2-trifluoromethyl-3-aminoindole compounds and methods for their preparation

Abstract

The application discloses a 2-trifluoromethyl-3-amino indole compound and a preparation method thereof, and belongs to the technical field of organic synthesis. The preparation method of the 2-trifluoromethyl-3-amino indole compound comprises the following steps: under the action of visible light induction and a tertiary amine organic base, free radical cascade cyclization reaction of CF3Br and an aryl isonitrile derivative is carried out in an organic solvent to obtain the 2-trifluoromethyl-3-amino indole compound. The application firstly proposes a method for preparing the 2-trifluoromethyl-3-amino indole compound in one step, which uses the aryl isonitrile derivative as a raw material, uses CF3Br as a trifluoromethylating reagent, and under the action of visible light induction and the tertiary amine organic base, free radical cascade cyclization reaction of trifluorobromomethane and the aryl isonitrile derivative is carried out. The raw material is cheap and easy to obtain, no noble metal photosensitizer needs to be added, the operation is simple, the reaction condition is mild, the reaction is green and safe, the reaction yield is good and the like, and the method has good application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a 2-trifluoromethyl-3-aminoindole compound and its preparation method. Background Technology

[0002] 3-Aminoindole compounds are common structural units in organic intermediates and indole alkaloids, and some of them have been successfully used in the total synthesis of complex drug molecules such as (-)-Mersiclavine and 8-Desbromohinckdentine A (J. Am. Chem. Soc. 2010, 132, 1236–1237; J. Am. Chem. Soc. 2003, 125, 4240–4252). 3-Aminoindole compounds possess a wide range of biological activities. In the pharmaceutical field, some known 3-aminoindole compounds can act as specific kinase inhibitors and are used to treat hyperactive proliferative disorders, vascular-related infections, inflammation and neurodegeneration, depression, and anxiety disorders (Anti Cancer Agents Med. Chem. 2009, 9, 336–347; Bioorg. Med. Chem. 2011, 19, 2659–2665; Curr. Pharmaceut. Des. 2005, 11, 1679–1693; Bioorg. Med. Chem. 2006, 14, 153–163). For example, compounds with the following chemical structures A–E:

[0003]

[0004] Studies have shown that compound A exhibits good therapeutic activity against human breast cancer cell lines (T47D, BT549, and MDA-MB-231) and can be used to inhibit human breast cell proliferation (Eur. J. Med. Chem. 2019, 166, 281–290); compound B can secrete insulin in vitro and has good activity in the treatment of type II diabetes (Bioorg. Med. Chem. 2007, 15, 3248–3265); compound C is an antimitotic inhibitor that can strongly inhibit cancer cell growth and microtubule polymerization and cause mitotic arrest, and can be effectively applied in tumor treatment (J. Med. Chem. 2008, 51, 1464–1468); compound D is an m-PGES-1 inhibitor with anti-inflammatory and anti-tumor functions (Green Chem. 2021, 23, 9610–9616); and compound E is a quorum sensing inhibitor that is effective against Pseudomonas aeruginosa MH. 602 exhibited significant QSI activity, and this compound was not found to be toxic in the normal human embryonic kidney cell line (HEK 293) (Chemistry Select.; 2018, 3, 9170–9180). Given the good biological activity and wide range of applications of 3-aminoindole compounds, it is essential to explore synthetic methods for these compounds.

[0005] Currently, there are two methods for synthesizing 3-aminoindole compounds: (1) directly introducing an amino group into the C-3 position of the indole molecule to obtain 3-aminoindole compounds; (2) using an amino aromatic hydrocarbon derivative as a substrate, introducing an amino group into the C-3 position of the indole while constructing the pyrrole ring, thereby obtaining 3-aminoindole compounds.

[0006] (1) Introducing an amino group directly into the C-3 position of an indole molecule to obtain 3-aminoindole compounds.

