6-aminoquinoxaline compound, and preparation method and application thereof
By reacting tetrahydroquinoxaline compounds with amine compounds under a nitrogen-doped carbon heterogeneous catalyst, the problems of selectivity and catalyst recovery in the synthesis of quinoxaline compounds were solved, realizing the efficient and green preparation of 6-aminoquinoxaline compounds, which are suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SOUTH CHINA UNIV OF TECH
- Filing Date
- 2024-01-05
- Publication Date
- 2026-05-19
AI Technical Summary
Existing methods for synthesizing quinoxaline compounds suffer from difficulties in controlling regioselectivity and chemoselectivity, as well as the difficulty in recovering precious metal catalysts, leading to challenging synthesis methods and high costs.
6-Aminoquinoxaline compounds were prepared by reacting tetrahydroquinoxaline compounds, amine compounds, nitrogen-doped carbon heterogeneous catalysts and additives in an organic solvent, controlling the reaction conditions, and using recyclable catalysts and simple post-processing steps.
The highly selective synthesis of 6-aminoquinoxaline compounds was achieved. The catalyst is recyclable and reusable. The synthesis steps are simple and safe, suitable for large-scale industrial applications, with wide applicability and good economic benefits.
Smart Images
Figure CN118005569B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, specifically to a 6-aminoquinoxaline compound, its preparation method, and its application. Background Technology
[0002] Quinoxaline compounds, especially those containing amino groups, have been widely used in the development of bioactive molecules, diagnostic molecules, and functional materials (e.g., JSP-1 inhibitors, in vitro HCV inhibitors, acidic chromium sensors, etc.). Currently, the synthesis of amino-containing quinoxaline compounds mainly relies on palladium or nickel-catalyzed amination reactions between halogenated quinoxalines and amines, or nucleophilic substitution reactions between fluorinated quinoxalines and amines. However, the difficulty in controlling regioselectivity and chemoselectivity during halogenation makes it challenging to prepare the desired chloroquinoxalines. Furthermore, the noble metal catalysts used also suffer from problems such as difficulty in recovery and non-reusability.
[0003] Therefore, it is of great significance to develop a green, efficient, and easy-to-operate method for synthesizing quinoxaline compounds and to synthesize more quinoxaline compounds containing amino groups. Summary of the Invention
[0004] The purpose of this invention is to provide a 6-aminoquinoxaline compound, its preparation method, and its application.
[0005] The technical solution adopted in this invention is:
[0006] A 6-aminoquinoxaline compound, with the following structural formula: In the formula, R 1 It is one of hydrogen, methyl, benzyl, 1H-indolyl, 2-methyl-1H-indolyl, 1H-quinolinyl, and benzomorpholinyl, R 2 R is one of phenyl, ester-substituted hydrocarbon groups, 2-methylphenyl, 2-hydroxymethylphenyl, and 2-amino-4,5-dimethylphenyl. 3 It is one of hydrogen, bromine, diphenyl, difuranyl, and cyclohexyl.
[0007] Preferably, the 6-aminoquinoxaline compound has any one of the structures shown in 3a to 3n:
[0008]
[0009] A method for preparing a 6-aminoquinoxaline compound as described above includes the following steps:
[0010] Tetrahydroquinoxaline compounds, amine compounds, nitrogen-doped carbon heterogeneous catalysts, and additives were added to an organic solvent. The structural formula of the tetrahydroquinoxaline compound is as follows: The structural formula of amine compounds is The reaction is then carried out in an oxygen-containing atmosphere to obtain 6-aminoquinoxaline compounds.
[0011] Preferably, the tetrahydroquinoxaline compound is one of tetrahydroquinoxaline, 2,3-diphenyltetrahydroquinoxaline, 6-(naphthalene-2-oxy)tetrahydroquinoxaline, 6-bromotetrahydroquinoxaline, 5-oxonaphthyltetrahydroquinoxaline, 5-bromotetrahydroquinoxaline, 2,3-di(furan-2-yl)tetrahydroquinoxaline, and cyclohexyl-[2,3-b]-tetrahydroquinoxaline.
