Synthetic method of indazolo [2, 3-a] quinoline compound

Abstract

The invention provides a synthesis method of an indazolo [2, 3-a] quinoline compound, which is characterized in that o-nitrobenzaldehyde and aniline are taken as starting raw materials, and the indazolo [2, 3-a] quinoline compound with various substituent groups is successfully synthesized through three-step reaction of synthesis of 2-aryl indazole, synthesis of 3-bromo-2-aryl indazole and synthesis of the indazolo [2, 3-a] quinoline compound. And by introducing the halogenated 2-phenyl indazole intermediate, the yield is remarkably improved. The synthesis method provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions and good industrialization prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing indazolo[2,3-a]quinoline compounds. Background Art

[0002] Compounds with a 2-arylindazole skeleton have extensive applications in the fields of biomedicine, optoelectronic materials, photocatalytic synthesis, etc. Indazolo[2,3-a]quinoline compounds have attracted attention due to their excellent optical properties. Currently, the following several methods have been reported for the synthesis of indazolo[2,3-a]quinoline compounds:

[0003] (1) In 2008, the Naoya Shindoh team reported a self-tandem catalytic reaction for synthesizing substituted quinolines using aldehyde amines and electron-rich olefins as raw materials. This reaction first synthesizes an imine from aniline and o-nitrobenzaldehyde, and forms the target product through cyclization, oxidation, and dehydration. The bis(trifluoromethylsulfonyl)amine used in this route has strict operating conditions, high danger, a long reaction time, and poor selectivity for disubstituted diaryl olefins. The reaction principle of this method is as follows:

[0004]

[0005] (2) In 2013, the ChaoFeng research group reported the efficient synthesis of allenes substituted at the 3-position of 2-arylindazoles through the cross-coupling of 2-alkynylazobenzenes and terminal alkynes catalyzed by Pd / Cu. This reaction path is relatively cumbersome, the method of using dual-metal catalysis has poor economic applicability, and the allene cyclization reaction has a high temperature and a long reaction time, which needs to be optimized. The reaction principle of this method is as follows:

[0006]

[0007] (3) In 2012 and 2016, the Li research group and the Wang research group respectively reported the synthesis of indazolo[2,3-a]quinoline compounds by cyclizing N-based pyridinium salts with benzyne and the synthesis of N-aryl butanone salts from N-aryl glycine as raw materials, followed by cyclization under the catalysis of rhodium metal and then reaction with benzyne to generate indazolo[2,3-a]quinoline compounds. Both routes have a relatively low reaction temperature, but they both require the prior synthesis of ionic intermediates, the process is relatively cumbersome, and the reaction process has a long cycle. The reaction principle of this method is as follows:

[0008]

[0009] (4) In 2016, the research group of Sundaravel Vivek Kumar reported a rhodium-catalyzed cyclization reaction of 2-arylindazoles and diarylacetylenes to produce indazolo[2,3-a]quinoline compounds. This reaction has mild conditions and excellent results, but the rhodium catalyst is relatively expensive, resulting in high production costs. The reaction principle of this method is as follows:

[0010]

[0011] Therefore, it is necessary to provide a synthesis method of indazolo[2,3-a]quinoline compounds with inexpensive and easily available raw materials, mild reaction conditions, and good industrialization prospects. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to provide a synthesis method of indazolo[2,3-a]quinoline compounds in view of the deficiencies of the above-mentioned prior art. The synthesis method of the present invention has inexpensive and easily available raw materials, mild reaction conditions, short reaction time, and high yield.

