Nitrification method of indole derivative

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a nitration method of an indole derivative. According to the invention, acetonitrile is taken as a solvent, indole or substituted indole is taken as a substrate, copper nitrate trihydrate is taken as a nitration reagent, paratoluensulfonyl chloride is taken as an accelerant, and a series of 3-nitroindole derivatives are obtained under mild conditions in a simple and high-yield manner. The synthesis method disclosed by the invention has the characteristics of easily available raw materials, wide substrate application range, short reaction time, simplicity in operation, easiness in amplification and the like.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for nitrating indole derivatives. Background Technology

[0002] Compounds with an indole core are important skeletons for a large number of natural products and drugs. Drugs with an indole core are mainly used for antirheumatism, anti-inflammation, and antidepressant purposes, and indole drugs, in particular, have broad biological activity in the field of antitumor therapy. 3-Nitroindole, as a versatile reaction substrate, has the characteristic of high functional group plasticity, which can be further derivatized and modified into drug molecules, thereby optimizing pharmacological activity and pharmacokinetic properties. After introducing a nitro group into the indole ring, it can be reduced to intermediate groups such as nitroso, hydroxylamine, and amino groups; in addition to reduction reactions, the electron-withdrawing effect of the nitro group can activate the hydrogen atom adjacent to the nitro group, followed by nucleophilic substitution, ultimately achieving substitution or functionalization of the indole ring nitro group, thus modifying the structure of the drug molecule.

[0003] Despite the high reactivity of indole itself, introducing a nitro group into the indole ring remains challenging. Since the indole ring is an electron-rich aromatic ring, the nitro group typically enters the C3 position via electrophilic substitution. The literature reports six main methods for the C3 nitration of indole: (1) The C3 nitration of indole is achieved by reacting indole substrate with tetramethylammonium nitrate in 6 steps; (2) C3 nitration of indole was achieved by phosphine catalysis with benzoyl chloride / iodine and silver nitrate system, with a yield of 61%; (3) Indole C3 nitration was achieved in two steps using a trichloroisocyanuric acid and sodium nitrite system under the action of oxidants such as potassium persulfate, with a yield of 72%. (4) C3 nitration is achieved through a two-step reaction using copper acetate as a catalyst and tert-butyl nitrate as a nitrating agent; (5) Indole C3 nitration was achieved using an N-bromosuccinimide and silver nitrate system, with a yield of 24%; (6) Nitration of indole and copper nitrate under microwave conditions and high temperature conditions in an acetic acid system.

[0004] The above methods require the use of hazardous or strong oxidizing reagents, or involve multi-step reactions, resulting in low reaction efficiency and yield; or they use precious metal nitrating reagents such as silver nitrate, which are costly; or they use harsh reaction conditions, such as strong acid conditions, microwaves, and high temperatures; which greatly limits the industrial application of these methods.

[0005] Given the significant application value of 3-nitroindole and the current lack of reliable preparation methods, the technical problem to be solved by this invention is to develop a mild, efficient, and industrially suitable indole nitration method. Summary of the Invention

[0006] The purpose of this invention is to provide a method for the C3-position nitration of indole that is mild, low-cost, simple to process, and uses readily available raw materials.

[0007] This invention provides a method for the C3-position nitration of indole derivatives, the reaction formula of which is as follows:

[0008]

[0009] In the presence of a reaction solvent, compound 1 and copper nitrate trihydrate were synthesized into 3-nitroindole derivative 2 by means of a promoter. Wherein, R is H, a C1-C6 straight-chain or branched alkyl group, or a C3-C6 cycloalkyl group; R 1 H, C1-C6 straight-chain or branched alkyl, C3-C6 cycloalkyl, nitro, cyano, alkoxy, halogen, carboxyl, ester, and trifluoromethyl groups are substituted at any position on the benzene ring; R 2 It can be H, C1~C6 alkyl, C3~C6 cycloalkyl, ester, nitro or cyano.

[0010] Preferably, R is H or a C1-C4 alkyl group; R 1 The groups are H, nitro, cyano, methoxy, fluorine, chlorine, bromine, iodine, carboxyl, ester, and trifluoromethyl; R 2 It consists of H, methyl, ester, and cyano groups.