[0007] This method primarily involves the reaction of indole derivatives with aniline or benzylamine compounds to generate 3-aminoindole compounds. Currently, only two papers have reported on this method. For example:

[0008] In 2021, Mo Dongliang et al. reported a method for obtaining 3-aminoindole compounds via the condensation coupling reaction of indole and benzylamine under the catalysis of iron salts (Green Chem. 2021, 23, 9610-9616). This method uses tert-butyl nitrite (TBN) as the nitrating agent, iron salt as the catalyst, and acetonitrile as the solvent. The reaction is carried out at 100℃ for 10–18 h, yielding a series of 3-aminoindole compounds in 52%–99% yields. The advantages of this method are readily available substrates, good functional group tolerance, and excellent yields; the disadvantage is the relatively high reaction temperature.

[0009] The reaction formula is as follows:

[0010]

[0011] In 2014, Wang Yangguang's research group reported a method for obtaining 3-aminoindole compounds from 2-imine-3-diazoindoline compounds and aniline derivatives under the catalysis of a rhodium complex (Org. Lett. 2014, 16, 5096-5099). The greatest advantages of this method are its excellent regioselectivity, short reaction time, wide substrate applicability, and high yield. The disadvantages are the demanding reaction conditions, such as the need for a nitrogen atmosphere and a reaction temperature of 110℃. The reaction formula is as follows:

[0012]

[0013] (2) Using amino aromatic hydrocarbon derivatives as substrates, an amino group is introduced into the C-3 position of indole while constructing the pyrrole ring, thereby obtaining 3-aminoindole compounds.

[0014] This method has become the main synthetic method for 3-aminoindole compounds in recent years. For example:

[0015] In 2021, Liu Yuanhong et al. reported a method for synthesizing 3-aminoindole compounds from N-alkynylbenzonitrile and aniline derivatives via β-regioselective amination / cyclization reactions catalyzed by nickel and Lewis acids (Org. Lett. 2021, 23, 1296-1301). This method is the first to propose using N-alkynylbenzonitrile and aniline derivatives as substrates, with 1,4-dioxane as solvent under the catalysis of nickel and Lewis acids, at 80 °C to obtain the target product. The advantage of this method is its high regioselectivity; the disadvantage is that the reaction conditions are relatively harsh. The reaction formula is as follows:

[0016]

[0017] In 2022, Li Zheng's research group synthesized 2-methylene-3-aminoindole and 2-methyl-3-aminoindole compounds in a one-pot reaction using calcium acetylide as a solid acetylene source and N-(2-formylaryl)sulfonamide and secondary amine as starting materials (Org. Lett. 2022, 24, 8067-8071). This method uses inexpensive, abundant, and easily processed calcium acetylide instead of flammable and explosive gaseous acetylene as the primary acetylene source, improving reaction safety. This method has advantages such as a broad substrate range, high yield, and simple post-processing. The reaction formula is as follows:

[0018]

[0019] In 2022, Xu Xianxiu's research group reported a novel method for synthesizing 3-aminoindole compounds from aryl isonitrile derivatives via chemiselective trimerization under catalyst-free conditions (Org. Lett. 2022, 24, 105-109). This method involves a head-to-head heterodimerization reaction between a 2-isocyanostyrene compound and one molecule of an aryl isonitrile derivative in 1,2-dichloroethane at 150°C. The dimer then undergoes a further polymerization reaction with another molecule of the aryl isonitrile derivative, ultimately yielding a series of 3-aminoindole compounds in yields ranging from 60% to 96%. The advantages of this method are high chemiselectivity, no need for a catalyst, readily available and inexpensive raw materials, simple operation, and short reaction time. The disadvantage is the relatively high reaction temperature. The reaction formula is as follows:

[0020]

[0021] In 2016, Studer's research group used trifluoro-iodine, pentafluoro-iodine, and heptafluoro-iodine reagents as fluorine sources. Under the action of lithium iodide, these polyfluoro-iodine reagents generated fluoroalkyl radicals, which then underwent a radical tandem cyclization reaction with aryl isonitriles to obtain 3-aminoindole compounds with the C-2 position of indole substituted by trifluoromethyl, pentafluoroethyl, or heptafluoroisopropyl groups (Chem. Commun. 2016, 52, 5997-6000). Eleven 2-trifluoromethyl-3-aminoindole compounds were synthesized in yields ranging from 14% to 60%; one 2-pentafluoroethyl-3-aminoindole compound was obtained in 53% yield; and one 2-heptafluoroisopropyl-3-aminoindole compound was obtained in 58% yield. From a fluorine chemistry perspective, the biggest problems with this method are the high cost of the polyfluoro-iodine reagents, the need for prior preparation, the cumbersome preparation steps, and the low atom utilization. The reaction formula is as follows:

