2-trifluoromethyl-3-aminoindole compound and preparation method thereof

Abstract

The invention 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-aminoindole compound comprises the following step: under the existence of visible light induction and tertiary amine organic alkali, CF3Br and an aryl isonitrile derivative are subjected to a free radical tandem cyclization reaction in an organic solvent, and the 2-trifluoromethyl-3-aminoindole compound is obtained. The invention provides a method for preparing the 2-trifluoromethyl-3-aminoindole compound in one step by taking the aryl isonitrile derivative as a raw material and CF3Br as a trifluoromethylation reagent through free radical tandem cyclization reaction of bromotrifluoromethane and the aryl isonitrile derivative under the action of visible light induction and tertiary amine organic alkali for the first time. The method has the characteristics of cheap and easily available raw materials, no need of adding a noble metal photosensitizer, simplicity in operation, mild reaction conditions, greenness, safety, good reaction yield and the like, and has a very good application value.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a 2-trifluoromethyl-3-aminoindole compound and a preparation method thereof. Background Art

[0002] 3-Aminoindole compounds are common structural units in organic intermediates and indole alkaloids, some of which have been successfully used in the total synthesis of complex drug molecules such as (-)-Mersiclavine and 8-DesbromohinckdentineA (J.Am.Chem.Soc.2010,132,1236-1237; J.Am.Chem.Soc.2003,125,4240-4252). 3-aminoindole compounds have a wide range of biological activities. In the field of medicine, some known 3-aminoindole compounds can be used as special kinase inhibitors and can be used to treat hyperactive proliferative diseases, vascular-related infections, inflammation and neurodegeneration, depression and anxiety (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 to E:

[0003]

[0004] Studies have shown that compound A shows 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 2 diabetes (Bioorg. Med. Chem. 2007, 15, 3248–3265); compound C is an anti-mitotic inhibitor that can strongly inhibit cancer cell growth and microtubule polymerization, and cause mitotic arrest, and can be effectively used 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); compound E is a quorum sensing inhibitor that is effective against Pseudomonas aeruginosa MH 602 showed significant QSI activity, and the compound was not found to be toxic in normal human embryonic kidney cell lines (HEK 293) (Chemistry Select.; 2018, 3, 9170–9180). In view of the good biological activity and wide application value of 3-aminoindole compounds, it is very necessary to explore the synthesis methods of this type of 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 aminoaromatic derivatives as substrates and introducing an amino group into the C-3 position of the indole while constructing a pyrrole ring to obtain 3-aminoindole compounds.

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

[0007] This method mainly generates 3-aminoindole compounds by the reaction of indole derivatives with aniline or benzylamine compounds. At present, this method has only been reported in two documents. For example:

[0008] In 2021, Mo Dongliang et al. reported a method for obtaining 3-aminoindole compounds by condensation coupling reaction of indole and benzylamine under the catalysis of metal iron salt (Green Chem. 2021, 23, 9610-9616). This method uses tert-butyl nitrite (TBN) as a nitrating agent, iron salt as a catalyst, acetonitrile as a solvent, and reacts at 100°C for 10 to 18 hours to obtain a series of 3-aminoindole compounds with a yield of 52% to 99%. The advantages of this method are easy availability of substrates, good functional group tolerance, and excellent yield; the disadvantage is that the reaction temperature is relatively high.

[0009] The reaction formula is as follows:

[0010]

[0011] In 2014, Wang Yanguang's research group reported a method for obtaining 3-aminoindole compounds by reacting 2-imine-3-diazoindoline compounds with aniline derivatives under the catalysis of rhodium complexes (Org. Lett. 2014, 16, 5096-5099). The biggest advantage of this method is that it has excellent regioselectivity, short reaction time, wide substrate applicability, and high yield; the disadvantage is that the reaction conditions of this method are harsh, such as the reaction needs to be carried out in a nitrogen atmosphere and the reaction temperature needs to be 110°C. The reaction formula is as follows:

[0012]

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

[0014] This method is the main method for synthesizing 3-aminoindole compounds in recent years. For example:

