2,3-Hydrogen substituted aminoindole derivatives and preparation method and application thereof

Abstract

The present invention relates to a 2,3-hydrogen substituted aminoindole derivative and a preparation method and application thereof, and relates to the field of organic synthesis. The structural formula of the aminoindole derivative is shown in formula (I): wherein R 1 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 2 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 3 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 4 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 5 The 2,3-hydrogen substituted aminoindole derivative has biological activity and good modification and derivatization properties.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, in particular to 2,3-hydrogen substituted aminoindole derivatives and preparation methods and applications thereof. Background Art

[0002] 1-Aminoindole derivatives have a variety of biological activities and are widely used in biomedicine. For example, they are used as antidepressants, antispasmodics, analgesics, and potential therapeutic agents for Alzheimer's disease. Therefore, efficient and safe methods for synthesizing 1-aminoindole derivatives are of great research value. In recent decades, many researchers have developed various effective methods for synthesizing this structure.

[0003] Traditional methods for synthesizing 1-aminoindole derivatives mainly include palladium-catalyzed intramolecular cyclization of (2-chlorophenyl)acetaldehyde dimethylhydrazone and palladium-catalyzed intermolecular condensation of o-chlorophenylacetylene and NN disubstituted hydrazine. However, these methods have many problems, such as the need for amination, low conversion rate of starting materials, complex synthesis steps, and limited synthesis range.

[0004] In response to the above problems, in recent years, some researchers have synthesized 1-aminoindole derivatives through alkynes, diazo compounds, sulfur ylide compounds, etc., but these methods have the following problems: oxidants are required; the diazo compounds used in the raw materials are dangerous and explosive, and unsafe; the synthesized products are all 1-aminoindole derivatives with substituents on C2 and C3. Summary of the invention

[0005] In view of the above technical problems, the present invention provides a 2,3-hydrogen substituted aminoindole derivative, which has biological activity and good modifiability and derivatization performance.

[0006] The present invention provides a 2,3-hydrogen substituted aminoindole derivative, the structural formula of the aminoindole derivative is shown in formula (I):

[0007]

[0008] Among them, R 1 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 2 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 3 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 4 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 5 It is an alkyl group.

[0009] The 2,3-hydrogen substituted aminoindole derivatives have biological activity and good modification and derivatization properties.

[0010] In one embodiment, the aminoindole derivative is of formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-22), or formula (I-23);

[0011]

[0012] The present invention also provides a method for preparing a 2,3-hydrogen substituted aminoindole derivative, comprising the following steps: acylphenylhydrazine derivative and vinylene carbonate are subjected to a cyclization reaction by means of a rhodium catalyst to obtain a 2,3-hydrogen substituted aminoindole derivative.

[0013] The preparation method utilizes a rhodium (III) catalyst to catalyze an acylphenylhydrazine derivative to activate the CH bond of its benzene ring, and undergoes a cyclization reaction with vinylene carbonate as a C2 source to efficiently synthesize a 2,3-hydrogen-substituted aminoindole derivative. The preparation method is green and effective, and vinylene carbonate is a safe and readily available commercial raw material on the market.

[0014] At the same time, an acylphenylhydrazine derivative is used as one of the raw materials, and its amide group has a good guiding effect on promoting the activation of carbon-hydrogen bonds, so that the above-mentioned synthesis reaction does not need to additionally add aldehydes or ketone compounds as one of the raw materials in the existing synthesis method.

[0015] In one embodiment, the preparation method comprises the following steps: mixing an acylphenylhydrazine derivative, vinylene carbonate, a rhodium catalyst, a Lewis acid and an organic solvent, and performing a cyclization reaction in nitrogen to obtain a 2,3-hydrogen-substituted aminoindole derivative.

[0016] The preparation method uses safe and readily available commercial vinylene carbonate to replace unsafe acetylene in conventional technical means as a C2 source, making the reaction process safer and more reliable as a whole, and making the preparation method free of oxidants and mild reaction conditions.

[0017] In one embodiment, the structural formula of the 2,3-hydrogen substituted aminoindole derivative is shown in formula (I):

[0018]

[0019] The structural formula of the acylphenylhydrazine derivative is shown in formula (II):

[0020]

[0021] The structural formula of the vinylene carbonate is shown in formula (III):

[0022]

[0023] Among them, R 1 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 2 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 3 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 4 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 5 It is an alkyl group.

