Deuterated method for indole compounds and applications thereof

Abstract

This invention belongs to the field of deuterated labeled compound synthesis technology, and discloses a method for deuterating indole compounds and its application. The deuteration method of this invention includes the following steps: mixing an indole compound, a transition metal catalyst, a complex ligand, an additive, and a deuteration solvent, reacting to obtain a deuterated product; the complex ligand includes a first ligand and a second ligand; the first ligand includes a lactam compound; the second ligand includes a pyridone compound; and the deuteration solvent includes deuterated acetic acid. The deuteration method of this invention achieves highly selective hydrogen-deuterium exchange at multiple sites on the indole ring of indole compounds (especially the difficult-to-modify C4-C7 sites) through the synergistic effect of the catalyst, the dual ligand, and the deuteration solvent system. Furthermore, it can be applied to the deuteration synthesis of drugs such as the anti-inflammatory drug indomethacin, the cancer adjuvant therapy drug tropisetron, and the neuromodulator melatonin, providing key technical support for the development of deuterated drugs.

Description

Technical Field

[0001] This invention relates to the field of deuterated labeled compound synthesis technology, specifically to a deuteration method for indole compounds and its application. Background Technology

[0002] Deuteration labeling technology plays a crucial role in drug development. By replacing hydrogen atoms in drug molecules with deuterium atoms, it leverages the kinetic isotope effect to effectively modulate pharmacokinetic properties, such as prolonging half-life, improving metabolic stability, reducing toxicity, and minimizing individual variability. In recent years, with the successful approval of several deuterated drugs, deuteration strategies have become an important tool for optimizing lead compounds in drug development. Indole compounds, as important structural units in natural products and drug molecules (such as anti-inflammatory drugs, 5-HT receptor modulators, and anticancer compounds), have significant implications for pharmaceutical research due to their deuteration.

[0003] Currently, traditional deuteration methods for indole compounds mainly include acid / base-catalyzed hydrogen / deuterium exchange reactions, transition metal-catalyzed hydrogen / deuterium exchange reactions, and metal-mediated direct deuteration reactions. Among these, traditional hydrogen / deuterium exchange methods typically require strong acid or strong base media, resulting in harsh reaction conditions. These methods not only exhibit poor tolerance to functional groups but also struggle to control regioselectivity, often leading to multi-site non-specific deuteration or skeletal degradation, thus limiting their application in the late-stage modification of complex molecules. Transition metal catalytic systems, such as iridium, rhodium, and ruthenium complexes, can achieve hydrogen / deuterium exchange reactions of aromatics and heteroaromatics under relatively mild conditions, significantly improving the compatibility of functional groups. However, for indole substrates, existing transition metal catalytic systems are usually limited by directing strategies or electronic effects, with reaction sites mostly concentrated at the highly reactive C2 or C3 positions. For C4 to C7 positions, which have lower electron cloud density and more significant steric hindrance, especially C4 and C7, the deuteration efficiency is still not ideal, making it difficult to achieve uniform deuteration at multiple or even all sites on the indole ring. Palladium-catalyzed C-H bond functionalization has been widely used in organic synthesis due to its advantages such as mild conditions, broad functional group tolerance, and strong tunability of the catalytic system. However, in the undirected deuteration reaction of indole C-H bonds, the acidity and reactivity of C-H bonds at different sites of the indole skeleton vary significantly. In addition, palladium catalysts are prone to deactivation or aggregation during the reaction, which makes it difficult to achieve efficient deuteration of C2, C3 and C4-C7 sites simultaneously.

[0004] In summary, although various deuteration methods have been reported, there is still a lack of universal and practical technical solutions for achieving efficient and highly selective deuteration of C-H bond positions (especially challenging C4-C7 sites) on indole rings under mild conditions. Therefore, developing a new method that is simple to operate, operates under mild conditions, has excellent functional group compatibility, and can achieve efficient deuteration of all sites in indole compounds is of great significance for enriching the structural diversity of deuterated drug molecules and promoting the widespread application of deuteration technology in medicinal chemistry. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method and application for the deuteration of indole compounds.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for the deuteration of indole compounds, comprising the following steps: Indole compounds, transition metal catalysts, complex ligands, additives, and deuterated solvents are mixed and reacted to obtain deuterated products. The complex ligand includes a first ligand and a second ligand; the first ligand includes a lactam compound; the second ligand includes a pyridone compound. The deuterated solvent includes deuterated acetic acid.

[0007] The deuteration method for indole compounds of the present invention achieves highly selective hydrogen-deuterium exchange at multiple sites on the indole ring (especially the difficult-to-modify C4-C7 sites) through the synergistic effect of a catalyst, a dual-ligand system, and a deuteration solvent system. Specifically, a palladium catalyst, under the co-coordination of the dual-ligand system, forms an active palladium species with specific electronic and spatial configurations. The first ligand, through its electron-rich nitrogen heterocyclic structure, forms a stable chelate with the palladium center, regulating the electrophilicity of the metal center. The second ligand, acting as an auxiliary ligand, further optimizes the coordination environment of the active center, enhancing its recognition and activation ability for indole substrates. Furthermore, under the protonated medium and deuterium source environment provided by the deuteration solvent, this active palladium species can synergistically promote the hydrogen-deuterium exchange reaction at C2 to C7 sites on the indole ring, achieving efficient and regioselective introduction of deuterium atoms through reversible CH bond activation and deuteration protonation.

[0008] As a preferred embodiment of the deuteration method for indole compounds according to the present invention, the chemical structural formula of the indole compounds is shown below: ; Wherein, R1 is selected from any one of hydrogen, methyl or benzyl; R2 is selected from any one of hydrogen, methyl, acetate, methyl formate or methyl acetate; and R3 is selected from any one of hydrogen, methyl, fluorine, chlorine, bromine, methoxy, cyano, nitro or methyl formate.

[0009] Preferably, the indole compound includes at least one of the compounds shown in the following formula: .

[0010] In a preferred embodiment of the deuteration method for indole compounds according to the present invention, the lactam compound includes at least one of the compounds shown in the following formula: .

[0011] In a preferred embodiment of the deuteration method for indole compounds according to the present invention, the pyridone compound includes at least one of the compounds shown in the following formula: .

[0012] As a preferred embodiment of the deuteration method for indole compounds described in this invention, the transition metal catalyst includes at least one of bis(triphenylphosphine)palladium dichloride, palladium acetate, tris(dibenzylacetone)palladium, and tetra(triphenylphosphine)palladium; and / or, the additive includes hexafluoroisopropanol.

[0013] Preferably, the transition metal catalyst comprises palladium acetate.

[0014] In a preferred embodiment of the deuteration method for indole compounds described in this invention, the deuteration solvent further includes at least one of heavy water, deuterated methanol, dichloromethane, acetonitrile, and dimethyl sulfoxide.

[0015] Preferably, the deuterated solvent further includes heavy water and acetonitrile; the volume ratio of the deuterated acetic acid, heavy water, and acetonitrile is 1:2:2.

[0016] In a preferred embodiment of the deuteration method for indole compounds according to the present invention, the molar ratio of the indole compound, the transition metal catalyst, and the additive is 1:(0.02-0.1):(0.8-1.5); and / or, the molar amount of the composite ligand is 3%-15% of the molar amount of the indole compound; and / or, the molar ratio of the first ligand to the second ligand is 1:(0.5-2).

[0017] Preferably, the molar ratio of the indole compound, the transition metal catalyst, and the additive is 1:0.05:1.

[0018] Preferably, the molar amount of the complex ligand is 10% of the molar amount of the indole compound.

[0019] The molar ratio of the first ligand to the second ligand is 1:1.

[0020] In a preferred embodiment of the deuteration method for indole compounds described in this invention, the reaction temperature is 110℃-130℃ and the reaction time is 12h-48h.

