Fluorine-containing indole derivatives and methods for their preparation

Abstract

The application belongs to the technical field of heterocyclic compounds, and particularly relates to a fluorine-containing indole derivative and a preparation method thereof. A solvent and difluoroalkyl bromide are added to enyne derivatives, a catalyst, a ligand and a base, and stirring is performed to obtain a mixture; the mixture is stirred and reacted under light irradiation, coarse silica gel is added, the solvent is removed, and separation is performed to obtain the fluorine-containing indole derivative. The application combines a palladium radical reaction with photocatalysis, uses difluoroalkyl bromide as a reaction starting point, initiates a difluoroalkyl radical at room temperature, and the radical reacts with enyne derivatives to occur cross-coupling / tandem cyclization, which not only efficiently constructs a polycyclic molecular skeleton while introducing two fluorine atoms, but also has the significant advantages of high atom economy and mild reaction conditions, conforms to the green synthesis concept, and has a wide application prospect in industrial production.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound technology, specifically relating to a fluorinated indole derivative and its preparation method. Background Technology

[0002] Fluorinated indole derivatives are a class of fluorinated heterocyclic compounds with significant biological activity and broad application prospects, demonstrating unique advantages in innovative drug development. These compounds combine the rigid planarity of the indole core with the enhanced electronic effects, lipophilicity, and metabolic stability resulting from the introduction of fluorine atoms, making them widely used in various therapeutic areas such as antitumor, antiviral, central nervous system disease treatment, and anti-inflammatory applications. Studies have shown that the introduction of fluorine atoms can significantly modulate the pK ratio of the molecule. a Fluorinated indole molecules, with their high molecular weight, membrane permeability, and ability to interact with biological targets, readily bind with key targets such as kinases and G protein-coupled receptors, forming high-affinity binding bonds. Fluorinated indole drugs exhibit superior pharmacokinetic properties while maintaining high activity; for example, lead compounds with fluorinated indole skeletons, such as Ladostigil, have entered preclinical or clinical research stages. However, despite the significant potential of fluorinated indole derivatives in enhancing drug-like properties, their synthesis still faces multiple challenges, including difficulties in constructing carbon-fluorine bonds, poor regioselectivity, and challenges in stereocontrol, especially in achieving three-dimensional structural diversity modifications while maintaining planar aromaticity. Therefore, developing efficient and highly selective cyclization functionalization strategies for fluorinated indole has become an important research direction at the intersection of synthetic chemistry and medicinal chemistry.

[0003] Chinese patent CN112724065A discloses a method for synthesizing 2-fluoroindole compounds. The method involves adding an o-aminochalcone compound, ethyl bromodifluoroacetate, a base, and an organic solvent into a pressure-resistant, sealed reaction vessel. The mixture is stirred and reacted at 50-100°C for 10-15 hours under a nitrogen atmosphere. After cooling the resulting material to room temperature, ethyl acetate is added and thoroughly mixed. The mixture is then filtered and washed with ethyl acetate to obtain an organic phase. The organic solvent in the organic phase is evaporated, and the mixture is then purified and washed with an eluent to obtain the 2-fluoroindole compound. However, this patent relies on high-temperature and high-pressure reaction conditions, resulting in high energy consumption, long reaction time, and operational difficulties. Furthermore, it only allows for monofluorine atom substitution at the 2-position of indole and cannot construct a polycyclic molecular skeleton. Summary of the Invention

[0004] The purpose of this invention is to provide a fluorinated indole derivative with a complex structure that allows for diverse three-dimensional structural modifications. This invention also provides a method for preparing the fluorinated indole derivative, which integrates a synergistic strategy of photocatalysis and palladium catalysis. This method enables the tandem cyclization reaction of ethyl difluorobromoacetate with an enyne derivative at room temperature. It not only efficiently constructs a polycyclic molecular framework while introducing two fluorine atoms, but also possesses significant advantages such as high atom economy and mild reaction conditions, aligning with the concept of green synthesis and showing broad application prospects in industrial production.

[0005] The structural formula of the fluorinated indole derivative of this invention is as follows:

[0006] ,

[0007] Among them, R 1 Including -H or -CH3, R 2 This includes one of -H, -COOMe, or -NO2.

