Method for synthesizing isoindolo [2, 1-a] pyrrolo [2, 1-c] quinoxaline compound

Abstract

The invention provides a method for synthesizing an isoindolo [2, 1-a] pyrrolo [2, 1-c] quinoxaline compound, and relates to the technical field of organic synthesis. The isoindolo [2, 1-a] pyrrolo [2, 1-c] quinoxaline compound is obtained by mixing a compound 1, a compound 2, trifluoromethanesulfonic anhydride and a polar solvent and carrying out cyclization reaction under a protective atmosphere. A one-pot method is adopted for one-step synthesis, the synthesis process is simple, and the product yield is high. According to the method provided by the invention, the preparation raw materials are safe, dangerous reagents such as azide and the like and raw materials such as a metal catalyst and a toxic oxidant which are commonly used in a traditional two-step synthesis route are avoided, potential safety hazards are fundamentally eliminated, and the method conforms to the development trend of green chemistry, has higher operation safety and environmental friendliness, and is suitable for industrial production. The production cost is low. Furthermore, the method provided by the invention is mild in reaction condition, low in energy consumption, short in time consumption and high in production efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds. Background Art

[0002] Isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds have important application values in medicinal chemistry, fluorescent materials, organic light-emitting diodes (OLEDs) and chemical space exploration. For example, this compound has significant potential in the development of anticancer drugs; its excellent fluorescence characteristics make it suitable for fluorescent dyes and bioimaging probes; in OLEDs, pyrazole-fused ring compounds exhibit good blue light emission performance and are suitable for optoelectronic materials; through modular synthesis methods, various heterocyclic fragments can be introduced to expand the diversity of chemical space and provide more possibilities for the design of novel functional molecules.

[0003] Currently, the synthesis method of isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds is mainly a two-step method, and the reaction route is as follows:

[0004]

[0005] However, the synthesis steps of the above-mentioned synthesis method for isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds are complex, and the total yield is only 69%, with a relatively low product yield. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a method for synthesizing isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds. The method provided by the present invention can obtain isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds in one step, with simple steps and high product yield.

[0007] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0008] The present invention provides a method for synthesizing isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds, comprising the following steps:

[0009] Mix compound 1, compound 2, an acidic catalyst and a polar solvent, and carry out a cyclization reaction under a protective atmosphere to obtain an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound;

[0010]

[0011] Preferably, the molar ratio of compound 1 to compound 2 is 1:1 to 2.

[0012] Preferably, the acidic catalyst includes trifluoromethanesulfonic anhydride and / or trifluoromethanesulfonic acid;

[0013] The molar ratio of the compound 1 to the acidic catalyst is 1:0.2 - 2.

[0014] Preferably, the polar solvent includes one or more of benzene solvents, chloroalkane solvents, and nitrile solvents.

[0015] Preferably, the benzene solvents include one or more of toluene, xylene, and chlorobenzene;

[0016] The chloroalkane solvents include dichloromethane;

[0017] The nitrile solvents include acetonitrile.

[0018] Preferably, the polar solvent includes a mixed solvent of benzene solvents and chloroalkane solvents, chloroalkane solvents, or nitrile solvents.

[0019] Preferably, the volume ratio of the chloroalkane solvents to the benzene solvents in the mixed solvent of benzene solvents and chloroalkane solvents is 1:1 - 20.

[0020] Preferably, the temperature of the cyclization reaction is 0 - 80 °C, and the time is 3 - 6 h.

[0021] Preferably, after the cyclization reaction, it further includes: concentrating the reaction solution obtained from the cyclization reaction and then separating and purifying it by silica gel column chromatography. The eluent used for the silica gel column chromatography separation and purification includes petroleum ether and ethyl acetate.

[0022] Preferably, the volume ratio of the petroleum ether to the ethyl acetate is 4 - 20:1.

[0023] The present invention adopts a one-pot one-step synthesis method, with a simple synthesis process and a high product yield. The method provided by the present invention uses safe raw materials for preparation, avoiding dangerous reagents such as azides, metal catalysts, and toxic oxidants commonly used in the traditional two-step synthesis route. It fundamentally eliminates potential safety hazards, conforms to the development trend of green chemistry, has higher operational safety and environmental friendliness, low production costs, and is suitable for industrial production. As shown by the test results of the examples, the total yield of the isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound provided by the present invention is 90.2%.