[0012] Preferably, the amine compound is one of N-methylaniline, indole, 2-methylindole, tetrahydroquinoline, 4,5-dimethyl-o-phenylenediamine, 2-methylaniline, o-aminobenzyl alcohol, aniline, benzomorpholine, and ethylbenzylglycine.
[0013] Preferably, the molar ratio of the tetrahydroquinoxaline compound and the amine compound is 1:1 to 2.
[0014] Preferably, the ratio of tetrahydroquinoxaline, nitrogen-doped carbon heterogeneous catalyst, and additives is 1 mol: 100 g to 200 g: 0.5 mol to 1.0 mol.
[0015] Preferably, the nitrogen-doped carbon heterogeneous catalyst is prepared by the following method: adding phthalocyanine and silica-like dispersion to N,N-dimethylformamide, heating and stirring until all solvent evaporates, calcining in a protective atmosphere, etching with hydrofluoric acid, and then filtering and drying.
[0016] Preferably, the protective atmosphere is a nitrogen atmosphere or an argon atmosphere.
[0017] Preferably, the calcination is carried out at a temperature of 500℃ to 1100℃ for a time of 1h to 3h.
[0018] Preferably, the additive is at least one of pyridine, sodium trifluoromethanesulfonate, triethylamine, and potassium carbonate.
[0019] More preferably, the additive is pyridine.
[0020] Preferably, the organic solvent is at least one selected from hexafluoroisopropanol, trifluoroethanol, methanol, and dimethyl sulfoxide.
[0021] More preferably, the organic solvent is hexafluoroisopropanol.
[0022] Preferably, the oxygen-containing atmosphere is an oxygen atmosphere.
[0023] Preferably, the reaction is carried out at a temperature of 20°C to 35°C for a time of 1 hour to 3 hours.
[0024] Preferably, after the reaction is completed, the reaction solution is filtered, concentrated, and purified.
[0025] Preferably, the concentration method is vacuum concentration.
[0026] Preferably, the purification method is column chromatography.
[0027] Preferably, the eluent used in the column chromatography is prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1 to 5:1.
[0028] Application of a 6-aminoquinoxaline compound as described above in the preparation of bioactive molecules, optoelectronic materials, organic pigments or organic dyes.
[0029] The synthetic reaction of the 6-aminoquinoxaline compounds of the present invention is shown below:
[0030]
[0031] The beneficial effects of this invention are: the 6-aminoquinoxaline compounds of this invention have novel structures and can be used to prepare bioactive molecules, optoelectronic materials, organic pigments / dyes, etc. Moreover, the preparation method has the advantages of simple synthesis steps, safe operation, inexpensive and readily available raw materials, wide applicability, high atom economy, and recyclable catalysts, making it suitable for large-scale industrial applications.
[0032] Specifically:
[0033] 1) The 6-aminoquinoxaline compounds of the present invention have novel structures and can be used as active units to synthesize bioactive molecules, as luminescent materials to prepare organic optoelectronic functional devices, and as color-developing framework structures to synthesize organic pigments / dyes.
[0034] 2) The preparation method of the 6-aminoquinoxaline compounds of the present invention is a green synthesis method that can construct the target product with high selectivity in one step. The catalytic system is simple and mild, the operation is safe, the substrate applicability is wide, the post-processing is simple, saving time and effort, and it has good step economy and atom economy. The catalyst can be recycled and reused, and the route for synthesizing bioactive molecules can be simplified, which has good prospects for industrial application. Attached Figure Description
[0035] Figure 1 Compound 3a obtained in Example 1 1 H NMR spectrum.
[0036] Figure 2 Compound 3a obtained in Example 1 13 C10 NMR spectrum.
[0037] Figure 3 Compound 3b obtained in Example 2 1 H NMR spectrum.
[0038] Figure 4 Compound 3b obtained in Example 2 13 C10 NMR spectrum.
[0039] Figure 5 Compound 3c obtained in Example 3 1 H NMR spectrum.
[0040] Figure 6 Compound 3c obtained in Example 3 13 C10 NMR spectrum.
[0041] Figure 7 Compound 3d obtained in Example 4 1 H NMR spectrum.
[0042] Figure 8 Compound 3d obtained in Example 4 13 C10 NMR spectrum.