[0022]

[0023] In summary, although some progress has been made in the research of existing synthetic methods for 3-aminoindole compounds, each method has its own shortcomings and limitations, and further improvements are still needed. Therefore, in order to further explore new synthetic methods for 3-aminoindole compounds and improve their biological activity, it is essential to explore a novel, efficient, and simple synthetic method to prepare 3-aminoindole compounds containing trifluoromethyl groups. Summary of the Invention

[0024] The purpose of this invention is to provide a 2-trifluoromethyl-3-aminoindole compound and its preparation method, so as to solve the above-mentioned problems in the background art.

[0025] To achieve the above objectives, the present invention provides the following technical solution:

[0026] One of the technical solutions of this invention is to provide a 2-trifluoromethyl-3-aminoindole compound with the following structural formula: Or it could be the following general structural formula:

[0027]

[0028] In the general structural formula, R is Et, OEt, OCOCH3, or Cl.

[0029] The second technical solution of the present invention provides a method for preparing the above-mentioned 2-trifluoromethyl-3-aminoindole compounds, comprising the following steps:

[0030] In the presence of visible light and tertiary amine organic bases, CF3Br and aryl isonitrile derivatives were subjected to a free radical tandem cyclization reaction in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound.

[0031] The structural formula of the aryl isonitrile derivative is as follows: Or it could be the following general structural formula:

[0032]

[0033] In the general structural formula, R is Et, OEt, OCOCH3, or Cl.

[0034] Furthermore, the tertiary amine organic base is N,N,N',N'-tetramethylethylenediamine (TMDETA).

[0035] Furthermore, the molar ratio of the aryl isonitrile derivative to the tertiary amine organic base is 1.0:(1.0-3.0).

[0036] Furthermore, the CF3Br is added in the form of CF3Br gas, the pressure of the CF3Br gas is 1.0 atm, and the amount added is in excess.

[0037] Furthermore, the visible light is blue light with a wavelength of 410–420 nm and a power of 20 W.

[0038] Furthermore, the organic solvent is acetonitrile (CH3CN).

[0039] Furthermore, the free radical tandem cyclization reaction takes 24–72 h.

[0040] Furthermore, the free radical tandem cyclization reaction is performed at room temperature.

[0041] Furthermore, after the free radical tandem cyclization reaction is completed, a purification step is also included; the purification method is column chromatography; the column chromatography uses silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents; the volume ratio of petroleum ether and ethyl acetate is (3-30):1.

[0042] The third technical solution of the present invention provides the application of the above-mentioned 2-trifluoromethyl-3-aminoindole compound in the preparation of a drug with therapeutic effects on diabetes.

[0043] The technical principle of this invention is as follows:

[0044]

[0045]

[0046] First, trifluorobromomethane reacts with N,N,N',N'-tetramethylethylenediamine to form an electron donor-acceptor complex (EDA complex). Under visible light irradiation, the EDA complex undergoes a single electron transfer (SET) to generate a trifluoromethyl radical, simultaneously producing a bromide anion and an N,N,N',N'-tetramethylethylenediamine radical cation. Next, the trifluoromethyl radical undergoes a radical addition reaction with the isocyanate group (carbon-nitrogen triple bond) in one molecule of aryl isonitrile 1, generating an imine radical intermediate A. Radical intermediate A then undergoes a radical addition reaction with the isocyanate group in another molecule of aryl isonitrile 1, generating another imine radical intermediate B. Imine radical intermediate B further undergoes molecular... An internal radical addition cyclization reaction generates a cyclic carbon radical intermediate C. Then, the cyclic carbon radical intermediate C extracts a hydrogen radical from the methylene group of the N,N,N',N'-tetramethylethylenediamine radical cation, i.e., carbon radical intermediate C undergoes hydrogen atom transfer (HAT) to generate compound D. Simultaneously, the N,N,N',N'-tetramethylethylenediamine radical cation is converted into an imine cation formed by N,N,N',N'-tetramethylethylenediamine. Finally, compound D, as a non-aromatic compound, has a high internal energy and exhibits instability, thus readily undergoing hydrogen migration to generate the target product, a 2-trifluoromethyl-3-aminoindole compound 3, which has a lower internal energy and higher stability.

