Green and efficient carbonyl alkylation pyrrolo [1, 2-a] indole synthesis method

Abstract

The invention discloses a green and efficient carbonyl alkylation pyrrolo [1, 2-a] indole synthesis method, and relates to the technical field of organic synthesis. An alpha-bromocarbonyl compound is used as a carbonyl alkyl source, Ir (ppy) 3 is used as a photosensitizer, potassium hydroxide is used as alkali, sodium dimethyl dithiocarbamate is used as an additive, acetonitrile is used as a solvent, a carbonyl alkylation / cyclization reaction of N-alkenyl substituted indole is realized under the condition of visible light, and corresponding carbonyl alkylation pyrrolo [1, 2-a] indole is obtained. The method is convenient to operate, green and efficient in reaction and wide in substrate applicability.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a green and efficient method for synthesizing carbonyl alkylated pyrrolo[1,2-a]indole. Background Art

[0002] Since carbonyl groups are active building blocks in a variety of natural products and pharmaceutical molecules, the introduction of carbonyl groups into organic molecules is of great significance. Compared with direct esterification, carbonyl alkylation [-CH2C(O)R] is a more convenient and less toxic strategy.

[0003] The pyrrolo[1,2-a]indole skeleton is present in many bioactive compounds and drug molecules. Introducing [-CH2C(O)R] into the pyrrolo[1,2-a]indole skeleton to form carbonylalkylated pyrrolo[1,2-a]indoles has potential application.

[0004] At present, no literature on the visible light catalytic synthesis of carbonyl alkylated pyrrolo[1,2-a]indole has been found, but similar literature on the visible light-promoted generation of other carbonyl alkylated heterocyclic compounds can be found, such as: (a) Yang Z, Chen L, Sun Q, et al. Tetrahydroxydiboron and Nickel Chloride Cocatalyzed Rapid Radical Cyclization toward Pyrrolizidine and Indolizidine Alkaloids[J]. The Journal of Organic Chemistry, 2022, 87(5): 3788-3793. (b) Jin HX, Zhu Y, Zhang J, et al. Photoinduced catalyst-free difluoromethylation-cyclization of indolederivatives via electron donor-acceptor complexes under visible light[J]. Organic Chemistry Frontiers, 2024, 11(20): 5762-5768.

[0005] Therefore, in order to further expand related research, it is of great significance to develop a green, efficient, substrate-applicable, and easy-to-operate carbonylalkylation method for synthesizing pyrrolo[1,2-a]indole. Summary of the Invention

[0006] The present invention aims to provide a green and efficient method for synthesizing carbonyl-alkylated pyrrolo[1,2-a]indoles. Using Ir(ppy)3 as a photosensitizer, the method achieves carbonyl-alkylation / cyclization of N-alkenyl-substituted indoles under visible light conditions to yield the corresponding carbonyl-alkylated pyrrolo[1,2-a]indoles. The method is easy to operate, exhibits green and efficient reactions, and has a wide range of substrate applicability.

[0007] In order to achieve the above object, the technical solution of the present invention is as follows:

[0008] A green and efficient method for synthesizing carbonyl-alkylated pyrrolo[1,2-a]indole, comprising: using an N-alkenyl-substituted indole represented by formula (1) and an α-bromocarbonyl compound represented by formula (2) as reaction raw materials; reacting in a reaction solvent in the presence of a photosensitizer, an additive, and a base to obtain a carbonyl-alkylated pyrrolo[1,2-a]indole represented by formula (3);

[0009]

[0010] Where: n = 0, 1 or 2; R 1 is H, F, Br or CO2Me; R 2 is Ph, H or C(O)Me; R 3 Me or H; R 4 is Et or Ph; R 5 F or H; R 6 F or H.

[0011] The molar mass ratio of the N-alkenyl substituted indole to the α-bromocarbonyl compound is 0.2:0.6.

[0012] The photosensitizer is Ir(ppy)3; the additive is sodium thiamethoxam; the base is potassium hydroxide; and the reaction solvent is acetonitrile.

[0013] Furthermore, the green and efficient carbonyl alkylation pyrrolo[1,2-a]indole synthesis method comprises the following steps:

[0014] In an argon atmosphere, 0.2 mmol of N-alkenyl-substituted indole, 0.6 mmol of α-bromocarbonyl compound, 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube in sequence, and then 2 mL of acetonitrile was added. The mixture was stirred at room temperature for 24 h under 450 nm blue light and monitored by thin layer chromatography. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate three times, washed with salt once, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and separated by column chromatography to obtain the carbonyl-alkylated pyrrolo[1,2-a]indole.