[0043] Figure 9 The compound 3e obtained in Example 5 1 H NMR spectrum.
[0044] Figure 10 The compound 3e obtained in Example 5 13 C10 NMR spectrum.
[0045] Figure 11 Compound 3f obtained in Example 6 1 H NMR spectrum.
[0046] Figure 12 Compound 3f obtained in Example 6 13 C10 NMR spectrum.
[0047] Figure 13 3g of the compound obtained in Example 7 1 H NMR spectrum.
[0048] Figure 14 3g of the compound obtained in Example 7 13 C10 NMR spectrum.
[0049] Figure 15 The compound obtained in Example 8 was 3h 1 H NMR spectrum.
[0050] Figure 16 The compound obtained in Example 8 was 3h13 C10 NMR spectrum.
[0051] Figure 17 Compound 3i obtained in Example 9 1 H NMR spectrum.
[0052] Figure 18 Compound 3i obtained in Example 9 13 C10 NMR spectrum.
[0053] Figure 19 Compound 3j obtained in Example 10 1 H NMR spectrum.
[0054] Figure 20 Compound 3j obtained in Example 10 13 C10 NMR spectrum.
[0055] Figure 21 The compound 3k obtained in Example 11 1 H NMR spectrum.
[0056] Figure 22 The compound 3k obtained in Example 11 13 C10 NMR spectrum.
[0057] Figure 23 Compound 3l obtained in Example 12 1 H NMR spectrum.
[0058] Figure 24 Compound 3l obtained in Example 12 13 C10 NMR spectrum.
[0059] Figure 25 The compound 3m obtained in Example 13 1 H NMR spectrum.
[0060] Figure 26 The compound 3m obtained in Example 13 13 C10 NMR spectrum.
[0061] Figure 27 The compound 3n obtained in Example 14 1 H NMR spectrum.
[0062] Figure 28 The compound 3n obtained in Example 14 13 C10 NMR spectrum.
[0063] Figure 29 For compound 3o 1 H NMR spectrum.
[0064] Figure 30 For compound 3o 13 C10 NMR spectrum. Detailed Implementation
[0065] The present invention will be further explained and described below with reference to specific embodiments.
[0066] Unless otherwise specified, all materials and reagents used in the embodiments are commercially available.
[0067] The nitrogen-doped carbon heterogeneous catalysts in Examples 1-14 were prepared by the following method: 1 g of phthalocyanine and 12 g of silica dispersion were added to 80 mL of N,N-dimethylformamide (DMF) (refer to "Cell Rep. Phys. Sci., 2020, 1, 100145"). The mixture was heated and stirred until all the solvent evaporated. The mixture was then calcined at 800 °C for 2 h in an argon atmosphere. The calcined product was then added to 5% hydrofluoric acid to etch away the silica. The mixture was filtered, and the solid was vacuum dried to obtain the nitrogen-doped carbon heterogeneous catalyst.
[0068] Example 1:
[0069] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0070] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of N-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 5:1, to obtain compound 3a (yellow oil; yield 90%).
[0071] The proton NMR spectrum of compound 3a is as follows: Figure 1 As shown, the carbon NMR spectrum is as follows: Figure 2 As shown.
[0072] The spectral data for proton and carbon NMR spectra are as follows:
[0073] 1 H NMR (400MHz, CDCl3): δ8.58(s,1H),8.46(s,1H),7.70(s,1H),5.97-5.78(m,7H),3.73(s,3H).
[0074] 13C NMR (100MHz, CDCl3): δ150.0,147.6,145.1,141.1,138.3,129.9,129.3,125.8,125.5,122.9,108.6,40.8.
[0075] The high-resolution mass spectrometry data of compound 3a are as follows:
[0076] HRMS(ESI): calcd for [M+H] + :236.1182; found:m / z 236.1183.
[0077] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3a synthesized in this embodiment is as follows: Example 2:
[0078] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0079] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of indole, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain compound 3b (yellow solid, mp 108.3 °C–109.0 °C; yield 96%).
[0080] The proton NMR spectrum of compound 3b is as follows: Figure 3 As shown, the carbon NMR spectrum is as follows: Figure 4 As shown.
