84(s,2H),2.19(s,3H),2.13-1.98(m,5H),1.52-1.41(m,8H). 13 C NMR(150MHz,DMSO-d6)δ165.1,156.4,153.7,136.0,132.0,131.0,130.0,129.6,128 .5,123.0,122.5,120.4,114.8,111.9,67.6,41.8,35.4,26.0,24.9,21.0,15.5.HRMS Calcd for C 22 H 27 N2O[M+H] + :m / z 373.1892,Found:373.1879.

[0114] Embodiment 24

[0115] 3,4-dihydroquinoxaline-2(1H)-one (0.2mmol), 1,3-dihydroisoindole-2-(4-isobutylphenyl) propionate (0.4mmol), DABCO (0.4mmol), 4CzIPN (0.01mmol) and anhydrous DMC (2.5mL) were added to a 10mL reaction tube equipped with a magnetic electron, and stirred at room temperature for 12h under irradiation with a blue LED lamp with a wavelength of 455nm. After the reaction, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate, and 33.7mg of the target product was obtained by column chromatography. The target product was a white solid. The yield of the target product was 55% based on the molar amount of 3,4-dihydroquinoxaline-2(1H)-one as 100%. This embodiment is a late modification of the antiviral drug ibuprofen. The structural formula of the target product is as follows:

[0116]

[0117] The above white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),7.81-7.78(m,1H),7.53-7.46(m,1H),7.23(dd,J=28,7.2Hz,4H),7.03(d,J=6 .4Hz,2H),4.68(d,J=6Hz,1H),2.35(d,J=6Hz,2H),1.76-1.74(m,1H),1.54(d,J=6.0Hz,3H),0.81(d,J=5.6Hz,6H). 13 C NMR (150MHz, DMSO-d6) δ173.4,161.8,154.6,131.7,131.7,129.4,128.1,123.1,115.2,51.2,33.2,32.5,28.3,25.7,24.3.HRMS Calcd forC 20 H 23 N2O[M+H] + :m / z 307.1805,Found:307.1808.

[0118] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A visible light-mediated synthesis method of 3-alkylquinoxaline-2(1H)one compounds, characterized in that The specific steps are: adding the reaction raw materials 3,4-dihydro-1H-2-quinoxalinone compounds and alkyl NHPI ester compounds, catalyst 4CzIPN, base DABCO and reaction solvent anhydrous dimethyl carbonate into a reaction container in sequence, and using blue light to induce reaction to obtain the target product 3-alkylquinoxaline-2(1H)one compounds; wherein the structure of the 3,4-dihydro-1H-2-quinoxalinone compounds is shown in formula A, the structure of the alkyl NHPI ester compounds is shown in formula B, and the structure of the 3-alkylquinoxaline-2(1H)one compounds is shown in formula C: R in Formula A and Formula C 1 is H, Cl, Br, F, methyl, methoxy or methyl ester, and R in formula B and formula C 2 C 1-6 Straight chain or branched alkyl, substituted C 1-6 Straight or branched alkyl, C 3-6 Cycloalkyl or heterocycloalkyl, wherein the substitution C 1-6 The substituent in the straight chain or branched alkyl group is C 3-6 Cycloalkyl, phenyl, ester or phenol; The blue light source is a blue LED lamp with a wavelength of 450-460nm and a power of 5-10W.

2. The method for synthesizing 3-alkylquinoxaline-2(1H)-one compounds mediated by visible light according to claim 1, characterized in that The compound corresponding to formula C is:

3. The method for synthesizing 3-alkylquinoxaline-2(1H)one compounds mediated by visible light according to claim 1, characterized in that: The molar ratio of the 3,4-dihydro-1H-2-quinoxalinone compound, the alkyl NHPI ester compound, the catalyst and the base is 1:1-3:0.01-0.1:1-3.

4. The method for synthesizing 3-alkylquinoxaline-2(1H)one compounds mediated by visible light according to claim 1, characterized in that: The reaction temperature of the reaction process is 25-40°C, and the reaction time is 6-24h.

5. The method for synthesizing 3-alkylquinoxaline-2(1H)one compounds mediated by visible light according to claim 1, characterized in that: After the reaction, a saturated NaCl solution was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate. The target compound 3-alkylquinoxaline-2(1H)one compound was separated by column chromatography.

6. The method for synthesizing 3-alkylquinoxaline-2(1H)one compounds mediated by visible light according to claim 1, characterized in that The synthetic route is: R 1 is H, Cl, Br, F, methyl, methoxy or methyl ester, R 2 C 1-6 Straight chain or branched alkyl, substituted C 1-6 Straight or branched alkyl, C 3-6 Cycloalkyl or heterocycloalkyl, wherein the substitution C 1-6 The substituent in the straight chain or branched alkyl group is C 3-6 Cycloalkyl, phenyl, ester or phenol.

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