[0021] Preferably, the reaction temperature is 120°C and the reaction time is 24 hours.

[0022] Secondly, the present invention provides a deuterated indole compound, which is prepared by the aforementioned deuteration method.

[0023] Thirdly, this invention provides the application of the aforementioned deuterated indole compounds in the preparation of pharmaceutical intermediates. Compared with existing technologies, the beneficial effects of this invention are as follows: First, the deuteration method of this invention effectively overcomes the technical challenges of low deuteration efficiency and poor selectivity at challenging sites (such as C4-C7) on the indole ring through a dual-ligand synergistic strategy, achieving precise introduction of deuterium atoms into the benzene ring region. Second, the deuteration method of this invention operates under mild reaction conditions, eliminating the need for harsh conditions such as strong acids, strong bases, or high temperatures and pressures, exhibiting good functional group tolerance and applicability to structurally diverse indole compounds, demonstrating excellent substrate versatility. Furthermore, the deuteration method of this invention is simple to operate, with concise steps and high deuteration efficiency, providing an efficient and reliable practical tool for the synthesis of deuterated drug intermediates. Simultaneously, the established dual-ligand synergistic design paradigm also provides new ideas and references for the functionalization reactions of other inert CH bonds. Detailed Implementation

[0024] To better illustrate the objectives, technical solutions, and advantages of this invention, the invention will be further described below with reference to specific embodiments. Those skilled in the art should understand that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0025] The following description, in conjunction with specific embodiments, illustrates the practical effects of the present invention.

[0026] Unless otherwise specified, the experimental methods used in the examples are conventional methods; the materials, reagents, equipment, etc. used are all commercially available unless otherwise specified.

[0027] The raw materials and reagents used in the following examples and comparative examples were all commercially available, analytical grade; the solvents used were all deuterated reagents or analytical grade solvents; 1H NMR spectroscopy (NMR) was used. 1 H NMR and carbon spectroscopy (H NMR) 13¹³C NMR was performed using a Bruker AVANCEIII 400MHz NMR spectrometer, with dibromomethane (internal standard, chemical shift δ 5.40ppm) as the quantitative internal standard. The deuteration rate at each position was calculated by integration. High-resolution mass spectrometry was performed using an Agilent 6230 TOF LC / MS instrument.

[0028] The specific structural formulas and manufacturer information of the indole compounds used in the following examples and comparative examples are shown in the table below: Table 1: Structural formulas and manufacturer information for indole compounds The specific synthesis methods and NMR data of the first ligand intraamide compounds used in the following examples and comparative examples are shown below.

[0029] The reaction formula for the first ligand L1 is shown below: (1) Reaction process: Under nitrogen protection, 1H-indazole (1.05 g, 8.47 mmol), 6-chloropyridin-2(1H)-one (purchased from Bid Pharmaceutical) (1.09 g, 8.47 mmol), anhydrous cesium carbonate (2.76 g, 8.47 mmol) and cuprous iodide (0.08 g, 0.42 mmol, 5 mol%) were added sequentially to a dry 100 mL reaction tube containing a magnetic ball. After the reaction system was evacuated and replaced with nitrogen three times, anhydrous DMF (20 mL) was added under nitrogen atmosphere. The reaction mixture was placed in an oil bath at 100 °C and stirred for 12 h.

[0030] (2) Post-processing: After the reaction is completed, cool to room temperature and add an appropriate amount of water to quench; extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure; the crude product obtained is purified by silica gel column chromatography (the chromatographic purification method is as described in the "0512 column chromatography" of the General Chapter of Part IV of the 2020 edition of the Chinese Pharmacopoeia).

[0031] The specific operation is as follows: 200-300 mesh silica gel is used as the packing material. The sample is dissolved in ethyl acetate, mixed, and then loaded onto the sample using a dry method. A mixed solution of petroleum ether and ethyl acetate is used as the mobile phase for elution. The ratio of the mobile phase is determined in advance by thin-layer chromatography (TLC) according to the polarity of the target product. The volume ratio of petroleum ether to ethyl acetate is 2:1. The fraction containing the target product is collected, combined, and concentrated under reduced pressure to obtain a pure product (the product yield is calculated based on the ratio of the mass of the pure product obtained from the separation to the theoretical yield, the same below). A white solid product L1 (1.36 g, yield 72.6%) is obtained. The product structure is confirmed by NMR detection.

[0032] The reaction formula for the first ligand L2 is shown below: (1) Reaction process: Under nitrogen protection, 1H-pyrrolo[2,3-b]pyridine (1.00 g, 8.47 mmol), 6-chloropyridin-2(1H)-one (1.09 g, 8.47 mmol), anhydrous cesium carbonate (2.76 g, 8.47 mmol) and cuprous iodide (0.08 g, 0.42 mmol) were added sequentially to a dry 100 mL reaction tube containing a magnetic ball. After the reaction system was evacuated and replaced with nitrogen three times, anhydrous DMF (20 mL) was added under nitrogen atmosphere. The reaction mixture was placed in an oil bath at 100 °C and stirred for 12 h.

[0033] (2) Post-processing: After the reaction was completed, the mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 3:1) to obtain a white solid product L2 (1.18 g, yield 66.0%). The structure of the product was confirmed by NMR detection.

[0034] The reaction formula for the first ligand L3 is shown below: (1) Reaction process: Under nitrogen protection, 1,2-dihydro-3H-indazole-3-one (1.06 g, 7.91 mmol), 2-bromopyridine (1.23 g, 7.91 mmol), anhydrous cesium carbonate (2.58 g, 7.91 mmol) and cuprous iodide (0.06 g, 0.40 mmol) were added sequentially to a dry 100 mL reaction tube containing a magnetic ball. After the reaction system was evacuated and replaced with nitrogen three times, anhydrous DMF (20 mL) was added under nitrogen atmosphere. The reaction mixture was placed in an oil bath at 120 °C and stirred for 12 h.

[0035] (2) Post-processing: After the reaction was completed, the mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 5:1) to obtain a white solid product L3 (1.14 g, yield 68.2%). The structure of the product was confirmed by NMR detection.

[0036] The reaction formula for the first ligand L4 is shown below: Step 1: Synthesize intermediate L4-IN01 (1) Reaction process: Under nitrogen protection, 6-chloro-2,2'-bipyridine (1.02 g, 5.26 mmol) and sodium hydroxide (0.20 g, 5.26 mmol) were added sequentially to a dry 50 mL reaction tube containing a magnetic ball; the reaction system was evacuated and replaced with nitrogen three times, and then methanol (15 mL) was added under nitrogen atmosphere; the reaction mixture was placed in an oil bath at 120 °C and stirred for 12 h.

[0037] (2) Post-processing: After the reaction was completed, the mixture was cooled to room temperature, diluted with dichloromethane, and filtered through diatomaceous earth. The filtrate was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 10:1) to obtain a white solid intermediate L4-IN01 (0.69 g, yield 70.4%).

[0038] Step 2: Synthesize L4 from L4-IN01 (1) Reaction process: Under nitrogen protection, the intermediate L4-IN01 (0.69g, 3.70mmol) and hydrobromic acid (0.3g, 3.70mmol, calculated as HBr) obtained in the previous step were added sequentially to a dry 50mL reaction tube containing a magnetic ball; after the reaction system was evacuated and replaced with nitrogen three times, the reaction mixture was placed in an oil bath at 100℃ and stirred for 12h.

[0039] (2) Post-processing: After the reaction was completed, the mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 3:1) to obtain a white solid product L4 (0.47 g, yield 73.7%). The structure of the product was confirmed by NMR detection.