[0015] Furthermore, the N-alkenyl substituted indole is 1-(1-buten-1-yl)indol-3-yl)ethane-1-one, (1-(but-3-ene-1-yl)-1H-indol-3-yl)(phenyl)methanone, 1-(but-3-ene-1-yl)-1H-indole-3-carboxaldehyde, 3-acetyl-1-(but-3-ene-1-yl)-1H-indole-4-carboxylic acid methyl ester, 1-((but-3-ene-1-yl)-5-chloro-1H-indol-3-yl)ethan-1-one, 1-((3-ene-1 -yl)-6-fluoro-1H-indol-3-yl)ethan-1-one, 1-(1-(but-3-ene-1-yl)-7-methyl-1H-indol-3-yl)ethan-1-one, 1-(1-(but-3-ene-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one, 1-(1-(pent-4-ene-1-yl)-1H-indol-3-yl)ethan-1-one, Vemurafenib-1, any one of Vemurafenib-2 is used as the reaction raw material.

[0016] Furthermore, the α-bromocarbonyl compound uses any one of ethyl bromoacetate, 2-bromoacetophenone, and ethyl bromodifluoroacetate as a reaction raw material.

[0017] Compared with the prior art, the technical effects of the present invention are:

[0018] The present invention provides a green and efficient carbonyl-alkylated pyrrolo[1,2-a]indole synthesis method. By using N-alkenyl-substituted indole, an α-bromocarbonyl compound, Ir(ppy)3, potassium hydroxide, sodium thiamin, and acetonitrile, carbonyl-alkylated pyrrolo[1,2-a]indole is efficiently synthesized under visible light conditions. This method not only achieves high reaction efficiency and efficient conditions, but also avoids high-temperature reaction conditions, improving the safety of the reaction process. Furthermore, the method has wide substrate applicability, simple operation, few byproducts, and high product purity. The carbonyl-alkylated pyrrolo[1,2-a]indole product obtained by the method of the present invention is a very important organic fragment that is widely present in natural products and drug molecules. Therefore, the obtained product has considerable application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 and Figure 2 The hydrogen spectrum and carbon spectrum of compound 3a provided in Example 1 of the present invention.

[0020] Figure 3 and Figure 4 The hydrogen spectrum and carbon spectrum of compound 3b provided in Example 2 of the present invention.

[0021] Figure 5 and Figure 6 The hydrogen spectrum and carbon spectrum of compound 3c provided in Example 3 of the present invention.

[0022] Figure 7 and Figure 8 The hydrogen spectrum and carbon spectrum of compound 3d provided in Example 4 of the present invention.

[0023] Figures 9-11 The hydrogen spectrum, carbon spectrum and fluorine spectrum of compound 3e provided in Example 5 of the present invention.

[0024] Figure 12-14 The hydrogen spectrum, carbon spectrum and fluorine spectrum of compound 3f provided in Example 6 of the present invention.

[0025] Figure 15 and Figure 16 The hydrogen spectrum and carbon spectrum of compound 3g provided in Example 7 of the present invention.

[0026] Figure 17 and Figure 18 The hydrogen spectrum and carbon spectrum of compound 3h provided in Example 8 of the present invention.

[0027] Figure 19 and Figure 20 The hydrogen spectrum and carbon spectrum of compound 3i provided in Example 9 of the present invention.

[0028] Figure 21 and Figure 22 The hydrogen spectrum and carbon spectrum of compound 3j provided in Example 10 of the present invention.

[0029] Figure 23-25 The hydrogen spectrum, carbon spectrum and fluorine spectrum of compound 3k provided in Example 11 of the present invention.

[0030] Figure 26-Figure 28 These are the hydrogen spectrum, carbon spectrum and fluorine spectrum of Vemurafenib-3, the compound in Example 12.

[0031] Figures 29-31 These are the hydrogen spectrum, carbon spectrum and fluorine spectrum of Vemurafenib-4, the compound in Example 13.

[0032] Figure 32 The fluorescence spectrum of compound 3d of the present invention and imaging in HepG2 cells.

[0033] Figure 33 The fluorescence spectrum of the compound of the present invention for 3 h and imaging in HepG2 cells.

