Synthesis Method and Application of Benzopyranone-Fused Indoline Compounds

Abstract

The present invention relates to the field of compound synthesis, and discloses a method for synthesizing benzopyranone-fused indoline compounds and their applications. The method includes: mixing a catalyst, a compound represented by formula II, a compound represented by formula III, and a solvent uniformly, stirring at 0-150 °C until the reaction is completed, and separating to obtain a benzopyranone-containing fused ring indolinone compound represented by formula I; R 1 is selected from any one of alkyl and phenyl, and R 2 is selected from any one of hydrogen, halogen, and alkyl. The indoline compounds provided by the present invention have good pharmaceutical activities and are a class of novel pharmaceutical intermediates. The preparation method of the present invention has cheap and easily available raw materials and catalysts; the reaction conditions are mild, and good yields can be obtained at room temperature, and the operation is simple and convenient; the substrate has wide generality, and high yields can be obtained for a series of benzopyranone-containing fused ring indolinone compounds.

Description

Technical Field

[0001] The present invention relates to the field of compound synthesis, specifically to a synthesis method and application of benzopyranone-fused indoline compounds. Background Art

[0002] Benzopyranone is an important organic heterocyclic skeleton with a simple structure, strong biological activity, and wide distribution in nature. It is the core structure of many natural products and synthetic molecules, and has various biological activities such as anticoagulation, anti-inflammatory, antibacterial, antioxidant, and antiviral. For example, the compound dicoumarol isolated from Melilotus officinalis is an important anticoagulant drug and has antibacterial activity against various pathogenic bacteria. Scutellaria baicalensis is a commonly used traditional Chinese medicine. The natural product baicalin extracted from its roots has antibacterial, diuretic, and anti-inflammatory effects, and also has strong anti-cancer reactions and other physiological effects. Quercetin is widely distributed in the plant kingdom and has antioxidant, analgesic, and anti-inflammatory effects. Silymarin is extracted from the fruits and seeds of Silybum marianum and has a strong antioxidant function, which can protect liver cells from toxic substances and promote the repair of the cell membranes of damaged liver cells.

[0003]

[0004] The indoline structure is a common heterocyclic structure in drug molecules and is also widely distributed in natural products. It is widely used in medicine and pesticides. Such derivatives also exhibit excellent biological activities. For example, akuammiline alkaloids extracted from the Yunnan characteristic natural ethnic medicine Alstonia scholaris are commonly used for relieving cough and asthma and treating chronic bronchitis, and have anti-inflammatory and analgesic effects. Vinblastine extracted from Catharanthus roseus is used as a chemotherapy drug in anti-cancer due to its high anti-cancer biological activity and unique pharmacological effects. At the same time, its sulfate is currently the first choice drug for treating Hodgkin's lymphoma.

[0005]

[0006] In summary, by analyzing benzopyranone-fused indolinone compounds, they may inherit the structures and properties of both. Therefore, the combination of these benzopyran structural units and indoline structures may obtain new drugs. For this reason, the present invention proposes a synthesis method and application of new benzopyranone-fused indoline compounds. Summary of the Invention

[0007] (1) Technical Problems to be Solved

[0008] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing benzopyranone-fused indoline compounds and their applications to solve the above problems.

[0009] (II) Technical Solution

[0010] To achieve the above object, the present invention provides the following technical solutions:

[0011] A method for synthesizing benzopyranone-fused indoline compounds, comprising the following steps:

[0012] Mix a catalyst, a compound represented by formula II, a compound represented by formula III, and a solvent uniformly, stir at 0 - 150 °C until the reaction is complete, and separate to obtain a benzopyranone-containing fused ring indolinone compound represented by formula I;

[0013] Among them, the structural formulas of the compound represented by formula II, the compound represented by formula III, and the compound represented by formula I are as follows:

[0014]

[0015] R 1 is selected from any one of alkyl and phenyl, and R 2 is selected from any one of hydrogen, halogen, and alkyl.

[0016] Preferably, the catalyst is any one of 1,1,3,3-tetramethylguanidine, triethylamine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, 1,2,2,6,6-pentamethylpiperidine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, and cesium carbonate.