[0011] The reaction solvent is selected from one or more solvents selected from toluene, chlorobenzene, N,N'-dimethylformamide, tetrahydrofuran, 1,4'-dioxane, water, ethylene glycol dimethyl ether, acetonitrile, and acetic acid; preferably acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, 1,4'-dioxane, and N,N-dimethylformamide; more preferably acetonitrile.

[0012] The molar ratio of compound 1, copper nitrate trihydrate, and accelerator is 1:0.5~2.0:1.0~2.0; preferably 1:0.5~1.0:1.0~2.0; more preferably 1:0.5~0.75:1.0~1.5.

[0013] The reaction temperature is 50℃~130℃; the preferred reaction temperature is 50℃~100℃.

[0014] The accelerator used is one of benzoyl chloride, p-toluenesulfonyl chloride and N-fluorobisbenzenesulfonylimide, preferably p-toluenesulfonyl chloride.

[0015] The reaction time is 0.5-24 hours; the preferred reaction time is 1-5 hours.

[0016] This invention utilizes acetonitrile as a solvent, indole or substituted indole as a substrate, copper nitrate trihydrate as a nitrating agent, and p-toluenesulfonyl chloride as a promoter to obtain a series of 3-nitroindole derivatives simply and in relatively high yields under mild conditions. Compared with the prior art, the advantages of this invention are as follows:

[0017] (1) The yield of nitration products is moderate to high. After a 10-fold scale-up, the yield does not decrease, and the highest yield reaches 86%.

[0018] (2) Raw materials are relatively economical, with the amount of nitrifying agent used being 0.55 equiv and the amount of accelerator used being 1.1 equiv.

[0019] (3) The reaction time is short, ranging from 1 to 5 hours;

[0020] (4) The reaction temperature is moderate and the equipment requirements are low.

[0021] The nitration method was scaled up to gram levels without yield reduction, indicating that the process is suitable for industrial application. Furthermore, the structures of most compounds were confirmed by 1H NMR and mass spectrometry. This method is characterized by readily available starting materials, a wide substrate range, short reaction time, simple operation, and ease of scale-up. Detailed Implementation

[0022] The present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0023] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0024] Unless otherwise specified, all reagents and materials mentioned in the examples are commercially available products.

[0025] Example 1

[0026] 3-Nitro-1H-Indole

[0027]

[0028] Indole (117 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 133 mg of a yellow powder solid, with a yield of 82%.

[0029] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.66 (s, 1H), 8.66 (d, J = 3.3 Hz,1H), 8.13 – 8.06 (m, 1H), 7.61 – 7.55 (m, 1H), 7.40 – 7.33 (m, 2H). MS (ESI):[MH] - calcd. for C8H5N2O2,161.1; found, 161.5.

[0030] Example 2

[0031] 3-Nitro-1-methyl-1H-indole

[0032]

[0033] 1-Methylindole (131 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 130 mg of a yellow powder solid, with a yield of 74%.

[0034] 1 H NMR (400 MHz, DMSO) δ (ppm): 8.73 (s, 1H), 8.14 – 8.08 (m, 1H), 7.72 – 7.67 (m, 1H), 7.45 – 7.40 (m, 2H), 3.93 (s, 3H). MS (ESI): [M+H] + calcd. for C9H9N2O2,177.0; found, 176.9.

[0035] Example 3

[0036] 3,4-Dinitro-1H-indole

[0037]

[0038] 4-Nitroindole (162 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 166 mg of a yellow powder solid, with a yield of 80%.

[0039] 1 H NMR (400 MHz, DMSO) δ (ppm): 13.28 (s, 1H), 8.88 (s, 1H), 7.96 –7.91 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H)..MS (ESI):[MH] - calcd. for C8H4N3O4, 206.0; found, 205.9.

[0040] Example 4

[0041] 3,5-Dinitro-1H-indole

[0042]

[0043] 5-Nitroindole (162 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 167 mg of a yellow powder solid, with a yield of 81%.

[0044] 1 H NMR (400 MHz, DMSO) δ (ppm): 13.18 (s, 1H), 8.86 (d, J = 20.7 Hz,2H), 8.17 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H). MS (ESI): [MH] -calcd. for C8H4N3O4,206.0; found, 205.9.

[0045] Example 5

[0046] 3,6-Dinitro-1H-indole

[0047]

[0048] 6-Nitroindole (162 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 135 mg of a yellow powder solid, with a yield of 65%.