[0040] The reaction formula for the first ligand L5 is shown below: (1) Reaction process: Under nitrogen protection, 6-aminopyridine-2(1H)-one (purchased from Bid Pharmaceutical) (1.03g, 9.40mmol), acetyl chloride (0.73g, 9.40mmol), anhydrous cesium carbonate (3.06g, 9.40mmol) and cuprous iodide (0.09g, 0.47mmol, 5mol%) were added sequentially to a dry 100mL reaction tube containing a magnetic ball; the reaction system was evacuated and replaced with nitrogen three times, and then anhydrous DMF (20mL) was added under nitrogen atmosphere; the reaction mixture was placed in an oil bath at 120℃ and stirred for 24h.

[0041] (2) Post-processing: After the reaction was completed, the mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 2:1) to obtain a white solid product L5 (1.09 g, yield 76.3%). The structure of the product was confirmed by NMR detection.

[0042] The NMR and mass spectrometry data of the first ligand intraamide compounds used in the following examples and comparative examples are shown below: (1H-indazol-1-yl)pyridin-2(1H)-one (L1): 1 H NMR (400 MHz, DMSO-d6) δ11.02 (s, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 7.87 (d, J = 8.0 Hz,1H), 7.80 (t, J = 7.9 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ162.5, 151.9, 141.7, 138.1, 137.1, 127.8, 125.6, 122.5, 121.1,115.5, 104.8, 103.4; HRMS (ESI) m / z calcd. for C 12 H 10 N3O [M+H] + 212.0818, found 212.0827. (1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2(1H)-one (L2): 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 7.87(d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.45(d, J= 7.8 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H). 13 C NMR(100 MHz, CDCl3): δ162.5, 151.9, 141.7, 138.1, 137.1, 127.8, 125.6, 122.5,121.1, 115.5, 104.8, 103.4; HRMS (ESI) m / z calcd. for C 12 H 10 N3O [M+H] + 212.0818,found 212.0827. (1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2(1H)-one (L3): 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.51 – 8.43 (m, 1H),7.90 (t, J = 7.8 Hz, 1H), 7.74 (dd, J = 16.2, 8.2 Hz, 2H), 7.54 (t, J = 7.6Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 5.6 Hz, 1H). 13 C NMR (100 MHz,DMSO-d6): δ157.0, 153.7, 147.8, 139.3, 138.8, 128.9, 121.6, 120.1, 118.6,116.0, 115.0, 111.5; HRMS (ESI) m / z calcd. for C 12 H 10 N3O [M+H] + 212.0818, found212.0829. [2,2'-bipyridin]-6(1H)-one (L4): 1 H NMR (400 MHz, DMSO-d6) δ11.03 (s,1H), 8.69 (d, J = 4.5 Hz, 1H), 8.17 – 8.13 (m, 1H), 7.99 – 7.94 (m, 1H), 7.65– 7.59 (m, 1H), 7.50 – 7.46 (m, 1H), 7.23 (s, 1H), 6.51 (d, J = 8.9 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ162.3, 149.3, 140.9, 137.7, 124.6, 120.6; HRMS(ESI) m / z calcd. for C 10 H9N2O [M+H] + 173.0709, found 173.0712. [2,2'-bipyridin]-6(1H)-one (L5): 1 H NMR (400 MHz, CDCl3): δ7.47 (t, J =7.8 Hz, 1H), 6.36 (dd, J = 7.6, 5.1 Hz, 2H), 4.50 (s, 2H), 2.27 (s, 3H). 13 CNMR (100 MHz, CDCl3): δ169.2, 158.2, 156.8, 140.1, 106.3, 104.6, 21.4; HRMS(ESI) m / z calcd. for C7H9N2O2[M+H] + 153.0659, found 153.0660. The specific structural formulas and manufacturer information of the second ligands used in the following embodiments and comparative examples are shown in the table below: Table 2: Structural Formulas and Manufacturer Information of Second Ligands Example 1: This embodiment provides a method for the deuteration of an indole compound (methyl indole-3-acetate), the specific reaction of which is carried out according to the following reaction formula; The specific reaction procedure was as follows: 1.0 mmol of indole-3-acetic acid methyl ester, 0.05 mmol of palladium acetate, 1.0 mmol of hexafluoroisopropanol, 0.1 mmol of a complex ligand (the complex ligand includes a first ligand L1 and a second ligand P1, with a molar ratio of 1:1), and 5 mL of deuterated solvent (the deuterated solvent includes deuterated acetic acid, heavy water, and acetonitrile; the volume ratio of deuterated acetic acid, heavy water, and acetonitrile is 1:2:2) were mixed and reacted at 120 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography (using a mixed solvent of petroleum ether and ethyl acetate as the eluent) to obtain the product. The structure of the product was confirmed by NMR.

[0043] The product was tested for deuteration rate ( 1 The deuteration rates of the C2-C7 sites were obtained by ¹H NMR integration method and column chromatography, specifically C2: 96%, C4: 96%, C5: 97%, C6: 97%, and C7: 97%, with a yield of 85% (byproducts were unreacted substrate and decarboxylation impurities).