[0017] Preferably, the amount of the compound represented by formula III is y times the amount of the compound represented by formula II, where y = 0.2 - 200.

[0018] Preferably, the solvent is at least one of chloroform, acetone, acetonitrile, ether, methanol, ethanol, toluene, ethyl acetate, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, epoxyethane, tetrahydrofuran, and nitromethane.

[0019] Preferably, the benzopyranone-containing fused ring indolinone compound has a chemical structure selected from one of the following structural formulas:

[0020]

[0021] Preferably, the chemical structure of the condensed-ring hydrogenated indole ketone compound containing benzopyrone is selected from one of the following structural formulas:

[0022]

[0023] The benzopyrone-fused hydrogenated indole compound prepared by the above method and its application in the preparation of antibacterial drugs.

[0024] Preferably, the benzopyrone-fused hydroindole compound is used in the preparation of antibacterial drugs for normal human liver cells.

[0025] (III) Beneficial effects

[0026] Compared with the prior art, the synthesis method and application of benzopyrone-fused hydroindole compounds provided by the present invention have the following beneficial effects:

[0027] 1. The synthesis method and application of the benzopyrone-fused hydrogenated indole compound have good pharmaceutical activity and can be used as a new type of drug intermediate.

[0028] 2. The method for preparing condensed-ring hydrogenated indole ketone compounds containing benzopyrone provided by the present invention has the following advantages: the raw materials and catalysts are cheap and easily available; the reaction conditions are mild, a good yield can be obtained at room temperature, and the operation is simple and convenient; the substrate has wide universality, and a high yield can be obtained for a series of condensed-ring hydrogenated indole ketone compounds containing benzopyrone. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] The compound of formula Ⅲ of the present invention is a quinone amine compound and can be synthesized according to the following literature methods [(a) D. Xu, Y. Zhao, D. Song, Z. Zhong, S. Feng, X. Xie, X. Wang, X. She, Org. Lett. 2017, 19, 3600 - 3603; (b) K. Kishi, F. A. Arteaga, S. Takizawa, H. Sasai, Chem. Commun. 2017, 53, 7724 - 7727; (c) L. Pantaine, V. Coeffard, X. Moreau, C. Greck, Org. Lett. 2015, 17, 3674 - 3677; (d) K.-W. Hu, X. You, X. Wen, H. Yuan, Q.-L. Xu, Z. Lai, J. Org. Chem. 2022, DOI: org / 10.1021 / acs.joc.2c01031.]. The compound of formula Ⅱ is chromone-3-carbaldehyde and can be synthesized according to the following literature methods [(a) N. Sepay, S. P. Dey, J. Heterocyclic Chem. 2014, 51, E1 - E24; (b) S. J. Degen, K. L. Mueller, G. M Golding, L.-L. Wei, C. A. Zificsak, A. Neeno-Eckwall, R. P. Hsung, Bioorg. Med. Chem. Lett. 1999, 9, 973 - 978; (c) B. C. Raju, R. N. Rao, P. Suman, P. Yogeeswari, D. Sriram, T. B. Shaik, V. Kalivendi, Bioorg. Med. Chem. Lett. 2011, 21, 2855 - 2859; (d) B. Baskar, P.-Y. Dakas, K. Kumar, Org. Lett. 2011, 13, 1988 - 1991; (e) K. Wittstein, A. B. García, M. Schürmann, K. Kumar, Synlett 2012, 2012, 227 - 232.]

[0031] Example 1

[0032] Synthesis method and application of benzopyranone-fused indoline compounds, the specific content is as follows:

[0033] The synthesis steps of the benzopyranone-containing fused ring indolinone compounds shown in formula I-1 are as follows:

[0034]

[0035] Under nitrogen protection, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (30.48 mg, 0.11 mmol), chromone-3-carbaldehyde II-1 (17.40 mg, 0.10 mmol), catalyst sodium hydroxide [NaOH] (4.00 mg, 0.10 mmol) and solvent acetonitrile CH3CN (2.0 mL) were successively added to a 10 mL reaction flask. After stirring the reaction solution at 15 °C for 12 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 4 / 1) was used to obtain 27.50 mg of white solid product I-1 with a yield of 65%.