[0034] Figure 34 The fluorescence spectrum of the compound Vemurafenib-3 of the present invention and imaging in HepG2 cells.

[0035] Figure 35 The fluorescence spectrum of the compound Vemurafenib-4 of the present invention and imaging in HepG2 cells. DETAILED DESCRIPTION

[0036] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0037] Example 1

[0038] In an argon atmosphere, 0.2 mmol of 1-(1-butene-1-yl)indol-3-yl)ethane-1-one (1a), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube, followed by 2 mL of acetonitrile. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3a) was separated by column chromatography to obtain 56.4 mg of yellow oil with a yield of 94%. The hydrogen and carbon spectra of compound 3a are shown in Figure 2. Figure 1 and 2 The reaction equation is as follows:

[0039]

[0040] Example 2

[0041] In an argon atmosphere, 0.2 mmol of (1-(but-3-en-1-yl)-1H-indol-3-yl)(phenyl)methanone (1b), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube, followed by 2 mL of acetonitrile. The mixture was stirred at room temperature under 450 nm blue light for 24 h. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3b) was separated by column chromatography to obtain 50.2 mg of yellow oil with a yield of 69%. The hydrogen and carbon spectra of compound 3b are shown in Figure 2. Figure 3 and 4 The reaction equation is as follows:

[0042]

[0043] Example 2 investigated the applicability of the substrate when the C3 position of N-(but-3-enyl)indole was benzoyl. The results of the example showed that the substrate was also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3b).

[0044] Example 3

[0045] Under an argon atmosphere, 0.2 mmol of 1-(but-3-en-1-yl)-1H-indole-3-carboxaldehyde (1c), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3c) was separated by column chromatography to obtain 10.4 mg of a yellow oil with a yield of 18%. The hydrogen and carbon spectra of compound 3c are shown in Figure 2. Figure 5 and 6 The reaction equation is as follows:

[0046]

[0047] Example 3 primarily examined the suitability of the substrate when the C3 position of N-(but-3-enyl)indole was an aldehyde. The results of this example demonstrate that this substrate is also suitable for the reaction to yield carbonyl-alkylated pyrrolo[1,2-a]indole (3c). However, due to the substrate's low reactivity, excess starting material resulted, ultimately resulting in a low yield.

[0048] Example 4

[0049] Under an argon atmosphere, 0.2 mmol of methyl 3-acetyl-1-(but-3-en-1-yl)-1H-indole-4-carboxylate (1d), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3d) was separated by column chromatography to obtain 58.2 mg of a yellow solid in an 81% yield. The H and C spectra of compound 3d are shown in Figure 2. Figure 7 and 8 The reaction equation is as follows:

[0050]

[0051] Example 4 mainly examines the applicability of the substrate when the C4 position of N-(but-3-enyl)indole contains an electron-withdrawing ester group. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3d).

[0052] Example 5

[0053] Under an argon atmosphere, 0.2 mmol of 1-((but-3-en-1-yl)-5-fluoro-1H-indol-3-yl)ethan-1-one (1e), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3e) was separated by column chromatography to obtain 60.3 mg of a yellow oil with a yield of 90%. The hydrogen, carbon, and fluorine spectra of compound 3e are shown in Figure 2. Figure 9 、 10 and 11. The reaction equation is as follows:

[0054]

[0055] Example 5 mainly examines the applicability of the substrate when the C5 position of N-(but-3-enyl)indole contains an electron-withdrawing group fluorine. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3e).

[0056] Example 6

[0057] Under an argon atmosphere, 0.2 mmol of 1-((3-en-1-yl)-6-fluoro-1H-indol-3-yl)ethan-1-one (1f), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After the reaction was completed, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3f) was separated by column chromatography to obtain 60.6 mg of a yellow solid with a yield of 95%. The hydrogen, carbon, and fluorine spectra of compound 3f are shown in Figure 2. Figure 12 、 13 and 14. The reaction equation is as follows:

[0058]

[0059] Example 6 mainly examines the applicability of the substrate when the C6 position of N-(but-3-enyl)indole is an electron-withdrawing group fluorine. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3f).

[0060] Example 7

[0061] Under an argon atmosphere, 0.2 mmol of 1-(7-bromo-1-(but-3-en-1-yl)-1H-indol-3-yl)ethan-1-one (1g), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3g) was separated by column chromatography as a yellow solid (68.9 mg, 91% yield). The H and C spectra of compound 3g are shown in Figure 2. Figure 15 and 16 The reaction equation is as follows:

[0062]

[0063] Example 7 mainly examines the applicability of the substrate when the C7 position of N-(but-3-enyl)indole is an electron-withdrawing group bromine. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3g).

