Synthesis method of a γ-carbolinone compound

Abstract

The present invention discloses a method for synthesizing γ-carbolinone compounds, comprising the following steps: in the presence of a cobalt catalyst, an oxidant and a base, a 3-indolecarboxamide compound and an alkyne are reacted in a solvent, and after the reaction is completed, the γ-carbolinone compound is obtained through post-treatment. This method uses inexpensive metals cobalt and manganese as a catalytic system, does not require additional ligands and indole nitrogen protecting groups, and provides an organic synthesis method for synthesizing γ-carbolinone compounds with wide application value.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing γ-carbolinone compounds. Background Art

[0002] Compounds containing the γ-carbolinone skeleton have received extensive attention due to their good biological activities. For example, Compound I is a 5-HT3 receptor antagonist, Compound II is a topoisomerase I inhibitor, and Compound III is the natural product aspidospermidine with antibacterial activity.

[0003]

[0004] Traditional synthesis of γ-carbolinone compounds often uses intramolecular cyclization reactions. For example, the Clark group reported that N,2-dimethylindole-3-carboxamide was first reacted with n-butyllithium and DMF, and then the hydroxyl group was removed by hydrochloric acid to obtain γ-carbolinone derivatives (Formula 2, eq. 1); the Fresneda group used ylide reagents and aldehydes as raw materials to obtain 3-(2-azidophenyl)substituted quinolinone after eight steps, and then heated to 150 °C in o-xylene to obtain the target compound (Formula 2, eq. 2); the Chen group developed a method using 4-hydroxyquinolinone as a raw material, first reacting with hydrazine to obtain 4-hydrazinoquinolinone, then reacting with cyclohexanone to prepare hydrazone, and finally synthesizing γ-carbolinone compounds under the condition of Pd / C (Formula 2, eq. 3); in addition, the Beccalli group reported a method for synthesizing γ-carbolinone compounds based on intramolecular Heck reaction (Formula 2, eq. 4). In summary, these methods all require long synthesis steps and high reaction costs. Therefore, developing efficient and rapid methods for synthesizing such compounds has very important research value.

[0005]

[0006] Formula 2 Traditional methods for synthesizing γ-carbolinone compounds

[0007] In recent years, transition metal-catalyzed C-H bond activation reactions have gradually become an important approach for synthesizing and modifying complex molecules, and thus have been widely used in biomedicine, materials science, pharmacy and other industries. Based on this method, the Li group developed a method based on palladium-catalyzed intramolecular double C(sp 2) -H activation and 1,2-acyl migration reaction for the preparation of γ-carbolinone (Equation 3, eq.1); The Yao & Lin research group reported a method for the synthesis of the target compound by palladium-catalyzed double C-H activation reactions of indole-3-carboxamide and iodobenzene (Equation 3, eq.2); In addition, the Jiao research group reported the preparation of γ-carbolinone by palladium-catalyzed [4+2] cycloaddition reaction of indole-3-carboxamide and internal alkyne (Equation 3, eq.3). Subsequently, the Zhang research group developed a method for the preparation of such compounds by copper-catalyzed [4+2] cyclization reaction of indole-3-carboxamide and benzyne assisted by a double directing group (Equation 3, eq.4). However, the above methods all require precious metal palladium or use a relatively large amount of copper as a catalyst. The development of a method for the synthesis of γ-carbolinone using inexpensive metals as catalysts has attracted the attention of chemists. Based on the work of our research group and other research groups in cobalt-catalyzed C-H activation reactions, we have developed a method for the efficient synthesis of γ-carbolinone compounds by cobalt-catalyzed [4+2] cycloaddition reactions of indole-3-carboxamide with diyne, internal alkyne and monoalkyne. The advantages of this method are: (1) using inexpensive metal cobalt as a catalyst; (2) no ligand needs to be added; (3) using inexpensive metal manganese as an oxidant; (4) the indole nitrogen does not require a protecting group, reducing the cost of the reaction (Equation 3, eq.6).

[0008]

[0009] Method for synthesizing γ-carbolinone compounds by transition metal-catalyzed C-H activation reaction

[0010] In summary, the development of a green, environmentally friendly and non-toxic method for the synthesis of γ-carbolinone compounds has very important research significance and broad application value. Summary of the Invention

[0011] The present invention provides a method for the synthesis of γ-carbolinone compounds, which has inexpensive and readily available raw materials and high atom economy.