[0008] The preparation method of the fluorinated indole derivative of the present invention includes the following steps:

[0009] (1) Add solvent and difluoroalkyl bromide to alkenyne derivatives, catalysts, ligands and bases and stir to obtain a mixture;

[0010] (2) The mixture was stirred under light, crude silica gel was added, the solvent was removed, and the mixture was separated to obtain a fluorinated indole derivative;

[0011] In step (1), the difluoroalkyl bromide is ethyl difluorobromoacetate.

[0012] In step (1), the catalyst is tetra(triphenylphosphine)palladium, the ligand is bis(2-diphenylphosphine) ether, the base is cesium carbonate, and the solvent is anhydrous tetrahydrofuran.

[0013] In step (1), the molar ratio of alkenyne derivative, catalyst, ligand, base and difluoroalkyl bromide is 1:0.1-0.15:0.15-0.225:2-2.5:3-4.

[0014] In step (1), the ratio of alkenyne derivative to solvent is 1:15-20, where alkenyne derivative is expressed in mmol and solvent in mL.

[0015] The stirring time in step (1) is 3-5 minutes, and the stirring temperature is room temperature.

[0016] The structural formula of the enyne derivative in step (1) is as follows:

[0017] ,

[0018] Among them, R1 Including -H or -CH3, R 2 This includes one of -H, -COOMe, or -NO2.

[0019] In step (2), the light source is an LED blue light lamp with a power of 40-50W and a wavelength of 455-460nm.

[0020] In step (2), the stirring reaction is carried out at room temperature for 3-6 hours.

[0021] In step (2), the ratio of crude silica gel to alkenyne derivative is 15-20:1, where crude silica gel is expressed in g and alkenyne derivative in mmol.

[0022] The reaction equation of this invention is as follows:

[0023] ,

[0024] Among them, R 1 Including -H or -CH3, R 2 This includes one of -H, -COOMe, or -NO2.

[0025] The enyne derivative was prepared from an indole derivative, 3-phenyl-2-propyn-1-ol, and 3-chloro-2-chloromethylpropene, using the following synthetic route:

[0026] ,

[0027] Among them, R 1 Including -H or -CH3, R 2 Includes one of -H, -COOMe, or -NO2;

[0028] Specifically, the steps include the following:

[0029] (1) Add 80-82 mL of LDMF to a dry 250 mL round-bottom flask, then add 43.5-44 mmol of commercially available NaH (60%), followed by slowly adding 28.5-28.8 mmol of indole derivative A to obtain a suspension; add 20-22 mL of LDMF to a dry 250 mL round-bottom flask, then add 72.5-72.8 mmol of compound B, and under stirring, slowly add the suspension dropwise through a dropping funnel. After the addition is complete, stir the reaction at room temperature for 30-35 minutes, and then perform thin-layer chromatography. The reaction was detected by TLC (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the developing solvent). After the reaction was completed, water was added to quench the reaction and the mixture was transferred to a separatory funnel. 100-102 mL of dichloromethane was added to the separatory funnel, and the mixture was washed with water (80 mL × 4 times) to remove DMF, yielding an organic phase. The organic phase was dried with anhydrous sodium sulfate and then transferred to a round-bottom flask. An appropriate amount of crude silica gel powder was added, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1 as the eluent) to obtain compound C.

[0030] (2) Add 15-18 mL of DMF to a dry 50 mL round-bottom flask, then add 3.8-3.82 mmol of compound D and 4.6-4.62 mmol of commercially available NaH (60% concentration). Under stirring, slowly add 10-12 mL of a DMF solution of compound C (3.8-3.82 mmol) dropwise to the round-bottom flask. After the addition is complete, stir the reaction at room temperature for 30-35 minutes and detect the reaction by thin-layer chromatography (TLC). The reaction was completed by using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the developing solvent. Water was added to quench the reaction and the mixture was transferred to a separatory funnel. 30-33 mL of DMF was added to the separatory funnel and the mixture was washed with water (20 mL × 4 times) to obtain the organic phase. The organic phase was dried with anhydrous sodium sulfate and then transferred to a round-bottom flask. An appropriate amount of crude silica gel powder was added and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent) to obtain the enyne derivative 1.

[0031] The beneficial effects of this invention are as follows:

[0032] (1) The reaction conditions of this invention are mild, energy consumption is low, cost is low, yield is high, process is simple, and it has high atom economy, making it suitable for large-scale production.

[0033] (2) The raw materials used in this invention are inexpensive, the synthesis route is mature, the yield is high, and the raw materials are stable and do not require special storage, which is in line with the concept of green chemistry.