[0081] The spectral data for proton and carbon NMR spectra are as follows:
[0082] 1 H NMR (400MHz, CDCl3): δ8.69(s,1H),8.60(s,1H),8.99(d,J=12.0Hz,1H),7.85(d,J=12.0Hz,1H),7.57(s,1H),7.37(d,J=8.0Hz,1H),7.22(d,J=4.0Hz ,1H),7.14(t,J1=16.0Hz,J2=8.0Hz,1H),6.87(t,J1=12.0Hz,J2=8.0Hz,1 H), 4.09 (t, J1=16.0Hz, J2=8.0Hz, 2H), 3.19 (t, J1=16.0Hz, J2=8.0Hz, 2H).
[0083] 13 C NMR (100MHz, CDCl3): δ145.3,145.2,145.1,144.6,141.8,138.7,132.0,129.8,127.2,125.4,122.5,120.7,111.2,109.3.
[0084] The high-resolution mass spectrometry data of compound 3b are as follows:
[0085] HRMS(ESI): calcd for [M+H] + :248.1182; found:m / z 248.1180.
[0086] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3b synthesized in this embodiment is as follows: Example 3:
[0087] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0088] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of 2-methylindole, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 3:1, to obtain compound 3c (yellow oil; yield 93%).
[0089] The proton NMR spectrum of compound 3c is as follows: Figure 5 As shown, the carbon NMR spectrum is as follows: Figure 6 As shown.
[0090] The spectral data for proton and carbon NMR spectra are as follows:
[0091] 1 H NMR (400MHz, CDCl3): δ8.62(s,1H),8.53(s,1H),7.92(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.61(s,1H),7.15(dd,J1=16.0Hz, J2=8.0Hz,1H),7.05(s,1H),6.78(s,1H),4.51(s,1H),3.35(t,J1=24.0Hz, J2=12.0Hz,1H),2.67(d,J=16.0Hz,1H),1.34(s,3H).
[0092] 13 C NMR (100MHz, CDCl3): δ145.2,144.8,144.6,142.1,139.1,130.6,130.0,127.2,125.6,123.6,120.8,112.8,110.2,59.6,27.0,20.1.
[0093] The high-resolution mass spectrometry data of compound 3c are as follows:
[0094] HRMS(ESI): calcd for [M+H] + :262.1339; found:m / z 262.1341.
[0095] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3c synthesized in this embodiment is as follows: Example 4:
[0096] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0097] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of tetrahydroquinoxaline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 2:1, to obtain compound 3d (yellow solid, mp 121.9 °C–122.0 °C; yield 96%).
[0098] The 1H NMR spectrum of compound 3d is as follows Figure 7 As shown, the carbon NMR spectrum is as follows: Figure 8 As shown.
[0099] The spectral data for proton and carbon NMR spectra are as follows:
[0100] 1H NMR (400MHz, CDCl3): δ8.70(s,1H),8.63(s,1H),7.90(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.60(s,1H),7.14(d,J=8.0Hz,2H),7.05(t,J1=16. 0Hz, J2=8.0Hz, 1H), 6.90 (t, J1=16.0Hz, J2=8.0Hz, 1H), 3.79 (t, J1=12.0Hz, J2=8.0Hz, 2H), 2.81 (t, J1=12.0Hz, J2=8.0Hz, 2H), 2.10-2.05 (m, 2H).
[0101] 13 C NMR (100MHz, CDCl3): δ149.3,145.0,144.9,142.3,142.1,139.7,129.3,129.2,129.1,126.5,126.3,121.5,118.5,115.7,49.3,27.4,23.9.
[0102] The high-resolution mass spectrometry data of compound 3d are as follows:
[0103] HRMS(ESI): calcd for [M+H] + :262.1339; found:m / z 262.1343.
[0104] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3d synthesized in this embodiment is as follows: Example 5:
[0105] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0106] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of 4,5-dimethyl-o-phenylenediamine, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3e (yellow solid, mp 174.1 °C–174.2 °C; yield 48%).
[0107] The proton NMR spectrum of compound 3e is as follows: Figure 9 As shown, the carbon NMR spectrum is as follows: Figure 10 As shown.
