CN119899197B - A 2-trifluoromethyl-3-aminoindole compound and its preparation method - Google Patents

A 2-trifluoromethyl-3-aminoindole compound and its preparation method

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CN119899197B
CN119899197B CN202510249837.8A CN202510249837A CN119899197B CN 119899197 B CN119899197 B CN 119899197B CN 202510249837 A CN202510249837 A CN 202510249837A CN 119899197 B CN119899197 B CN 119899197B
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trifluoromethyl
aminoindole
amino
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CN119899197A (en
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胡雨来
温欢
潘晓娜
赵明琪
黄丹凤
王克虎
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Northwest Normal University
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Abstract

本发明公开了一种2‑三氟甲基‑3‑氨基吲哚类化合物及其制备方法，属于有机合成技术领域。本发明的2‑三氟甲基‑3‑氨基吲哚类化合物的制备方法包括以下步骤：在可见光诱导及叔胺类有机碱的存在下，将CF3Br和芳基异腈衍生物在有机溶剂中进行自由基串联环化反应，得到所述2‑三氟甲基‑3‑氨基吲哚类化合物。本发明首次提出以芳基异腈衍生物为原料，以CF3Br为三氟甲基化试剂，在可见光诱导及叔胺类有机碱作用下，通过三氟溴甲烷与芳基异腈衍生物发生自由基串联环化反应，一步制备2‑三氟甲基‑3‑氨基吲哚类化合物的方法。本发明的原料价廉易得，无需添加贵金属光敏剂，操作简单，反应条件温和，绿色安全，反应产率良好等特点，有很好的应用价值。

This invention discloses a 2-trifluoromethyl-3-aminoindole compound and its preparation method, belonging to the field of organic synthesis technology. The preparation method of the 2-trifluoromethyl-3-aminoindole compound of this invention includes the following steps: under visible light induction and in the presence of a tertiary amine organic base, CF3Br and an aryl isonitrile derivative undergo a free radical tandem cyclization reaction in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound. This invention is the first to propose a method for preparing 2-trifluoromethyl-3-aminoindole compounds in one step using an aryl isonitrile derivative as a raw material and CF3Br as a trifluoromethylating agent, under visible light induction and the action of a tertiary amine organic base, through a free radical tandem cyclization reaction between trifluorobromomethane and the aryl isonitrile derivative. The raw materials of this invention are inexpensive and readily available, require no addition of precious metal photosensitizers, the operation is simple, the reaction conditions are mild, it is green and safe, and the reaction yield is good, making it of great application value.

Description

2-Trifluoromethyl-3-aminoindole compound and preparation method thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a 2-trifluoromethyl-3-aminoindole compound and a preparation method thereof.
Background
3-Aminoindoles are common building blocks in organic intermediates and indole alkaloids, some of which have been successfully employed 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-aminoindoles have a wide range of biological activities, and in the medical field, some of the known 3-aminoindoles are useful as specific kinase inhibitors and for the treatment of overactive proliferative diseases, 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 having the following chemical structures A-E:
Studies have shown that Compound A shows good therapeutic activity against human breast cancer cell lines (T47D, BT549 and MDA-MB-231), can be used for anti-human breast cell proliferation (Eur.J.Med. Chem.2019,166, 281-290), that Compound B can secrete insulin in vitro, has good activity against type II diabetes mellitus (Bioorg. Med. Chem.2007,15, 3248-3265), that Compound C is an anti-mitotic inhibitor that strongly inhibits cancer cell growth and tubulin polymerization and results in mitotic arrest, can be effectively used in tumor therapy (J.Med. Chem.2008,51, 1464-1468), that Compound D is an m-PGES-1 inhibitor with anti-inflammatory and anti-tumor functions (Green chem.2021,23, 9610-9616), that Compound E is a group-inducing inhibitor, that shows significant QSI activity against Pseudomonas aeruginosa MH 602, and that has not been found in the kidney 293 cell line (HEK) that has been found to be a non-toxic in the human embryo line (2018,3,9170). In view of the good biological activity and wide application value of 3-aminoindole compounds, it is very necessary to explore the synthetic method of the compounds.