[0034] (3) The fluorinated indole derivative in this invention exhibits a good inhibitory effect on HepG2 liver cancer cells: the indole ring can bind to the active sites of related proteins in HepG2 liver cancer cells through π-π stacking and hydrophobic interactions, interfering with their normal function; the oxo-heterocyclic ring and the adjacent five-membered ring increase the structural rigidity and conformational diversity of the molecule, which is beneficial to the spatial adaptability of the molecule to the target active pocket and enhances the stability of the binding between the two. 1 -CH3 or R 2 When the atom is -COOMe or -NO2, the oxygen heterocycle and the adjacent five-membered ring can also be fluorine atoms with R. 1 Groups or fluorine atoms with R 2 The precise binding of functional groups provides structural support, preventing conformational distortion of the molecule. Furthermore, oxygen in the oxygen heterocycle can participate in hydrogen bond formation, further enhancing the interaction strength between the molecule and the target. Fluorine in fluorinated indole derivatives can enhance the lipophilicity of the molecule, increase cell membrane permeability, making it easier for the compound to enter the cell and exert its effects. Simultaneously, fluorine can form electrostatic interactions with polar residues of the target protein, strengthening the binding force between the molecule and the target and improving molecular metabolic stability. When R... 1 -CH3 or R 2 When R is -COOMe or -NO2, 1 Group or R 2 Groups can adjust the spatial fit between the molecule and the target active pocket, stabilizing the preferred conformation by filling hydrophobic regions or steric hindrance. Meanwhile, R... 1 Group or R 2 The functional group, through its own electronic effects and the high electronegativity of the fluorine atom, synergistically modulates the molecular electron cloud, achieving precise electron cloud polarization. This, in turn, enhances the π-π stacking efficiency between the indole ring and the target site, optimizes the electrostatic interaction between the fluorine atom and the target residue, and further stabilizes the R group. 1 Group or R 2 Groups participate in the molecular conformation after electron cloud regulation, preventing electron cloud redistribution and facilitating R 1 Group or R 2 The functional groups continuously and stably exert electronic regulation, thereby ensuring the specificity and stability of the compound's binding to the target.

[0035] (4) This invention combines palladium radical reaction with photocatalysis, using difluoroalkyl bromide as the reaction starting point to initiate difluoroalkyl radical at room temperature. The radical undergoes cross-coupling / tandem cyclization reaction with alkenyne derivatives to efficiently construct fluorinated indole derivatives with complex structures. Attached Figure Description

[0036] Figure 1 This is the 1H NMR spectrum of product 3a from Example 1.

[0037] Figure 2This is the carbon NMR spectrum of product 3a from Example 1.

[0038] Figure 3 This is the 1H NMR spectrum of product 3b from Example 2.

[0039] Figure 4 This is the carbon NMR spectrum of product 3b from Example 2.

[0040] Figure 5 This is the 1H NMR spectrum of product 3c from Example 3.

[0041] Figure 6 This is the carbon NMR spectrum of product 3c from Example 3.

[0042] Figure 7 The graphs show the effects of compound 3a on HepG2 cell viability. The left graph is a bar chart showing the effect of compound 3a on HepG2 cell viability, with ** indicating significance (p≤0.01). The right graph shows the IC50 of compound 3a inhibiting HepG2 cell viability. 50 picture.

[0043] Figure 8 The graphs show the effects of compound 3b on HepG2 cell viability. The left graph is a bar chart showing the effect of compound 3b on HepG2 cell viability, with ** indicating significance (p≤0.01). The right graph shows the IC50 of compound 3b inhibiting HepG2 cell viability. 50 picture.

[0044] Figure 9 The graphs show the effects of compound 3c on HepG2 cell viability. The left graph is a bar chart showing the effect of compound 3c on HepG2 cell viability, with ** indicating significance (p≤0.01). The right graph shows the IC50 of compound 3c inhibiting HepG2 cell viability. 50 picture. Detailed Implementation

[0045] The present invention will be further described below with reference to embodiments.