[0036] Analysis data of the benzopyranone-fused polycyclic indolinone compound shown in Formula I-1: 1 H NMR (400 MHz, CDCl3): δ 1.65 (s, 3H), 2.48 (s, 3H), 2.55 (dd, J = 17.6, 2.8 Hz, 1H), 2.81 (d, J = 18 Hz, 1H), 2.89 (t, J = 2.4 Hz, 2H), 5.98 (d, J = 10.4 Hz, 1H), 6.23 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.37 7.41 (m, 3H), 7.50 - 7.55 (m, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 193.95, 189.56, 157.74, 149.81, 144.13, 139.09, 136.96, 129.40, 128.15, 127.14, 126.75, 122.65, 119.44, 117.98, 89.80, 66.12, 49.87, 45.37, 33.96, 23.72, 21.60. HRMS (ESI): Exact mass calcd for C 23 H 21 NO5SNa [M+Na] + : 446.1033, Found: 446.1037.

[0037] Example 2

[0038] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Example 1, the synthesis steps of the benzopyranone-fused polycyclic indolinone compound shown in Formula I-2 are as follows:

[0039]

[0040] Under nitrogen protection, in a 10 mL reaction flask, N-(1-methyl-4-oxocyclohex-2,5-dien-1-yl)methanesulfonamide Ⅲ-2 (28.15 mg, 0.14 mmol), chromone-3-carbaldehyde Ⅱ-1 (17.40 mg, 0.10 mmol), catalyst potassium hydroxide [KOH] (5.61 mg, 0.10 mmol) and solvent dichloroethane DCE (1.0 mL) were added successively. After stirring the reaction solution at 30 °C for 5 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 3 / 1) was used to obtain 26.03 mg of white solid of product I-2, with a yield of 75%.

[0041] Analysis data of the benzopyranone-fused polycyclic indolinone compound shown in Formula I-2: 1 H NMR (400 MHz, CDCl3): δ 1.91 (s, 3H), 2.62 (dd, J = 18, 6.4 Hz, 1H), 2.84 - 2.91 (m, 2H), 3.01 3.07 (m, 1H), 3.35 (s, 3H), 5.97 (d, J = 10.4 Hz, 1H), 6.08 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.19 (td, J = 10.4, 1.6 Hz, 1H), 7.53 - 7.57 (m, 1H), 7.88 (td, J = 8.0, 1.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 193.88, 189.27, 157.43, 149.74, 137.10, 127.27, 126.65, 122.90, 119.52, 118.06, 89.91, 65.80, 49.88, 45.93, 45.54, 34.00, 23.47. HRMS (ESI): Exact mass calcd for C 17 H 17 NO5SNa [M+Na] + : 370.0720, Found: 370.0725.

[0042] Example 3

[0043] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1 and 2, the synthesis steps of the benzopyranone-fused polycyclic indolinone compound shown in Formula I-3 are as follows:

[0044]

[0045] Under nitrogen protection, N-(4-oxo-[1,1'-biphenyl]-1(4H)-yl)methanesulfonamide Ⅲ-3 (47.35 mg, 0.18 mmol), chromone-3-carbaldehyde Ⅱ-1 (17.40 mg, 0.10 mmol), catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene [DBU] (5.32 mg, 0.035 mmol) and solvent ethyl acetate EA (3.0 mL) were successively added into a 10 mL reaction flask. After stirring the reaction solution at 60 °C for 10 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 7 / 1) was used to obtain 27.00 mg of white solid of product I-3, with a yield of 66%.

[0046] Analysis data of the benzopyranone-fused indolinone compounds represented by formula Ⅰ-3: 1 H NMR (400 MHz, CDCl3): δ 2.32 (dd, J = 18, 5.6 Hz, 1H), 2.74 (td, J = 17.6, 1.2 Hz, 1H), 2.95 (s, 3H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 3.44 - 3.50 (m, 1H), 6.29 - 6.32 (m, 2H), 7.10 - 7.17 (m, 2H), 7.39 - 7.48 (m, 3H), 7.59 - 7.63 (m, 3H), 7.67 (ddd, J = 10.8, 2.0, 0.8 Hz, 1H), 7.92 (ddd, J = 8.0, 1.2, 0.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 194.28, 189.09, 157.57, 147.44, 137.43, 137.23, 129.37, 128.97, 128.79, 127.43, 127.40, 123.11, 119.72, 118.21, 90.06, 71.22, 50.42, 49.44, 44.71, 33.48. HRMS (ESI): Exact mass calcd for C 22 H 19 NO5SNa [M+Na] + : 432.0876, Found: 432.0881.