[0044] NMR data for indole-3-acetate methyl ester: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.96 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.2, 124.1, 121.1, 118.6, 111.4, 107.0, 51.5, 30.6, 23.0 (dibromomethane). NMR data of the product: 1¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.48 (s, 0.04H, 96% D), 7.37 (s, 0.03H, 97% D), 7.26 (s, 0.04H, 96% D), 7.08 (s, 0.03H, 97% D), 6.99 (s, 0.03H, 97% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.0, 127.2, 124.2, 120.8, 118.3, 111.3, 106.9, 51.6, 30.6, 23.1. (dibromomethane). Example 2-15: The deuteration method for indole compounds (methyl indole-3-acetate) in Examples 2-15 differs from that in Example 1 only in the use of the complex ligand, deuteration solvent, and / or reaction time, as detailed in the table below: Table 3: Deuteration methods in Examples 1-15, including the complex ligands used, deuteration solvents, reaction times, and deuteration rates and yields at various points in the products. NMR data of the product from Example 2: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.23H, 77% D), 7.36 (s, 0.30H, 70% D), 7.26 (s, 0.24H, 76% D), 7.08 (s, 0.26H, 74% D), 6.99 (s, 0.18H, 82% D), 5.41 (s, 2H, dibromomethane internal standard), 3.74 (s, 2H), 3.59 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.0, 127.1, 124.2, 120.9, 118.3, 111.3, 106.9, 51.5, 30.6, 23.1. (dibromomethane). NMR data of the product from Example 3: 1¹H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.50 (s, 0.08H, 92% D), 7.38 (s, 0.12H, 88% D), 7.27 (s, 0.10H, 90% D), 7.10 (s, 0.09H, 91% D), 7.00 (s, 0.06H, 94% D), 5.42 (s, 2H, dibromomethane internal standard), 3.77 (s, 2H), 3.62 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.0, 127.1, 124.1, 121.0, 118.4, 111.3, 106.9, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product from Example 4: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.14H, 86% D), 7.36 (s, 0.15H, 85% D), 7.26 (s, 0.18H, 82% D), 7.09 (s, 0.15H, 85% D), 6.99 (s, 0.12H, 88% D), 5.41 (s, 2H, dibromomethane internal standard), 3.77 (s, 2H), 3.602 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.2, 127.0, 124.1, 120.9, 118.5, 111.3, 106.9, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product from Example 5: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.48 (s, 0.04H, 96% D), 7.37 (s, 0.04H, 96% D), 7.26 (s, 0.05H, 95% D), 7.08 (s, 0.05H, 95% D), 6.99 (s, 0.03H, 97% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 172.1, 136.0, 127.0, 124.1, 120.9, 118.3, 111.3, 106.8, 51.5, 30.6, 23.1. (dibromomethane). NMR data of the product from Example 6: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.9 (s, 1H), 7.48 (s, 0.18H, 82% D), 7.35 (s, 0.16H, 84% D), 7.25 (s, 0.18H, 82% D), 7.07 (s, 0.17H, 83% D), 6.99 (s, 0.10H, 90% D), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.0, 127.0, 124.2, 120.9, 118.3, 111.4, 106.8, 51.6, 30.6, 23.1. (dibromomethane). NMR data of the product from Example 7: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.48 (s, 0.16H, 84% D), 7.36 (s, 0.15H, 85% D), 7.24 (s, 0.19H, 81% D), 7.10 (s, 0.12H, 88% D), 6.98 (s, 0.11H, 89% D), 5.40 (s, 2H, dibromomethane internal standard), 3.73 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.3, 136.1, 127.0, 124.1, 120.7, 118.3, 111.3, 106.9, 51.5, 30.6, 23.1. (dibromomethane). NMR data of the product from Example 8: 1¹H NMR (400 MHz, DMSO-d⁶): δ 10.95 (s, 1H), 7.49 (s, 0.19H, 81% D), 7.37 (s, 0.17H, 83% D), 7.24 (s, 0.23H, 77% D), 7.07 (s, 0.18H, 82% D), 6.98 (s, 0.11H, 89% D), 5.41 (s, 2H, dibromomethane internal standard), 3.73 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.1, 127.2, 124.0, 120.8, 118.4, 111.3, 106.8, 51.5, 30.6, 23.1. (dibromomethane). Comparative Examples 1-18: The deuteration methods for indole compounds (methyl indole-3-acetate) in Comparative Examples 1-18 differ from those in Example 1 only in the use of the complex ligands, deuteration solvents, and / or reaction times, as detailed in the table below: Table 4: Deuteration methods used in Comparative Examples 1-15, including the complex ligands, deuteration solvents, reaction times, and deuteration rates and yields at various points in the products. NMR data of the product of Comparative Example 1: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.49 (s, 0.97H, 3% D), 7.37 (s, 0.97H, 3% D), 7.25 (s, 0.96H, 4% D), 7.09 (s, 0.98H, 2% D), 6.99 (s, 0.96H, 4% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.1, 124.1, 120.9, 118.3, 111.4, 106.8, 51.6, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 2: 1¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.48 (s, 0.19H, 81% D), 7.37 (s, 0.17H, 83% D), 7.26 (s, 0.23H, 77% D), 7.08 (s, 0.18H, 82% D), 6.99 (s, 0.11H, 89% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.0, 127.0, 124.2, 120.9, 118.4, 111.3, 106.8, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product of Comparative Example 3: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.34H, 66% D), 7.35 (s, 0.33H, 67% D), 7.24 (s, 0.44H, 56% D), 7.08 (s, 0.24H, 76% D), 6.99 (s, 0.27H, 73% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.0, 127.0, 124.1, 120.8, 118.3, 111.3, 106.7, 51.5, 30.5, 23.1. (dibromomethane). NMR data of the product of Comparative Example 4: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.48 (s, 0.28H, 72% D), 7.36 (s, 0.44H, 56% D), 7.27 (s, 0.42H, 58% D), 7.10 (s, 0.22H, 78% D), 6.99 (s, 0.22H, 78% D), 5.41 (s, 2H, dibromomethane internal standard), 3.77 (s, 2H), 3.61 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 172.1, 136.2, 127.0, 124.2, 120.9, 118.5, 111.3, 106.8, 51.7, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 5: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.26H, 74% D), 7.37 (s, 0.33H, 67% D), 7.26 (s, 0.48H, 52% D), 7.10 (s, 0.30H, 70% D), 6.99 (s, 0.27H, 73% D), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.0, 127.2, 124.1, 121.0, 118.3, 111.3, 106.9, 51.5, 30.8, 23.1. (dibromomethane). NMR data of the product of Comparative Example 6: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.48 (s, 0.38H, 62% D), 7.36 (s, 0.38H, 62% D), 7.25 (s, 0.37H, 63% D), 7.08 (s, 0.34H, 66% D), 7.00 (s, 0.27H, 73% D), 5.41 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.62 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.0, 127.1, 124.1, 120.9, 118.3, 111.4, 106.8, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product of Comparative Example 7: 1¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.49 (s, 0.88H, 12% D), 7.36 (s, 0.87H, 13% D), 7.256 (s, 0.96H, 4% D), 7.08 (s, 0.88H, 12% D), 6.99 (s, 0.85H, 15% D), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.0, 124.1, 120.8, 118.3, 111.2, 106.8, 51.4, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 8: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.50 (s, 0.47H, 53% D), 7.38 (s, 0.52H, 48% D), 7.26 (s, 0.54H, 46% D), 7.09 (s, 0.45H, 55% D), 7.00 (s, 0.35H, 65% D), 5.42 (s, 2H, dibromomethane internal standard), 3.77 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.1, 127.0, 124.3, 120.9, 118.3, 111.5, 106.8, 51.6, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 9: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.95 (s, 1H), 7.49 (s, 0.34H, 66% D), 7.35 (s, 0.33H, 67% D), 7.26 (s, 0.44H, 56% D), 7.10 (s, 0.24H, 76% D), 6.98 (s, 0.27H, 73% D), 5.39 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.61 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 172.1, 136.0, 127.0, 124.2, 120.8, 118.3, 111.2, 106.8, 51.5, 30.5, 23.1. (dibromomethane). NMR data of the product of Comparative Example 10: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.48 (s, 0.28H, 72% D), 7.35 (s, 0.44H, 56% D), 7.26 (s, 0.42H, 58% D), 7.09 (s, 0.22H, 78% D), 6.98 (s, 0.22H, 78% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.1, 127.1, 124.0, 120.8, 118.3, 111.3, 106.7, 51.5, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 11: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.49 (s, 0.26H, 74% D), 7.36 (s, 0.33H, 67% D), 7.25 (s, 0.48H, 52% D), 7.08 (s, 0.30H, 70% D), 7.00 (s, 0.27H, 73% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.0, 124.2, 120.9, 118.4, 111.2, 106.7, 51.5, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 12: ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, ¹H), 7.48 (s, 0.38H, 62% D), 7.37 (s, 0.38H, 62% D), 7.25 (s, 0.37H, 63% D), 7.09 (s, 0.34H, 66% D), 6.99 (s, 0.27H, 73% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.62 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.2, 127.1, 124.1, 120.9, 118.2, 111.2, 106.8, 51.6, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 13: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.40H, 60% D), 7.35 (s, 0.44H, 56% D), 7.26 (s, 0.46H, 54% D), 7.10 (s, 0.42H, 58% D), 7.00 (s, 0.35H, 65% D), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.0, 136.1, 127.1, 124.2, 121.0, 118.3, 111.3, 106.9, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product of Comparative Example 14: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.68H, 32% D), 7.37 (s, 0.62H, 38% D), 7.24 (s, 0.63H, 37% D), 7.09 (s, 0.59H, 41% D), 6.99 (s, 0.52H, 48% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.0, 124.1, 120.9, 118.5, 111.2, 106.8, 51.6, 30.7, 23.1. (dibromomethane). NMR data of the product of Comparative Example 15: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.94 (s, 1H), 7.48 (s, 0.55H, 45% D), 7.37 (s, 0.52H, 48% D), 7.26 (s, 0.53H, 47% D), 7.10 (s, 0.48H, 52% D), 6.99 (s, 0.45H, 55% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.3, 136.0, 127.0, 124.2, 120.9, 118.4, 111.3, 106.9, 51.5, 30.5, 23.1. (dibromomethane). NMR data of the product of Comparative Example 16: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.49 (s, 0.68H, 32% D), 7.37 (s, 0.60H, 40% D), 7.26 (s, 0.67H, 33% D), 7.09 (s, 0.60H, 40% D), 7.00 (s, 0.56H, 44% D), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.1, 127.1, 124.2, 120.9, 118.4, 111.3, 106.8, 51.5, 30.7, 23.1. (dibromomethane). NMR data of the product of Comparative Example 17: 1¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.50 (s, 0.58H, 42% D), 7.35 (s, 0.52H, 48% D), 7.25 (s, 0.54H, 46% D), 7.08 (s, 0.50H, 50% D), 7.00 (s, 0.49H, 51% D), 5.40 (s, 2H, dibromomethane internal standard), 3.77 (s, 2H), 3.62 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.0, 124.2, 120.9, 118.5, 111.2, 106.8, 51.6, 30.6, 23.1. (dibromomethane). NMR data of the product of Comparative Example 18: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.47 (s, 0.49H, 51% D), 7.37 (s, 0.56H, 44% D), 7.25 (s, 0.57H, 43% D), 7.08 (s, 0.51H, 49% D), 6.99 (s, 0.47H, 53% D), 5.41 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.2, 136.0, 127.1, 124.1, 120.9, 118.3, 111.4, 106.8, 51.6, 30.7, 23.1. (dibromomethane). The comparison results of the above embodiments and comparative examples show that the core advantage of the embodiments of the present invention compared with comparative examples 1-8 lies in the systematic design of "dual-ligand synergy - ternary solvent microenvironment - precise condition control", which achieves efficient and highly selective deuteration of indole substrates at C2-C7 sites. Specifically: the reaction in comparative example 1 was almost impossible to occur without ligand (deuteration rate ≤5%), proving that the ligand of the present invention is indispensable for the activation of the palladium catalytic center; the deuteration rate of comparative examples 2-6 was significantly lower than that of the embodiments when only a single ligand was used, verifying the synergistic effect between the dual ligands of the present invention and its key role in accurately locating the palladium center and guiding deuteration migration; thus, it can be seen that the present invention achieves a breakthrough improvement in deuteration rate (96-97%) and yield (85%) through the synergistic cooperation of each component, overcoming the technical difficulties of low deuteration efficiency and poor selectivity of traditional methods at challenging sites.