[0046] Example 1

[0047] (1) 0.2 mmol of enyne derivative 1a, 0.02 mmol of tetra(triphenylphosphine)palladium, 0.03 mmol of bis(2-diphenylphosphine) ether and 0.4 mmol of cesium carbonate were added sequentially to a dry 10 mL Schlenk reaction tube, the tube was evacuated and nitrogen gas was introduced three times; under a nitrogen atmosphere, 3 mL of anhydrous tetrahydrofuran and 0.6 mmol of ethyl difluorobromoacetate were added to the Schlenk reaction tube, and the mixture was stirred at room temperature for 5 minutes to obtain a mixture;

[0048] (2) The mixture was placed under a 40W LED blue light lamp with a wavelength of 455nm and stirred at room temperature for 4 hours. TLC detection showed that the reaction was complete and the reactant was obtained. The reactant was transferred to a round bottom flask, 3g of crude silica gel was added, the solvent was removed under reduced pressure, and the product 3a was purified by silica gel column chromatography to obtain a colorless oily product 3a, namely methyl 3a-(3-ethoxy-2,2-difluoro-3-oxopropyl)-11-phenyl-3a,4-dihydro-1H,3H-furano[3',4':4,5]pyrido[1,2-a]indole-7-carboxylic acid ester with a yield of 79%.

[0049] The reaction equation is as follows:

[0050] .

[0051] The 1H NMR spectrum of product 3a is shown below. Figure 1 , 1 H NMR(400 MHz, CDCl3, δ ppm):8.07(s, 1H),7.78(dd, J=8.4, 1.6 Hz, 1H), 7.53(d, J=8.4 Hz, 1H), 7.46-7.36(m, 5H), 6.32(s,1H), 4.86(d, J=15.2 Hz, 1H), 4.82(d, J=12.8 Hz, 1H), 4.43(d, J = 9.2 Hz, 1H), 4.31(d, J=14.8 Hz, 1H), 4.20-4.06(m, 2H), 3.95(s, 3H), 3.83(d, J=12.4 Hz,1H), 3.78(d, J = 9.2 Hz, 1H), 2.60–2.32 (m, 2H), 1.21 (t, J = 6.8 Hz, 3H); C NMR spectrum is shown below. Figure 2 , 13 C NMR (100 MHz, CDCl3, δ ppm): 167.9, 163.4 (t, J=32.2 Hz), 140.2, 138.3, 136.3, 135.8, 132.4, 128.8, 128.5, 128.5, 125.7, 123.9, 121.1, 120.4,115.9(t, J=250.3 Hz), 111.2, 101.5, 75.5(d, J=3.7 Hz), 68.6, 63.2, 52.0, 46.7(d, J=1.7 Hz), 45.5, 36.6 (t, J=21.9 Hz), 13.7, 19F NMR (376 MHz, CDCl3, δppm): -100.4 (d, J=267.7 Hz, 1F), -102.3 (d, J=267.7 Hz, 1F).

[0052] Example 2

[0053] (1) 0.2 mmol of enyne derivative 1b, 0.026 mmol of tetra(triphenylphosphine)palladium, 0.036 mmol of bis(2-diphenylphosphine) ether and 0.46 mmol of cesium carbonate were added sequentially to a dry 10 mL Schlenk reaction tube, the tube was evacuated and nitrogen gas was introduced three times; under a nitrogen atmosphere, 3.5 mL of anhydrous tetrahydrofuran and 0.7 mmol of ethyl difluorobromoacetate were added to the Schlenk reaction tube, and the mixture was stirred at room temperature for 3 minutes to obtain a mixture;

[0054] (2) The mixture was placed under a 45W LED blue light lamp with a wavelength of 460nm and stirred at room temperature for 6 hours. TLC detection showed that the reaction was complete and the reactant was obtained. The reactant was transferred to a round bottom flask, 3.5g of crude silica gel was added, the solvent was removed under reduced pressure, and the product 3b was obtained by silica gel column chromatography purification and separation, namely ethyl 2,2-difluoro-3-(8-nitro-11-phenyl-1H,3H-2 22,2-difluoro[3',4':4,5]2 2 2,2-difluoro-3-(8-nitro-11-phenyl-1H,3H)propionate, with a yield of 75%.

[0055] The reaction equation is as follows:

[0056] .