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

[0016]

[0017] In 2022, Li Zheng's research group used calcium acetylide as a solid alkyne source, N-(2-formylaryl)sulfonamide and secondary amine as starting materials, and synthesized 2-methylene-3-aminoindole and 2-methyl-3-aminoindole compounds in a one-pot method (Org. Lett. 2022, 24, 8067-8071). This method uses cheap, abundant and easy-to-handle calcium acetylide instead of flammable and explosive gaseous acetylene as the original alkyne source, which improves the safety of the reaction. This method has the advantages of a wide 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 new method for synthesizing 3-aminoindole compounds by chemically selective trimerization of aromatic isocyanide derivatives under catalyst-free conditions (Org. Lett. 2022, 24, 105-109). The method is that 2-isocyanatostyrene compounds and a molecule of aromatic isocyanide derivatives undergo a heterodimerization reaction in a "head-to-head" manner in a 1,2-dichloroethane solvent at 150°C, and then the dimer undergoes polymerization again with another molecule of aromatic isocyanide derivative, and finally a series of 3-aminoindole compounds are obtained with a yield of 60% to 96%. The advantages of this method are high chemical selectivity, no need to add catalysts, cheap and easy-to-obtain raw materials, simple operation, and short reaction time; the disadvantage of this reaction is that the reaction temperature is relatively high. The reaction formula is as follows:

[0020]

[0021] In 2016, the Studer research group used trifluoroperiodine reagent, pentafluoroperiodine reagent and heptafluoroperiodine reagent as fluorine sources. Under the action of lithium iodide, these polyfluoroperiodine reagents produced fluoroalkyl radicals, which then underwent a free radical tandem cyclization reaction with aromatic isonitriles to obtain 3-aminoindole compounds in which the C-2 position of indole was substituted by trifluoromethyl, pentafluoroethyl, or heptafluoroisopropyl (Chem. Commun. 2016, 52, 5997-6000). Among them, 11 2-trifluoromethyl-3-aminoindole compounds were synthesized with a yield of 14% to 60%; a 2-pentafluoroethyl-3-aminoindole compound was obtained with a yield of 53%; and a 2-heptafluoroisopropyl-3-aminoindole compound was obtained with a yield of 58%. From the perspective of fluorine chemistry, the biggest problem of this method is that the polyfluoroperiodine reagents used are expensive, need to be prepared in advance, and the preparation steps are cumbersome, as well as low atomic utilization. The reaction formula is as follows:

[0022]

[0023] In summary, although some achievements have been made in the research on the synthesis method of 3-aminoindole compounds in the prior art, each method has its own shortcomings and limitations and still needs to be further improved. In order to further explore new synthesis methods of 3-aminoindole compounds and improve and enhance the biological activity of 3-aminoindole compounds, it is very necessary to explore a new, efficient and simple synthesis method to prepare 3-aminoindole compounds containing trifluoromethyl. Summary of the invention

[0024] The object of the present invention is to provide a 2-trifluoromethyl-3-aminoindole compound and a preparation method thereof to solve the above-mentioned problems in the background technology.

[0025] To achieve the above object, the present invention provides the following technical solutions:

[0026] One of the technical solutions of the present invention is to provide a 2-trifluoromethyl-3-aminoindole compound having the structural formula Or the following 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 is to provide a method for preparing the above-mentioned 2-trifluoromethyl-3-aminoindole compounds, comprising the following steps:

[0030] Under the induction of visible light and in the presence of a tertiary amine organic base, CF3Br and an aromatic isonitrile derivative are 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 aromatic isonitrile derivative is Or the following 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 aromatic 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 added amount is excessive.

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

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

[0039] Furthermore, the free radical tandem cyclization reaction time is 24 to 72 hours.

[0040] Furthermore, the temperature of the free radical tandem cyclization reaction is 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 to ethyl acetate is (3-30):1.

[0042] The third technical solution of the present invention is to provide an application of the above-mentioned 2-trifluoromethyl-3-aminoindole compounds in the preparation of drugs for treating diabetes.