[0024] Furthermore, the method provided by the present invention has mild reaction conditions, low energy consumption, short time consumption, and high production efficiency. Description of the Drawings

[0025] Figure 11H NMR spectrum of the isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound synthesized in Example 1;

[0026] Figure 2 13C NMR spectrum of the isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound synthesized in Example 1. Detailed implementation manners

[0027] The present invention provides a method for synthesizing an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound, comprising the following steps: mixing Compound 1, Compound 2, an acidic catalyst and a polar solvent, and carrying out a cyclization reaction under a protective atmosphere to obtain an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound;

[0028]

[0029] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0030] In the present invention, the molar ratio of Compound 1 to Compound 2 is preferably 1:1 to 2, and in the detailed implementation manners, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0031] In the present invention, the acidic catalyst preferably includes trifluoromethanesulfonic anhydride and / or trifluoromethanesulfonic acid. In the present invention, the molar ratio of Compound 1 to trifluoromethanesulfonic anhydride is preferably 1:0.2 to 2, and in the detailed implementation manners, it can be 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0032] In the present invention, the polar solvent preferably includes one or more of benzene solvents, chloroalkane solvents, and nitrile solvents, more preferably a mixed solvent of benzene solvents and chloroalkane solvents, a chloroalkane solvent, or a nitrile solvent; the volume ratio of the chloroalkane solvent to the benzene solvent in the mixed solvent of benzene solvents and chloroalkane solvents is preferably 1:1 to 20, and in specific embodiments, it can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20. In the present invention, the benzene solvent preferably includes one or more of toluene, xylene, and chlorobenzene; the chloroalkane solvent preferably includes dichloromethane; the nitrile solvent preferably includes acetonitrile. In the present invention, the mixed solvent of benzene solvents and chloroalkane solvents preferably includes a mixed solvent of toluene and dichloromethane, a mixed solvent of xylene and dichloromethane, or a mixed solvent of chlorobenzene and dichloromethane. In the present invention, the molar amount of Compound 1 to the volume of the polar solvent is preferably 1 mol: 10 to 40 L, and in specific embodiments, it can be 1 mol: 10 L, 1 mol: 15 L, 1 mol: 20 L, 1 mol: 25 L, 1 mol: 30 L, 1 mol: 35 L, or 1 mol: 40 L.

[0033] In the present invention, the protective atmosphere preferably includes nitrogen, argon, or helium.

[0034] In the present invention, the temperature of the cyclization reaction is preferably 0 to 80 °C, and in specific embodiments, it can be 0 °C, 10 °C, 20 °C, 25 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, or 80 °C; the time of the cyclization reaction is preferably 3 to 6 h, and in specific embodiments, it can be 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, or 6 h; the cyclization reaction is preferably carried out under stirring conditions.

[0035] After completing the cyclization reaction, the present invention preferably further includes: concentrating the reaction solution obtained from the cyclization reaction and then separating and purifying it by silica gel column chromatography to obtain an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound. The present invention has no special limitation on the concentration, and any concentration method well-known to those skilled in the art can be used to remove the solvent. In the present invention, the eluent used for the silica gel column chromatography separation and purification preferably includes petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 4 to 20:1, and in specific embodiments, it can be 4:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, or 20:1.

[0036] Compared with the traditional two-step method, the present invention adopts a one-pot method for one-step synthesis, which has a simple process, high yield, mild conditions, solves the cumbersome reaction process, shortens the reaction time, and has a high product yield. Moreover, the present invention abandons dangerous reagents such as azides commonly used in the traditional synthesis route, fundamentally eliminates potential safety hazards, conforms to the development trend of green chemistry, has higher operational safety and environmental friendliness, is green and environmentally friendly, has low production costs, and is suitable for industrial production.

[0037] To further illustrate the present invention, the method for synthesizing isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compounds provided by the present invention will be described in detail below in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

[0038] Example 1

[0039]

[0040] Compound 1 (0.1 mmol), a mixed solvent of toluene and dichloromethane (20:1, V:V, 2 mL), compound 2 (0.12 mmol) and trifluoromethanesulfonic anhydride (0.1 mmol) were added, nitrogen was filled, and the reaction was carried out at 25 °C under stirring conditions for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete (the raw material spot of compound 1 disappeared). The obtained reaction solution was concentrated and then separated and purified by silica gel column chromatography (the eluent was petroleum ether:ethyl acetate volume ratio = 10:1) to obtain isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound (23.2 mg, yield 90.2%, purity 99.5%).

[0041] The hydrogen spectrum of the isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound is shown in Figure 1 , and the carbon spectrum is shown in Figure 2 , and the NMR data are as follows: 1 H NMR (400 MHz, CDCl3, ppm): δ 8.73 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.91 - 7.84 (m, 2H), 7.79 (s, 1H), 7.56 - 7.45 (m, 3H), 7.24 - 7.21 (m, 1H), 7.06 (d, J = 4.0 Hz, 1H), 6.85 - 6.84 (m, 1H); 13 C NMR (100 MHz, CDCl3, ppm): δ 148.5, 127.0, 126.3, 125.4, 124.9, 124.6, 124.3, 121.3, 120.6, 119.6, 117.6, 116.1, 115.1, 114.0, 112.6, 112.5, 102.9.