At present, two methods for synthesizing 3-aminoindole compounds are available, namely (1) directly introducing amino into the C-3 position of indole molecules to obtain 3-aminoindole compounds, and (2) using amino aromatic hydrocarbon derivatives as substrates, introducing amino into the C-3 position of indole while constructing pyrrole rings to obtain 3-aminoindole compounds.
(1) Directly introducing amino into C-3 position of indole molecule to obtain 3-aminoindole compound
The method mainly generates 3-amino indole compounds through the reaction of indole derivatives and aniline or benzylamine compounds. Currently, this method is reported only in two documents. For example:
2021, mo Dongliang et al reported a method for obtaining 3-aminoindoles by condensation coupling of indole with benzylamine under catalysis of a metallic iron salt (Green chem.2021,23, 9610-9616). According to the method, tert-butyl nitrite (TBN) is used as a nitrifying reagent, ferric salt is used as a catalyst, acetonitrile is used as a solvent, the reaction is carried out for 10-18 h at 100 ℃, and a series of 3-aminoindole compounds are obtained at a yield of 52% -99%. The method has the advantages of easily available substrate, good tolerance of functional groups, good yield and higher reaction temperature.
The reaction formula is as follows:
In 2014, wang Yanan reports a method for obtaining 3-aminoindole compounds by using 2-imine-3-diazoindoline compounds and aniline derivatives under the catalysis of rhodium complex (org. Lett.2014,16, 5096-5099). The method has the greatest advantages of excellent regioselectivity, short reaction time, wide substrate applicability range and high yield, and has the defects of harsh reaction conditions, such as the reaction needs to be carried out in a nitrogen atmosphere, and the reaction temperature needs to be 110 ℃. The reaction formula is as follows:
(2) Amino aromatic hydrocarbon derivative is used as substrate, amino is introduced into the C-3 position of indole while pyrrole ring is constructed, thus obtaining 3-amino indole compound
This method is the main synthesis method of 3-aminoindole compounds in recent years. For example:
2021, liu Yuangong et al reported a process for synthesizing 3-aminoindoles by beta-regioselective amination/cyclization of N-alkynylbenzonitrile with aniline derivatives under the catalysis of metallic nickel with Lewis acids (org. Lett.2021,23, 1296-1301). The method firstly provides that N-alkynyl benzonitrile and aniline derivatives are used as substrates, 1, 4-dioxane is used as a solvent under the catalysis of metallic nickel and Lewis acid, and a target product can be obtained under the condition of 80 ℃. The method has the advantages of high regioselectivity and severe reaction conditions. The reaction formula is as follows:
In 2022, the Li Zheng group synthesized 2-methylene-3-aminoindole and 2-methyl-3-aminoindole compounds (org. Lett.2022,24, 8067-8071) in one pot using calcium acetylide as a solid alkyne source and N- (2-formylaryl) sulfonamide and secondary amine as starting materials. The method uses cheap, abundant and easy-to-process calcium acetylide to replace flammable and explosive gaseous acetylene as an original alkyne source, so that the safety of the reaction is improved. The method has the advantages of wide substrate range, high yield, simple post-treatment and the like. The reaction formula is as follows:
In 2022, xu Xianxiu group reported a novel method for synthesizing 3-aminoindoles from aryl isonitrile derivatives by chemoselective trimerization (org. Lett.2022,24, 105-109) in the absence of a catalyst. The method comprises the steps of carrying out heterodimerization reaction on a 2-isocyano styrene compound and one molecule of aryl isonitrile derivative in a1, 2-dichloroethane solvent at 150 ℃ in a head-to-head mode, carrying out polymerization reaction on the dimer and the other molecule of aryl isonitrile derivative again, and finally obtaining a series of 3-aminoindole compounds with the yield of 60% -96%. The method has the advantages of high chemical selectivity, no need of adding catalyst, cheap and easily available raw materials, simple operation and short reaction time, and the reaction has the disadvantage of higher reaction temperature. The reaction formula is as follows:
In 2016, the Studies group used trifluoroperiodate, pentafluoro periodate and heptafluoro periodate as fluorine sources, and these polyfluoro periodates produced fluoroalkyl radicals under the action of lithium iodide, which then underwent radical tandem cyclization with aryl isonitriles to give 3-aminoindoles with trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl substituted at the C-2 position of indole (chem. Commun.2016,52, 5997-6000). Wherein, 11 2-trifluoromethyl-3-aminoindole compounds are synthesized with the yield of 14% -60%, one 2-pentafluoroethyl-3-aminoindole compound is obtained with the yield of 53%, and one 2-heptafluoroisopropyl-3-aminoindole compound is obtained with the yield of 58%. From the perspective of fluorine chemistry, the method has the greatest problems that the used polyfluoro-periodate reagent is expensive, needs to be prepared in advance, has complicated preparation steps, has low atom utilization rate and the like. The reaction formula is as follows:
In summary, although some efforts have been made in the prior art to investigate the synthetic methods of 3-aminoindoles, each method has its own drawbacks and limitations, and further improvements are needed. In order to further explore a novel method for synthesizing 3-aminoindole compounds, and to improve and enhance the biological activity of 3-aminoindole compounds, it is necessary to explore a novel, efficient and simple synthetic method for preparing 3-aminoindole compounds containing trifluoromethyl.