[0043] The technical principles of the present invention are as follows:

[0044]

[0045]

[0046] First, bromotrifluoromethane reacts with N,N,N',N'-tetramethylethylenediamine to form an electron donor-acceptor complex (EDA complex); under the irradiation of visible light, the electron donor-acceptor complex undergoes single electron transfer (SET) to produce a trifluoromethyl radical, and simultaneously generates a bromine anion and an N,N,N',N'-tetramethylethylenediamine radical cation; then, the trifluoromethyl radical reacts with the isocyanate group, i.e., the carbon-nitrogen triple bond, in the aromatic isonitrile 1 molecule to form an imine radical intermediate A; the radical intermediate A then reacts with the isocyanate group in another aromatic isonitrile 1 molecule to form another imine radical intermediate B; the imine radical intermediate B further undergoes a molecular addition reaction. The internal radical addition cyclization reaction generates a cyclic carbon radical intermediate C; then, the cyclic carbon radical intermediate C grabs a hydrogen radical from the methylene group in the N,N,N',N'-tetramethylethylenediamine radical cation, that is, the carbon radical intermediate C undergoes hydrogen atom transfer (HAT) to generate compound D, and at the same time, the N,N,N',N'-tetramethylethylenediamine radical cation is converted into an iminium cation formed by N,N,N',N'-tetramethylethylenediamine; finally, compound D, as a non-aromatic compound, has a high molecular energy and exhibits instability, so it is easy to undergo hydrogen migration to generate the target product 2-trifluoromethyl-3-aminoindole compound 3 with lower molecular energy and higher stability.

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

[0048] (1) The present 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 an aromatic isonitrile derivative under the induction of visible light and the action of a tertiary amine organic base.

[0049] (2) The present invention uses CF3Br for the first time to construct trifluoromethyl-substituted 3-aminoindole compounds. CF3Br is a non-toxic and tasteless industrial raw material with the advantages of stable chemical properties, low price, easy availability, economic benefits, high atomic utilization rate, etc., which provides greater possibilities for industrial-scale synthesis.

[0050] (3) The present invention realizes for the first time the generation of trifluoromethyl radicals under visible light induction through an electron donor-acceptor (EDA) complex formed by CF3Br and a tertiary amine organic base. For the free radical tandem cyclization reaction involving CF3Br under visible light induction, trifluoromethyl radicals often need to be generated in the presence of photocatalysts such as precious metals or organic dyes. The technical solution provided by the present invention effectively avoids the use of photocatalysts such as precious metals or organic dyes, greatly reducing the reaction cost.

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

[0052] (5) The 2-trifluoromethyl-3-aminoindole compounds synthesized by the present invention are 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection showed that the obtained product was a pure target compound with high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

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

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

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

[0057] Figure 4 This is a high-resolution mass spectrum monitoring diagram of 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) prepared in Example 1;

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

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

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

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

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

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

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

[0065] Fig.12 This is a high-resolution mass spectrum monitoring diagram of 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) prepared in Example 3;

[0066] Fig.13 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 1 HNMR spectra;

[0067] Fig.14 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 13 CNMR images;

[0068] Fig.15 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4 19 FNMR images;

[0069] Fig.16 This is the high-resolution mass spectrum monitoring chart of 2-trifluoromethyl-3-[N-(4-chlorophenyl)]amino-5-chloroindole (3d) prepared in Example 4.

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

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

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

[0073] Fig. 20 This is a high-resolution mass spectrum monitoring chart of 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) prepared in Example 5. DETAILED DESCRIPTION