[0047] Example 4

[0048] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1 - 3, the synthesis steps of the benzopyranone-fused indolinone compounds represented by formula Ⅰ-4 are as follows:

[0049]

[0050] Under nitrogen protection, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (55.41 mg, 0.20 mmol), 6-methyl-chromone-3-carbaldehyde II-2 (18.80 mg, 0.10 mmol), catalyst triethylamine [Et3N] (5.06 mg, 0.05 mmol) and solvent dimethyl sulfoxide DMSO (8.0 mL) were successively added into a 10 mL reaction flask. After stirring the reaction solution at 85 °C for 8 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 3 / 1) was used to obtain 31.47 mg of white solid product I-4, with a yield of 72%.

[0051] Analysis data of the benzopyranone-containing fused-ring hydroindolone compound shown in Formula I-4: 1 H NMR (400 MHz, CDCl3): δ 1.63 (s, 3H), 2.30 (s, 3H), 2.48 (s, 3H), 2.51 - 2.57 (m, 1H), 2.82 (d, J = 17.6 Hz, 1H), 2.87 - 2.88 (m, 2H), 5.98 (d, J = 10.4 Hz, 1H), 6.19 - 6.21 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 7.29 - 7.34 (m, 1H), 7.37 - 7.41 (m, 3H), 7.63 - 7.64 (m, 1H), 8.05 (d, J = 8.0 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 194.05, 189.80, 155.77, 149.92, 144.09, 139.13, 138.00, 132.32, 129.39, 128.16, 127.82, 126.74, 126.70, 119.16, 118.33, 117.78, 89.75, 66.10, 49.83, 45.34, 33.96, 23.69, 21.61, 20.43. HRMS (ESI): Exact mass calcd for C 24 H 23 NO5SNa [M + Na] + : 460.1189, Found: 460.1183.

[0052] Example 5

[0053] Synthesis method and application of benzopyranone-fused indoline compounds. Based on Examples 1-4, the synthesis steps of the benzopyranone-containing fused-ring indolinone compounds shown in Formula I-5 are as follows:

[0054]

[0055] Under nitrogen protection, in a 10 mL reaction flask, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (110.83 mg, 0.4 mmol), 6-fluoro-chromone-3-carbaldehyde II-3 (19.20 mg, 0.10 mmol), catalyst cesium carbonate [Cs2CO3] (14.66 mg, 0.045 mmol) and solvent 1,4-dioxane (8.0 mL) were added in sequence. After stirring the reaction solution at 100 °C for 10 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent was (petroleum ether / ethyl acetate = 8 / 1), to obtain 29.11 mg of the product I-5 as a white solid, with a yield of 66%.

[0056] Analysis data of the benzopyranone-containing fused-ring indolinone compounds shown in Formula I-5: 1 H NMR(400MHz,CDCl3):δ1.65(s,3H),2.48(s,3H),2.53 - 2.59(m,1H),2.79(d,J = 17.6Hz,1H),2.88 - 2.89(m,2H),5.98(d,J = 10.4Hz,1H),6.21(d,J = 3.2Hz,1H),6.87(dd,J = 9.2,4.0Hz,1H),7.21 - 7.26(m,1H),7.37 - 7.40(m,3H),7.49(dd,J = 8.0,3.2Hz,1H),8.03(d,J = 8.4S12 Hz,2H); 13 C NMR(100MHz,CDCl3):δ193.84,188.94(d,J = 2.2Hz),157.79(d,J = 243Hz),153.92,149.70,144.25,138.96,129.44,128.10,126.78,124.61,124.37,120.15(d,J = 6.7Hz),119.79(d,J = 7.4Hz),112.23(d,J = 23.5Hz),90.02,66.21,49.58,45.19,33.90,23.70,21.60.HRMS(ESI):Exact mass calcd for C 23 H 20FNO5SNa[M+Na] + : 464.0938, Found: 464.0942.