[0024] In one embodiment, the rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0025] The use of the catalyst makes the synthesis steps of the preparation method simple, the atom economy is good, and the requirements of green chemistry are met.

[0026] In one embodiment, the Lewis acid comprises at least one of the following raw materials: zinc acetate, sodium acetate; the organic solvent comprises at least one of the following raw materials: tert-butyl alcohol, toluene, N,N-dimethylformamide, tert-amyl alcohol, dioxane, 1,2-dichloroethane, methanol, acetonitrile, or ethylene glycol dimethyl ether.

[0027] The use of the above-mentioned Lewis acid can promote cyclization in the synthesis reaction.

[0028] In one embodiment, the molar ratio of the acylphenylhydrazine derivative, the vinylene carbonate, the rhodium catalyst, and the Lewis acid is 1:1.5-2.5:0.03-0.07:0.15-0.25; and the amount of the organic solvent is 8-12 L / 1 ​​mol of the acylphenylhydrazine derivative.

[0029] In one embodiment, the temperature of the cyclization reaction is 60-100° C., and the time of the cyclization reaction is 12-20 h.

[0030] The reaction conditions of the above cyclization reaction are mild.

[0031] The present invention also provides the use of the 2,3-hydrogen substituted aminoindole derivative in the preparation of medicines.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention discloses a 2,3-hydrogen substituted aminoindole derivative and a preparation method and application thereof. The 2,3-hydrogen substituted aminoindole derivative has biological activity and good modifiability and derivatization performance. The preparation method adopts safe and readily available commercial vinylene carbonate to replace unsafe acetylene in conventional technical means as a C2 source, so that the reaction process is safer and more reliable as a whole. The preparation method does not require an oxidant, has mild reaction conditions, and has simple synthesis steps, so that various types of 1-aminoindole derivatives can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a schematic diagram of the reaction process of Example 1;

[0035] Figure 2 is a schematic diagram of the structural formula of the target product in Example 1;

[0036] Figure 3 Schematic diagram of the substrate expansion process in Example 1;

[0037] Figure 4 It is a schematic diagram of the reaction process in Example 2;

[0038] Figure 5 is a schematic diagram of the structural formula of the target product in Example 2;

[0039] Figure 6 is a schematic diagram of the structural formula of the target product in Example 3;

[0040] Figure 7 is a schematic diagram of the structural formula of the target product in Example 4;

[0041] Figure 8 is a schematic diagram of the structural formula of the target product in Example 5;

[0042] Fig. 9 is a schematic diagram of the structural formula of the target product in Example 6;

[0043] Fig.10 is a schematic diagram of the structural formula of the target product in Example 7;

[0044] Fig.11 is a schematic diagram of the structural formula of the target product in Example 8;

[0045] Fig.12 is a schematic diagram of the structural formula of the target product in Example 9;

[0046] Fig.13 is a schematic diagram of the structural formula of the target product in Example 10;

[0047] Fig.14 Schematic diagram of the structural formula of the target product in Example 11. DETAILED DESCRIPTION

[0048] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0050] source:

[0051] Unless otherwise specified, the reagents, materials, and equipment used in this example are all commercially available; the experimental methods are all conventional experimental methods in the art unless otherwise specified.

[0052] Example 1

[0053] Preparation of 1-(acetylamino)-1H-indole.

[0054] 1. The preparation method is as follows:

[0055] In a pre-dried 25mL Schlenk tube equipped with a magnet, acetophenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (i.e. [Cp*RhCl2]2), 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL of dry tert-butanol (i.e. t-BuOH), and the reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16h. The reaction was removed from the heat source, and then dichloromethane was added and transferred to a round-bottom flask. The solvent was removed by a rotary evaporator, and ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 32.9mg of the target product with a yield of 94%.

[0056] The above reaction process is as follows Figure 1 As shown, the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, the additive is Lewis acid, in this embodiment, zinc acetate, the solvent is tert-butyl alcohol, and the target product 1-(acetylamino)-1H-indole has the structural formula as shown Figure 2 shown.