[0074] Trifluoromethyl is a common fluorine-containing group. The introduction of trifluoromethyl into organic compounds can significantly change the acidity, dipole moment, polarity, lipophilicity and chemical and metabolic stability of the parent compound. The results of literature survey show that the research on the introduction of trifluoromethyl into 3-aminoindole molecules has been reported very little. For example, up to now, only one document (Chem. Commun. 2016, 52, 5997-6000) has been reported on the synthesis method of 2-trifluoromethyl-3-aminoindole compounds. In this document, when synthesizing 3-aminoindole compounds containing trifluoromethyl, the trifluoromethylation reagent used is Togni reagent. As a trifluoromethylation reagent, Togni reagent has the serious disadvantage of poor atom economy in addition to the defects of being expensive, cumbersome to prepare and difficult to store. Because in the reaction, while providing trifluoromethyl, the reagent also produces waste organic matter such as o-iodobenzoic acid. In order to further explore new synthesis methods of 3-aminoindole compounds and improve and enhance the biological activity of 3-aminoindole compounds, it is very necessary to explore a new, efficient and simple synthesis method to prepare 3-aminoindole compounds containing trifluoromethyl.

[0075] Now, various exemplary embodiments of the present invention are described in detail, and this detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention.

[0076] In addition, for the numerical range in the present invention, it is understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0077] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention.

[0078] The words “include,” “including,” “have,” “contain,” etc. used in the present invention are open-ended terms, meaning including but not limited to.

[0079] Unless otherwise specified, the "room temperature" in the present invention is 25±2°C.

[0080] The aromatic isocyanide derivatives used in the following embodiments and comparative examples of the present invention: 4-ethoxyphenyl isocyanide, 4-ethylphenyl isocyanide, 4-acetoxyphenyl isocyanide, 4-chlorophenyl isocyanide and 3,4-dienedioxyphenyl isocyanide are prepared according to the literature (Palladium-catalyzed synthesis of α-diimines from triarylbismuthines andisocyanides.Org.Lett.2015,17,14,3490-3493; Radical perfluoroalkylation-easyaccess to 2-perfluoroalkylindol-3-imines via electroncatalysis.Chem.Commun.2016,52,5997-6000.), and the remaining reagents and drugs are commercially available products unless otherwise specified.

[0081] Example 1

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

[0083] The synthetic route is as follows:

[0084]

[0085] The specific preparation process is as follows:

[0086] 4-Ethoxyphenyl isocyanide (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 to vacuum and filled with CF3Br gas, and the process was repeated three times. Finally, the 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, and 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 obtain 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) as 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, the results are shown in Figure 1-4 ,from Figure 1-4 It can be concluded that the product obtained in Example 1 is a pure target compound.

[0088] The 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 synthetic route is as follows:

[0096]

[0097] The specific preparation process is as follows:

[0098] 4-Ethylphenyl isocyanide (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 to vacuum and then filled with CF3Br gas, and the process was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the 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, and the remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=30:1, volume ratio) to obtain 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, the results are shown in Figure 5-8 ,from Figure 5-8 It can be concluded that the product obtained in Example 2 is a pure target compound.

[0100] The 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 synthetic route is as follows:

[0108]

[0109] The specific preparation process is as follows:

[0110] 4-Acetoxyphenyl isonitrile (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 to vacuum and then filled with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the 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, and the remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=3:1, volume ratio) to obtain 2-trifluoromethyl-3-[N-(4-acetoxyphenyl)]amino-5-acetoxyindole (3c) as 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, the results are shown in Figure 9-12 ,from Figure 9-12 It can be concluded that the product obtained in Example 3 is a pure target compound.

[0112] The 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 synthetic route is as follows:

[0120]

[0121] The specific preparation process is as follows:

[0122] 4-Chlorophenyl isocyanide (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 to vacuum and then filled with CF3Br gas, and the process was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the 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, and the remaining residue was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE:EA=15:1, volume ratio) to obtain 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, the results are shown in Figure 13-16 ,from Figure 13-16 It can be concluded that the product obtained in Example 4 is a pure target compound.