[0057] Example 6

[0058] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1-5, synthesis of fused-ring hydroindolone compounds containing benzopyranone shown in Formula I-6:

[0059]

[0060] Under nitrogen protection, in a 10 mL reaction flask, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (69.27 mg, 0.25 mmol), 6-chloro-chromone-3-carbaldehyde II-4 (20.80 mg, 0.10 mmol), catalyst triethylenediamine [DABCO] (5.61 mg, 0.05 mmol) and solvent toluene (25.0 mL) were added in sequence. After stirring the reaction solution at 60 °C for 7 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. After extraction of the reaction solution, column chromatography was carried out,

[0061] Eluent (petroleum ether / ethyl acetate = 10 / 1), to obtain 36.57 mg of white solid of product I-6, with a yield of 80%.

[0062] Analysis data of fused-ring hydroindolone compounds containing benzopyranone shown in Formula I-6: 1 H NMR (400 MHz, CDCl3): δ 1.65 (s, 3H), 2.48 (s, 3H), 2.56 (dd, J = 18, 5.2 Hz, 1H), 2.79 (d, J = 18 Hz, 1H), 2.84 - 2.94 (m, 2H), 5.99 (d, J = 10.8 Hz, 1H), 6.23 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 7.37 - 7.41 (m, 3H), 7.45 - 7.48 (m, 1H), 7.81 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H); 1313C NMR(100MHz, CDCl3): δ 193.73, 188.57, 156.16, 149.63, 144.30, 138.93, 136.79, 129.48, 128.25, 128.11, 126.85, 126.51, 120.23, 119.72, 90.04, 66.20, 49.62, 45.33, 33.89, 23.75, 21.63. HRMS(ESI): Exact mass calcd for C 23 H 20 ClNO5SNa [M+Na] + : 480.0643, Found: 480.0647.

[0063] Example 7

[0064] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1-6, the synthesis steps of the fused-ring hydroindolone compounds containing benzopyranone shown in Formula I-7 are as follows:

[0065]

[0066] Under nitrogen protection, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (83.123 mg, 0.30 mmol), 6-chloro-7-methyl-chromone-3-carbaldehyde II-5 (22.20 mg, 0.10 mmol), catalyst 1,2,2,6,6-pentamethylpiperidine [PMP] (4.32 mg, 0.03 mmol) and solvent ethyl acetate EA (8 mL) were successively added to a 10 mL reaction flask. After stirring the reaction solution at 15 °C for 24 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 2 / 1) was used to obtain 29.21 mg of white solid product I-7, with a yield of 62%.

[0067] Analysis data of the fused-ring hydroindolone compounds containing benzopyranone shown in Formula I-7: 1 1H NMR(400MHz, CDCl3): δ 1.63(s, 3H), 2.39(s, 3H), 2.49(s, 3H), 2.52 - 2.57(m, 1H), 2.76 - 2.81(m, 1H), 2.84 - 2.87(m, 2H), 5.99(dd, J = 10.8, 1.2 Hz, 1H), 6.20(d, J = 3.6 Hz, 1H), 6.76(d, J = 0.8 Hz, 1H), 7.38 - 7.41(m, 3H), 7.80(s, 1H), 8.03(d, J = 8.8 Hz, 2H);13 C NMR (100 MHz, CDCl3): δ 193.84, 188.35, 155.96, 149.65, 146.34, 144.23, 138.97, 129.48, 128.89, 128.09, 126.83, 126.79, 120.02, 118.37, 89.97, 66.13, 49.53, 45.38, 33.91, 23.76, 21.63, 20.97. HRMS (ESI): Exact mass calcd for C 24 H 22 ClNO5SNa [M+Na] + : 494.0799, Found: 494.0794.