[0064] Example 8

[0065] Under an argon atmosphere, 0.2 mmol of 1-(1-(but-3-en-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (1h), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature under 450 nm blue light for 24 h. The reaction was monitored by thin-layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3h) was isolated by column chromatography as a yellow solid (46.9 mg, yield 78%). The H and C spectra of compound 3h are shown in Figure 2. Figure 17 and 18 The reaction equation is as follows:

[0066]

[0067] Example 8 primarily examines the applicability of the substrate when the carbon atom at the C7 position of N-(but-3-enyl)indole is substituted with a nitrogen atom. The results of this example demonstrate that the substrate is also suitable for this reaction to yield carbonyl-alkylated pyrrolo[1,2-a]indole (3h).

[0068] Example 9

[0069] Under an argon atmosphere, 0.2 mmol of 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethan-1-one (1i), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube, followed by 2 mL of acetonitrile. The mixture was stirred at room temperature for 24 h under 450 nm blue light and monitored by thin layer chromatography. After the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3i) was separated by column chromatography to obtain 48.9 mg of a yellow oil with a yield of 77%. The hydrogen and carbon spectra of compound 3i are shown in Figure 2. Figure 19 and 20 The reaction equation is as follows:

[0070]

[0071] Example 9 mainly investigates the applicability of the substrate when the N1 position of the raw indole is an allylic group. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3i).

[0072] Example 10

[0073] Under an argon atmosphere, 0.2 mmol of 1-(1-butene-1-yl)indol-3-yl)ethane-1-one (1a), 0.6 mmol of 2-bromoacetophenone (2b), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature under 450 nm blue light for 24 h. The reaction was monitored by thin-layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3j) was separated by column chromatography to obtain 11.8 mg of a yellow oil in an 18% yield. The hydrogen and carbon spectra of compound 3j are shown in Figure 2. Figure 21 and 22 The reaction equation is as follows:

[0074]

[0075] Example 10 primarily examined the suitability of the substrate when the carbonyl radical source was 2-bromoacetophenone. The results of this example demonstrate that this substrate is also suitable for this reaction to yield carbonyl-alkylated pyrrolo[1,2-a]indole (3j). However, due to the substrate's low reactivity, excess starting material resulted, ultimately resulting in a low yield.

[0076] Example 11

[0077] Under an argon atmosphere, 0.2 mmol of 1-(1-buten-1-yl)indol-3-yl)ethane-1-one (1a), 0.6 mmol of ethyl bromodifluoroacetate (2c), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube. 2 mL of acetonitrile was then added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin-layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl pyrrolo[1,2-a]indole (3k) was separated by column chromatography to obtain 54.5 mg of a yellow solid in an 81% yield. The H, C, and F spectra of compound 3k are shown in Figure 2. Figure 23 、 24 and 25. The reaction equation is as follows:

[0078]

[0079] Example 11 mainly investigates the applicability of the substrate when the source of the carbonyl radical is ethyl bromodifluoroacetate. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrrolo[1,2-a]indole (3k).

[0080] Example 12

[0081] In an argon atmosphere, 0.2 mmol of a vemurafenib derivative (Vemurafenib-1), 0.6 mmol of ethyl bromoacetate (2a), 0.008 mmol of Ir(ppy)3, 0.3 mmol of sodium thiamin, and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube, followed by 2 mL of acetonitrile. The mixture was stirred at room temperature for 24 h under 450 nm blue light and monitored by thin layer chromatography. After completion of the reaction, water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (15 mL each), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and column chromatography was used to separate the carbonyl pyrido[3,2-b]pyrrolidine (Vemurafenib-3), resulting in 49.8 mg of a yellow oil with a yield of 40%. The hydrogen, carbon, and fluorine spectra of the compound Vemurafenib-3 are shown in Figure 2. Figure 26 、 27 and 28. The reaction equation is as follows:

[0082]

[0083] Example 12 mainly investigated the applicability of the substrate when the N1 position of the drug Vemurafenib was substituted with an olefinic butyl group. The results of the example show that the substrate is also suitable for this reaction to obtain carbonyl pyrido[3,2-b]pyrrolidine (Vemurafenib-3).