[0012] A method for the synthesis of γ-carbolinone compounds, comprising the following steps:

[0013] In the presence of a cobalt catalyst, an oxidant and a base, a 3-indolecarboxamide compound and an alkyne react in a solvent, and after the reaction is completed, the γ-carbolinone compound is obtained through post-treatment;

[0014] The structure of the 3-indolecarboxamide compound is shown in formula (I):

[0015]

[0016] The structure of the γ-carbolinone compound is shown in formula (II):

[0017]

[0018] In formulas (I) to (II), R 1 is a substituted alkynyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted C1-C10 alkyl group; R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted C1-C10 alkyl group, or hydrogen;

[0019] The substituent on the alkynyl group is a substituted or unsubstituted phenyl group or a substituted or unsubstituted C1-C10 alkyl group

[0020] The substituent on the phenyl group is selected from C1-C4 alkyl groups and C1-C4 alkoxy groups;

[0021] The substituent on the C1-C10 alkyl group is selected from halogen or phenoxy groups.

[0022] Preferably, the R 1 is phenylethynyl, p-tolylethynyl, p-ethylphenylethynyl, p-tert-butylphenylethynyl, p-methoxyphenylethynyl, 6-chlorohex-1-ynyl, cyclohexylethynyl, 3-phenoxypropynyl, phenyl, p-nitrophenyl, p-cyanophenyl, or phenoxymethyl;

[0023] R 2 is phenyl, p-tolyl, p-ethylphenyl, p-tert-butylphenyl, p-methoxyphenyl, 4-chlorobutyl, cyclohexyl, phenoxymethyl, or hydrogen.

[0024] Preferably, the cobalt catalyst is Co(OAc)2, CoCl2, CoF2, CoSO4·7H2O, or Co(acac)2.

[0025] Preferably, the oxidant is Mn(OAc)2, AgOAc, Ag2O, Ag2CO3, or Mn(acac)3.

[0026] Preferably, the base is NaOPiv, NaH2PO4, K2HPO4, Na2CO3, NaHCO3, KHCO3, or NaOAc.

[0027] Preferably, the solvent is trifluoroethanol, methanol, ethanol, hexafluoroisopropanol, 1,2-dichloroethane, or toluene.

[0028] Preferably, the cobalt catalyst is Co(acac)2, the oxidant is Mn(acac)3, the base is NaOPiv, and the solvent is trifluoroethanol.

[0029] Preferably, the reaction temperature is 80-140 °C and the reaction time is 3-24 hours.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] The present invention uses 3-indolecarboxamide and alkyne as raw materials, and realizes the synthesis of γ-carbolinone compounds through the method of C-H / N-H bond activation under the catalysis of cheap and easily available metal cobalt, with higher atom economy and stronger operability of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 1H NMR spectrum of the product obtained in Example 2;

[0033] Figure 2 13C NMR spectrum of the product obtained in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention will be further described below in conjunction with specific embodiments.

[0035] The synthesis process of the raw material 3-indolecarboxamide in Example 1 is as follows:

[0036] In a dry 100 mL round-bottom flask equipped with a magnetic stirrer, add 3-indolecarboxylic acid (1611.6 mg, 10 mmol, 1.0 equiv.), 3 drops of DMF, dissolve it with anhydrous dichloromethane (20 mL), protect it with nitrogen, and cool it to 0 °C in an ice-water bath. Oxalyl chloride (12 mmol, 1.2 equiv.) was added dropwise to the reaction system. Stir the reaction at room temperature, and monitor the reaction progress by TLC. After the reaction is completed, concentrate under reduced pressure to obtain 3-indolecarbonyl chloride (dark red solid).

[0037] In a dry 100 mL round-bottom flask equipped with a magnetic stirrer, add 8-aminoquinoline (1874.2 mg, 13 mmol, 1.3 equiv.), triethylamine (2.8 mL, 20 mmol, 2.0 equiv.), add anhydrous dichloromethane (20 mL), protect it with nitrogen, and stir to dissolve at room temperature. Cool the reaction system to 0 °C in an ice-water bath, and add 3-indolecarbonyl chloride dissolved in anhydrous dichloromethane dropwise. The reaction gradually warms up to room temperature. Monitor the reaction progress by TLC. After the reaction is completed, add saturated sodium bicarbonate solution (30 mL) to quench the reaction. Separate the layers, extract the aqueous phase with dichloromethane (30 mL × 3). Combine the organic phases, wash them successively with dilute hydrochloric acid (50 mL, 1 mol / L) and saturated brine (50 mL), dry the organic phase over anhydrous sodium sulfate, filter through diatomaceous earth, concentrate under reduced pressure, and use silica gel as the stationary phase, and acetone and dichloromethane as the eluent (1:100 - 1:50) for separation to obtain 1a (86%).