[0068] Example 8

[0069] Synthesis method and application of benzopyran-fused indoline compounds. On the basis of Examples 1-7, the synthesis steps of the benzopyran-containing fused-ring indolinone compounds shown in Formula I-8 are as follows:

[0070]

[0071] Under nitrogen protection, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (138.54 mg, 0.50 mmol), 8-chloro-chromone-3-carbaldehyde II-6 (20.80 mg, 0.10 mmol), catalyst 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene [MTBD] (45.97 mg, 0.30 mmol) and solvent tetrahydrofuran THF (10.0 mL) were successively added to a 10 mL reaction flask. After stirring the reaction solution at 55 °C for 9 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. After extraction of the reaction solution, column chromatography was carried out, and the eluent (petroleum ether / ethyl acetate = 4 / 1) was used to obtain 20.11 mg of the white solid product I-8, with a yield of 44%.

[0072] Analysis data of the benzopyran-containing fused-ring indolinone compounds shown in Formula I-8: 11H NMR (400 MHz, CDCl3): δ 1.56 (s, 3H), 2.47 (s, 3H), 2.56 (dd, J = 18, 5.6 Hz, 1H), 2.77 - 2.84 (m, 1H), 2.89 - 2.95 (m, 1H), 2.99 (dd, J = 13.2, 4.0 Hz, 1H), 6.01 (d, J = 10.8, 1.2 Hz, 1H), 6.38 (d, J = 3.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 7.36 (dd, J = 8.4, 0.8 Hz, 2H), 7.51 (dd, J = 10.4, 2.0 Hz, 1H), 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H); 13 13C NMR (100 MHz, CDCl3): δ 193.72, 189.13, 153.73, 149.81, 144.18, 138.66, 137.23, 129.60, 128.41, 126.99, 125.78, 123.10, 122.69, 120.96, 90.61, 66.06, 49.55, 45.18, 33.79, 23.54, 21.61. HRMS (ESI): Exact mass calcd for C 23 H 20 ClNO5SNa [M + Na] + : 480.0643, Found: 480.0639.

[0073] Example 9

[0074] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1 - 8, synthesis of fused-ring indolinone compounds containing benzopyranone shown in Formula I-9:

[0075]

[0076] Under nitrogen protection, 4-methyl-N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)benzenesulfonamide III-1 (41.56 mg, 0.15 mmol), 4-oxo-4-benzo[h]tryptamine-3-carbaldehyde II-7 (22.40 mg, 0.10 mmol), catalyst sodium methoxide [MeONa] (1.62 mg, 0.03 mmol) and solvent acetonitrile CH3NO2 (12.0 mL) were successively added to a 10 mL reaction flask. After stirring the reaction solution at 85 °C for 8 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 5 / 1) was used to obtain 25.07 mg of white solid product I-9, with a yield of 53%.

[0077] Analysis data of the benzopyranone-fused indolinone compound represented by Formula I-9: 1 H NMR (400 MHz, CDCl3): δ 1.88 (s, 3H), 2.58 (s, 3H), 2.59 - 2.64 (m, 1H), 2.88 (d, J = 18 Hz, 1H), 2.99 - 3.00 (m, 2H), 6.05 (dd, J = 10.4, 1.2 Hz, 1H), 6.31 - 6.32 (m, 1H), 7.38 - 7.43 (m, 2H), 7.47 - 7.51 (m, 3H), 7.57 7.63 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 194.00, 189.14, 156.30, 149.40, 144.34, 139.19, 137.91, 130.01, 129.92, 127.99, 127.96, 127.11, 126.10, 124.33, 123.69, 122.14, 121.33, 113.75, 90.54, 67.23, 49.83, 45.73, 34.12, 24.48, 21.73. HRMS (ESI): Exact mass calcd for C 27 H 23 NO5SNa [M+Na] + : 496.1189, Found: 496.1182.

[0078] Example 10

[0079] Synthesis method and application of benzopyranone-fused indoline compounds. On the basis of Examples 1 - 9, the synthesis steps of the benzopyranone-fused indolinone compound represented by Formula I-10 are as follows:

[0080]

[0081] Under nitrogen protection, N-(1-methyl-4-oxocyclohexa-2,5-dien-1-yl)methanesulfonamide III-2 (24.12 mg, 0.12 mmol), 7-bromo-chromone-3-carbaldehyde II-8 (25.19 mg, 0.10 mmol), the catalyst sodium tert-butoxide t BuONa](2.88 mg, 0.03 mmol) and the solvent dichloromethane DCM (12.0 mL) were successively added into a 10 mL reaction flask. After stirring the reaction solution at 75 °C for 7 h, TLC detection showed that the raw materials had basically reacted completely, and the reaction was stopped. The reaction solution was directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 2 / 1) was used to obtain 27.20 mg of the white solid of product I-10, with a yield of 64%.