[0057] 2. The NMR characterization of 1-(acetylamino)-1H-indole is as follows:

[0058] 1 H NMR (400MHz, DMSO-d6): δ11.15(s,1H),7.60(dt,J=7.9,1.0Hz,1H),7.33–7.25(m,2H),7.20(ddd,J =8.1,6.9,1.2Hz,1H),7.11(ddd,J=8.0,6.9,1.2Hz,1H),6.50(dd,J=3.3,0.9Hz,1H),2.13(s,3H); 13 C NMR(101MHz,DMSO)δ169.19,135.58,129.16(d,J=6.9Hz),125.92,122.05–121.70(m),1 20.59, 119.98–119.60 (m), 108.97 (d, J = 2.9Hz), 99.95 (d, J = 8.5Hz), 20.55 (q, J = 4.8Hz).

[0059] 3. Expand the substrate and synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional groups from Example 1. The flow chart is as follows: Figure 3 shown.

[0060] Example 2

[0061] Preparation of 1-(acetylamino)-5-methylindole.

[0062] 1. The preparation method is as follows. The reaction process is as follows Figure 4 As shown:

[0063] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-4-methylphenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH. The reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16h. The reaction was removed from the heat source, and then dichloromethane was added. The mixture was transferred to a round-bottom flask and the solvent was removed by a rotary evaporator. Ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 26.8mg of the target product, with a yield of 71%. The structure of the target product 1-(acetylamino)-5-methylindole is as follows Figure 5 shown.

[0064] 2. The NMR characterization of 1-(acetylamino)-5-methylindole is as follows:

[0065] 1H NMR (400MHz, DMSO-d6): δ11.06(s,1H),7.35(s,1H),7.21(d,J=3.4Hz,1H),7.13(d,J= 8.3Hz,1H),7.00(dd,J=8.3,1.6Hz,1H),6.39–6.34(m,1H),2.39(s,3H),2.09(s,3H); 13 CNMR (101MHz, DMSO): δ169.09, 134.01, 129.12 (d, J = 8.5Hz), 128.38, 126.14, 123.51–123.25 (m), 120.1 5(d,J=5.3Hz), 108.66(dd,J=5.2,3.1Hz), 99.38(d,J=6.8Hz), 21.03(q,J=9.1Hz), 20.51(q,J=4.3Hz).

[0066] Example 3

[0067] Preparation of 1-(acetylamino)-5-chloroindole.

[0068] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0069] 1. The preparation method is as follows:

[0070] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-4-chlorophenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH. The reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16h. The reaction was removed from the heat source, and then dichloromethane was added. The mixture was transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator. Ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 32.2mg of the target product, with a yield of 77%. The structure of the target product 1-(acetylamino)-5-chloroindole is as follows Figure 6 shown.

[0071] 2. The NMR characterization of 1-(acetylamino)-5-chloroindole is as follows:

[0072] 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),7.63(d,J=2.0Hz,1H),7.37(d,J=3.4Hz,1H), 7.28(d,J=8.7Hz,1H),7.18(dd,J=8.7,2.0Hz,1H),6.49–6.45(m,1H),2.09(s,3H); 13 C NMR (101MHz, DMSO): δ169.15, 134.09, 130.87 (d, J = 6.0Hz), 126.99, 124.46, 122.08 –121.70(m),119.77,110.57(t,J=3.3Hz),99.70(d,J=8.8Hz),20.49(q,J=4.4Hz).

[0073] Example 4

[0074] Preparation of 1-(acetylamino)-5-bromoindole.

[0075] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0076] 1. The preparation method is as follows:

[0077] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-4-bromophenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH, and the reaction tube was placed in a preheated 80°C oil bath, reacted in a nitrogen atmosphere for 16h, removed from the heat source, and then added with dichloromethane, transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator, and ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 40.4mg of the target product, with a yield of 80%. The structural formula of the target product 1-(acetylamino)-5-bromoindole is as follows Figure 7 shown.

[0078] 2. The NMR characterization of 1-(acetylamino)-5-bromoindole is as follows:

[0079] 1 H NMR (400MHz, DMSO-d6): δ11.19(s,1H),7.78(d,J=1.9Hz,1H),7.35(d,J=3.4Hz,1H),7.32–7.21(m,2H),6.47(d,J=3.4Hz,1H),2.10(s,3H); 13C NMR (101MHz, DMSO): δ169.13, 134.34, 130.71 (d, J = 6.2Hz), 127.69, 124.41 (t, J = 3.1Hz), 122.81(d,J=1.8Hz), 112.34, 111.23–110.90(m), 99.62(d,J=8.7Hz), 20.50(q,J=4.5Hz).