[0013] To solve the above technical problems, the technical solution adopted by the present invention is: a synthesis method of indazolo[2,3-a]quinoline compounds, the synthesis method comprising the following steps:

[0014] S1. Synthesis of 2-arylindazole: Mix o-nitrobenzaldehyde, aniline, and isopropanol solution evenly, then under a nitrogen atmosphere, stir and react for a certain time, add tri-n-butylphosphine, and continue to react to obtain an organic solution; Wash the organic solution with saturated ammonium chloride and saturated brine respectively, then extract with ethyl acetate, dry with anhydrous sodium sulfate, and then rotary evaporate. After purification by column chromatography, 2-arylindazole is obtained;

[0015] S2. Synthesis of 3-bromo-2-arylindazole: Dissolve NBS and the 2-arylindazole obtained in S1 in ethanol, heat up and react under air, then rotary evaporate, add distilled water to wash, extract with ethyl acetate to obtain an organic phase; Dry the organic phase with anhydrous sodium sulfate and then rotary evaporate, and then purify by column chromatography to obtain 3-bromo-2-arylindazole;

[0016] S3. Synthesis of indazolo[2,3-a]quinoline compounds: Mix the 3-bromo-2-arylindazole obtained in S2, 2-arylacetylene, palladium acetate, lithium chloride, and sodium acetate evenly, then add DMF, stir and dissolve under a nitrogen atmosphere, and then react under microwave heating conditions to obtain a solution; Wash the solution with distilled water a, then extract with ethyl acetate a to obtain an organic phase a; Wash the organic phase a with saturated brine a, then dry with anhydrous sodium sulfate, rotary evaporate, and finally purify by column chromatography to obtain indazolo[2,3-a]quinoline compounds.

[0017] Preferably, the mass-volume ratio of o-nitrobenzaldehyde, aniline, isopropanol solution and tri-n-butylphosphine in S1 is 200 mg: 0.13 mL: 5 mL: 1 mL. The temperature of the stirring reaction is 80 °C and the time is 2 h. The temperature for the continued reaction is 80 °C and the time is 8 h. The volume ratio of PE to EA in the column chromatography is 50:1.

[0018] Preferably, the mass-volume ratio of NBS, 2-arylindazole and ethanol solution in S2 is 0.178 g: 0.194 g: 10 mL. The temperature of the temperature-raising reaction is 50 °C and the time is 2 h. The dosage of distilled water for washing is 30 mL. The volume ratio of PE to EA in the column chromatography is 10:1.

[0019] Preferably, the molar-volume ratio of 3-bromo-2-arylindazole, 2-arylacetylene, palladium acetate, lithium chloride, sodium acetate and DMF in S3 is 0.1 mmol: 0.11 mmol: 10 mol: 0.1 mmol: 0.2 mmol: 2 mL. The temperature of the microwave temperature-raising is 160 °C and the reaction time under the microwave temperature-raising condition is 2 - 3 h. The dosage of distilled water a for washing is 10 mL. The dosage of ethyl acetate a is 20 mL. The dosage of saturated brine a is 10 mL. The volume ratio of PE to EA in the column chromatography is 100:1.

[0020] The present invention has the following advantages compared with the prior art:

[0021] The synthesis method of the present invention is a reaction route for synthesizing indazolo[2,3-a]quinoline compounds using halogenated 2-phenylindazole as an intermediate. The reaction conditions for synthesizing indazolo[2,3-a]quinoline compounds by ligand-free catalysis with a palladium catalyst. And microwave assistance is adopted to shorten the reaction time.

[0022] The present invention will be further described in detail below with reference to the accompanying drawings and examples. Description of the Drawings

[0023] Figure 1 It is the synthesis process of the indazolo[2,3-a]quinoline compound of the present invention.

[0024] Figure 2 It is the 1H NMR spectrum of (2-arylindazole) obtained in S1 of Example 1.

[0025] Figure 3 It is the 1H NMR spectrum of (3-bromo-2-arylindazole) obtained in S2 of Example 1.

[0026] Figure 4 It is the 1H NMR spectrum of the indazolo[2,3-a]quinoline compound synthesized in Example 1.