Disclosure of Invention
The invention aims to provide a 2-trifluoromethyl-3-aminoindole compound and a preparation method thereof, which are used for solving the problems in the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions:
The technical scheme of the invention provides a 2-trifluoromethyl-3-aminoindole compound with a structural formula of Or the structural general formula is as follows:
In the structural general formula, R is Et, OEt, OCOCH 3 or Cl.
The second technical scheme of the invention is to provide a preparation method of the 2-trifluoromethyl-3-aminoindole compound, which comprises the following steps:
In the presence of visible light induction and tertiary amine organic alkali, carrying out free radical series cyclization reaction on CF 3 Br and aryl isonitrile derivatives in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound;
The structural formula of the aryl isonitrile derivative is Or the structural general formula is as follows:
In the structural general formula, R is Et, OEt, OCOCH 3 or Cl.
Further, the tertiary amine organic base is N, N, N ', N' -tetramethyl ethylenediamine (TMDETA).
Further, the molar ratio of the aryl isonitrile derivative to the tertiary amine organic base is 1.0 (1.0-3.0).
Further, the CF 3 Br is added as CF 3 Br gas, the pressure of the CF 3 Br gas is 1.0atm, and the addition amount is excessive.
Further, the visible light is blue light with the wavelength of 410-420 nm and the power of 20W.
Further, the organic solvent is acetonitrile (CH 3 CN).
Further, the time of the radical tandem cyclization reaction is 24-72 h.
Further, the temperature of the radical tandem cyclization reaction is room temperature.
Further, after the free radical tandem cyclization reaction is finished, the method further comprises a purification step, wherein the purification mode is column chromatography, silica gel is used as a stationary phase in the column chromatography, petroleum ether and ethyl acetate are used as eluents, and the volume ratio of the petroleum ether to the ethyl acetate is (3-30): 1.
The invention also provides an application of the 2-trifluoromethyl-3-aminoindole compound in preparing a medicament for treating diabetes.
The technical principle of the invention is as follows:
Firstly, trifluoro methyl bromide and N, N, N ', N ' -tetramethyl ethylenediamine generate electron donor-acceptor complex (EDA complex), under the irradiation of visible light, the electron donor-acceptor complex generates trifluoromethyl free radical, and simultaneously generates bromide negative ions and N, N, N ', N ' -tetramethyl ethylenediamine free radical cations, then, the trifluoromethyl free radical and isocyano in aryl isonitrile 1 molecules, namely carbon nitrogen triple bond, undergo free radical addition reaction to generate imine free radical intermediate A, the free radical intermediate A and isocyano in another molecule aryl isonitrile 1 molecules undergo free radical addition cyclization reaction to generate another imine free radical intermediate B, the imine free radical intermediate B further undergoes intramolecular free radical addition cyclization reaction to generate cyclic carbon free radical intermediate C, and then the cyclic carbon free radical intermediate C is extracted from methylene in N, N ', N ' -tetramethyl ethylenediamine free radical cations, namely the carbon free radical intermediate C undergoes hydrogen atom transfer reaction with isocyano in the aryl isonitrile 1 molecules, namely, and is more easily converted into N-tetramethyl ethylenediamine free radical D through N ', N-methyl diamine, and is more stable than N-tetramethyl ethylenediamine, and can be used as target product, and can be formed into more stable amino-3-N-tetramethyl ethylenediamine, and more stable product.