[0080] Example 5

[0081] Preparation of 1-(acetylamino)-5-trifluoromethylindole.

[0082] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0083] 1. The preparation method is as follows:

[0084] In a pre-dried 25 mL Schlenk tube equipped with a magnetic device, N-acetyl-4-trifluoromethylphenylhydrazine (0.2 mmol), vinylene carbonate compound (0.4 mmol), 6.2 mg (0.01 mmol, 5%) [Cp*RhCl2]2, 7.3 mg (0.04 mmol, 20%) zinc acetate were added, followed by 2.0 mL of dry t-BuOH. The reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16 hours. The reaction was removed from the heat source, and then dichloromethane was added. The mixture was transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator. Ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 42.6 mg of the target product, with a yield of 88%. The structure of the target product 1-(acetylamino)-5-trifluoromethylindole is as follows Figure 8 shown.

[0085] 2. The NMR characterization of 1-(acetylamino)-5-trifluoromethylindole is as follows:

[0086] 1 H NMR (400MHz, DMSO-d6): δ11.30(s,1H),7.99(s,1H),7.50–7.43(m,3H),6.65(d,J=3.4Hz,1H),2.12(s,3H); 13C NMR (101MHz, DMSO): δ169.68, 137.54, 131.99 (d, J = 4.1Hz), 127.22, 125.81, 124.52, 121.39 (q,J=31.1Hz),118.84(d,J=4.3Hz),110.34,101.59(d,J=10.7Hz),20.98(q,J=4.9Hz); 19F NMR (376MHz, DMSO) delta -58.64.

[0087] Example 6

[0088] Preparation of 1-(acetylamino)-5-cyanoindole.

[0089] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0090] 1. The preparation method is as follows:

[0091] In a pre-dried 25 mL Schlenk tube equipped with a magnetic device, add N-acetyl-4-cyanophenylhydrazine (0.2 mmol), vinylene carbonate compound (0.4 mmol), 6.2 mg (0.01 mmol, 5%) [Cp*RhCl2]2, 7.3 mg (0.04 mmol, 20%) zinc acetate, and then add 2.0 mL of dry t-BuOH. Place the reaction tube in a preheated 80°C oil bath and react for 16 hours in a nitrogen atmosphere. Remove the heat source from the reaction, then add dichloromethane, transfer to a round-bottom flask, remove the solvent with a rotary evaporator, and pass ethyl acetate / petroleum ether = 1:1 through a silica gel column to obtain 30.0 mg of the target product, with a yield of 75%. The structural formula of the target product 1-(acetylamino)-5-cyanoindole is as follows Fig. 9 shown.

[0092] 2. The NMR characterization of 1-(acetylamino)-5-cyanoindole is as follows:

[0093] 1 H NMR (400MHz, DMSO-d6): δ11.33(s,1H),8.13(d,J=1.6Hz,1H),7.57–7.49(m,2H),7.45(d,J=8.5Hz,1H),6.66–6.62(m,1H),2.12(s,3H); 13C NMR (101MHz, DMSO) δ169.23, 137.25, 131.92 (d, J = 3.5Hz), 126.28 (d, J = 5.9Hz), 125.71, 124.85, 120.33, 110.41 (t, J = 2.0Hz), 102.23, 101.04 (d, J = 10.9Hz), 20.52 (d, J = 5.2Hz).

[0094] Example 7

[0095] Preparation of 1-(acetylamino)-5-methoxyindole.

[0096] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0097] 1. The preparation method is as follows:

[0098] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-4-methoxyphenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH, and the reaction tube was placed in a preheated 80°C oil bath, reacted in a nitrogen atmosphere for 16h, removed from the heat source, and then added with dichloromethane, transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator, and ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 26.8mg of the target product, with a yield of 66%. The structural formula of the target product 1-(acetylamino)-5-methoxyindole is as follows Fig.10 shown.