[0108] The spectral data for proton and carbon NMR spectra are as follows:
[0109] 1 H NMR (500MHz, CDCl3): δ8.61(s,1H),8.52(s,1H),7.87(d,J=7.2Hz,1H),7.24( d,J=8.0Hz,1H),7.04(s,1H),6.93(s,1H),6.64(s,1H),5.84(s,1H),3.63(br s,2H),2.20(s,3H),2.14(s,3H).
[0110] 13 C NMR (126MHz, CDCl3): δ147.8,145.1,145.0,140.9,140.5,138.4,135.9,130.3,128.0,127.4,123.6,121.9,118.0,106.8,19.5,18.8.
[0111] The high-resolution mass spectrometry data of compound 3e are as follows:
[0112] HRMS(ESI): calcd for [M+H] + :265.1448; found:m / z 265.1443.
[0113] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3e synthesized in this embodiment is as follows: Example 6:
[0114] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0115] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of 2-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 5:1, to obtain compound 3f (yellow oil; yield 25%).
[0116] The proton NMR spectrum of compound 3f is as follows: Figure 11 As shown, the carbon NMR spectrum is as follows: Figure 12 As shown.
[0117] The spectral data for proton and carbon NMR spectra are as follows:
[0118] 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.57(s,1H),7.93(d,J=8.0Hz,1H),7.37(d,J=8.0Hz,2H),7.27(d,J=4. 0Hz, 1H), 7.23 (t, J1 = 16.0Hz, J2 = 8.0Hz, 2H), 7.13 (t, J1 = 16.0Hz, J2 = 8.0Hz, 1H), 5.91 (s, 1H), 2.29 (s, 3H).
[0119] 13 C NMR (100MHz, CDCl3): δ146.7,145.1,141.3,138.8,138.7,131.9,131.4,130.4,127.1,125.0,123.2,122.7,108.1,18.0.
[0120] The high-resolution mass spectrometry data of compound 3f are as follows:
[0121] HRMS(ESI): calcd for [M+H] + :236.1182; found:m / z 236.1180.
[0122] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3f synthesized in this embodiment is as follows: Example 7:
[0123] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0124] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of o-aminobenzyl alcohol, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, yielding 3 g of the compound (yellow solid, mp 130.4 °C–131.0 °C; yield 40%).
[0125] The proton NMR spectrum of compound 3g is as follows: Figure 13 As shown, the carbon NMR spectrum is as follows: Figure 14 As shown.
[0126] The spectral data for proton and carbon NMR spectra are as follows:
[0127] 1H NMR (400MHz, CDCl3): δ8.59(s,1H),8.50(s,1H),7.88(d,J=8.0Hz,1H),7.58-7.40(m,4 H),7.32-7.22(m,2H),6.99(t,J1=16.0Hz,J2=8.0Hz,1H),4.75(s,2H),3.16(brs,1H).
[0128] 13 C NMR (100MHz, CDCl3): δ145.4,145.0,144.8,141.3,141.0,138.8,130.8,130.2,129.7,129.2,123.7,122.8,119.6,108.9,64.2.
[0129] The high-resolution mass spectrometry data of compound 3g are as follows:
[0130] HRMS(ESI): calcd for [M+H] + :252.1131; found:m / z 252.1131.
[0131] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of the 3g compound synthesized in this embodiment is as follows: Example 8:
[0132] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0133] Under an oxygen atmosphere, 0.2 mmol of 2,3-diphenyltetrahydroquinoxaline, 0.3 mmol of tetrahydroquinoxaline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3h (yellow solid, mp 176.4 °C–177.4 °C; yield 95%).
[0134] The proton NMR spectrum of compound 3h is as follows: Figure 15 As shown, the carbon NMR spectrum is as follows: Figure 16 As shown.
[0135] The spectral data for proton and carbon NMR spectra are as follows:
[0136] 1H NMR (400MHz, CDCl3): δ7.98(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.70(s, 1H),7.48(s,4H),7.32(s,6H),7.15(dd,J1=16.0Hz,J2=8.0Hz,2H),7.06(t, J1=12.0Hz, J2=4.0Hz, 1H), 6.89(t, J1=16.0Hz, J2=8.0Hz, 1H), 3.80(t, J1=1 2.0Hz, J2=4.0Hz, 2H), 2.81(t, J1=12.0Hz, J2=4.0Hz, 2H), 2.14-2.01(m, 2H).