[0057] The 1H NMR spectrum of product 3b is shown below. Figure 3 , 1 H NMR(400 MHz, CDCl3, δ ppm):8.46(d, J=2.0Hz, 1H), 8.13(dd, J=9.2, 2.4 Hz, 1H), 7.48-7.33(m, 6H), 6.43(s, 1H), 4.87-4.83(m, 2H), 4.43(d, J=9.2 Hz, 1H), 4.33(d, J=15.2 Hz, 1H), 4.23-4.10(m, 2H), 3.87(d, J=12.4 Hz, 1H), 3.79(d, J=9.2 Hz, 1H), 2.61-2.49(m, 1H), 2.38-2.25(m,1H), 1.23 (t, J=7.2 Hz, 3H); C NMR spectrum shown below. Figure 4 , 13C NMR (100 MHz, CDCl3, δ ppm): 163.4 (t, J=31.9 Hz), 141.8, 140.7, 139.7, 138.2, 135.4, 128.7, 128.7, 128.6, 128.0, 125.5, 118.2, 117.9, 115.9(t, J=250.8 Hz), 108.8, 103.0, 75.3 (d, J=4.3 Hz), 68.5, 63.3, 46.7 (d, J=2.3 Hz), 45.6, 36.3(t, J=22.0 Hz), 13.7; 19 FNMR (376 MHz, CDCl3, δ ppm): -100.4(d, J=267.7 Hz, 1F), -102.3(d, J=267.7 Hz, 1F).

[0058] Example 3

[0059] (1) 0.2 mmol of enyne derivative 1c, 0.02 mmol of tetra(triphenylphosphine)palladium, 0.03 mmol of bis(2-diphenylphosphine) ether and 0.4 mmol of cesium carbonate were added sequentially to a dry 10 mL Schlenk reaction tube, the tube was evacuated and nitrogen gas was introduced three times; under a nitrogen atmosphere, 3 mL of anhydrous tetrahydrofuran and 0.6 mmol of ethyl difluorobromoacetate were added to the Schlenk reaction tube, and the mixture was stirred at room temperature for 4 minutes to obtain a mixture;

[0060] (2) The mixture was placed under a 40W LED blue light lamp with a wavelength of 458nm and stirred at room temperature for 3 hours. TLC detection showed that the reaction was complete and the reactant was obtained. The reactant was transferred to a round bottom flask, 4g of crude silica gel was added, the solvent was removed under reduced pressure, and the product 3c was purified and separated by silica gel column chromatography, namely ethyl 2,2-difluoro-3-(10-methyl-11-phenyl-1H,3H-furano[3',4':4,5]pyrido[1,2-a]indol-3a(4H)-yl)propionate, with a yield of 80%.

[0061] The reaction equation is as follows:

[0062] .

[0063] The 1H NMR spectrum of product 3C is shown below. Figure 5 , 1H NMR(400 MHz, CDCl3, δ ppm):7.49(d, J=8.0Hz, 1H), 7.44-7.34(m, 3H), 7.28-7.22(m, 4H), 7.10-7.06(m, 1H), 4.74(d, J=14.4Hz, 1H), 4.66(d, J=12.4 Hz, 1H), 4.39(d, J=9.2 Hz, 1H), 4.17(d, J=14.4 Hz,1H), 4.18-4.03 (m, 2H), 3.77(d, J = 9.2 Hz, 1H), 3.73(d, J=12.4 Hz, 1H),2.55-2.26(m, 2H), 1.74 (s, 3H), 1.19 (t, J=7.2 Hz, 3H); C NMR spectrum shown below. Figure 6 , 13 C NMR (100 MHz, CDCl3, δ ppm): 163.6 (t, J=32.3 Hz), 139.3, 137.0, 136.0, 130.1,129.9, 128.8, 128.5, 128.0, 126.8, 122.7, 119.1, 119.0, 116.0(t, J=250.0 Hz),109.8, 108.7, 75.4(d, J=3.7 Hz), 68.8, 63.1, 46.8(d, J=1.9 Hz), 45.5, 36.1(t,J=22.0 Hz), 13.7, 9.8; 19 F NMR (376 MHz, CDCl3, δ ppm): -100.6 (d, J = 266.6 Hz, 1F), -102.2 (d, J = 266.6 Hz, 1F).