The beneficial technical effects of the invention are as follows:
(1) The invention discloses a method for preparing 2-trifluoromethyl-3-aminoindole compounds by a radical tandem cyclization reaction of CF 3 Br and aryl isonitrile derivatives under the action of visible light induction and tertiary amine organic base for the first time.
(2) The invention uses CF 3 Br for constructing trifluoromethyl substituted 3-aminoindole compounds for the first time. CF 3 Br is a nontoxic and odorless industrial raw material, has the advantages of stable chemical property, low price, easy acquisition, economy, high atom utilization rate and the like, and provides greater possibility for industrial scale synthesis.
(3) The invention realizes that under the induction of visible light, trifluoromethyl free radicals are generated through an electron donor-acceptor (EDA) complex formed by CF 3 Br and tertiary amine organic base for the first time. For the free radical serial cyclization reaction participated by CF 3 Br under the induction of visible light, trifluoromethyl free radicals can be generated usually in the presence of a photocatalyst such as noble metal or organic dye, and the technical scheme provided by the invention effectively avoids the use of the photocatalyst such as noble metal or organic dye, and greatly reduces the reaction cost.
(4) The synthesis method provided by the invention has the characteristics of short reaction steps, high atom utilization rate, simplicity in operation, mild reaction conditions, environment friendliness, safety, good yield and the like.
(5) The 2-trifluoromethyl-3-aminoindole compound synthesized by the method is detected by 1H NMR、13C NMR、19 F NMR and high-resolution mass spectrum, and the obtained product is a pure target compound and has high purity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a 1 H NMR chart of 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) prepared in example 1;
FIG. 2 is a 13 C NMR chart of 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) prepared in example 1;
FIG. 3 is a 19 F NMR chart of 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) prepared in example 1;
FIG. 4 is a high resolution mass spectrum monitoring of 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) prepared in example 1;
FIG. 5 is a 1 H NMR chart of 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b) prepared in example 2;
FIG. 6 is a 13 C NMR chart of 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b) prepared in example 2;
FIG. 7 is a 19 F NMR chart of 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b) prepared in example 2;
FIG. 8 is a high resolution mass spectrum monitoring of 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b) prepared in example 2;
FIG. 9 is a 1 H NMR chart of 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c) prepared in example 3;
FIG. 10 is a 13 C NMR chart of 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3C) prepared in example 3;
FIG. 11 is a 19 F NMR chart of 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c) prepared in example 3;
FIG. 12 is a high resolution mass spectrum monitoring of 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c) prepared in example 3;
FIG. 13 is a 1 HNMR diagram of 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d) prepared in example 4;
FIG. 14 is a 13 C NMR chart of 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d) prepared in example 4;
FIG. 15 is a 19 F NMR chart of 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d) prepared in example 4;
FIG. 16 is a high resolution mass spectrum monitoring of 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d) prepared in example 4.
FIG. 17 is a 1 H NMR chart of 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) prepared in example 5;
FIG. 18 is a 13 C NMR chart of 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) prepared in example 5;
FIG. 19 is a 19 F NMR chart of 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) prepared in example 5
FIG. 20 is a high resolution mass spectrum monitoring of 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) prepared in example 5.
Detailed Description
Trifluoromethyl is a common fluorine-containing group, and the introduction of trifluoromethyl into organic compounds can significantly change the acidity, dipole moment, polarity, lipophilicity, chemical and metabolic stability and the like of the parent compound. Literature studies have shown that little research into the incorporation of trifluoromethyl groups into 3-aminoindole molecules has been reported. For example, only one document (chem. Commun.2016,52, 5997-6000) has been reported to date for the synthesis of 2-trifluoromethyl-3-aminoindoles. In this document, the trifluoromethyl reagent used in the synthesis of 3-aminoindoles containing trifluoromethyl is Togni reagent. Togni reagent as trifluoromethyl reagent has the defects of high price, complicated preparation and difficult storage, and has the serious defect of poor atom economy. Because in the reaction, the reagent provides trifluoromethyl and also produces waste organic substances such as o-iodobenzoic acid. In order to further explore a novel method for synthesizing 3-aminoindole compounds, and to improve and enhance the biological activity of 3-aminoindole compounds, it is necessary to explore a novel, efficient and simple synthetic method for preparing 3-aminoindole compounds containing trifluoromethyl.