[0082] Analytical data of the benzopyranone-containing fused-ring hydroindolone compound represented by Formula I-10: 1 H NMR (400 MHz, CDCl3): δ 1.91 (s, 3H), 2.63 (dd, J = 18, 6.0 Hz, 1H), 2.84 (tt, J = 17.6, 1.2 Hz, 1H), 2.90 (dd, J = 13.2, 4.0 Hz, 1H), 3.00 (ddt, J = 13.2, 6.0, 1.6 Hz, 1H), 3.33 (s, 3H), 5.97 (dd, J = 10.4, 0.8 Hz, 1H), 6.09 (d, J = 4.0 Hz, 1H), 7.18 - 7.21 (m, 2H), 7.24 (dd, J = 8.4, 1.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 193.63, 188.40, 157.62, 149.52, 131.68, 128.47, 126.75, 126.54, 121.35, 118.30, 90.34, 65.88, 49.77, 45.94, 45.62, 33.95, 23.50. HRMS (ESI): Exact mass calcd for C 17 H 16 BrNO5SNa [M+Na] + : 447.9825, Found: 447.9821.

[0083] Example 11

[0084] Synthesis method and application of benzopyranone-fused indoline compounds. Based on Examples 1-10, synthesis of fused-ring hydroindolone compounds containing benzopyranone shown in Formula I-11:

[0085]

[0086] Under nitrogen protection, in a 10 mL reaction flask, successively add N-(1-methyl-4-oxocyclohex-2,5-dien-1-yl)methanesulfonamide III-2 (70.37 mg, 0.35 mmol), 8-bromo-chromone-3-carbaldehyde II-9 (25.19 mg, 0.10 mmol), the catalyst potassium tert-butoxide t BuOK](5.61 mg, 0.05 mmol) and the solvent isopropyl alcohol IPA (10.0 mL). After stirring the reaction solution at 110 °C for 24 h, TLC detection shows that the raw materials have basically reacted completely, and the reaction is stopped. The reaction solution is directly subjected to column chromatography, and the eluent (petroleum ether / ethyl acetate = 4 / 1) is used to obtain 20.40 mg of white solid product I-11, with a yield of 48%.

[0087] Analysis data of the fused-ring hydroindolone compound containing benzopyranone shown in Formula I-11: 1 H NMR(400 MHz, CDCl3): δ1.94(s, 3H), 2.64(dd, J = 17.6, 6.0 Hz, 1H), 2.86(dd, J = 17.6, 0.8 Hz, 1H), 2.92 - 2.97(m, 1H), 3.03 - 3.09(m, 1H), 3.49(s, 3H), 5.98(d, J = 10.4 Hz, 1H), 6.15(d, J = 4.0 Hz, 1H), 7.01(d, J = 8.0 Hz, 1H), 7.20(d, J = 10.4 Hz, 1H), 7.80(d, J = 7.6 Hz, 1H), 7.86(d, J = 8.0 Hz, 1H); 13 C NMR(100 MHz, CDCl3): δ193.68, 188.80, 154.12, 149.70, 140.11, 126.67, 123.55, 120.90, 112.11, 90.66, 65.95, 49.64, 45.83, 45.49, 33.94 23.44. HRMS(ESI): Exact mass calcd for C 17 H 16 BrNO5SNa[M + Na] +: 447.9825, Found: 447.9827.

[0088] Example 12

[0089] Application of the aforementioned benzopyran-containing fused-ring indolinone compounds, and specifically, its antibacterial activity test is carried out as follows:

[0090] The background technology introduced that Dicoumarol has antibacterial activity against various pathogenic bacteria, and the benzopyran-containing fused-ring indolinone compounds synthesized by the method of the present invention have a certain similar structure to it. Therefore, in this example, Dicoumarol is used as a control sample, and Staphylococcus aureus, Escherichia coli, and Candida albicans are used as test strains to test the antibacterial activity of 11 compounds in the following table.