[0084] Example 13

[0085] In an argon atmosphere, 0.2 mmol of Vemurafenib-2, 1.2 mmol of ethyl bromoacetate (2), 30.016 mmol of Ir(ppy), 0.6 mmol of sodium thiamin, and 0.8 mmol of potassium hydroxide were added to a 25 mL reaction tube in sequence, and then 2 mL of acetonitrile was added. The mixture was stirred at room temperature for 24 h under 450 nm blue light. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate three times (15 mL each time), washed with salt once (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and carbonyl alkylated pyrido[3,2-b]pyrrolizine (Vemurafenib-4) was obtained by column chromatography as a yellow oil (86.4 mg) with a yield of 56%. The hydrogen spectrum, carbon spectrum, and fluorine spectrum of the compound Vemurafenib-4 are shown in FIG. Figure 29 、 30 and 31. The reaction equation is as follows:

[0086]

[0087] Example 13 examines the suitability of the substrate when the N1 and N3 positions of the drug Vemurafenib are substituted with butyl groups. The results of this example demonstrate that the substrate is also suitable for this reaction to yield carbonyl-alkylated pyrido[3,2-b]pyrrolizine (Vemurafenib-4).

[0088] The following will further verify the superior effect of the technical solution of the present invention compared with the existing technology, the specific content is as follows:

[0089] Fluorescence spectroscopy analysis of compound 3d: The experiment was performed using an F-7100 fluorescence spectrophotometer. 1 mM solutions of DMSO, 1,4-dioxane, toluene, DCM, EtOH, and PBS were added to 1 cm quartz cuvettes and excited in the range of 300-400 nm. The best result was the fluorescence curve at 340 nm, as shown in Figure 2. Figure 32 As shown in (a).

[0090] Imaging of compound 3d in HepG2 cells: HepG2 cells were cultured in DMEM medium at 37°C in a cell culture incubator with 5% CO2. To obtain fluorescence imaging of compound 3d, HepG2 cells were incubated with 0.05 μM compound 3d for 2 h, washed three times with PBS, and then treated with 4% paraformaldehyde (15 min). Images were taken using a Leica STELLARIS 5 laser confocal microscope. Figure 32 (b) (c) (d) show the cell imaging after 2 hours of incubation, (b) bright field, (c) DAPI channel: λ ex=405 nm, (d) Merged image, indicating that compound 3d has good biocompatibility and low cytotoxicity.

[0091] Fluorescence spectroscopy analysis of compound 3h: The experiment was performed using an F-7100 fluorescence spectrophotometer. 1 mM solutions of DMSO, 1,4-dioxane, toluene, DCM, EtOH, and PBS were added to 1 cm quartz cuvettes and excited in the range of 300-460 nm. The best result was the fluorescence curve at 360 nm, as shown in the figure below. Figure 33 As shown in (a).

[0092] Imaging of compound 3h in HepG2 cells: HepG2 cells were cultured in DMEM medium at 37°C in a cell culture incubator with 5% CO2. To obtain fluorescence imaging of compound 3h, HepG2 cells were incubated with 0.05 μM compound 3h for 2 h, washed three times with PBS, and then treated with 4% paraformaldehyde (15 min). Images were taken using a Leica STELLARIS 5 laser confocal microscope. Figure 33 (b) (c) (d) show the cell imaging after 2 hours of incubation, (b) bright field, (c) DAPI channel: λ ex =405 nm, (d) Merged image, indicating that compound 3h has good biocompatibility and low cytotoxicity.

[0093] Fluorescence spectroscopy analysis of the compound Vemurafenib-3: The experiment was performed using an F-7100 fluorescence spectrophotometer. 1 mM solutions of DMSO, 1,4-dioxane, toluene, DCM, EtOH, and PBS were added to 1 cm quartz cuvettes and excited in the range of 300-460 nm. The best result was the fluorescence curve at 380 nm, as shown in the figure below. Figure 34 As shown in (a).

[0094] Imaging of compound Vemurafenib-3 in HepG2 cells: HepG2 cells were cultured in DMEM medium at 37°C in a cell culture incubator with 5% CO2 concentration. To obtain fluorescence imaging of compound Vemurafenib-3, HepG2 cells were incubated with 0.05 μM compound Vemurafenib-3 for 2 hours, washed 3 times with PBS, and then treated with 4% paraformaldehyde (15 minutes). Images were taken using a Leica STELLARIS 5 laser confocal microscope. Figure 34 (b) (c) (d) show the cell imaging after 2 hours of incubation, (b) bright field, (c) DAPI channel: λ ex=405 nm, (d) Merged image, indicating that the compound Vemurafenib-3 has good biocompatibility and low cytotoxicity.