[0047] The beneficial technical effects of the present invention are as follows:

[0048] (1) This invention discloses for the first time a method for preparing 2-trifluoromethyl-3-aminoindole compounds in one step by a free radical tandem cyclization reaction of CF3Br and aryl isonitrile derivatives under visible light induction and the action of tertiary amine organic bases.

[0049] (2) This invention is the first to use CF3Br to construct trifluoromethyl-substituted 3-aminoindole compounds. CF3Br is a non-toxic and odorless industrial raw material with advantages such as stable chemical properties, low price and easy availability, economic efficiency and high atom utilization, which provides greater possibilities for industrial-scale synthesis.

[0050] (3) This invention is the first to realize the generation of trifluoromethyl radicals through an electron donor-acceptor (EDA) complex formed by CF3Br and a tertiary amine organic base under visible light induction. For the radical tandem cyclization reaction involving CF3Br under visible light induction, trifluoromethyl radicals often require the presence of photocatalysts such as noble metals or organic dyes to be generated. The technical solution provided by this invention effectively avoids the use of photocatalysts such as noble metals or organic dyes, and greatly reduces the reaction cost.

[0051] (4) The synthesis method provided by the present invention has the characteristics of short reaction steps, high atom utilization, simple operation, mild reaction conditions, green and safe, and good yield.

[0052] (5) The 2-trifluoromethyl-3-aminoindole compounds synthesized in this invention, after being subjected to… 1 H NMR, 13 C NMR, 19 The product obtained by F NMR and high-resolution mass spectrometry detection is a pure target compound with high purity. Attached Figure Description

[0053] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0054] Figure 1 The 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) prepared in Example 1 1 H NMR spectrum;

[0055] Figure 2 The 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) prepared in Example 1 13 C NMR spectrum;

[0056] Figure 3 The 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) prepared in Example 1 19 F NMR spectrum;

[0057] Figure 4 Here is a high-resolution mass spectrometry (HMS) image of 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) prepared in Example 1;

[0058] Figure 5 The 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b) prepared in Example 2 1 H NMR spectrum;

[0059] Figure 6 The 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b) prepared in Example 2 13 C NMR spectrum;

[0060] Figure 7 The 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b) prepared in Example 2 19 F NMR spectrum;

[0061] Figure 8 Here is a high-resolution mass spectrometry (HMS) image of 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b) prepared in Example 2;

[0062] Figure 9 The 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) prepared in Example 3 1 H NMR spectrum;

[0063] Figure 10 The 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) prepared in Example 3 13 C NMR spectrum;

[0064] Figure 11 The 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) prepared in Example 3 19 F NMR spectrum;

[0065] Figure 12 Here is a high-resolution mass spectrometry image of 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) prepared in Example 3;

[0066] Figure 13 The 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 1 HNMR spectrum;

[0067] Figure 14 The 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 13 CNMR plot;

[0068] Figure 15 The 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 19 FNMR plot;

[0069] Figure 16 The high-resolution mass spectrometry monitoring image is of 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4.

[0070] Figure 17 The 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) prepared in Example 5 1 H NMR spectrum;

[0071] Figure 18 The 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) prepared in Example 5 13 C NMR spectrum;

[0072] Figure 19 The 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) prepared in Example 5 19 F NMR spectrum

[0073] Figure 20 High-resolution mass spectrometry (HMS) image of 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) prepared in Example 5. Detailed Implementation

[0074] Trifluoromethyl is a common fluorine-containing group. Introducing trifluoromethyl into organic compounds can significantly alter the acidity, dipole moment, polarity, lipophilicity, and chemical and metabolic stability of the parent compound. Literature review results show that research on introducing trifluoromethyl into 3-aminoindole molecules is rarely reported. For example, to date, only one paper has reported a synthetic method for 2-trifluoromethyl-3-aminoindole compounds (Chem. Commun. 2016, 52, 5997-6000). In this paper, the trifluoromethylating reagent used in the synthesis of 3-aminoindole compounds containing trifluoromethyl is the Togni reagent. Besides being expensive, cumbersome to prepare, and difficult to store, the Togni reagent also suffers from poor atom economy. This is because, in the reaction, while providing the trifluoromethyl group, it also generates waste organic compounds such as o-iodobenzoic acid. To further explore new synthetic methods for 3-aminoindole compounds and improve their biological activity, it is essential to explore a novel, efficient, and simple synthetic method to prepare 3-aminoindole compounds containing trifluoromethyl groups.