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
The terms "comprising," "including," "having," "containing," and the like as used herein are open-ended terms, meaning including, but not limited to.
The room temperature in the invention is calculated by 25+/-2 ℃ unless otherwise specified.
The arylisonitrile derivatives used in the following examples and comparative examples of the present invention, 4-ethoxyphenylisonitrile, 4-ethylphenylisonitrile, 4-acetoxyphenylisonitrile, 4-chlorophenyl isonitrile and 3, 4-methylenedioxyphenylisonitrile were prepared according to literature (Palladium-catalyzed synthesis ofα-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.), and the remaining reagents and medicines were commercially available unless otherwise specified.
Example 1
Synthesis of 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a)
The synthetic route is as follows:
the specific preparation process is as follows:
4-ethoxyphenylisonitrile (29.4 mg,0.2mmol,1.0 equiv.) and TMDETA (46.48 mg,0.4mmol,2.0 equiv.) and 3mL CH 3 CN were added to a 50mL Schlenk flask, the Schlenk flask was then evacuated and charged with CF 3 Br gas, and repeated three times, the pressure in the Schlenk flask was maintained at 1.0atm (as seen from a barometer), the reaction system was then placed under 20W (410-420 nm) blue light at room temperature and stirred for 72 hours at room temperature, after the end of the reaction, the organic phase was concentrated by a rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as a stationary phase, petroleum ether and ethyl acetate as an eluent (PE: EA=8:1, volume ratio) to give 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) as a yellow oily liquid, 21.2mg, with a yield of 58%.
The 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) synthesized in example 1 was subjected to 1HNMR、13C NMR、19 F NMR and high resolution mass spectrometry, and as a result, see FIGS. 1-4, it was revealed from FIGS. 1-4 that the product obtained in example 1 was the pure target compound.
Characterization data of the product are specifically as follows:
1H 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).
13C{1H}NMR(150MHz,CDCl3)δ153.6,152.6,139.4,131.1,129.7,121.7(q,JC-F＝267.0Hz),124.2,121.2,120.1,117.4(q,JC-F＝35.7Hz),116.8,116.3,115.4,112.9,102.4,64.0,63.9,14.9,14.7.
19F NMR(376MHz,CDCl3)δ-58.92(s).
HRMS(ESI):m/z calcd for C19H20F3N2O2[M+H]+365.1471,found 365.1463.
Example 2
Synthesis of 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b)
The synthetic route is as follows:
the specific preparation process is as follows:
4-ethylphenyl isonitrile (39.4 mg,0.3mmol,1.0 equiv.) TMDETA (69.7 mg,0.6mmol,2.0 equiv.) and 3mL CH 3 CN were added to a 50mL Schlenk flask. The Schlenk flask was evacuated and refilled with CF 3 Br gas, repeated three times, and finally the pressure in the Schlenk flask was maintained at 1.0atm (observed from a barometer). The reaction system was placed under 20W (410 to 420 nm) blue light and stirred at room temperature for 24 hours. After the reaction was completed, the organic phase was concentrated by a rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as a stationary phase, petroleum ether and ethyl acetate as eluent (PE: ea=30:1, volume ratio) to give 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b), as a yellow oily liquid, 24.1mg, yield was 48%.
The 2-trifluoromethyl-3- [ N- (4-ethylphenyl) ] amino-5-ethylindole (3 b) synthesized in example 2 was subjected to 1H NMR、13C NMR、19 F NMR and high resolution mass spectrometry, and as a result, see FIGS. 5-8, it was found from FIGS. 5-8 that the product obtained in example 2 was the pure target compound.
Characterization data of the product are specifically as follows:
1H 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＝8.4Hz,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).
13C{1H}NMR(150MHz,CDCl3)δ143.9,136.8,135.0,133.1,128.4,126.0,121.7(q,JC-F＝266.6Hz),124.3,121.7,119.1,117.5(q,JC-F＝35.7Hz),114.7,111.8,28.9,28.0,16.3,15.8.
19F NMR(376MHz,CDCl3)δ-58.98(s).