[0049] 1 H NMR (400 MHz, DMSO) δ (ppm): 13.22 (s, 1H), 8.98 (s, 1H), 8.45 (d,J = 2.0 Hz, 1H), 8.30 – 8.21 (m, 2H). MS (ESI): [MH] - calcd. for C8H4N3O4,206.0; found, 205.9.

[0050] Example 6

[0051] 3-Nitro-4-methoxy-1H-indole

[0052]

[0053] 10 mL of 4-methoxyindole (147 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 66 mg of a yellow powder solid, with a yield of 34%.

[0054] 1H NMR (400 MHz, DMSO) δ (ppm): 12.46 (s, 1H), 8.47 (d, J = 3.3 Hz,1H), 7.24 (t, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.3, 0.8 Hz, 1H), 6.81 (d, J =7.8 Hz, 1H), 3.87 (s, 3H). MS (ESI): [MH] - calcd. for C9H7N2O3, 191.0; found,191.0.

[0055] Example 7

[0056] 3-Nitro-5-methoxy-1H-indole

[0057]

[0058] 10 mL of 5-methoxyindole (147 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 156 mg of a yellow powder solid, with a yield of 81%.

[0059] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.55 (s, 1H), 8.56 (d, J = 3.5 Hz,1H), 7.55 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.84(s, 3H). MS (ESI): [MH] - calcd. for C9H7N2O3, 191.0; found, 191.1.

[0060] Example 8

[0061] 3-Nitro-6-methoxy-1H-indole

[0062]

[0063] 6-Methoxyindole (147 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 167 mg of a yellow powder solid, with a yield of 87%.

[0064] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.42 (s, 1H), 8.52 (s, 1H), 7.95 (d,J = 8.7 Hz, 1H), 7.05 – 6.98 (m, 2H), 3.82 (s, 3H). MS (ESI): [MH] - calcd.for C9H7N2O3, 191.0; found, 190.9.

[0065] Example 9

[0066] 3-Nitro-2-methyl-1H-indole

[0067]

[0068] 2-Methylindole (131 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 153 mg of a brownish-yellow powdery solid, with a yield of 87%.

[0069] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.59 (s, 1H), 8.09 – 8.01 (m, 1H), 7.50 – 7.44 (m, 1H), 7.34 – 7.26 (m, 2H), 2.77 (s, 3H). MS (ESI): [MH] - calcd. for C9H7N2O2, 175.1; found, 174.9.

[0070] Example 10

[0071] 3-Nitro-5-methyl-1H-indole

[0072]

[0073] 5-Methylindole (131 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 144 mg of a yellow powder solid, with a yield of 82%.

[0074] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.55 (s, 1H), 8.58 (s, 1H), 7.90 (s,1H), 7.45 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H). MS(ESI): [MH] - calcd. for C9H7N2O2, 175.1; found, 175.1.

[0075] Example 11

[0076] 3-Nitro-7-methyl-1H-indole

[0077]

[0078] 7-Methylindole (131 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 139 mg of a yellow powder solid, with a yield of 79%.

[0079] 1H NMR (400 MHz, DMSO) δ (ppm): 12.69 (s, 1H), 8.65 (s, 1H), 7.92 (d,J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.14 (dt, J = 7.2, 1.1 Hz, 1H),2.52 (s, 3H). MS (ESI): [MH] - calcd. for C9H7N2O2, 175.1; found, 174.9.

[0080] Example 12

[0081] 3-Nitro-4-chloro-1H-indole

[0082]

[0083] 10 mL of 4-chloroindole (152 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1~3:1) to give 161 mg of a brownish-yellow powdery solid, with a yield of 82%.

[0084] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.86 (s, 1H), 8.70 (d, J = 3.5 Hz,1H), 7.54 (d, J = 7.9 Hz, 1H), 7.41 – 7.24 (m, 2H). MS (ESI): [MH] - calcd.for C8H4ClN2O2,195.0; found, 194.9.

[0085] Example 13

[0086] 3-Nitro-5-trifluoromethyl-1H-indole

[0087]

[0088] 5-Trifluoromethyl-1H-indole (185 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 173 mg of a yellow powder solid, with a yield of 75%.

[0089] 1 H NMR (400 MHz, DMSO) δ (ppm): 13.03 (s, 1H), 8.85 (s, 1H), 8.37 (d,J = 1.8 Hz, 1H), 7.79 (d,J = 8.6 Hz, 1H), 7.66 (dd,J = 8.6, 1.9 Hz, 1H). MS(ESI): [MH] - calcd. for C9H4F3N2O2, 229.0; found, 229.0.