[0095] Fluorescence spectroscopy analysis of the compound Vemurafenib-4: The experiment was performed using an F-7100 fluorescence spectrophotometer. 1 mM solutions of DMSO, 1,4-dioxane, toluene, DCM, EtOH, and PBS were added to 1 cm quartz cuvettes and excited in the range of 300-460 nm. The best result was the fluorescence curve at 380 nm, as shown in the figure below. Figure 35 As shown in (a).

[0096] Imaging of compound Vemurafenib-4 in HepG2 cells: HepG2 cells were cultured in DMEM medium at 37°C in a cell culture incubator with 5% CO2 concentration. To obtain fluorescence imaging of compound Vemurafenib-4, HepG2 cells were incubated with 0.05 μM compound Vemurafenib-4 for 2 hours, washed 3 times with PBS, and then treated with 4% paraformaldehyde (15 minutes). Images were taken using a Leica STELLARIS 5 laser confocal microscope. Figure 35 (b) (c) and (d) show cell imaging after 2 hours of incubation, (b) bright field, (c) DAPI channel: λ ex =405 nm, (d) Merged image, indicating that the compound Vemurafenib-4 has good biocompatibility and low cytotoxicity.

[0097] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A green and efficient method for synthesizing carbonyl alkylated pyrrolo[1,2-a]indole, characterized in that: The N-alkenyl substituted indole represented by formula (1) and the α-bromocarbonyl compound represented by formula (2) are used as reaction raw materials, and react in a reaction solvent under the action of a photosensitizer, an additive and a base to obtain a carbonyl alkylated pyrrolo[1,2-a]indole represented by formula (3); Where: n = 0, 1 or 2; R 1 is H, F, Br or CO2Me; R 2 is Ph, H or COMe; R 3 Me or H; R 4 is Et or Ph; R 5 F or H; R 6 F or H. The molar mass ratio of the N-alkenyl substituted indole to the α-bromocarbonyl compound is 0.2:0.

6. The photosensitizer is Ir(ppy)3; the additive is sodium thiamethoxam; the base is potassium hydroxide; and the reaction solvent is acetonitrile.

2. The green and efficient carbonyl alkylated pyrrolo[1,2-a]indole synthesis method according to claim 1, characterized in that: The following steps are involved: In an argon atmosphere, 0.2 mmol of N-alkenyl-substituted indole, 0.6 mmol of α-bromocarbonyl compound, 0.008 mmol of Ir(ppy), 0.3 mmol of sodium thiamin and 0.4 mmol of potassium hydroxide were added to a 25 mL reaction tube in sequence, and then 2 mL of acetonitrile was added. The mixture was stirred at room temperature for 24 h under 450 nm blue light and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate three times, washed with salt once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the carbonyl pyrrolo[1,2-a]indole was separated by column chromatography.

3. The green and efficient carbonyl alkylated pyrrolo[1,2-a]indole synthesis method according to claim 1, characterized in that: The N-alkenyl substituted indole is 1-(1-buten-1-yl) indol-3-yl) ethane-1-one, (1-(but-3-en-1-yl)-1H-indol-3-yl)(phenyl)methanone, 1-(but-3-en-1-yl)-1H-indole-3-carboxaldehyde, 3-acetyl-1-(but-3-en-1-yl)-1H-indole-4-carboxylic acid methyl ester, 1-((but-3-en-1-yl)-5-chloro-1H-indol-3-yl) ethane-1-one, 1-((3-en-1-yl)-1H-indole-3-yl) methyl ester. Any one of )-6-fluoro-1H-indol-3-yl)ethan-1-one, 1-(1-(but-3-en-1-yl)-7-methyl-1H-indol-3-yl)ethan-1-one, 1-(1-(but-3-en-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one, 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethan-1-one, Vemurafenib-1, and Vemurafenib-2 is used as the reaction raw material.

4. The green and efficient carbonyl alkylated pyrrolo[1,2-a]indole synthesis method according to claim 1, characterized in that: The α-bromocarbonyl compound uses any one of ethyl bromoacetate, 2-bromoacetophenone and ethyl bromodifluoroacetate as a reaction raw material.

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