[0027] Figure 5Fluorescence photograph of the indazolo[2,3-a]quinoline compound synthesized in Example 1 under an ultraviolet lamp (365 nm). Detailed implementation manners

[0028] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0029] Example 1

[0030] The synthesis method of the indazolo[2,3-a]quinoline compound in this example includes the following steps:

[0031] S1. Synthesis of 2-arylindazole: Add 200 mg of o-nitrobenzaldehyde, 0.13 mL of aniline, and 5 mL of isopropanol solution to a 100 mL reaction test tube in sequence. After mixing evenly, under a nitrogen atmosphere and at a temperature of 80 °C, stir and react for 2 h. Then add 1 mL of tri-n-butylphosphine with a syringe and continue to react at a temperature of 80 °C for 8 h. After TLC detection shows that the raw materials have completely reacted, obtain an organic solution; wash the organic solution with saturated ammonium chloride and saturated brine respectively, then extract with ethyl acetate, dry with anhydrous sodium sulfate and then spin-dry, and obtain 2-arylindazole after column chromatography purification;

[0032] The 2-arylindazole is a white solid, and the yield of the 2-arylindazole is 78%; the volume ratio of petroleum ether (PE) to ethyl acetate (EA) in the column chromatography is 50:1; saturated ammonium chloride is used to quench the reaction;

[0033] S2. Synthesis of 3-bromo-2-arylindazole: Add 0.194 g of the 2-arylindazole obtained in S1 and 0.178 g of NBS (N-bromosuccinimide) to a 50 mL round-bottom flask in sequence, dissolve with 10 mL of ethanol, heat to 50 °C under air and stir and react for 2 h. After TLC detection shows that the raw materials have completely reacted, spin-dry, then add 30 mL of distilled water for washing, and then extract with ethyl acetate to obtain an organic phase; dry the organic phase with anhydrous sodium sulfate and then spin-dry, and then obtain 3-bromo-2-arylindazole after column chromatography purification;

[0034] The 3-bromo-2-arylindazole is a white solid, and the yield of the 3-bromo-2-arylindazole is 92%; the volume ratio of petroleum ether (PE) to ethyl acetate (EA) in the column chromatography is 10:1;

[0035] S3. Synthesis of indazolo[2,3-a]quinoline compounds: 0.1 mmol of 3-bromo-2-arylindazole obtained in S2, 0.11 mmol of (bis(4-bromophenyl)acetylene), 10 mmol of palladium acetate, 0.1 mmol of lithium chloride and 0.2 mmol of sodium acetate were successively added into a microwave reaction vial. Then, 2 mL of DMF (N,N-dimethylformamide) was added, and the mixture was stirred and dissolved under a nitrogen atmosphere. The reaction was carried out at 160 °C under microwave heating for 2.5 h. After the raw materials were completely reacted as detected by TLC, a solution was obtained. The solution was washed with 10 mL of distilled water a, then extracted with 20 mL of ethyl acetate a to obtain organic phase a. Organic phase a was washed with 10 mL of saturated brine a, then dried over anhydrous sodium sulfate, and then concentrated by rotary evaporation. Finally, it was purified by column chromatography to obtain indazolo[2,3-a]quinoline compounds;

[0036] The indazolo[2,3-a]quinoline compound is a bright yellow solid, and the yield of the indazolo[2,3-a]quinoline compound is 60%; the volume ratio of petroleum ether (PE) to ethyl acetate (EA) in the column chromatography is 100:1;

[0037] In this example S3, the reaction time under the condition of microwave heating to 160 °C can also be 2 h, 2.1 h, 2.2 h, 2.3 h, 2.4 h, 2.6 h, 2.7 h, 2.8 h, 2.9 h or 3 h.

[0038] The reaction principle of this example is as follows:

[0039]

[0040] Figure 2 This is the 1H NMR spectrum of 1a (2-arylindazole) obtained in S1 of this example, as Figure 2 shown 1 H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.13–8.07 (m, 2H), 7.78 (dd, J = 8.5, 1.3 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.65–7.55 (m, 2H), 7.50–7.42 (m, 1H), 7.36–7.29 (m, 1H), 7.16–7.09 (m, 1H).

[0041] Figure 3 This is the 1H NMR spectrum of 2a (3-bromo-2-arylindazole) obtained in S2 of this example, as Figure 3 shown 11H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 1.0 Hz, 1H), 7.91 (dd, J = 8.1, 1.4 Hz, 1H), 7.81 (dt, J = 8.4, 1.1 Hz, 1H), 7.71 (td, J = 8.2, 1.4 Hz, 2H), 7.62 (td, J = 7.6, 1.4 Hz, 1H), 7.54 (td, J = 7.7, 1.8 Hz, 1H), 7.34 (ddd, J = 8.9, 6.6, 1.1 Hz, 1H), 7.19–7.08 (m, 1H).