[0137] 13 C NMR (100MHz, CDCl3): δ153.5,150.9,149.4,143.0,139.5,139.4,137.9,129.8,129.2,1 29.1,129.0,128.6,128.4,128.2,126.6,126.4,121.3,118.7,115.8,49.4,27.5,23.9.
[0138] The high-resolution mass spectrometry data of compound 3h are as follows:
[0139] HRMS(ESI): calcd for [M+H] + :414.1965; found:m / z 414.1971.
[0140] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3h synthesized in this embodiment is as follows: Example 9:
[0141] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0142] Under an oxygen atmosphere, 0.2 mmol of 6-(naphthyl-2-oxy)tetrahydroquinoxaline, 0.3 mmol of N-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3i (yellow solid, mp 88.3 °C–88.4 °C; yield 93%).
[0143] The proton NMR spectrum of compound 3i is as follows: Figure 17As shown, the carbon NMR spectrum is as follows: Figure 18 As shown.
[0144] The spectral data for proton and carbon NMR spectra are as follows:
[0145] 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.54(s,1H),7.36-7.31(m,2H),7.26(d,J=8.0Hz,2H) ,7.18(s,1H),7.07(t,J1=16.0Hz,J2=8.0Hz,1H),6.76(s,1H),6.55(s,1H),3.98(s,3H).
[0146] 13 C NMR (100MHz, CDCl3): δ154.8,153.2,149.0,143.7,143.6,143.5,141.3,141.2,134.2,130.7 ,130.0,128.9,127.8,127.2,126.6,125.1,122.3,121.5,119.7,118.8,115.8,115.1,41.34.
[0147] The high-resolution mass spectrometry data of compound 3i are as follows:
[0148] HRMS(ESI): calcd for [M+H] + :378.1601; found:m / z 378.1601.
[0149] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3i synthesized in this embodiment is as follows: Example 10:
[0150] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0151] Under an oxygen atmosphere, 0.2 mmol of 6-bromotetrahydroquinoxaline, 0.3 mmol of aniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain compound 3j (yellow solid, mp 115.4 °C–116.2 °C; yield 85%).
[0152] The proton NMR spectrum of compound 3j is as follows: Figure 19As shown, the carbon NMR spectrum is as follows: Figure 20 As shown.
[0153] The spectral data for proton and carbon NMR spectra are as follows:
[0154] 1 H NMR (400MHz, CDCl3): δ8.65(s,1H),8.55(s,1H),8.30(s,1H),7.62(s,1H),7.40(t ,J1=16.0Hz, J2=8.0Hz,2H),7.32(d,J=4.0Hz,2H),7.23-7.12(m,1H),6.57(s,1H).
[0155] 13 C NMR (100MHz, CDCl3): δ145.5,143.8,143.2,142.1,139.8,138.2,133.1,129.8,124.8,122.5,117.7,107.6.
[0156] The high-resolution mass spectrometry data of compound 3j are as follows:
[0157] HRMS(ESI): calcd for [M+H] + :300.0131; found:m / z 300.0129,302.0109.
[0158] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3j synthesized in this embodiment is as follows: Example 11:
[0159] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0160] Under an oxygen atmosphere, 0.2 mmol of 2,3-bis(furan-2-yl)tetrahydroquinoxaline, 0.3 mmol of N-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3K (yellow solid, mp 120.3 °C–121.3 °C; yield 91%).
[0161] The proton NMR spectrum of compound 3k is as follows: Figure 21 As shown, the carbon NMR spectrum is as follows: Figure 22 As shown.
[0162] The spectral data for proton and carbon NMR spectra are as follows:
[0163] 1 H NMR (400MHz, CDCl3): δ7.83 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.31-7.24 (m, 5H), 6.62-6.51 (m, 4H), 3.48 (s, 3H).
[0164] 13 C NMR (100MHz, CDCl3): δ151.4,151.1,150.5,147.5,144.0,143.3,142.9,142.8,138.9 ,135.8,130.0,129.1,126.1,125.7,122.9,112.6,111.8,111.7,111.4,108.2,40.9.