[0099] 2. The NMR characterization of 1-(acetylamino)-5-methoxyindole is as follows:

[0100] 1 H NMR (400MHz, DMSO-d6): δ11.05(s,1H),7.23(d,J=3.3Hz,1H),7.14(d,J=8.9Hz,1H),7.08( d,J=2.4Hz,1H),6.82(dd,J=8.8,2.4Hz,1H),6.39–6.36(m,1H),3.77(s,3H),2.08(s,3H); 13C NMR (101MHz, DMSO): δ169.13, 154.04, 130.75, 129.56 (d, J = 8.0Hz), 126.32, 111.88 (d, J = 8.4Hz), 10 9.85–109.52 (m), 102.48 (d, J = 8.8Hz), 99.56 (d, J = 6.8Hz), 55.42 (q, J = 12.0Hz), 20.50 (q, J = 4.1Hz).

[0101] Example 8

[0102] Preparation of 1-(acetylamino)-5-trifluoromethoxyindole.

[0103] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0104] 1. The preparation method is as follows:

[0105] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-4-trifluoromethoxyphenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH, and the reaction tube was placed in a preheated 80°C oil bath, reacted in a nitrogen atmosphere for 16h, removed from the heat source, and then added with dichloromethane, transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator, and ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 43.4mg of the target product, with a yield of 84%. The structural formula of the target product 1-(acetylamino)-5-trifluoromethoxyindole is as follows Fig.11 shown.

[0106] 2. The NMR characterization of 1-(acetylamino)-5-trifluoromethoxyindole is as follows:

[0107] 1 H NMR (400MHz, DMSO-d6): δ11.24(s,1H),7.60–7.57(m,1H),7.43(d,J=3.4Hz,1H ),7.36(d,J=8.8Hz,1H),7.18–7.13(m,1H),6.56(d,J=3.4Hz,1H),2.11(s,3H); 13C NMR (101MHz, DMSO): δ169.25, 142.47 (q, J = 1.9Hz), 134.06, 131.43 (d, J = 4.9Hz), 126.07, 121.74 ,115.58(d,J=6.8Hz),112.96,110.18(t,J=2.7Hz),100.43(d,J=9.7Hz),20.48(q,J=4.8Hz); 19F NMR (376MHz, DMSO) δ-57.08.

[0108] Example 9

[0109] Preparation of 1-(acetylamino)-6-bromoindole.

[0110] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0111] 1. The preparation method is as follows:

[0112] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-3-bromophenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH, and the reaction tube was placed in a preheated 80°C oil bath, reacted in a nitrogen atmosphere for 16h, removed from the heat source, and then added with dichloromethane, transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator, and ethyl acetate / petroleum ether = 1:2 was passed through a silica gel column to obtain 40.6mg of the target product, with a yield of 80%. The structural formula of the target product 1-(acetylamino)-6-bromoindole is as follows Fig.12 shown.

[0113] 2. The NMR characterization of 1-(acetylamino)-6-bromoindole is as follows:

[0114] 1 H NMR (400MHz, DMSO-d6): δ11.17(s,1H),7.56–7.47(m,2H),7.32(d,J=3.4Hz,1H),7.22(dd,J=8.4,1.8Hz,1H),6.51(dd,J=3.3,1.0Hz,1H),2.11(s,3H); 13C NMR(101MHz,DMSO)δ169.25,136.42,130.21(d,J=7.0Hz),124.95,122.91–122.63( m), 122.40, 114.91, 111.77 (d, J = 3.4Hz), 100.28 (d, J = 9.2Hz), 20.56 (q, J = 4.8Hz).

[0115] Example 10

[0116] Preparation of 1-(acetylamino)-6-methylindole.

[0117] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0118] 1. The preparation method is as follows:

[0119] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, N-acetyl-3-methylphenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL dry t-BuOH. The reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16h. The reaction was removed from the heat source, and then dichloromethane was added. The mixture was transferred to a round-bottom flask, and the solvent was removed by a rotary evaporator. Ethyl acetate / petroleum ether = 1:2.5 was passed through a silica gel column to obtain 28.4mg of the target product, with a yield of 75%. The structural formula of the target product 1-(acetylamino)-6-methylindole is as follows Fig.13 shown.