[0045] Examples 9-32: The deuteration method of indole compounds in Examples 9-32 differs from that in Example 1 only in that the indole compounds used are different, and the specific reaction is carried out according to the following reaction formula; The specific reaction procedure was as follows: 1.0 mmol of an indole compound, 0.05 mmol of palladium acetate, 1.0 mmol of hexafluoroisopropanol, 0.1 mmol of a complex ligand (the complex ligand includes a first ligand L1 and a second ligand P1, with a molar ratio of 1:1), and 5 mL of a deuterated solvent (the deuterated solvent includes deuterated acetic acid, heavy water, and acetonitrile; the volume ratio of deuterated acetic acid, heavy water, and acetonitrile is 1:2:2) were mixed and reacted at 120 °C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography (using a mixed solvent of petroleum ether and ethyl acetate) to obtain the product. The structure of the product was confirmed by NMR.

[0046] The product was tested for deuteration rate ( 1 The deuteration rate and yield of the C2-C7 sites were obtained by ¹H NMR integration method and column chromatography separation.

[0047] The specific structures of the indole compounds and deuterated products of Examples 9-32 are shown in the table below: Table 5: Structural formulas of indole compounds and deuterated products from Examples 9-32, and deuteration rates at each point of the products. The NMR data of the indole compounds and deuterated products of Examples 9-32 are shown below: Example 9: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.07 (s, ¹H), 7.54 (d, J = 7.8 Hz, ¹H), 7.40 (d, J = 8.1 Hz, ¹H), 7.33 (d, J = 2.2 Hz, ¹H), 7.08 (t, J = 7.5 Hz, ¹H), 6.99 (t, J = 7.3 Hz, ¹H), 6.42 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13C NMR (100 MHz, DMSO-d6): δ 135.8, 127.6, 125.1, 120.8, 120.0, 118.7, 111.4, 100.9, 23.0 (dibromomethane). NMR data of the deuterated product in Example 9: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 7.53 (s, 0.16H, 84%D), 7.39 (s, 0.04H, 96%D), 7.32 (s, 0.06H, 94%D), 7.07 (s, 0.13H, 87%D), 6.98 (s, 0.08H, 92%D), 6.41 (s, 0.67H, 33%D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 135.7, 127.5, 124.9, 120.6, 119.8, 118.4, 111.2, 100.7, 23.0 (dibromomethane). Example 10: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 7.55 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 7.1 Hz, 1H), 6.42 (s, 1H), 5.41 (s, 2H, dibromomethane internal standard), 3.77 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ136.3, 129.5, 128.0, 120.9, 120.3, 118.8, 109.6, 100.2, 32.4, 23.0 (dibromomethane). NMR data of deuterated products in Example 10: 1¹H NMR (400 MHz, DMSO-d⁶): δ 7.54 (s, 0.09H, 91% D), 7.42 (s, 0.03H, 97% D), 7.31 (s, 0.04H, 96% D), 7.14 (s, 0.06H, 94% D), 7.02 (s, 0.03H, 97% D), 6.41 (s, 0.42H, 58% D), 5.41 (s, 2H, dibromomethane internal standard), 3.78 (s, 2.36H, 21% D). 13 C NMR (100 MHz, DMSO-d6): δ 136.3, 129.5, 127.9, 120.7, 120.1, 118.6, 109.5, 100.0, 32.4, 23.1 (dibromomethane). Example 11: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 7.57 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.33 – 7.17 (m, 5H), 7.10 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.50 (s, 1H), 5.41 (s, 4H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 138.3, 135.7, 129.1, 128.5, 128.3, 127.3, 126.9, 121.1, 120.4, 119.1, 110.1, 100.9, 49.1, 23.0 (dibromomethane). NMR data of deuterated products in Example 11: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 7.57 (s, 0.14H, 86% D), 7.49 (s, 0.06H, 94% D), 7.44 (s, 0.05H, 95% D), 7.32 – 7.18 (m, 4H, 25% D), 7.09 (s, 0.24H, 76% D), 7.02 (s, 0.22H, 78% D), 6.49 (s, 0.21H, 79% D), 5.47 – 5.36 (m, 4H, dibromomethane internal standard). 13C NMR (100 MHz, DMSO-d6): δ 138.3, 135.6, 128.5, 127.3, 126.9, 120.9, 120.3, 118.8, 110.0, 100.7, 49.1, 23.0 (dibromomethane). Example 12: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.87 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.11 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard), 2.38 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 136.0, 135.4, 128.6, 119.8, 118.9, 118.5, 110.4, 100.0, 23.0 (dibromomethane), 13.4. NMR data of deuterated products in Example 12: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.81 (s, 1H), 8.01 (s, 0.15H, 85% D), 7.36 (s, 0.05H, 95% D), 7.13 (s, 0.18H, 82% D), 5.40 (s, 2H, dibromomethane internal standard), 2.67 (s, 0.68H, 77% D). 13 C NMR (100 MHz, DMSO-d6): δ 193.1, 144.1, 134.6, 126.9, 121.5, 120.4, 113.5, 111.0, 23.0 (dibromomethane), 15.0. Example 13: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.72 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.98 (t, J = 7.4 Hz, 1H), 5.40 (s, 2H, dibromomethane internal standard), 2.26 (s, 3H). 13C NMR (100MHz, DMSO-d6): δ136.2, 127.9, 122.6, 120.8, 118.0, 111.2, 109.2, 23.0 (dibromomethane), 9.6. NMR data of deuterated products in Example 13: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.47 (s, 0.04H, 96% D), 7.32 (s, 0.03H, 97% D), 7.09 (s, 0.10H, 90% D), 7.06 (s, 0.03H, 97% D), 6.97 (s, 0.03H, 97% D), 5.40 (s, 2H, dibromomethane internal standard), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 136.1, 127.8, 122.6, 122.4, 120.6, 117.8, 111.1, 109.0, 23.0 (dibromomethane), 9. Example 14: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.04 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 6.9 Hz, 1H), 6.45 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard), 2.47 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 135.5, 128.7, 127.6, 124.4, 120.9, 118.8, 109.0, 99.6, 23.0 (dibromomethane), 18.7. NMR data of deuterated products in Example 14: 1¹H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.30 (s, 0.04H, 96% D), 7.21 (s, 0.04H, 96% D), 6.97 (s, 0.27H, 73% D), 6.78 (s, 0.1H, 90% D), 6.43 (s, 0.85H, 15%), 5.40 (s, 2H, dibromomethane internal standard), 2.47 (s, 1.75H, 42%). 