[0064] Example 4

[0065] (1) 0.2 mmol of enyne derivative 1a, 0.03 mmol of tetra(triphenylphosphine)palladium, 0.045 mmol of bis(2-diphenylphosphine) ether and 0.5 mmol of cesium carbonate were added sequentially to a dry 10 mL Schlenk reaction tube, the tube was evacuated and nitrogen gas was introduced three times; under a nitrogen atmosphere, 4 mL of anhydrous tetrahydrofuran and 0.8 mmol of ethyl difluorobromoacetate were added to the Schlenk reaction tube, and the mixture was stirred at room temperature for 5 minutes to obtain a mixture;

[0066] (2) The mixture was placed under a 50W LED blue light with a wavelength of 460nm and stirred at room temperature for 4 hours. TLC detection showed that the reaction was complete and the reactant was obtained. The reactant was transferred to a round-bottom flask, 3g of crude silica gel was added, the solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain a colorless oily product 3a, namely methyl 3a-(3-ethoxy-2,2-difluoro-3-oxopropyl)-11-phenyl-3a,4-dihydro-1H,3H-furano[3',4':4,5]pyrido[1,2-a]indole-7-carboxylic acid ester, with a yield of 78%. The reaction equation is the same as in Example 1.

[0067] Antitumor activity experiment:

[0068] HepG2 hepatocellular carcinoma cells, cultured at 80-90% confluence, were used to prepare cell suspensions. 10 μL of the cell suspension was counted using a hemocytometer, and then seeded into 96-well plates at a seeding density of 3000 cells / 100 μL. After cell attachment, the culture medium in the 96-well plates was replaced with different concentrations of compound-containing media: 0 μM, 1 μM, 5 μM, 10 μM, 50 μM, and 100 μM. The compounds were product 3a from Example 1, product 3b from Example 2, product 3c from Example 3, and doxorubicin. The 0 μM compound-containing medium was DMSO-containing medium with a DMSO volume fraction of 0.1%. Each group had three replicates. After cells were grown in culture media containing different concentrations of the compound for 24 hours, 10 μL of CCK-8 solution was added to each well, and the 96-well plates were then incubated at 37°C for 2 hours. The absorbance of each well at 450 nm was measured using a microplate reader. The results of the measurements 24 hours after drug administration were statistically analyzed, cell growth curves were plotted, and IC50 was calculated. 50 value.

[0069] The experimental results of the antitumor activities of different compounds are shown in Table 1. The data on the effect of compound 3a on the viability of HepG2 cells are shown in the figure below. Figure 7 The effect of compound 3b on HepG2 cell viability is shown in the figure. Figure 8 The effect of compound 3c on HepG2 cell viability data is shown in the figure. Figure 9 .

[0070] Table 1. Experimental results of the antitumor activity of different compounds

[0071]

[0072] As shown in Table 1, compared with doxorubicin, compounds 3a, 3b, and 3c prepared in this invention all exhibited better inhibitory effects on the growth of HepG2 liver cancer cells, especially compound 3a (IC50). 50 The value is 7.451) and compound 3c (IC 50 With a value of 11.97, it has excellent anti-tumor activity and application value.

Claims

1. A fluorinated indole derivative, characterized in that... The structure is as follows: or .

2. A method for preparing the fluorinated indole derivative according to claim 1, characterized in that... Includes the following steps: (1) Add solvent and difluoroalkyl bromide to alkenyne derivatives, catalysts, ligands and bases and stir to obtain a mixture; (2) The mixture was stirred under light, crude silica gel was added, the solvent was removed, and the mixture was separated to obtain a fluorinated indole derivative; In step (1), the difluoroalkyl bromide is ethyl difluorobromoacetate; In step (1), the catalyst is tetra(triphenylphosphine)palladium, the ligand is bis(2-diphenylphosphine) ether, and the base is cesium carbonate; The structural formula of the enyne derivative in step (1) is as follows: or ; In step (2), the light source is an LED blue light.

3. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... The solvent in step (1) is anhydrous tetrahydrofuran.

4. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... In step (1), the molar ratio of alkenyne derivative, catalyst, ligand, base and difluoroalkyl bromide is 1:0.1-0.15:0.15-0.225:2-2.5:3-4.

5. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... In step (1), the ratio of alkenyne derivative to solvent is 1:15-20, where alkenyne derivative is expressed in mmol and solvent in mL.

6. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... The stirring time in step (1) is 3-5 minutes, and the stirring temperature is room temperature.

7. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... In step (2), the power of the LED blue light is 40-50W and the wavelength of the LED blue light is 455-460nm.

8. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... In step (2), the stirring reaction is carried out at room temperature for 3-6 hours.

9. The method for preparing the fluorinated indole derivative according to claim 2, characterized in that... In step (2), the ratio of crude silica gel to alkenyne derivative is 15-20:1, where crude silica gel is expressed in g and alkenyne derivative in mmol.

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