[0165] The high-resolution mass spectrometry data of compound 3k are as follows:
[0166] HRMS(ESI): calcd for [M+H] + :368.1394; found:m / z 368.1400.
[0167] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3k synthesized in this embodiment is as follows: Example 12:
[0168] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0169] Under an oxygen atmosphere, 0.2 mmol of cyclohexyl[2,3-b]tetrahydroquinoxaline, 0.3 mmol of N-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3l (yellow oil; yield 65%).
[0170] The proton NMR spectrum of compound 3l is as follows: Figure 23 As shown, the carbon NMR spectrum is as follows: Figure 24 As shown.
[0171] The spectral data for proton and carbon NMR spectra are as follows:
[0172] 1 H NMR (400MHz, CDCl3): δ7.70(d,J=8.0Hz,2H),7.39(t,J1=16.0Hz,J2=8.0Hz,2H),7.25(t,J1=16.0Hz,J2= 8.0Hz, 4H), 7.18 (t, J1 = 16.0Hz, J2 = 8.0Hz, 1H), 3.44 (s, 3H), 3.11 (d, J = 4.0Hz, 4H), 2.02 (d, J = 4.0Hz, 4H).
[0173] 13 C NMR (100MHz, CDCl3): δ153.8,150.0,149.3,148.0,142.9,136.5,129.7,128.2,125.1,124.8,122.1,108.9,40.8,33.1,32.7,23.0,22.9.
[0174] The high-resolution mass spectrometry data of compound 3l are as follows:
[0175] HRMS(ESI): calcd for [M+H] + :290.1652; found:m / z 290.1657.
[0176] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3l synthesized in this embodiment is as follows: Example 13:
[0177] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0178] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of benzylmorpholine, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3m (yellow oil; yield 51%).
[0179] The proton NMR spectrum of compound 3m is as follows: Figure 25 As shown, the carbon NMR spectrum is as follows: Figure 26 As shown.
[0180] The spectral data for proton and carbon NMR spectra are as follows:
[0181] H NMR (400MHz, CDCl3): δ8.70(s,1H),8.64(s,1H),8.08(d,J=8.0Hz,1H),7.80(d,J=
[0182] 12.0Hz, 1H), 7.65 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 7.99-6.87 (m, 2H), 6.81 (t, J1 = 12.0Hz, J2 = 8.0Hz, 1H), 4.33 (s, 2H), 3.68 (s, 2H).
[0183] 13 C NMR (100MHz, CDCl3): δ148.2,145.9,145.0,144.3,142.5,139.5,129.7,126.2,122.8,120.8 118.3,117.6,116.4,64.7,47.7.
[0184] The high-resolution mass spectrometry data of compound 3m are as follows:
[0185] HRMS(ESI): calcd for [M+H] + :264.1131; found:m / z 264.1131.
[0186] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3m synthesized in this embodiment is as follows: Example 14:
[0187] A 6-aminoquinoxaline compound, the preparation method of which is as follows:
[0188] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of ethylbenzylglycine, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 1:1, to obtain compound 3n (yellow oil; yield 55%).
[0189] The proton NMR spectrum of compound 3n is as follows: Figure 27 As shown, the carbon NMR spectrum is as follows: Figure 28 As shown.
[0190] The spectral data for proton and carbon NMR spectra are as follows:
[0191] 1H NMR (500MHz, CDCl3): δ8.65 (s, 1H), 8.54 (s, 1H), 7.91 (d, J = 10.0Hz, 1H), 7.37-7.29 (m, 6H), 7.13(d,J=5.0Hz,1H),4.82(s,2H),4.31-4.22(m,4H),1.27(t,J1=15.0Hz,J2=10.0Hz,3H).
[0192] 13 C NMR (126MHz, CDCl3): δ170.2,149.7,145.2,144.7,141.1,137.6,137.2,130.3,128.9,127.5,126.7,119.6,106.7,61.4,55.8,52.5,14.2.
[0193] The high-resolution mass spectrometry data of compound 3n are as follows:
[0194] HRMS(ESI): calcd for [M+H] + :322.1550; found:m / z 322.1545.