13 C NMR (100 MHz, DMSO-d6): δ 135.4, 128.7, 127.6, 124.3, 120.7, 118.8, 109.0, 99.4, 23.1 (dibromomethane), 18.6. Example 15: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.92 (s, 1H), 7.32 – 7.25 (m, 3H), 6.90 (d, J = 8.2 Hz, 1H), 6.32 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard), 2.37 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 134.2, 127.9, 127.1, 125.1, 122.5, 119.6, 111.0, 100.4, 23.0 (dibromomethane), 21.2. NMR data of deuterated products in Example 15: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.91 (s, 1H), 7.30 (s, 0.14H, 86% D), 7.27 (s, 0.05H, 95% D), 7.25 (s, 0.1H, 90% D), 6.89 (d, J = 8.1 Hz, 0.16H, 84% D), 6.30 (s, 0.21H, 79% D), 5.40 (s, 2H, dibromomethane internal standard), 2.36 (s, 0.39H, 87% D). 13 C NMR (100 MHz, DMSO-d6): δ 134.1, 127.8, 126.9, 124.9, 122.4, 119.6, 110.9, 100.2, 23.0 (dibromomethane), 21.1. Example 16: NMR data of indole compounds:1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.90 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.36 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard), 2.39 (s, 3H). 13 C NMR (100MHz, DMSO-d6): δ 136.3, 129.8, 125.5, 124.4, 120.5, 119.7, 111.2, 100.8, 23.0 (dibromomethane), 21.4. NMR data of deuterated products in Example 16: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 7.41 (s, 0.1H, 90% D), 7.22 (s, 0.02H, 98% D), 7.18 (s, 0.06H, 94% D), 6.81 (s, 0.03H, 97% D), 6.34 (s, 0.55H, 45% D), 5.39 (s, 2H, dibromomethane internal standard), 2.39 (s, 2.63H, 12%). 13 C NMR (100 MHz, DMSO-d6): δ 136.2, 129.6, 125.4, 124.2, 120.1, 119.5, 111.2, 100.5, 23.0 (dibromomethane), 21.0. Example 17: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.03 (s, ¹H), 7.37 (d, J = 7.2 Hz, ¹H), 7.32 (s, ¹H), 6.89 (m, 2H), 6.43 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 135.4, 127.3, 124.8, 121.3, 120.4, 118.9, 117.6, 101.4, 23.0 (dibromomethane), 16.9. NMR data of deuterated products in Example 17: 1¹H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.37 (s, 0.04H, 96% D), 7.31 (s, 0.04H, 96% D), 6.90 (s, 0.04H, 96% D), 6.87 (s, 0.04H, 96% D), 6.42 (s, 0.30H, 70% D), 5.40 (s, 2H, dibromomethane internal standard), 2.48 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 135.4, 127.1, 124.8, 120.9, 120.3, 118.7, 117.5, 101.2, 23.0 (dibromomethane), 16.9. Example 18: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.45 (s, ¹H), 7.48 – 7.45 (m, ¹H), 7.39 (d, J = 6.9 Hz, ¹H), 7.06 (s, 2H), 6.48 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ136.7, 126.4, 124.2, 121.7, 118.4, 110.6, 99.2, 23.0 (dibromomethane). NMR data of deuterated products in Example 18: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 7.45 (s, 0.04H, 96% D), 7.39 (s, 0.03H, 97% D), 7.07 (s, 0.15H, 92% D), 6.47 (s, 0.26H, 74% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ136.6, 126.4, 126.1, 124.1, 121.5, 118.0, 110.5, 99.1, 23.0 (dibromomethane). Example 19: NMR data of indole compounds: 1¹H NMR (400 MHz, DMSO-d⁶): δ 11.28 (s, ¹H), 7.58 (s, ¹H), 7.41 (d, J = 7.3 Hz, 2H), 7.07 (d, J = 8.6 Hz, ¹H), 6.42 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 134.3, 128.8, 127.0, 123.4, 120.8, 119.1, 112.8, 100.8, 23.0 (dibromomethane). NMR data of deuterated products in Example 19: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H), 7.57 (s, 0.08H, 92% D), 7.40 (s, 0.11H, 94% D), 7.07 (s, 0.04H, 96% D), 6.41 (s, 0.83H, 17% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 134.2, 128.7, 126.9, 123.2, 120.7, 119.1, 112.7, 100.6, 23.0 (dibromomethane). Example 20: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.45 (s, ¹H), 7.52 (d, J = 7.9 Hz, ¹H), 7.41 (s, ¹H), 7.16 (d, J = 7.6 Hz, ¹H), 6.99 (t, J = 8.3 Hz, ¹H), 6.54 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 132.7, 129.6, 126.6, 120.4, 119.8, 119.1, 115.9, 102.3, 23.0 (dibromomethane). NMR data of deuterated products in Example 20: 1¹H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 7.52 (s, 0.10H, 90% D), 7.41 (s, 0.05H, 95% D), 7.16 (s, 0.03H, 97% D), 6.99 (s, 0.06H, 94% D), 6.53 (s, 0.23H, 77% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 132.7, 129.4, 126.4, 120.3, 119.6, 119.0, 115.8, 102.1, 23.0 (dibromomethane). Example 21: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.29 (s, ¹H), 7.72 (s, ¹H), 7.37 (d, J = 14.8 Hz, 2H), 7.18 (d, J = 8.6 Hz, ¹H), 6.42 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ134.5, 129.5, 126.9, 123.3, 122.2, 113.3, 111.4, 100.7, 23.0 (dibromomethane). NMR data of deuterated products in Example 21: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 7.72 (s, 0.11H, 89% D), 7.36 (s, 0.11H, 94% D), 7.18 (s, 0.03H, 97% D), 6.41 (s, 0.22H, 78% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 134.5, 129.4, 126.8, 123.2, 122.1, 113.2, 111.1, 100.5, 23.0 (dibromomethane). Example 22: NMR data of indole compounds: 1¹H NMR (400 MHz, DMSO-d⁶): δ 11.18 (s, ¹H), 7.40 (s, 2H), 7.29 (d, J = 9.9 Hz, ¹H), 6.92 (t, J = 9.1 Hz, 1H), 6.42 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ158.0, 155.7, 132.6, 127.9, 127.3, 112.3, 109.1, 104.6, 101.2, 23.0 (dibromomethane). NMR data of deuterated products in Example 22: 1 ¹H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.39 (s, 0.02H, 98% D), 7.36 (s, 0.03H, 97% D), 7.26 (s, 0.01H, 99% D), 6.89 (s, 0.01H, 99% D), 6.40 (s, 0.28H, 72% D), 5.39 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 158.0, 155.7, 132.4, 127.7, 112.2, 108.5, 104.3, 101.0, 23.0 (dibromomethane). Example 23: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.67 (s, ¹H), 8.07 (s, ¹H), 7.55 (s, 2H), 7.42 (d, J = 8.3 Hz, ¹H), 6.58 (s, ¹H), 5.39 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 137.6, 128.1, 127.4, 125.7, 123.7, 120.8, 112.7, 102.1, 100.9, 23.0 (dibromomethane). NMR data of deuterated products in Example 23: 1¹H NMR (400 MHz, DMSO-d6): δ 11.66 (s, 1H), 8.08 (s, 0.26H, 74% D), 7.56 (s, 0.08H, 96% D), 7.42 (s, 0.04H, 96% D), 6.58 (s, 0.55H, 45% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 137.5, 128.1, 127.4, 125.7, 123.5, 120.8, 112.6, 101.9, 100.7, 23.0 (dibromomethane). NMR data of indole compounds in Example 24: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.90 (s, ¹H), 7.29 (d, J = 8.3 Hz, 2H), 7.03 (s, ¹H), 6.73 (d, J = 10.2 Hz, 1H), 6.34 (s, ¹H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ153.2, 131.0, 128.0, 125.7, 112.0, 111.1, 101.6, 100.8, 55.2, 23.0 (dibromomethane). NMR data of deuterated products in Example 24: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.28 (s, 0.34H, 83% D), 7.04 (s, 0.03H, 97% D), 6.72 (s, 0.05H, 95% D), 6.34 (s, 0.84H, 16% D), 5.39 (s, 2H, dibromomethane internal standard), 3.74 (s, 3H). 