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Preparation method of polysubstituted 2-aryl indole derivative

A technique for aryl indole derivatives and multi-substitution, which is applied in the field of preparation of multi-substituted 2-aryl indole derivatives, can solve the problems of limited substrate scope, unfavorable research, complex preparation and the like, and achieves easy operation and reaction. The effect of easy availability of raw materials, high chemoselectivity and regioselectivity

Active Publication Date: 2020-04-14
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses the precious metal iridium, and at the same time this method requires the use of a special ligand, and the preparation of the ligand is complex, which is not conducive to further research
Lu Xin's team (J.Org.Chem.2014, 79, 9000-9008) first realized the cheap copper-catalyzed coupling / cyclization reaction of 2-alkynyl aniline and boronic acid, realizing the one-pot preparation of N-alkyl 2 -Arylindole, but low efficiency and limited substrate range

Method used

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  • Preparation method of polysubstituted 2-aryl indole derivative
  • Preparation method of polysubstituted 2-aryl indole derivative
  • Preparation method of polysubstituted 2-aryl indole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Preparation of 1-phenyl-3-(2-phenyl-1H-indol-1-yl)propan-1-one (Ia)

[0021] 2-Phenylethynylaniline (96.6 mg, 0.5 mmol), propiophenone (80.5 mg, 0.6 mmol), Cu(OAc) were added to a 10 mL reactor 2 (9.1mg, 0.05mmol), 2,2'-bipyridine (15.6mg, 0.1mmol), 4-hydroxy-2,2,4,4-tetramethylpiperidine nitroxide radical (4-OH-TEMPO ) (86.1 mg, 0.5 mmol) and 3 mL of 1,2-dichlorobenzene. After heating at 120°C for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane / ethyl acetate=50 / 1, v / v) to obtain a white solid 1-phenyl-3-(2-benzene (133.4 mg, 82%), melting point: 134-137°C. 1 H NMR (400MHz, CDCl 3 , ppm) δ7.76(d, J=7.2Hz, 2H), 7.65(d, J=8.0Hz, 1H), 7.60-7.38(m, 9H), 7.25(d, J=7.2Hz, 1H), 7.16(d,J=7.6Hz,1H),6.61(s,1H), 4.75-4.64(m,2H),3.33-3.23(m,2H). 13 C NMR (100MHz, CDCl 3 ,ppm) δ197.8,141.1,137.2,136.2,133.4,132.7,129.4,128.7,128.6,128.5, 128.2,128.0,121.9,120.7,120.2,109.8,102.9,39.3,38.5.H...

Embodiment 2

[0022] Example 2: Preparation of 1-phenyl-3-(2-phenyl-1H-indol-1-yl)propan-1-one (Ia)

[0023] 2-Phenylethynylaniline (96.6 mg, 0.5 mmol), propiophenone (80.5 mg, 0.6 mmol), Cu(OAc) were added to a 10 mL reactor 2 (9.1mg, 0.05mmol), 2,2'-bipyridine (15.6mg, 0.1mmol), 2,2,4,4-tetramethylpiperidine nitroxide (TEMPO) (78.1mg, 0.5mmol) and 3 mL of 1,2-dichlorobenzene. After heating at 120°C for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane / ethyl acetate=50 / 1, v / v) to obtain a white solid Ia (120.4 mg, 74%), melting point: 134~137℃.

Embodiment 3

[0024] Example 3: Preparation of 1-phenyl-3-(2-phenyl-1H-indol-1-yl)propan-1-one (Ia)

[0025] 2-Phenylethynylaniline (96.6 mg, 0.5 mmol), propiophenone (80.5 mg, 1.0 mmol), Cu(OAc) were added to a 10 mL reactor 2 (9.1 mg, 0.05 mmol), 2,2'-bipyridine (15.6 mg, 0.1 mmol), TEMPO (78.1 mg, 0.5 mmol) and 3 mL of chlorobenzene. After heating at 120°C for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane / ethyl acetate=50 / 1, v / v) to obtain a white solid Ia (71.6 mg, 44%), melting point: 134~137℃.

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Abstract

The invention discloses a preparation method of a polysubstituted 2-aryl indole derivative. The method specifically comprises the following steps: by taking a 2-acetenyl aniline compound and a ketonecompound as raw materials, carrying out oxidative cyclization reaction on the 2-acetenyl aniline compound and the ketone compound under the action of a catalyst, a ligand and an oxidizing agent to prepare the polysubstituted 2-arylindole derivative. The method provided by the invention has the characteristics of easily available raw materials, simple operation, high chemical selectivity and regioselectivity, and the like, and has great implementation value and social and economic benefits.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, and in particular relates to a preparation method of multi-substituted 2-arylindole derivatives. Background technique [0002] After long-term research and summary, medicinal chemists have found that some small molecular frameworks in living organisms can bind to multiple receptors with high affinity, and may become new receptor agonists and antagonists after structural modification. In 1988, Evans et al. (J.Med. Chem., 1988, 31(12):2235-2246.) defined such structures as "Privileged structures". In the initial stage of drug discovery, modification of dominant structures is a feasible strategy for discovering new drugs. Indole is such a dominant structure, and compounds with indole skeletons also play an important role in organisms, so some people think that indole may be one of the most important structures in drug discovery. Among them, 2-arylindo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10C07D209/12C07D209/08C07D409/06
CPCC07D209/08C07D209/10C07D209/12C07D409/06
Inventor 凌飞宋定国肖莲钟为慧
Owner ZHEJIANG UNIV OF TECH
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