[0075] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0076] Furthermore, regarding the 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, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0077] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0078] The terms “comprising,” “including,” “having,” “containing,” etc., used in this invention are all open-ended terms, meaning that they include but are not limited to.

[0079] Unless otherwise specified, "room temperature" in this invention refers to 25±2℃.

[0080] The aryl isonitrile derivatives used in the following embodiments and comparative examples of this invention—4-ethoxyphenyl isonitrile, 4-ethylphenyl isonitrile, 4-acetoxyphenyl isonitrile, 4-chlorophenyl isonitrile, and 3,4-methylenedioxyphenyl isonitrile—were prepared according to the literature (Palladium-catalyzed synthesis of α-diimines from triarylbismuthines and isocyanides. Org. Lett. 2015, 17, 14, 3490-3493; Radical perfluoroalkylation-easy access to 2-perfluoroalkylindol-3-imines via electron catalysis. Chem. Commun. 2016, 52, 5997-6000.). Unless otherwise specified, all other reagents and pharmaceuticals are commercially available products.

[0081] Example 1

[0082] Synthesis of 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a)

[0083] The synthesis route is as follows:

[0084]

[0085] The specific preparation process is as follows:

[0086] 4-Ethoxyphenylisocyanate (29.4 mg, 0.2 mmol, 1.0 equiv.), TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was then evacuated and purged with CF3Br gas, and this process was repeated three times. Finally, the gas pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction system was then placed under 20 W (410–420 nm) blue light and stirred at room temperature for 72 h. After the reaction was completed, the organic phase was concentrated using a rotary evaporator. The remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 8:1, v / v) to obtain 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a), a yellow oily liquid, 21.2 mg, with a yield of 58%.

[0087] The 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) synthesized in Example 1 was subjected to... 1 HNMR,13 C NMR, 19 F NMR and high-resolution mass spectrometry detection results are shown in Figure 1-4 ,from Figure 1-4 It can be concluded that the product obtained in Example 1 is the pure target compound.

[0088] The specific characterization data of the product are as follows:

[0089] 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.28 (d, J = 8.8Hz, 1H), 6.98 (dd, J = 8.8, 2.4Hz, 1H), 6.78 -6.69(m,5H),5.28(s,1H),3.97(q,J=6.8Hz,2H),3.90(q,J=7.2Hz,2H),1.40-1.34(m,6H).

[0090] 13 C{ 1 H}NMR(150MHz,CDCl3)δ153.6,152.6,139.4,131.1,129.7,121.7(q,J C-F =267.0Hz),124.2,121.2,120.1,117.4(q,J C-F =35.7Hz),116.8,116.3,115.4,112.9,102.4,64.0,63.9,14.9,14.7.

[0091] 19 F NMR(376MHz, CDCl3)δ-58.92(s).

[0092] HRMS(ESI): m / z calcd for C 19 H 20 F3N2O2[M+H] + 365.1471, found 365.1463.

[0093] Example 2

[0094] Synthesis of 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b)

[0095] The synthesis route is as follows:

[0096]

[0097] The specific preparation process is as follows:

[0098] 4-Ethylphenylisocyanate (39.4 mg, 0.3 mmol, 1.0 equiv.), TMDETA (69.7 mg, 0.6 mmol, 2.0 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then purged with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction system was placed under 20 W (410–420 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the organic phase was concentrated using a rotary evaporator. The remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 30:1, v / v) to give 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b), a yellow oily liquid, 24.1 mg, with a yield of 48%.