13 C NMR (100MHz, DMSO-d6): δ153.2, 142.1, 131.0, 127.9, 125.5, 111.9, 100.6, 55.3, 23.0 (dibromomethane). Example 25: NMR data of indole compounds: 1¹H NMR (400 MHz, DMSO-d⁶): δ 11.82 (s, ¹H), 8.56 (s, ¹H), 7.98 (d, J = 8.8 Hz, ¹H), 7.61 (s, ¹H), 7.56 (d, J = 8.9 Hz, ¹H), 6.72 (s, ¹H), 5.39 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 140.6, 139.1, 129.3, 127.0, 117.2, 116.4, 111.8, 103.9, 23.0 (dibromomethane). NMR data of deuterated products in Example 25: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.81 (s, 1H), 8.56 (s, 0.69H, 31% D), 7.98 (s, 0.34H, 66% D), 7.56 (t, J = 4.4 Hz, 0.26H, 87% D), 6.72 (s, 0.09H, 91% D), 5.39 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 140.6, 139.0, 129.0, 126.9, 117.2, 116.2, 111.7, 103.7, 23.0 (dibromomethane). Example 26: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.48 (s, 1H), 8.28 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 5.40 (s, 2H, dibromomethane internal standard), 3.84 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 167.3, 138.5, 127.1, 122.8, 121.9, 120.4, 111.3, 102.6, 51.6, 23.0 (dibromomethane). NMR data of deuterated products in Example 26: 1¹H NMR (400 MHz, DMSO-d6): δ 11.47 (s, 1H), 8.27 (s, 0.63H, 37% D), 7.73 (s, 0.41H, 59% D), 7.47 (s, 0.07H, 96% D), 6.59 (s, 0.08H, 92% D), 5.40 (s, 2H, dibromomethane internal standard), 3.86 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 167.3, 138.4, 127.2, 125.6, 122.7, 121.8, 120.3, 111.3, 102.4, 51.6, 23.0 (dibromomethane). Example 27: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.95 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.23–7.17 (m, 2H), 5.40 (s, 2H, dibromomethane internal standard), 3.81 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 164.8, 136.4, 132.4, 125.7, 122.4, 121.3, 120.4, 112.4, 106.3, 50.6, 23.0 (dibromomethane). NMR data of deuterated products in Example 27: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 11.93 (s, 1H), 8.09 (dd, J = 3.1, 1.2 Hz, 0.04H, 96% D), 8.02 (s, 0.19H, 81% D), 7.49 (s, 0.03H, 97% D), 7.20 (s, 0.09H, 95% D), 5.40 (s, 2H, dibromomethane internal standard), 3.81 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 164.8, 136.3, 132.2, 125.6, 122.1, 121.0, 120.3, 112.2, 106.2, 50.6, 23.0. (dibromomethane). Example 28: NMR data of indole compounds:1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.96 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 2H), 3.61 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.1, 127.1, 124.1, 121.1, 118.4, 111.4, 107.0, 51.5, 30.6, 23.0 (dibromomethane). NMR data of deuterated products in Example 28: 1 ¹H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.48 (s, 0.03H, 97% D), 7.36 (s, 0.03H, 97% D), 7.25 (s, 0.07H, 93% D), 7.08 (s, 0.03H, 97% D), 6.99 (s, 0.03H, 97% D), 5.40 (s, 2H, dibromomethane internal standard), 3.75 (s, 2H), 3.60 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 136.0, 127.0, 124.1, 120.9, 118.3, 111.3, 106.8, 51.5, 30.6, 23.1. (dibromomethane). Example 29: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 12.17 (s, ¹H), 10.91 (s, ¹H), 7.52 (s, ¹H), 7.37 (d, J = 8.1 Hz, ¹H), 7.24 (s, ¹H), 7.09 (t, J = 7.5 Hz, ¹H), 7.00 (t, J = 7.4 Hz, ¹H), 5.40 (s, 2H, dibromomethane internal standard), 3.66 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 173.2, 136.1, 127.2, 124.0, 121.0, 118.4, 111.4, 107.7, 31.1, 23.1 (dibromomethane). NMR data of deuterated products in Example 29: 1 ¹H NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 10.90 (s, 1H), 7.50 (s, 0.06H, 94% D), 7.35 (s, 0.03H, 97% D), 7.23 (s, 0.06H, 94% D), 7.07 (s, 0.06H, 94% D), 6.98 (s, 0.03H, 97% D), 5.40 (s, 2H, dibromomethane internal standard), 3.64 (s, 1.45H, 27% D). 13 C NMR (100 MHz, DMSO-d6): δ 173.2, 136.0, 132.4, 127.2, 123.7, 120.8, 118.2, 111.0, 107.5, 31.0, 23.1 (dibromomethane). NMR data of indole compounds in Example 30: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 8.14 (d, J = 6.7 Hz, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.46 (s, 2H), 7.20 (s, 2H), 5.41 (s, 2H, dibromomethane internal standard), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 140.6, 125.6, 121.9, 120.2, 118.7, 109.0, 28.9, 23.0 (dibromomethane). NMR data of deuterated products in Example 30: 1 ¹H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 0.32H, 84% D), 7.57 (s, 0.07H, 96% D), 7.46 (s, 0.32H, 84% D), 7.20 (s, 0.06H, 97% D), 5.41 (s, 2H, dibromomethane internal standard), 3.86 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 140.5, 125.4, 121.8, 120.0, 118.4, 108.9, 28.9, 23.0 (dibromomethane). Example 31: NMR data of indole compounds: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 8.13 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.51 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 155.4, 127.5, 123.5, 123.0 (dibromomethane), 121.1, 111.6, 23.0 (dibromomethane). NMR data of deuterated products in Example 31: 1 ¹H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 0.36H, 82% D), 7.69 (s, 0.06H, 94% D), 7.51 (s, 0.41H, 79% D), 7.40 (s, 0.13H, 93% D), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ155.4, 127.3, 123.4, 122.8, 121.0, 111.5, 23.0 (dibromomethane). NMR data of indole compounds in Example 32: 1 ¹H NMR (400 MHz, DMSO-d6): δ 8.37–8.32 (m, 2H), 8.04–7.99 (m, 2H), 7.50 (p, J = 6.1 Hz, 4H), 5.40 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ 138.5, 135.0, 127.0, 124.7, 123.0, 122.0, 23.0 (dibromomethane). NMR data of deuterated products in Example 33: 1¹H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 0.85H, 57% D), 8.02 (s, 0.29H, 85% D), 7.51 (s, 0.83H, 79% D), 5.41 (s, 2H, dibromomethane internal standard). 13 C NMR (100 MHz, DMSO-d6): δ138.4, 134.9, 126.8, 124.4, 122.9, 121.9, 23.0 (dibromomethane). Application Examples 1-3: This application example is used to verify the practical application of the deuteration method of the present invention in the deuteration modification of real drug molecules, taking tropisetron, indomethacin, and melatonin as examples.