[0038] Synthesis steps of γ-carbolinone in Example 2:

[0039] In a dry 25 mL high-temperature pressure-resistant tube equipped with a magnetic stir bar, add N-(quinolin-8-yl)-3-indolecarboxamide (1a, 0.1 mmol), alkyne (0.2 mmol, 2.0 equiv.), cobalt(II) acetylacetonate (0.01 mmol, 10 mol%), manganese(III) acetylacetonate (0.1 mmol, 1.0 equiv.), sodium pivalate (0.2 mmol, 2.0 equiv.), and trifluoroethanol (2 mL). React at 120 °C for 24 hours. After the reaction is completed, cool to room temperature, dilute with dichloromethane, filter through diatomaceous earth, and wash three times with dichloromethane (5 mL × 3). Concentrate the filtrate under reduced pressure, and separate the target product using silica gel as the stationary phase and acetone and dichloromethane as the eluents. The reaction conditions and results are shown in Table 1:

[0040]

[0041]

[0042] c Mn(acac)3 (1.0 equiv.); d Mn(acac)3 (0.5 equiv.); e Mn(OAc)2 (1.0 equiv.); f The temperature is 80 °C; g The temperature is 120 °C; h The temperature is 140 °C.

[0043] Example 3 Synthesis of a series of γ-carbolinones:

[0044]

[0045] The characterization data of the obtained product are as follows: 4-phenyl-3-(phenylethynyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3a), 44 mg, 90% yield. Yellow solid. m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ: 11.68 (s, 1H), 8.85–8.87 (m, 1H), 8.54–8.56 (m, 1H), 8.22 - 8.24 (m, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.98–8.01 (m, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.73–7.74 (m, 2H), 7.52–7.64 (m, 5H), 7.35–7.37 (m, 1H), 7.20–7.28 (m, 2H), 7.13–7.15 (m, 2H), 6.34 (d, J = 8.0 Hz, 2H).13 13C NMR (100 MHz, DMSO-d6) δ: 158.6, 151.0, 144.6, 142.3, 138.7, 137.7, 136.4, 133.6, 130.8, 130.5, 130.2, 129.3, 129.1, 128.7, 128.6, 128.4, 126.7, 126.2, 124.5, 124.4, 121.9, 121.2, 120.6, 120.5, 114.9, 112.1, 107.8, 97.8, 84.4. HRMS (ESI+) exact mass calculated for [M+H] + (C 34 H 22 N3O): 488.1757, found: 488.1760.

[0046] 2-(8-Quinolyl)-4-(4-methylphenyl)-3-(4-methylphenyl ethynyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3b), 31 mg, 64% yield. Yellow solid, m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ: 11.61 (s, 1H), 8.84 8.86 (m, 1H), 8.53–8.55 (m, 1H), 8.20 - 8.23 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.96 - 7.98 (m, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.57–7.62 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 7.33–7.37 (m, 1H), 7.23–7.27 (m, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.25 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H), 2.17 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ: 158.6, 150.9, 144.6, 143.0, 142.4, 139.2, 138.6, 137.8, 137.6, 136.3, 130.7, 130.6, 130.2, 130.1, 129.6, 129.2, 129.0, 128.7, 126.7, 126.2, 124.4, 121.9, 121.1, 120.4, 117.6, 114.4, 112.1, 107.6, 98.1, 84.0, 20.9 (2C). HRMS (ESI+) exact mass for [M+H] + (C 36H 26 N3O): 516.2070, found: 516.2072. 4-(4-Ethylphenyl)-3-((4-ethylphenyl)ethynyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3c), 46 mg, 86% yield. Yellow solid, m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.84–8.85 (m, 1H), 8.54 (dd, J = 8.0, 4.0 Hz, 1H), 8.20–8.22 (m, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.95–7.97 (m, 1H), 7.79–7.83 (m, 1H), 7.56–7.65 (m, 4H), 7.43 (d, J = 8.0 Hz, 2H), 7.33–7.38 (m, 1H), 7.23–7.27 (m, 1H), 6.97 (d, J = 8.3 Hz, 2H), 6.26 (d, J = 8.0 Hz, 2H), 2.72 (q, J = 16.0 Hz, 8.0 Hz, 2H), 2.44 (q, J = 16.0 Hz, 8.0 Hz, 2H), 1.26 (t, J = 8.0 Hz, 3H), 1.01 (t, J = 8.0 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 158.7, 151.0, 145.5, 144.7, 143.9, 142.5, 138.7, 137.9, 136.4, 130.9, 130.8, 130.4, 130.3, 129.1, 128.7, 128.1, 128.0, 126.9, 126.3, 124.5, 124.4, 122.0, 121.2, 120.5, 118.0, 114.6, 112.2, 107.7, 98.2, 84.1, 28.1, 28.0, 15.6, 15.1. HRMS (ESI+) exact mass calculated for [M+H] + (C 38 H 30 N3O): 544.2383, found: 544.2390.