[0099] The 2-trifluoromethyl-3-[N-(4-ethylphenyl)]amino-5-ethylindole (3b) synthesized in Example 2 was subjected to... 1 HNMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection results are shown in Figure 5-8 ,from Figure 5-8 It can be concluded that the product obtained in Example 2 is the pure target compound.

[0100] The specific characterization data of the product are as follows:

[0101] 1 H NMR (400MHz, CDCl3) δ8.05(s,1H),7.33(d,J=8.4Hz,1H),7.25(s,1H),7.20(d,J=8.8Hz,1H),7.03(d,J=8.4 Hz,2H),6.70(d,J=8.4Hz,2H),5.39(s,1H),2.66(q,J=7.6Hz,2H),2.58(q,J=7.6Hz,2H),1.23-1.18(m,6H).

[0102] 13 C{ 1 H}NMR(150MHz,CDCl3)δ143.9,136.8,135.0,133.1,128.4,126.0,121.7(q,J C-F =266.6Hz),124.3,121.7,119.1,117.5(q,J C-F =35.7Hz),114.7,111.8,28.9,28.0,16.3,15.8.

[0103] 19 F NMR(376MHz, CDCl3)δ-58.98(s).

[0104] HRMS(ESI): m / z calcd for C 19 H 20 F3N2[M+H] + 333.1573, found 333.1572.

[0105] Example 3

[0106] Synthesis of 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c)

[0107] The synthesis route is as follows:

[0108]

[0109] The specific preparation process is as follows:

[0110] 4-Acetoxyphenylisocyanate (32.2 mg, 0.2 mmol, 1.0 equiv.), TMDETA (46.5 mg, 0.4 mmol, 2.0 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then purged with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction system was placed under 20 W (410–420 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the organic phase was concentrated using a rotary evaporator. The remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 3:1, v / v) to give 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c), a white solid, 24.2 mg, with a yield of 61%.

[0111] The 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) synthesized in Example 3 was subjected to... 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection results are shown in Figure 9-12 ,from Figure 9-12 It can be concluded that the product obtained in Example 3 is the pure target compound.

[0112] The specific characterization data of the product are as follows:

[0113] 1HNMR(400MHz,DMSO-d6)δ12.18(s,1H),7.65(s,1H),7.49(d,J=8.8Hz,1H),7.08- 7.03(m,2H),6.83(d,J=8.4Hz,2H),6.57(d,J=8.3Hz,2H),2.21(d,J=9.3Hz,6H).

[0114] 13 C{ 1 H}NMR(150MHz,DMSO-d6)δ170.11,170.07,145.85,144.59,142.20,132.99,121.91(q,J C-F =267.3Hz),124.24,122.46,120.49(q,J C-F =35.1Hz),120.02,119.45,113.91,113.68,112.01,21.22,21.18.

[0115] 19 F NMR(376MHz,DMSO-d6)δ-59.24(s).

[0116] HRMS(ESI): m / z calcd for C 19 H 16 F3N2O4[M+H] + 393.1057, found 393.1055.

[0117] Example 4

[0118] Synthesis of 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d)

[0119] The synthesis route is as follows:

[0120]

[0121] The specific preparation process is as follows:

[0122] 4-Chlorophenylisocyanate (41.3 mg, 0.3 mmol, 1.0 equiv.), TMDETA (69.7 mg, 0.6 mmol, 2.0 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then purged with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction system was placed under 20 W (410–420 nm) blue light and stirred at room temperature for 36 h. After the reaction was completed, the organic phase was concentrated using a rotary evaporator. The remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 15:1, v / v) to give 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d), a yellow oily liquid, 32.2 mg, with a yield of 62%.

[0123] The 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) synthesized in Example 4 was subjected to... 1 HNMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection results are shown in Figure 13-16 ,from Figure 13-16 It can be concluded that the product obtained in Example 4 is the pure target compound.

[0124] The specific characterization data of the product are as follows:

[0125] 1 H NMR (400MHz, CDCl3) δ8.33 (s, 1H), 7.39-7.29 (m, 3H), 7.14 (d, J = 8.8Hz, 2H), 6.63 (d, J = 8.4Hz, 2H), 5.38 (s, 1H).