[0048] The specific reaction process is as follows: 1.0 mmol of drug, 0.05 mmol of palladium acetate, 1.0 mmol of hexafluoroisopropanol, 0.1 mmol of complex ligand (the complex ligand includes the first ligand L1 and the second ligand P1, with a molar ratio of 1:1 for the first ligand L1 and the second ligand P1), and 5 mL of deuterated solvent (the deuterated solvent includes deuterated acetic acid, heavy water, and acetonitrile; the volume ratio of deuterated acetic acid, heavy water, and acetonitrile is 1:2:2) are mixed and reacted at 120 °C for 24 h. After the reaction was completed, the product was purified by column chromatography to obtain the deuterated drug product. The deuteration rate and product purity were characterized by HPLC and NMR.

[0049] The specific structures of the drug molecules and deuterated products used in Examples 1-3 are shown in the table below: Table 6: Structural formulas of drug molecules and deuterated products in Application Examples 1-3, and deuteration rates at each point of the products. Application of NMR data for drug in Example 1: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 12.20 (s, 1H), 11.05 (s, 1H), 8.07 (s, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.22 – 7.16 (m, 2H), 5.41 (s, 2H, dibromomethane internal standard), 5.12 (s, 1H), 3.87 (s, 2H), 2.80 – 2.57 (m, 5H), 2.29 (t, J = 9.0 Hz, 4H), 2.08 (d, J = 15.7 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 163.3, 136.5, 132.4, 125.8, 122.4, 121.3, 120.0, 112.5, 106.1, 63.4, 61.3, 57.3, 38.2, 34.2, 31.1, 28.4, 25.7, 23.9, 23.1. (dibromomethane). NMR data of deuterated products in Application Example 1: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 12.12 (s, 1H), 10.14 (s, 1H), 8.09 (s, 0.03H, 97% D), 8.03 (s, 0.23H, 77% D), 7.52 (s, 0.03H, 97% D), 7.21 (s, 0.11H, 94% D), 5.40 (s, 2H, dibromomethane internal standard), 5.15 (s, .082H, 18% D), 3.90 (s, 1.63H, 18% D), 2.72 (s, 2H), 2.44 (s, 1H), 2.32 (t, J = 10.3 Hz, 3H), 2.14 (d, J = 15.8 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 163.4, 158.5, 136.4, 132.3, 125.7, 122.3, 119.9, 112.2, 106.0, 63.2, 61.4, 57.7, 34.5, 31.2, 28.3, 25.8, 23.8, 23.0 (dibromomethane). Application of NMR data for drug in Example 2: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 12.38 (s, 1H), 7.67 (d, J = 7.0 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.04 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 3H), 3.67 (s, 2H), 2.22 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 172.1, 167.9, 155.6, 137.7, 135.2, 134.2, 131.2, 130.8, 130.2, 129.1, 114.6, 113.5, 111.3, 101.7, 55.4, 29.6, 23.0 (dibromomethane), 13.2. Application Example 2: NMR data of deuterated products: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 12.40 (s, 1H), 7.66 (q, J = 8.4 Hz, 4H), 7.04 (s, 0.14H, 86% D), 6.92 (s, 0.3H, 70% D), 6.71 (d, J = 5.4 Hz, 0.04H, 96% D), 5.43 – 5.37 (m, 2H, dibromomethane internal standard), 3.76 (s, 3H), 3.66 (s, 2H), 2.22 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 172.1, 167.9, 155.5, 137.6, 135.2, 134.2, 131.2, 130.7, 130.2, 129.1, 114.5, 113.4, 101.7, 55.4, 29.6, 23.0 (dibromomethane), 13.2. Application of NMR data for drug in Example 3: 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 10.64 (s, 1H), 7.95 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.10 (s, 1H), 7.02 (s, 1H), 6.72 (d, J = 8.7 Hz, 1H), 5.41 (s, 2H, dibromomethane internal standard), 3.76 (s, 3H), 3.31 (q, J = 6.5 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 1.82 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 169.0, 153.0, 131.4, 127.6, 123.3, 112.0, 111.7, 111.0, 100.1, 55.3, 25.3, 23.0 (dibromomethane), 22.7. Application Example 3: NMR data of deuterated products:1 ¹H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.03 – 7.98 (m, 1H), 7.95 (s, 0.6H, 40% D), 7.22 (s, 0.03H, 97% D), 7.10 (s, 0.03H, 97% D), 7.02 (s, 0.03H, 97% D), 5.40 (s, 2H, dibromomethane internal standard), 3.76 (s, 3H), 3.39 (s, 1H), 2.78 (s, 2H), 1.81 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 169.0, 153.6, 152.9, 132.4, 131.3, 127.5, 123.2, 119.2, 111.5, 100.1, 55.3, 25.3, 23.0 (dibromomethane), 22.7. This invention develops a highly efficient and regioselective deuteration method for indole compounds, successfully solving the challenging problem of deuteration at indole C4-C7 sites. This method has outstanding advantages such as mild reaction conditions, simple operation steps, high selectivity, environmental friendliness, and broad functional group compatibility, demonstrating extremely high scientific value and industrial application prospects. It can be applied to the deuteration synthesis of drugs such as the anti-inflammatory drug indomethacin, the cancer adjuvant therapy drug tropisetron, and the neuromodulator melatonin, providing key technical support for the development of deuterated drugs.

[0050] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for the deuteration of indole compounds, characterized in that, Includes the following steps: Indole compounds, transition metal catalysts, complex ligands, additives, and deuterated solvents are mixed and reacted to obtain deuterated products. The complex ligand includes a first ligand and a second ligand; the first ligand includes a lactam compound; the second ligand includes a pyridone compound. The deuterated solvent includes deuterated acetic acid.

2. The deuteration method for indole compounds as described in claim 1, characterized in that, The chemical structural formula of the indole compound is shown below: ； Wherein, R1 is selected from any one of hydrogen, methyl or benzyl; R2 is selected from any one of hydrogen, methyl, acetate, methyl formate or methyl acetate; and R3 is selected from any one of hydrogen, methyl, fluorine, chlorine, bromine, methoxy, cyano, nitro or methyl formate.

3. The deuteration method for indole compounds as described in claim 2, characterized in that, The indole compounds include at least one of the compounds shown in the following formulas: 。 4. The deuteration method for indole compounds as described in claim 1, characterized in that, The lactam compounds include at least one of the compounds shown in the following formula: 。 5. The deuteration method for indole compounds as described in claim 1, characterized in that, The pyridone compounds include at least one of the compounds shown in the following formula: 。 6. The deuteration method for indole compounds as described in claim 1, characterized in that, The transition metal catalyst includes at least one of bis(triphenylphosphine)palladium dichloride, palladium acetate, tris(dibenzylacetone)palladium, and tetra(triphenylphosphine)palladium; and / or, the additive includes hexafluoroisopropanol; and / or, the deuterated solvent further includes at least one of heavy water, deuterated methanol, dichloromethane, acetonitrile, and dimethyl sulfoxide.

7. The deuteration method for indole compounds as described in claim 1, characterized in that, The molar ratio of the indole compound, the transition metal catalyst, and the additive is 1:(0.02-0.1):(0.8-1.5); and / or, the molar amount of the composite ligand is 3%-15% of the molar amount of the indole compound; and / or, the molar ratio of the first ligand to the second ligand is 1:(0.5-2).

8. The deuteration method for indole compounds as described in claim 1, characterized in that, The reaction temperature is 110℃-130℃, and the time is 12h-48h.

9. A deuterated indole compound, characterized in that, It is prepared by the method described in any one of claims 1-8.

10. The use of the deuterated indole compound of claim 9 in the preparation of pharmaceutical intermediates.

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