[0042] Figure 4 This is the 1H NMR spectrum of the indazolo[2,3-a]quinoline compound synthesized in this example, as Figure 4 shown 1 1H NMR (500 MHz, DMSO-d6) δ 9.01 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.2, 5.3 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.48 (dd, J = 8.3, 4.0 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.02 (s, 1H), 6.56 (d, J = 8.3 Hz, 1H).

[0043] Figure 5 This is the fluorescence photograph of the indazolo[2,3-a]quinoline compound synthesized in this example under an ultraviolet lamp (365 nm).

[0044] The above are only the preferred embodiments of the present invention, and do not impose any limitations on the present invention. Any simple modifications, changes, and equivalent variations made to the above embodiments based on the technical essence of the invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an indazolo[2,3-a]quinoline compound, characterized in that: The synthesis method comprises the following steps: S1. Synthesis of 2-aryl indazole: o-nitrobenzaldehyde, aniline and isopropanol solution are mixed uniformly, and then stirred under nitrogen atmosphere for a certain period of time, and then tri-n-butylphosphine is added to continue the reaction to obtain an organic solution; the organic solution is washed with saturated ammonium chloride and saturated brine respectively, and then extracted with ethyl acetate, and then dried with anhydrous sodium sulfate and spin-dried, and purified by column chromatography to obtain 2-aryl indazole; S2, synthesis of 3-bromo-2-aryl indazole: dissolving NBS and the 2-aryl indazole obtained in S1 in ethanol, heating the mixture under air, and then spin-drying the mixture, washing the mixture with distilled water, and extracting the mixture with ethyl acetate to obtain an organic phase; drying the organic phase with anhydrous sodium sulfate, and then spin-drying the mixture, and then purifying the mixture by column chromatography to obtain 3-bromo-2-aryl indazole; S3, synthesis of indazolo[2,3-a]quinoline compound: 3-bromo-2-aryl indazole, 2-aryl acetylene, palladium acetate, lithium chloride and sodium acetate obtained in S2 are uniformly mixed, and then DMF is added, and the mixture is stirred and dissolved under a nitrogen atmosphere, and then reacted under microwave heating conditions to obtain a solution; the solution is washed with distilled water a, and then extracted with ethyl acetate a to obtain an organic phase a; the organic phase a is washed with saturated brine a, and then dried over anhydrous sodium sulfate, and then spin-dried, and finally purified by column chromatography to obtain an indazolo[2,3-a]quinoline compound.

2. The method for synthesizing an indazolo[2,3-a]quinoline compound according to claim 1, characterized in that: The mass volume ratio of o-nitrobenzaldehyde, aniline, isopropanol solution and tri-n-butylphosphine in S1 is 200 mg: 0.13 mL: 5 mL: 1 mL, the stirring reaction temperature is 80°C and the time is 2 h; the temperature for continuing the reaction is 80°C and the time is 8 h; the volume ratio of PE and EA in the column chromatography is 50:

1.

3. The method for synthesizing an indazolo[2,3-a]quinoline compound according to claim 1, characterized in that: The mass volume ratio of NBS, 2-aryl indazole and ethanol solution in S2 is 0.178g:0.194g:10mL; the temperature of the temperature-raising reaction is 50°C and the time is 2h; the amount of distilled water washing is 30mL; the volume ratio of PE and EA in the column chromatography is 10:

1.

4. The method for synthesizing an indazolo[2,3-a]quinoline compound according to claim 1, characterized in that: The molar volume ratio of 3-bromo-2-aryl indazole, 2-aryl acetylene, palladium acetate, lithium chloride, sodium acetate and DMF in S3 is 0.1mmol:0.11mmol:10mol:0.1mmol:0.2mmol:2mL; the microwave heating temperature is 160°C, and the reaction time under the microwave heating conditions is 2-3h; the amount of distilled water a used for washing is 10mL; the amount of ethyl acetate a used is 20mL; the amount of saturated salt water a used is 10mL; the volume ratio of PE and EA in the column chromatography is 100:1.

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