[0126] 13 C{ 1 H}NMR(150MHz,CDCl3)δ144.3,132.7,129.2,126.8,126.0,124.9,124.2,121.1(q,J C-F =267.3Hz), 119.9(q,J C-F =36.6Hz), 119.9, 119.1(q,J) C-F =2.7Hz), 115.5, 113.4.

[0127] 19 F NMR(376MHz, CDCl3)δ-59.42(s).

[0128] HRMS(ESI): m / z calcd for C 15 H 10 Cl2F3N2[M+H] + 345.0168, found 345.0174.

[0129] Example 5

[0130] Synthesis of 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e)

[0131] The synthesis route is as follows:

[0132]

[0133] The specific preparation process is as follows:

[0134] 3,4-Methylenedioxyphenylisocyanate (29.4 mg, 0.2 mmol, 1.0 equiv.), TMDETA (46.5 mg, 0.4 mmol, 2.0 equiv.), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then purged with CF3Br gas, repeated three times. Finally, the gas pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction system was placed under 20 W (410–420 nm) blue light and stirred at room temperature for 48 h. After the reaction was completed, the organic phase was concentrated using a rotary evaporator. The remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = 8:1, volume ratio) to give 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e), a yellow solid, 22.9 mg, with a yield of 63%.

[0135] The 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) synthesized in Example 5 was subjected to... 1 HNMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection results are shown in Figure 17-20 ,from Figure 17-20 It can be concluded that the product obtained in Example 5 is the pure target compound.

[0136] The specific characterization data of the product are as follows:

[0137] 1H NMR (400MHz, CDCl3) δ8.01(s,1H),6.79(s,1H),6.72(s,1H),6.65(d,J=8.4Hz,1H),6.3 2(d,J=2.4Hz,1H),6.20(dd,J=8.4,2.4Hz,1H),5.95(s,2H),5.87(s,2H),5.23(s,1H).

[0138] 13 C{ 1 H}NMR(150MHz,CDCl3)δ148.2,147.6,143.8,141.2,141.0,130.0,121.6(q,J C-F =266.1Hz),121.5,117.9,116.0(q,J C-F =36.5Hz),108.4,107.2,101.1,100.8,98.6,97.9,92.2.

[0139] 19 F NMR(376MHz,150MHz,CDCl3)δ-58.65(s).

[0140] HRMS(ESI): m / z calcd for C 17 H 12 F3N2O4[M+H] + 365.0744, found 365.0743.

[0141] Comparative Example 1

[0142] The only difference from Example 1 was that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with DIPEA (51.68 mg, 0.4 mmol, 2.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 6.2 mg, with a yield of 17%.

[0143] As can be seen from Comparative Example 1, compared with Example 1, the yield was significantly reduced when only the tertiary amine organic base was changed to DIPEA.

[0144] Comparative Example 2

[0145] The only difference from Example 1 was that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with Et3N (59.68 mg, 0.4 mmol, 2.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 7.3 mg, in a yield of 20%.

[0146] As can be seen from Comparative Example 2, compared with Example 1, the yield was significantly reduced when only the tertiary amine organic base was changed to Et3N.

[0147] Comparative Example 3

[0148] The only difference from Example 1 was that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with PMDETA (74.8 mg, 0.4 mmol, 2.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid with a yield of 26% at 9.5 mg.

[0149] As can be seen from Comparative Example 3, compared with Example 1, the yield was significantly reduced when only the tertiary amine organic base was changed to PMDETA.

[0150] Comparative Example 4

[0151] The only difference from Example 1 was that the solvent CH3CN was replaced with an equal volume of dichloromethane (DCM); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 10.3 mg, with a yield of 28%.

[0152] As can be seen from Comparative Example 4, compared with Example 1, the yield was significantly reduced when only the solvent was changed to DCM.

[0153] Comparative Example 5

[0154] The only difference from Example 1 was that the solvent CH3CN was replaced with an equal volume of acetone; 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 5.5 mg, with a yield of 15%.

[0155] As can be seen from Comparative Example 5, compared with Example 1, the yield was significantly reduced when only the solvent was changed to acetone.

[0156] Comparative Example 6

[0157] The only difference from Example 1 was that the solvent CH3CN was replaced with an equal volume of N,N-dimethylformamide (DMF); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 3.2 mg, with a yield of 9%.