[0047] 4-(4-Butylphenyl)-3-((4-butylphenyl)ethynyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3d), 53 mg, 88% yield. Yellow solid, m.p. > 300 °C; 11H NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 8.84–8.86 (m, 1H), 8.52–8.54 (m, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.95–7.96 (m, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.56–7.64 (m, 4H), 7.34–7.41 (m, 3H), 7.25 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 8.0 Hz, 2H), 2.69 (t, J = 8.0 Hz, 2H), 2.41 (t, J = 8.0 Hz, 2H), 1.60–1.67 (m, 2H), 1.31–1.41 (m, 4H), 1.12–1.18 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H), 0.79 (t, J = 8.0 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ: 158.7, 151.0, 144.7, 144.0, 142.5, 142.4, 138.7, 137.9, 136.4, 130.9, 130.7, 130.3, 130.2, 129.1, 128.7, 128.5, 126.9, 126.2, 124.4, 121.9, 121.2, 120.5, 118.0, 114.7, 112.1, 107.7, 98.2, 84.1, 34.7, 34.6, 33.1, 32.6, 21.7, 21.5, 13.8, 13.7. HRMS (ESI+) exact mass calculated for [M+H] + (C 42 19 38 N3O): 600.3009, found: 600.3027.

[0048] 4-(4-Methoxyphenyl)-3-((4-methoxyphenyl)ethynyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3e), 41 mg, 75% yield. Yellow solid, m.p. > 300 °C; 11H NMR (400 MHz, DMSO-d6) δ: 11.63 (s, 1H), 8.86 (d, J = 4.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.56–7.62 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H), 3.65 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ: 159.9, 159.2, 158.7, 151.0, 144.7, 142.8, 138.7, 138.0, 136.4, 132.0, 131.7, 130.8, 129.0, 128.7, 127.0, 126.2, 125.7, 124.5, 124.4, 121.9, 121.1, 120.5, 114.4, 114.1, 113.9, 112.6, 112.1, 107.5, 98.4, 83.4, 55.3 (2C). HRMS (ESI+) exact mass calculated for [M+H] + (C 36 H 26 N3O3): 548.1969, found: 548.1971.

[0049] 4-(4-Chlorobutyl)-3-(6-chlorohex-1-yn-1-yl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3f), 35 mg, 68% yield. Yellow solid, m.p. > 300 °C; 11H NMR (400 MHz, DMSO-d6) δ: 12.01 (s, 1H), 8.78–8.79 (m, 1H), 8.48–8.51 (m, 1H), 8.14 (dd, J = 8.0, 4.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.72–7.81 (m, 2H), 7.56–7.61 (m, 2H), 7.34–7.40 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 3.69 (t, J = 4.0 Hz, 2H), 3.27–3.29 (m, 2H), 2.93 (t, J = 8.0 Hz, 2H), 2.00–2.01 (m, 2H), 1.77–1.90 (m, 4H), 1.22–1.25 (m, 2H), 0.98–1.04 (m, 2H). 13 13C NMR (100 MHz, DMSO-d6) δ: 158.8, 150.8, 144.6, 143.5, 138.3, 138.0, 136.4, 130.6, 128.9, 128.8, 127.3, 126.2, 124.5, 124.3, 121.9, 121.0, 120.5, 112.4, 111.6, 107.2, 100.5, 74.8, 45.3, 44.6, 31.8, 30.3, 27.2, 26.6, 24.6, 17.7. HRMS (ESI+) exact mass calculated for + (C 30 H 28 Cl2N3O): 516.1604, found: 516.1600.