[0042] Comparative Example 1

[0043]

[0044] (1) At room temperature, to a stirred solution of 2-(1H-pyrrol-1-yl)aniline (1.25 mmol) in dichloromethane (10 mL), tert-butyl (2-formylphenyl)carbamate (1.25 mmol) and molecular sieve (1.25 g) were successively added. The resulting mixture was stirred at room temperature for 10 h. After confirming complete consumption of the starting materials by thin-layer chromatography plate monitoring, the solid was filtered off and the reaction solution was diluted with dichloromethane to 0.01 M. Subsequently, the solution was irradiated at room temperature under a UV LED light source system (365 nm) for 30 min to 1 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was dissolved in a 10 mL dichloromethane-trifluoroacetic acid (DCM:TFA, V / V = 5:1) mixed solution and stirred at room temperature for 3 h. After confirming complete reaction by thin-layer chromatography plate, the volatile components were removed, and the reaction system was neutralized with saturated NaHCO3 solution. Extraction was carried out 3 times with dichloromethane (30 mL each time), the organic phases were combined and the solvent was removed by concentration under reduced pressure, and purification was carried out by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate volume ratio = 10:1) to obtain 2-(pyrrolo[1,2-a]quinoxalin-4-yl)aniline (269.0 mg, yield 83.0%).

[0045] (2) 2-(Pyrrolo[1,2-a]quinoxalin-4-yl)aniline (0.65 mmol) was dissolved in an acetic acid-aqueous solution (3 mL, V / V = 2:1), and sodium nitrite (0.975 mmol) was added at 0 °C over 5 min, stirred at 0 °C for 90 min, sodium azide (0.975 mmol) was added at the same temperature, and stirring was continued for 60 min. After completion of the reaction, the reaction solution was diluted with dichloromethane (10 mL) and water (10 mL), the pH value was adjusted to 8 - 9 with saturated K2CO3 solution, phase separation was carried out to obtain an aqueous phase and an organic phase respectively. The aqueous phase was extracted 3 times with dichloromethane (20 mL each time) to obtain a dichloromethane phase. The organic phase and the dichloromethane phase were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by concentration under reduced pressure to obtain a crude azide product. The crude azide product was diluted with dichloromethane to 0.01 M, irradiated at room temperature under a UV LED light source system (365 nm) for 30 min, and the reaction process was monitored by thin-layer chromatography plate. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and purification was carried out by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate volume ratio = 10:1) to obtain an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound (140.5 mg, yield 84.0%).

[0046] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound, characterized in that, Comprising the following steps: Mix compound 1, compound 2, an acidic catalyst and a polar solvent, and carry out a cyclization reaction under a protective atmosphere to obtain an isoindolo[2,1-a]pyrrolo[2,1-c]quinoxaline compound; 2. The method according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1 to 2.

3. The method according to claim 1, characterized in that, The acidic catalyst includes trifluoromethanesulfonic anhydride and / or trifluoromethanesulfonic acid; The molar ratio of compound 1 to the acidic catalyst is 1:0.2 to 2.

4. The method according to claim 1, wherein The polar solvent includes one or more of benzene solvents, chloroalkane solvents and nitrile solvents.

5. The method according to claim 4, wherein The benzene solvents include one or more of toluene, xylene and chlorobenzene; The chloroalkane solvents include dichloromethane; The nitrile solvents include acetonitrile.

6. The method according to claim 1, 4 or 5, characterized in that The polar solvent includes a mixed solvent of benzene solvents and chloroalkane solvents, chloroalkane solvents or nitrile solvents.

7. The method according to claim 6, wherein In the mixed solvent of benzene solvents and chloroalkane solvents, the volume ratio of chloroalkane solvents to benzene solvents is 1:1 to 20.

8. The method according to any one of claims 1 to 5 and 7, characterized in that, The temperature of the cyclization reaction is 0 to 80 °C, and the time is 3 to 6 h.

9. The method according to claim 8, wherein After the cyclization reaction, it further includes: concentrating the reaction solution obtained from the cyclization reaction and then separating and purifying by silica gel column chromatography, and the eluent used for the silica gel column chromatography separation and purification includes petroleum ether and ethyl acetate.

10. The method according to claim 9, wherein The volume ratio of petroleum ether to ethyl acetate is 4 to 20:1.

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