HRMS(ESI):m/z calcd for C19H20F3N2[M+H]+333.1573,found 333.1572.
Example 3
Synthesis of 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c)
The synthetic route is as follows:
the specific preparation process is as follows:
4-Acetoxyphenylisonitrile (32.2 mg,0.2mmol,1.0 equiv.) TMDETA (46.5 mg,0.4mmol,2.0 equiv.) and 3mL CH 3 CN were added to a 50mL Schlenk flask. The Schlenk flask was evacuated and refilled with CF 3 Br gas, repeated three times, and finally the pressure in the Schlenk flask was maintained at 1.0atm (observed from a barometer). The reaction system was placed under 20W (410 to 420 nm) blue light and stirred at room temperature for 24 hours. After the reaction was completed, the organic phase was concentrated by a rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as a stationary phase, petroleum ether and ethyl acetate as an eluent (PE: ea=3:1, volume ratio) to give 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c), as a white solid, 24.2mg, yield 61%.
The 2-trifluoromethyl-3- [ N- (4-acetoxyphenyl) ] amino-5-acetoxyindole (3 c) synthesized in example 3 was subjected to 1H NMR、13C NMR、19 F NMR and high resolution mass spectrometry, and the results are shown in FIGS. 9-12, and it can be seen from FIGS. 9-12 that the product obtained in example 3 was the pure target compound.
Characterization data of the product are specifically as follows:
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).
13C{1H}NMR(150MHz,DMSO-d6)δ170.11,170.07,145.85,144.59,142.20,132.99,121.91(q,JC-F＝267.3Hz),124.24,122.46,120.49(q,JC-F＝35.1Hz),120.02,119.45,113.91,113.68,112.01,21.22,21.18.
19F NMR(376MHz,DMSO-d6)δ-59.24(s).
HRMS(ESI):m/z calcd for C19H16F3N2O4[M+H]+393.1057,found 393.1055.
Example 4
Synthesis of 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d)
The synthetic route is as follows:
the specific preparation process is as follows:
4-chlorophenyl isonitrile (41.3 mg,0.3mmol,1.0 equiv.) TMDETA (69.7 mg,0.6mmol,2.0 equiv.) and 3mL CH 3 CN were added to a 50mL Schlenk flask. The Schlenk flask was evacuated and refilled with CF 3 Br gas, repeated three times, and finally the pressure in the Schlenk flask was maintained at 1.0atm (observed from a barometer). The reaction system was stirred at room temperature for 36 hours under 20W (410 to 420 nm) of blue light. After the reaction was completed, the organic phase was concentrated by a rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as a stationary phase, petroleum ether and ethyl acetate as eluent (PE: ea=15:1, volume ratio) to give 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d), as a yellow oily liquid, 32.2mg, yield 62%.
The 2-trifluoromethyl-3- [ N- (4-chlorophenyl) ] amino-5-chloroindole (3 d) synthesized in example 4 was subjected to 1HNMR、13C NMR、19 F NMR and high-resolution mass spectrometry, and the results were shown in FIGS. 13-16, and it can be seen from FIGS. 13-16 that the product obtained in example 4 was the pure target compound.
Characterization data of the product are specifically as follows:
1H 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).
13C{1H}NMR(150MHz,CDCl3)δ144.3,132.7,129.2,126.8,126.0,124.9,124.2,121.1(q,JC-F＝267.3Hz),119.9(q,JC-F＝36.6Hz),119.9,119.1(q,JC-F＝2.7Hz),115.5,113.4.
19F NMR(376MHz,CDCl3)δ-59.42(s).
HRMS(ESI):m/z calcd for C15H10Cl2F3N2[M+H]+345.0168,found345.0174.
example 5
Synthesis of 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e)
The synthetic route is as follows:
the specific preparation process is as follows:
3, 4-methylenedioxyphenyl isonitrile (29.4 mg,0.2mmol,1.0 equiv.), -TMDETA (46.5 mg,0.4mmol,2.0 equiv.), 3mL CH 3 CN was added to a 50mL Schlenk flask. The Schlenk flask was evacuated and refilled with CF 3 Br gas, repeated three times, and finally the pressure in the Schlenk flask was maintained at 1.0atm (observed from a barometer). The reaction system was stirred at room temperature for 48 hours under 20W (410 to 420 nm) blue light. After the reaction was completed, the organic phase was concentrated by a rotary evaporator, and the remaining residue was purified by column chromatography using silica gel as a stationary phase, petroleum ether and ethyl acetate as an eluent (PE: ea=8:1, volume ratio) to give 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) as a yellow solid, 22.9mg, yield 63%.