[0050] 4-Cyclohexyl-3-(cyclohexylethynyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3g), 28 mg, 55% yield. Yellow solid, m.p. = 285–286 °C; 11H NMR (400 MHz, DMSO-d6) δ: 11.67 (s, 1H), 8.79–8.80 (m, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.09 (dd, J = 24.0, 8.0 Hz, 2H), 7.70–7.77 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.0, 4.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 2.18–2.24 (m, 3H), 1.86–1.91 (m, 2H), 1.72–1.75 (m, 3H), 0.78–1.25 (m, 14H). 13 13C NMR (100 MHz, DMSO-d6) δ 158.7, 150.7, 144.8, 142.6, 138.3, 136.2, 130.6, 128.8, 128.7, 126.4, 126.1, 124.3, 124.2, 121.7, 120.9, 120.4, 117.0, 111.7, 107.7, 105.2, 79.2, 75.5, 30.7, 29.9, 29.0, 28.1, 26.9, 25.1, 23.2, 23.1. HRMS (ESI+) exact mass calculated for [M+H] + (C 34 H 34 N3O): 500.2696, found: 500.2698.

[0051] 4-(phenoxymethyl)-3-(phenoxyprop-1-yn-1-yl)-2-(quinolin-8-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3h), 29 mg, 53% yield. Yellow solid, m.p. = 274–275 °C; 11H NMR (400 MHz, DMSO-d6) δ: 12.21 (s, 1H), 8.75–8.77 (m, 1H), 8.47–8.49 (m, 1H), 8.10–8.13 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.82–7.84 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.55–7.62 (m, 2H), 7.31–7.40 (m, 3H), 7.25 (t, J = 8.0 Hz, 1H), 7.05–7.10 (m, 4H), 7.00 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 2H), 5.33 (s, 2H), 4.50 (s, 2H). 13 13C NMR (100 MHz, DMSO-d6) δ: 158.7, 158.5, 156.7, 150.9, 144.3, 142.6, 138.5, 137.1, 136.4, 130.5, 129.5, 129.3, 128.6, 128.4, 126.1, 124.7, 124.1, 121.9, 121.2, 121.1, 120.9, 120.5, 114.9, 114.3, 111.9, 109.0, 107.8, 95.9, 78.8, 64.0, 55.0 (2C). HRMS (ESI+) exact mass calculated for [M+H] + (C 36 H 26 N3O3): 548.1969, found: 548.1971.

[0052] 3-Phenyl-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3i), 23 mg, 60% yield. Yellow solid, m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ: 11.97 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.46–7.52 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.97–7.06 (m, 3H), 6.66 (s, 1H). 13¹³C NMR (100 MHz, DMSO-d6) δ: 159.6, 150.6, 147.8, 144.6, 144.1, 137.9, 137.1, 136.5, 136.2, 131.6, 128.6 (2C), 128.3, 128.1, 127.2, 125.7, 124.4, 123.8, 121.7, 120.8, 120.3, 111.5, 105.8, 96.3. HRMS (ESI+) exact mass calculated for [M+H] + (C 26 H 18 N3O): 388.1444, found: 388.1448.

[0053] 3-(4-Nitrophenyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (3j), 12 mg, 28% yield. Yellow solid, m.p. > 300 °C; 1 ¹H NMR (400 MHz, DMSO-d6) δ: 12.04 (s, 1H), 8.82 - 8.84 (m, 1H), 8.33–8.35 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93–7.95 (m, 1H), 7.85–7.87 (m, 3H), 7.56–7.61 (m, 2H), 7.52 (dd, J = 8.0, 4.0 Hz, 1H), 7.45–7.47 (m, 2H), 7.34–7.38 (m, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.74 (s, 1H). 13 ¹³C NMR (100 MHz, DMSO) δ: 159.3, 150.9, 146.7, 145.5, 144.1, 143.5, 142.8, 137.9, 136.3, 131.9, 130.0, 129.0, 128.3, 125.8, 124.2, 124.1, 122.3, 121.8, 121.0, 120.4, 111.6, 106.2, 97.0. HRMS (ESI+) exact mass calculated for [M+H] + (C 26 H 17 N4O3): 433.1295, found: 433.1305.