[0195] Based on the combined data from 1H NMR, 1C NMR, and high-resolution mass spectrometry, the structural formula of compound 3n synthesized in this embodiment is as follows:
[0196] The method for preparing 6-aminoquinoxaline compounds of the present invention can also be used for compounds 3o (with the structural formula: ), which are known to have JSP-1 small molecule inhibitory activity. Synthesis of ).
[0197] The synthesis of compound 3o according to the reported method (CN 1966500 A) requires three steps, and the specific reaction steps are as follows:
[0198]
[0199] The method of this invention requires only one step to prepare the above compound 3o, thus simplifying the reaction route. The specific reaction formula is as follows:
[0200]
[0201] The specific preparation method is as follows:
[0202] Under an oxygen atmosphere, 0.2 mmol of tetrahydroquinoxaline, 0.3 mmol of N-methylaniline, 30 mg of nitrogen-doped carbon heterogeneous catalyst, 0.2 mmol of pyridine, and 1 mL of hexafluoroisopropanol were added to a reaction tube. The reaction was carried out at 30 °C for 2 h, filtered, and the filtrate was concentrated under vacuum. The crude product obtained from the concentration was then subjected to column chromatography. The eluent used in the column chromatography was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 2:1, to obtain compound 3o (yellow solid, mp 105.0 °C–106.0 °C; yield 60%).
[0203] The proton NMR spectrum of compound 3o is as follows: Figure 29 As shown, the carbon NMR spectrum is as follows: Figure 30 As shown.
[0204] The spectral data for proton and carbon NMR spectra are as follows:
[0205] 1 H NMR (400MHz, CDCl3): δ8.71 (s, 1H), 8.62 (s, 1H), 7.96 (d, J = 12.0 Hz, 1H), 7.53 (d, J = 12.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 3.92 (s, 4H), 3.38 (s, 4H).
[0206] 13 C NMR (100MHz, CDCl3): δ152.0,145.1,144.6,141.9,138.6,130.0,122.0,109.5,66.7,48.6.
[0207] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A method for preparing a 6-aminoquinoxaline compound, characterized in that, Includes the following steps: Tetrahydroquinoxaline compounds, amine compounds, nitrogen-doped carbon heterogeneous catalysts and additives are added to an organic solvent and then reacted in an oxygen-containing atmosphere to obtain 6-aminoquinoxaline compounds. The tetrahydroquinoxaline compound is one of tetrahydroquinoxaline, 2,3-diphenyltetrahydroquinoxaline, 6-(naphthalene-2-oxy)tetrahydroquinoxaline, 6-bromotetrahydroquinoxaline, 2,3-di(furan-2-yl)tetrahydroquinoxaline, and cyclohexyl[2,3-b]tetrahydroquinoxaline; The amine compound is one of N-methylaniline, indole, 2-methylindole, tetrahydroquinoline, 4,5-dimethyl-o-phenylenediamine, 2-methylaniline, o-aminobenzyl alcohol, aniline, benzomorpholine, and ethylbenzylglycine. The nitrogen-doped carbon heterogeneous catalyst is prepared by the following method: adding phthalocyanine and silica dispersion into N,N-dimethylformamide, heating and stirring until all solvent evaporates, calcining in a protective atmosphere, etching with hydrofluoric acid, and then filtering and drying. The additive is at least one of pyridine and triethylamine; The structural formula of the 6-aminoquinoxaline compound is as follows: , , , , , , , , , , , , or .
2. The preparation method according to claim 1, characterized in that: The molar ratio of the tetrahydroquinoxaline compounds and the amine compounds is 1:1 to 2.
3. The preparation method according to claim 1, characterized in that: The ratio of the tetrahydroquinoxaline compound, the nitrogen-doped carbon heterogeneous catalyst, and the additive is 1 mol: 100 g to 200 g: 0.5 mol to 1.0 mol.
4. The preparation method according to any one of claims 1 to 3, characterized in that: The organic solvent is at least one of hexafluoroisopropanol, trifluoroethanol, methanol, and dimethyl sulfoxide.
5. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction was carried out at a temperature of 20℃ to 35℃ for a time of 1h to 3h.