The 2-trifluoromethyl-3- [ N- (3, 4-methylenedioxyphenyl) ] amino-5, 6-methylenedioxyindole (3 e) synthesized in example 5 was subjected to 1HNMR、13C NMR、19 F NMR and high resolution mass spectrometry, and as a result, as shown in FIGS. 17-20, it was revealed from FIGS. 17-20 that the product obtained in example 5 was the pure target compound.
Characterization data of the product are specifically as follows:
1H NMR(400MHz,CDCl3)δ8.01(s,1H),6.79(s,1H),6.72(s,1H),6.65(d,J＝8.4Hz,1H),6.32(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).
13C{1H}NMR(150MHz,CDCl3)δ148.2,147.6,143.8,141.2,141.0,130.0,121.6(q,JC-F＝266.1Hz),121.5,117.9,116.0(q,JC-F＝36.5Hz),108.4,107.2,101.1,100.8,98.6,97.9,92.2.
19F NMR(376MHz,150MHz,CDCl3)δ-58.65(s).
HRMS(ESI):m/z calcd for C17H12F3N2O4[M+H]+365.0744,found 365.0743.
Comparative example 1
The difference from example 1 was only that TMDETA (46.48 mg,0.4mmol,2.0 equiv.) was replaced with DIPEA (51.68 mg,0.4mmol,2.0 equiv.); 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 6.2mg, 17% yield.
As can be seen from comparative example 1, the yield is significantly reduced in the case of changing only the tertiary amine organic base to DIPEA, as compared with example 1.
Comparative example 2
The difference from example 1 was only that TMDETA (46.48 mg,0.4mmol,2.0 equiv.) was replaced with Et 3 N (59.68 mg,0.4mmol,2.0 equiv.); 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 7.3mg, 20% yield.
As can be seen from comparative example 2, the yield is significantly reduced in the case of changing only the tertiary amine organic base to Et 3 N, as compared with example 1.
Comparative example 3
The difference from example 1 was only that TMDETA (46.48 mg,0.4mmol,2.0 equiv.) was replaced with PMDETA (74.8 mg,0.4mmol,2.0 equiv.); 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid in a yield of 26% 9.5 mg.
As can be seen from comparative example 3, in the case of changing only the tertiary amine organic base to PMDETA, the yield is significantly reduced as compared with example 1.
Comparative example 4
The only difference from example 1 was that solvent CH 3 CN was replaced by an equal volume of Dichloromethane (DCM) and 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 10.3mg in 28% yield.
As can be seen from comparative example 4, the yield was significantly reduced in the case of changing only the solvent to DCM, compared to example 1.
Comparative example 5
The difference from example 1 is only that the solvent CH 3 CN is replaced by an equal volume of acetone (acetone) and that 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) is prepared as a yellow oily liquid, 5.5mg, in 15% yield.
As can be seen from comparative example 5, the yield was significantly reduced in the case of changing only the solvent to acetone as compared with example 1.
Comparative example 6
The difference from example 1 was only that solvent CH 3 CN was replaced by an equal volume of N, N-Dimethylformamide (DMF) and 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 3.2mg in 9% yield.
As can be seen from comparative example 6, the yield was significantly reduced in the case of changing only the solvent to DMF as compared with example 1.
Comparative example 7
The difference from example 1 was only that solvent CH 3 CN was replaced by an equal volume of dimethyl sulfoxide (DMSO) and 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 10.2mg in 28% yield.
As can be seen from comparative example 7, the yield was significantly reduced in the case of changing only the solvent to DMSO, as compared with example 1.
Comparative example 8
The difference from example 1 was only that TMDETA (46.48 mg,0.4mmol,2.0 equiv.) was replaced with TMDETA (23.24 mg,0.2mmol,1.0 equiv.); 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 8.5mg, in 23% yield.