[0091] For the antibacterial activity screening, human normal liver cells WRL68 are used, and the specific method is as follows: WRL68 cells are routinely cultured in MEM medium containing 10% high-quality fetal bovine serum and 1% double antibiotics in an incubator at 37°C, 5% CO2, and 70%-80% humidity. The revived bacterial liquid is taken and centrifuged at 1200 r / min for 5 min in a centrifuge tube. The culture medium is removed and buffer solution is added to prepare a bacterial liquid of 1×10 6 CFU / mL. The autoclaved round filter paper (diameter 6.0 mm) is respectively pasted on the culture medium, and according to 1×10 6 CFU / mL, 100 μL of the cell suspension is added to the culture medium, and 10 μL of the test compound shown in the following table at 100 mg / L is added to each group. In addition, a blank control group is set up, and it is incubated at 37°C for 12 h, and the diameter of the inhibition zone is measured. Each group is repeated three times, and the test data are averaged.

[0092] Table 1 Inhibition zone diameters of dicoumarol and compounds of Examples 1-11 in the WRL68 cell culture dish

[0093]

[0094]

[0095] The results showed that compounds I-1 to I-11 could effectively inhibit the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans in WRL68 cells, and thus exhibited antibacterial effects. Among them, compound I-9 had significant antibacterial activity. When it was added to the cell culture dishes of the three colonies respectively, the diameters of the inhibition zones were 13.2±0.9 mm, 10.3±0.6 mm, and 10.2±0.5 mm, which were comparable to those of the reference dicoumarol (d = 10.2±0.1 mm, 9.3±0.3 mm, 10.5±0.1 mm); compounds I-4 and I-11 also had relatively good antibacterial activity. Generally speaking, the antibacterial activity test data in Table 1 indicated that the benzopyranone-containing fused-ring hydroindolone compounds described in the present invention had high antibacterial activity, providing an important basis for further research on such compounds and the development of new antibacterial drugs, and having good research value.

[0096] In summary, the hydroindole compounds provided by the present invention have good pharmaceutical activities and are a novel type of pharmaceutical intermediate. The preparation method of the present invention has the advantages that the raw materials and catalysts are cheap and easily available; the reaction conditions are mild, and good yields can be obtained at room temperature, and the operation is simple and convenient; the substrate has wide generality, and high yields can be obtained for a series of benzopyranone-containing fused-ring hydroindolone compounds.

[0097] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing benzopyranone-fused indoline compounds, characterized in that, It includes the following steps: Mix the catalyst, the compound shown in Formula II, the compound shown in Formula III and the solvent evenly, stir at 0-150 °C until the reaction is completed, and separate to obtain the polycyclic hydroindolone compound containing benzopyranone shown in Formula I; The structural formulas of the compound shown in Formula II, the compound shown in Formula III and the compound shown in Formula I are as follows: The chemical structure of Formula I is selected from one of the following structural formulas: The catalyst is any one of 1,1,3,3-tetramethylguanidine, triethylamine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, 1,2,2,6,6-pentamethylpiperidine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, cesium carbonate.

2. The synthetic method of the benzopyranone-fused indoline compounds according to claim 1, wherein: The amount of substance of the compound shown in Formula III is y times that of the compound shown in Formula II, and y = 0.2-200.

3. The synthetic method of the benzopyranone-fused indoline compounds according to claim 1, characterized in that: The solvent is at least one of chloroform, acetone, acetonitrile, ether, methanol, ethanol, toluene, ethyl acetate, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, ethylene oxide, tetrahydrofuran and nitromethane.

4. The method for synthesizing benzopyran-fused indoline compounds according to claim 1, characterized in that: The polycyclic hydroindolone compound containing benzopyranone, the chemical structure of which is selected from one of the following structural formulas:

5. Use of a benzopyranone-fused hydroindole compound obtained by the synthesis method according to any one of claims 1-4 in the preparation of antibacterial drugs.

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