[0054] 4-(1-Oxo-2(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-3-yl)benzonitrile (3k), 13 mg, 32% yield. Yellow solid, m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ: 12.35 (s, 1H), 8.81 - 8.83 (m, 1H), 8.34 - 8.36 (m, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.92 - 7.95 (m, 1H), 7.81–7.83 (m, 1H), 7.48–7.61 (m, 5H), 7.32–7.36 (m, 3H), 7.20 - 7.24 (m, 1H), 6.72 (s, 1H). 13 13C NMR (100 MHz, DMSO-d6) δ: 159.4, 150.9, 145.8, 144.2, 143.7, 141.0, 138.0, 136.4, 136.3, 131.9, 131.2, 129.6, 128.9, 128.3, 125.8, 124.2, 124.0, 121.9, 120.9, 120.4, 118.2, 111.7, 110.7, 106.0, 96.9. HRMS (ESI+) exact mass calculated for [M+H] + (C 27 19 17 N4O): 413.1397, found: 413.1402.

[0055] 3-(Phenoxymethyl)-2-(8-quinolyl)-2,5-dihydro-1H-pyrido[4,3,b]indol-1-one (3l), 20 mg, 48% yield. Yellow solid, m.p. > 300 °C; 1 1H NMR (400 MHz, DMSO-d6) δ: 11.94 (s, 1H), 8.85–8.87 (m, 1H), 8.47–8.49 (m, 1H), 8.07 - 8.09 (m, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91–7.93 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.54–7.62 (m, 2H), 7.31–7.35 (m, 1H), 7.12–7.23 (m, 3H), 6.83–6.90 (m, 2H), 6.64 (d, J = 12.0 Hz, 2H), 4.56 (q, J = 20.0 Hz, 12 Hz, 2H). 1313C NMR (100 MHz, DMSO-d6) δ: 159.9, 157.4, 151.1, 144.3, 143.9, 142.2, 137.8, 136.6, 135.2, 131.1, 129.4, 129.3, 128.8, 126.3, 124.3, 123.9, 122.1, 121.1, 120.8, 120.3, 114.5, 111.5, 106.1, 95.1, 66.5. HRMS (ESI+) exact mass calculated for [M+H] + (C 27 H 20 N3O2): 418.1550, found: 418.1553。

Claims

1. A method for synthesizing γ-carbolinone compounds, characterized in that, Comprising the following steps: In the presence of a cobalt catalyst, an oxidant and a base, a 3-indolecarboxamide compound and an alkyne react in a solvent, and after the reaction is completed, the γ-carbolinone compound is obtained through post-treatment; The structure of the 3-indolecarboxamide compound is shown as formula (I): The structure of the γ-carbolinone compound is shown as formula (II): In formulas (I) to (II), R 1 is a substituted alkynyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted C1-C 10 alkyl; R 2 is a substituted or unsubstituted phenyl, a substituted or unsubstituted C1-C 10 alkyl or hydrogen; The substituent on the alkynyl group is a substituted or unsubstituted phenyl group, a substituted or unsubstituted C1-C 10 alkyl group; The substituent on the phenyl group is selected from C1-C4 alkyl, C1-C4 alkoxy, nitro or cyano; The C1 to C 10 The substituents on the alkyl group are selected from halogen or phenoxy; The cobalt catalyst is Co(acac)2, the oxidant is Mn(acac)3, the base is NaOPiv, and the solvent is trifluoroethanol.

2. The synthesis method of the γ-carbolinone compound according to claim 1, wherein The described R 1 is phenylethynyl, p-tolylethynyl, p-ethylphenylethynyl, p-tert-butylphenylethynyl, p-methoxyphenylethynyl, 6-chlorohex-1-ynyl, 3-phenoxypropynyl, phenyl, p-nitrophenyl, p-cyanophenyl or phenoxymethyl; R 2 is phenyl, p-tolyl, p-ethylphenyl, p-tert-butylphenyl, p-methoxyphenyl, 4-chlorobutyl, phenoxymethyl or hydrogen.

3. The synthesis method of the γ-carbolinone compound according to claim 1, characterized in that, The reaction temperature is 80-140 °C, and the reaction time is 3-24 hours.

4. The synthesis method of the γ-carbolinone compound according to claim 1, characterized in that, The structural formula of the γ-carbolinone compound is as follows: Q is wherein represents the substitution position.

Images