[0090] Example 14

[0091] 3-Nitro-5-bromo-1H-indole

[0092]

[0093] 5-Bromoindole (196 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 180 mg of a yellow powder solid, with a yield of 75%.

[0094] 1 H NMR (400 MHz, DMSO) δ (ppm):12.93 – 12.72 (m, 1H), 8.70 (s, 1H),8.20 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.7, 2.0Hz, 1H). MS (ESI): [MH] -calcd. for C8H4BrN2O2, 238.9; found, 238.9, 241.0.

[0095] Example 15

[0096] 3-Nitro-5-iodo-1H-indole

[0097]

[0098] 5-Iodoindole (243 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 242 mg of a yellow powder solid, with a yield of 84%.

[0099] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.79 (s, 1H), 8.64 (d, J = 3.5 Hz,1H), 8.40 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.7 Hz, 1H), 7.42 (d, J =8.5 Hz, 1H). MS (ESI): [MH] - calcd. for C8H4IN2O2, 286.9; found, 286.8.

[0100] Example 16

[0101] 3-Nitro-1H-indole-5-carboxylic acid

[0102]

[0103] Indole-5-carboxylic acid (161 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 167 mg of a yellow powder solid, with a yield of 81%.

[0104] 1H NMR (400 MHz, DMSO) δ (ppm): 12.91 (s, 2H), 8.76 (d, J = 18.2 Hz,2H), 7.94 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H). MS (ESI): [MH] - calcd. for C9H5N2O4, 205.0; found, 204.9.

[0105] Example 17

[0106] 3-Nitro-5-cyano-1H-indole

[0107]

[0108] 5-Cyanoynindole (142 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 131 mg of a yellow powder solid, with a yield of 70%.

[0109] 1 H NMR (400 MHz, DMSO) δ (ppm):13.09 (s, 1H), 8.85 (s, 1H), 8.45 (s,1H), 7.77 – 7.69 (m, 2H). MS (ESI): [MH] - calcd. for C9H4N3O2,186.0; found,186.0.

[0110] Example 18

[0111] methyl 3-nitro-1H-indole-2-carboxylic acid

[0112]

[0113] In a 25 mL reaction flask, methyl indole-2-carboxylate (175 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 180 mg of a yellow powdery solid, with a yield of 82%.

[0114] 1 H NMR (400 MHz, DMSO) δ (ppm): 13.39 (s, 1H), 8.03 (d, J = 7.7 Hz,1H), 7.60 (d, J = 7.8 Hz, 1H), 7.42 (p, J = 7.1 Hz, 2H), 3.99 (s, 3H). MS(ESI): [MH] - calcd. for C 10 H7N2O4, 219.0; found, 219.0.

[0115] Example 19

[0116] 3-Nitro-2-cyano-1H-indole

[0117]

[0118] 2-Cyanoynindole (131 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 144 mg of a yellow powder solid, with a yield of 77%.

[0119] 1 H NMR (400 MHz, DMSO) δ (ppm): 14.20 (s, 1H), 8.16 (d, J = 7.8 Hz,1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 – 7.50 (m, 2H). MS (ESI): [MH] - calcd.for C9H4N3O2,186.0; found, 185.9.

[0120] Example 20

[0121] 5-Fluoro-2-methyl-3-nitro-1H-indole

[0122]

[0123] 5-Fluoro-2-methyl-indole (149 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), p-toluenesulfonyl chloride (210 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to give 163 mg of a yellow powder solid, with a yield of 84%.

[0124] 1 H NMR (400 MHz, DMSO) δ (ppm): 12.69 (s, 1H), 7.70 (dd, J = 9.7, 2.6Hz, 1H), 7.47 (dd, J = 8.8, 4.5 Hz, 1H), 7.13 (td, J = 9.2, 2.7 Hz, 1H), 2.75(s, 3H). MS (ESI): [MH] - calcd. for C9H6FN2O2,193.0; found, 192.9.