As can be seen from comparative example 8, in the case of replacing TMDETA (46.48 mg,0.4mmol,2.0 equiv.) with TMDETA (23.24 mg,0.2mmol,1.0 equiv.) only, the yield is significantly reduced compared to example 1.
Comparative example 9
The difference from example 1 was only that TMDETA (46.48 mg,0.4mmol,2.0 equiv.) was replaced with TMDETA (69.72 mg,0.6mmol,3.0 equiv.); 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) was prepared as a yellow oily liquid, 10.9mg, in 30% yield.
As seen from comparative example 9, in the case of replacing TMDETA (46.48 mg,0.4mmol,2.0 equiv.) with TMDETA (69.72 mg,0.6mmol,3.0 equiv.) alone, the yield was significantly reduced compared to example 1.
Comparative example 10
The difference from example 1 was that blue light having a visible light wavelength of 410 to 420nm and a power of 20W was replaced with blue light having a visible light wavelength of 420 to 425nm and a power of 20W, to prepare 2-trifluoromethyl-3- [ N- (4-ethoxyphenyl) ] amino-5-ethoxyindole (3 a) as a yellow oily liquid, 15.2mg, and a yield of 42%.
As is clear from comparative example 10, in comparison with example 1, when only blue light having a visible light wavelength of 410 to 420nm and a power of 20W was replaced with blue light having a visible light wavelength of 420 to 425nm and a power of 20W, the yield was lowered.
Comparative example 11
The difference from example 1 is that blue light with a visible light wavelength of 410 to 420nm and a power of 20W is replaced by blue light with a visible light wavelength of 460 to 460 nm and a power of 20W, and the reaction system is stirred at room temperature for reaction, and then the reaction is detected by TLC, so that the generation of the target product is not monitored even after the reaction for 72 hours.
As is clear from comparative example 11, in comparison with example 1, when only blue light having a visible light wavelength of 410 to 420nm and a power of 20W is replaced with blue light having a visible light wavelength of 460 to 460 nm and a power of 20W, no reaction occurs.
Indole skeleton itself has antibacterial, antiinflammatory and anticancer activities, and compound B is reported in bioorg.Med. Chem.2007,15,3248-3265 (structural formula) Can secrete insulin in vitro, and has good activity for treating type II diabetes. The invention provides a preparation method of a 2-trifluoromethyl-3-aminoindole compound, which shows that the compound prepared by the embodiment of the invention can be used for preparing medicines with the function of treating diabetes.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (4)

1. The preparation method of the 2-trifluoromethyl-3-aminoindole compound is characterized in that the structural general formula of the 2-trifluoromethyl-3-aminoindole compound is as follows:
;
In the structural general formula, R is Et, OEt, OCOCH 3 or Cl;
The preparation method of the 2-trifluoromethyl-3-aminoindole compound comprises the following steps:
In the presence of visible light induction and tertiary amine organic alkali, carrying out free radical series cyclization reaction on CF 3 Br and aryl isonitrile derivatives in an organic solvent to obtain the 2-trifluoromethyl-3-aminoindole compound;
The structural general formula of the aryl isonitrile derivative is as follows:
;
The tertiary amine organic base is N, N, N ', N' -tetramethyl ethylenediamine;
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 the wavelength of 410-420 nm and the power of 20W.
2. The method of claim 1, wherein CF 3 Br is added as CF 3 Br gas, the CF 3 Br gas having a pressure of 1.0 atm, and the amount added is in excess.
3. The method of claim 1, wherein the organic solvent is acetonitrile.
4. The method according to claim 1, wherein the time for the radical tandem cyclization reaction is 24 to 72 hours.
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CN119241435A (en) * 2024-09-28 2025-01-03 西北师范大学 A kind of synthesis method of 6-trifluoromethylthiophenanthridine compound
CN119431386A (en) * 2024-11-05 2025-02-14 西北师范大学 A method for synthesizing 2'-(trifluoromethyl)-4,5-dihydro-spiro[furan-2,3'-indoline] derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119241435A (en) * 2024-09-28 2025-01-03 西北师范大学 A kind of synthesis method of 6-trifluoromethylthiophenanthridine compound
CN119431386A (en) * 2024-11-05 2025-02-14 西北师范大学 A method for synthesizing 2'-(trifluoromethyl)-4,5-dihydro-spiro[furan-2,3'-indoline] derivatives

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