[0158] As can be seen from Comparative Example 6, compared with Example 1, the yield was significantly reduced when only the solvent was changed to DMF.

[0159] Comparative Example 7

[0160] The only difference from Example 1 was that the solvent CH3CN was replaced with an equal volume of dimethyl sulfoxide (DMSO); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 10.2 mg, with a yield of 28%.

[0161] As can be seen from Comparative Example 7, compared with Example 1, the yield was significantly reduced when only the solvent was changed to DMSO.

[0162] Comparative Example 8

[0163] The only difference from Example 1 was that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with TMDETA (23.24 mg, 0.2 mmol, 1.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 8.5 mg, with a yield of 23%.

[0164] As can be seen from Comparative Example 8, compared with Example 1, the yield was significantly reduced when only TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with TMDETA (23.24 mg, 0.2 mmol, 1.0 equiv.).

[0165] Comparative Example 9

[0166] The only difference from Example 1 was that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with TMDETA (69.72 mg, 0.6 mmol, 3.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared as a yellow oily liquid, 10.9 mg, with a yield of 30%.

[0167] As can be seen from Comparative Example 9, compared with Example 1, the yield was significantly reduced when only TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) was replaced with TMDETA (69.72 mg, 0.6 mmol, 3.0 equiv.).

[0168] Comparative Example 10

[0169] The only difference from Example 1 is that the blue light with a visible wavelength of 410-420 nm and a power of 20 W was replaced with blue light with a visible wavelength of 420-425 nm and a power of 20 W; 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) was prepared, a yellow oily liquid, 15.2 mg, with a yield of 42%.

[0170] As can be seen from Comparative Example 10, compared with Example 1, the yield was reduced when only the blue light with a visible wavelength of 410-420 nm and a power of 20 W was replaced with blue light with a visible wavelength of 420-425 nm and a power of 20 W.

[0171] Comparative Example 11

[0172] The only difference from Example 1 is that the blue light with a visible wavelength of 410-420 nm and a power of 20 W was replaced with blue light with a visible wavelength of 460-465 nm and a power of 20 W. After the reaction system was stirred at room temperature, the reaction was detected by TLC. It was found that even after 72 h of reaction, no target product was detected.

[0173] As can be seen from Comparative Example 11, compared with Example 1, the reaction did not occur when only the blue light with a visible wavelength of 410-420 nm and a power of 20 W was replaced with blue light with a visible wavelength of 460-465 nm and a power of 20 W.

[0174] The indole skeleton itself possesses biological activities such as antibacterial, anti-inflammatory, and anticancer properties; moreover, the literature Bioorg. Med. Chem. 2007, 15, 3248–3265 reports compound B (structural formula: It can secrete insulin in vitro and has good activity in the treatment of type II diabetes. This invention provides a method for preparing 2-trifluoromethyl-3-aminoindole compounds, indicating that the compounds prepared in the embodiments of this invention can all be used in the preparation of drugs with therapeutic effects on diabetes.

[0175] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing a 2-trifluoromethyl-3-aminoindole compound, characterized in that, The general structural formula of the 2-trifluoromethyl-3-aminoindole compounds is as follows: ； In the general structural formula, R is Et, OEt, OCOCH3, or Cl; The preparation method of the 2-trifluoromethyl-3-aminoindole compound includes the following steps: In the presence of visible light and tertiary amine organic bases, CF3Br and aryl isonitrile derivatives were subjected to a free radical tandem cyclization reaction in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound. The general structural formula of the aryl isonitrile derivative is as follows: ； The tertiary amine organic base is N,N,N',N'-tetramethylethylenediamine; The molar ratio of the aryl isonitrile derivative to the tertiary amine organic base is 1.0:(1.0~3.0); The visible light is blue light with a wavelength of 410~420 nm and a power of 20 W.

2. The preparation method according to claim 1, characterized in that, The CF3Br is added in the form of CF3Br gas at a pressure of 1.0 atm, and the amount added is in excess.

3. The preparation method according to claim 1, characterized in that, The organic solvent is acetonitrile.

4. The preparation method according to claim 1, characterized in that, The free radical tandem cyclization reaction takes 24–72 h.

Images