[0125] Example 21

[0126] The purpose of this example is to investigate the effect of organic solvents on the yield of the nitration reaction. The difference from Example 1 is the type of solvent used. See Table 1 below for details:

[0127] Table 1. Effect of different solvents on the yield of 3-nitro-1H-indole

[0128] solvent yield Tetrahydrofuran (reacts at 66℃) 50 N,N-Dimethylformamide 15 Dichloromethane (reaction at 40 °C) 0 1,4'-Dioxane 20 Acetonitrile 82 Ethylene glycol dimethyl ether 65 Ethyl acetate 20

[0129] Example 22

[0130] The difference between this example and Example 1 is that the molar ratio of indole, copper nitrate trihydrate, and p-toluenesulfonyl chloride is 1:1.0:1.0, specifically as follows: Indole (117 mg, 1.0 mmol), copper nitrate trihydrate (242 mg, 1.0 mmol), p-toluenesulfonyl chloride (191 mg, 1.0 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to obtain 123 mg of a yellow powdery solid, with a yield of 76%.

[0131] Example 23

[0132] The difference between this example and Example 1 is that the molar ratio of indole, copper nitrate trihydrate, and p-toluenesulfonyl chloride is 1:2.0:2.0, specifically as follows: Indole (117 mg, 1.0 mmol), copper nitrate trihydrate (484 mg, 2.0 mmol), p-toluenesulfonyl chloride (382 mg, 2.0 mmol), and acetonitrile (20 mL) were added to a 50 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to obtain 119 mg of a yellow powdery solid, with a yield of 73%.

[0133] Example 24

[0134] The difference between this example and Example 1 is that the promoter is N-fluorobisbenzenesulfonylimide. Specifically, indole (117 mg, 1.0 mmol), copper nitrate trihydrate (133 mg, 0.55 mmol), N-fluorobisbenzenesulfonylimide (347 mg, 1.1 mmol), and 10 mL of acetonitrile were added to a 25 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After the reaction was complete, the product was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1~3:1) to obtain 63 mg of a yellow powdery solid, with a yield of 39%.

[0135] Example 25

[0136] The difference between this embodiment and Example 1 is that the reaction time is 0.5 h, yielding 31 mg of yellow powdery solid, with a yield of 19%.

[0137] Example 26

[0138] The reaction system of Example 1 was scaled up 10 times to investigate its industrial feasibility, as follows: Indole (1.17 g, 10 mmol), copper nitrate trihydrate (1.33 g, 5.5 mmol), p-toluenesulfonyl chloride (2.1 g, 11 mmol), and acetonitrile (100 mL) were added to a 250 mL reaction flask, and the mixture was stirred at 75 °C for 3 h. After filtration, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was recrystallized from anhydrous methanol to give 1.37 g of a yellow solid, with a yield of 84.6%.

[0139] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for nitrating an indole derivative, characterized in that, In the presence of a reaction solvent and a accelerator, compound 1 reacts with copper nitrate trihydrate to give 3-nitroindole derivative 2, as shown in the following reaction formula: ， Wherein, R is H, C1~C6 straight-chain or branched alkyl, or C3~C6 cycloalkyl; R 1 H, C1-C6 straight-chain or branched alkyl, C3-C6 cycloalkyl, nitro, cyano, alkoxy, halogen, carboxyl, ester, or trifluoromethyl groups substituted at any position on the benzene ring; R 2 It can be H, C1~C6 alkyl, C3~C6 cycloalkyl, ester, nitro or cyano.

2. The nitration method for indole derivatives according to claim 1, characterized in that, R is H or a C1-C4 alkyl group; R 1 The groups are H, nitro, cyano, methoxy, fluorine, chlorine, bromine, iodine, carboxyl, ester, and trifluoromethyl; R 2 It consists of H, methyl, ester, and cyano groups.

3. The nitration method for indole derivatives according to claim 1, characterized in that, The accelerator is one of benzoyl chloride, p-toluenesulfonyl chloride, or N-fluorobisbenzenesulfonylimide.

4. The nitration method for indole derivatives according to claim 1, characterized in that, The reaction solvent is selected from one or more solvents selected from acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, 1,4'-dioxane, and N,N-dimethylformamide.

5. The nitration method for indole derivatives according to claim 1, characterized in that, The molar ratio of compound 1, copper nitrate trihydrate, and accelerator is 1:0.5~2.0:1.0~2.

0.

6. The nitration method for indole derivatives according to claim 1, characterized in that, The reaction temperature is 50℃~130℃.

7. The nitration method for indole derivatives according to claim 1, characterized in that, The method also includes separation and purification operations after the reaction is completed.

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