[0124] The 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 synthetic route is as follows:

[0132]

[0133] The specific preparation process is as follows:

[0134] 3,4-Methylenedioxyphenyl isonitrile (29.4 mg, 0.2 mmol, 1.0 equiv.), TMDETA (46.5 mg, 0.4 mmol, 2.0 equiv.), and 3 mL CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated to vacuum and then filled with CF3Br gas, and repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the 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, the organic phase was concentrated by rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as stationary phase and petroleum ether and ethyl acetate as eluent (PE:EA=8:1, volume ratio) to obtain 2-trifluoromethyl-3-[N-(3,4-methylenedioxyphenyl)]amino-5,6-methylenedioxyindole (3e) as a yellow solid, 22.9 mg, and 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, the results are shown in Figure 17-20 ,from Figure 17-20 It can be concluded that the product obtained in Example 5 is a pure target compound.

[0136] The 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 is that TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) is replaced by DIPEA (51.68 mg, 0.4 mmol, 2.0 equiv.); 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) is prepared as a yellow oily liquid, 6.2 mg, with a yield of 17%.

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

[0144] Comparative Example 2

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

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

[0147] Comparative Example 3

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

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

[0150] Comparative Example 4

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

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

[0153] Comparative Example 5

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

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

[0156] Comparative Example 6

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

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

[0159] Comparative Example 7

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

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

[0162] Comparative Example 8

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

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

[0165] Comparative Example 9

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

[0167] It can be seen from Comparative Example 9 that, compared with Example 1, the yield is significantly reduced when only TMDETA (46.48 mg, 0.4 mmol, 2.0 equiv.) is 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 light wavelength of 410 to 420 nm and a power of 20 W is replaced by blue light with a visible light wavelength of 420 to 425 nm and a power of 20 W; 2-trifluoromethyl-3-[N-(4-ethoxyphenyl)]amino-5-ethoxyindole (3a) is prepared as a yellow oily liquid, 15.2 mg, and a yield of 42%.

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

[0171] Comparative Example 11

[0172] The only difference from Example 1 is that the blue light with a visible light wavelength of 410-420 nm and a power of 20 W is replaced by blue light with a visible light wavelength of 460-465 nm and a power of 20 W; after the reaction system is stirred at room temperature, the reaction is detected by TLC, and it is found that the target product is not detected even after 72 hours of reaction.

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

[0174] The indole skeleton itself has antibacterial, anti-inflammatory and anti-cancer biological activities; and the literature Bioorg.Med.Chem.2007,15,3248-3265 reported compound B (structural formula ) can secrete insulin in vitro and has good activity in the treatment of type II diabetes. The present invention provides a method for preparing 2-trifluoromethyl-3-aminoindole compounds, which shows that the compounds prepared in the embodiments of the present invention can be used to prepare drugs for the treatment of diabetes.

[0175] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A 2-trifluoromethyl-3-aminoindole compound, characterized in that: Its structural formula is Or the following structural formula: In the general structural formula, R is Et, OEt, OCOCH3 or Cl.

2. A method for preparing the 2-trifluoromethyl-3-aminoindole compound according to claim 1, characterized in that: The following steps are involved: Under the induction of visible light and in the presence of a tertiary amine organic base, CF3Br and an aromatic isonitrile derivative are subjected to a free radical tandem cyclization reaction in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound; The structural formula of the aromatic isonitrile derivative is Or the following structural formula: In the general structural formula, R is Et, OEt, OCOCH3 or Cl.

3. The preparation method according to claim 2, characterized in that: The tertiary amine organic base is N,N,N',N'-tetramethylethylenediamine.

4. The preparation method according to claim 2, characterized in that: The molar ratio of the aromatic isonitrile derivative to the tertiary amine organic base is 1.0:(1.0-3.0).

5. The preparation method according to claim 2, characterized in that: The CF3Br is added in the form of CF3Br gas, the pressure of the CF3Br gas is 1.0 atm, and the added amount is excessive.

6. The preparation method according to claim 2, characterized in that: The visible light is blue light with a wavelength of 410-420nm and a power of 20W.

7. The preparation method according to claim 2, characterized in that: The organic solvent is acetonitrile.

8. The preparation method according to claim 2, characterized in that: The time of the free radical tandem cyclization reaction is 24 to 72 hours.

9. Use of the 2-trifluoromethyl-3-aminoindole compound according to claim 1 in the preparation of a drug for treating diabetes.

Images