[0120] 2. The NMR characterization of 1-(acetylamino)-6-methylindole is as follows:

[0121] 1 H NMR (400MHz, DMSO-d6): δ11.05(s,1H),7.45(d,J=8.0Hz,1H),7.18(d,J=3.3Hz,1H),7. 05(s,1H),6.92(dd,J=8.0,1.5Hz,1H),6.40(d,J=3.4Hz,1H),2.42(s,3H),2.10(s,3H); 13C NMR (101MHz, DMSO): δ169.58, 136.43, 131.66, 128.95 (d, J = 9.1Hz), 124.28, 122.01 (d, J = 9.1Hz), 120 .76(d,J=3.3Hz), 109.21(d,J=9.2Hz), 100.23(d,J=7.6Hz), 21.84(q,J=9.5Hz), 21.02(q,J=4.5Hz).

[0122] Embodiment 11

[0123] Preparation of 1-(acetylamino)-7-methylindole.

[0124] The substrates were expanded to synthesize 2,3-hydrogen substituted aminoindole derivatives with different functional group substitutions from Example 1.

[0125] 1. The preparation method is as follows:

[0126] In a pre-dried 25mL Schlenk tube equipped with a magnetic device, add N-acetyl-2-methylphenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 6.2mg (0.01mmol, 5%) [Cp*RhCl2]2, 7.3mg (0.04mmol, 20%) zinc acetate, and then add 2.0mL dry t-BuOH. Place the reaction tube in a preheated 80°C oil bath and react for 16h in a nitrogen atmosphere. Remove the heat source from the reaction, then add dichloromethane, transfer to a round-bottom flask, remove the solvent with a rotary evaporator, and pass ethyl acetate / petroleum ether = 1:2 through a silica gel column to obtain 24.3mg of the target product, with a yield of 64%. The structural formula of the target product 1-(acetylamino)-6-methylindole is as follows Fig.14 shown.

[0127] 2. The NMR characterization of 1-(acetylamino)-7-methylindole is as follows:

[0128] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.37(d,J=7.9Hz,1H),7.15(d,J=3.4Hz,1H),6.93 (t,J=7.5Hz,1H),6.86(d,J=7.1Hz,1H),6.42(d,J=3.4Hz,1H),2.47(s,3H),2.04(s,3H); 13C NMR (101MHz, DMSO): δ169.49, 133.81, 130.10, 130.01, 126.59, 120.05, 119.85, 118.65 (d, J = 4.6Hz), 100.19, 100.12, 20.37 (d, J = 3.5Hz).

[0129] Comparative Example 1

[0130] Preparation of 1-(acetylamino)-1H-indole.

[0131] The preparation method is as follows:

[0132] In a pre-dried 25mL Schlenk tube equipped with a magnet, acetophenylhydrazine (0.2mmol), vinylene carbonate compound (0.4mmol), 8.0mg (0.01mmol, 5%) dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (i.e. [Cp*IrCl2]2), 7.3mg (0.04mmol, 20%) zinc acetate were added, followed by 2.0mL of dry tert-butanol (i.e. t-BuOH), and the reaction tube was placed in a preheated 80°C oil bath and reacted in a nitrogen atmosphere for 16h. The reaction was removed from the heat source and it was found by TLC that the reaction did not occur.

[0133] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0134] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing an aminoindole derivative as represented by formula (I), characterized in that: The method comprises the following steps: mixing an acylphenylhydrazine derivative, vinylene carbonate, a rhodium catalyst, a Lewis acid and an organic solvent, and carrying out a cyclization reaction in nitrogen to obtain an aminoindole derivative as shown in formula (I); Formula (I) The structural formula of the acylphenylhydrazine derivative is shown in formula (II): Formula (II) The structural formula of the vinylene carbonate is shown in formula (III): Formula (III) Among them, R 1 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 2 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 3 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 4 is selected from hydrogen, halogen, alkyl, methoxy, or cyano; R 5 is an alkyl group; The rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer; The Lewis acid is zinc acetate; The organic solvent is tert-butyl alcohol; The molar ratio of the acylphenylhydrazine derivative, the vinylene carbonate, the rhodium catalyst, and the Lewis acid is 1:1.5-2.5:0.03-0.07:0.15-0.25; The temperature of the cyclization reaction is 60-100°C.

2. The preparation method according to claim 1, characterized in that: The amount of the organic solvent used is 8-12 L / 1 ​​mol of the acylphenylhydrazine derivative.

3. The preparation method according to claim 1, characterized in that: The cyclization reaction time is 12-20 hours.

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