Preparation method for polysubstituted indole derivatives

A technology of indole derivatives and multi-substitution, which is applied in the field of preparation of multi-substituted indole derivatives, can solve problems such as pollution and complex preparation methods, and achieve the effect of strong operability and simple technology

Active Publication Date: 2016-01-13
北京普诺旺康医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a method for preparing multi-substituted indole derivatives, which solves the problem of the preparation method in the prior art Complex and polluting technical issues

Method used

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  • Preparation method for polysubstituted indole derivatives
  • Preparation method for polysubstituted indole derivatives
  • Preparation method for polysubstituted indole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 16

[0016] Example 16-Methyl-2-phenyl-3-(phenylthio)-1H-indole

[0017]

[0018] In a 25mL three-neck flask, add B-2 (282mg, 1mmol), and then add Cs 2 CO 3 (652mg, 2mmol), diphenyl disulfide (109mg, 0.5mmol), L-proline (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol) , 5mLDMF, under the protection of nitrogen, react in an oil bath at 100°C for 24h, add 5mL water after cooling, extract with 5mL ethyl acetate each time, after repeating four times, the extract is washed with saturated brine, anhydrous sulfuric acid After drying over sodium, the filtered liquid was distilled under reduced pressure, and the distillate was separated through a silica gel column (eluent: petroleum ether: ethyl acetate = 10:1) to obtain 274.4 mg of a light yellow solid with a yield of 87%.

[0019] 1 HNMR (500MHz, CDCl 3 )δ8.48(s,1H),7.78(d,J=7.4Hz,2H),7.57(d,J=8.0Hz,1H),7.46(t,J=7.4Hz,2H),7.41(t, J=7.1Hz, 1H), 7.27(s, 1H), 7.22(t, J=7.6Hz, 2H), 7.17(d, J=7.4Hz, 2H)...

Embodiment 26

[0020] Example 26-Nitro-2-phenyl-3-(phenylthio)-1H-indole

[0021]

[0022] In a 25mL three-neck flask, add B-3 (313mg, 1mmol), and then add Cs 2 CO 3 (652mg, 2mmol), diphenyl disulfide (109mg, 0.5mmol), L-proline (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol) , 5mLDMF, under the protection of nitrogen, react in an oil bath at 100°C for 24h, add 5mL water after cooling, extract with 5mL ethyl acetate each time, after repeating four times, the extract is washed with saturated brine, anhydrous sulfuric acid After drying over sodium, the filtered liquid was distilled under reduced pressure, and the distillate was separated through a silica gel column (eluent: petroleum ether: ethyl acetate = 10:1) to obtain 294.4 mg of a yellow solid with a yield of 85%.

[0023] 1 HNMR (500MHz, CDCl 3 )δ8.54(s,1H),7.80(dd,J=7.1,1.2Hz,2H),7.62(dd,J=7.7,5.0Hz,1H),7.51-7.39(m,4H),7.26-7.19 (m,4H),7.17-7.07(m,2H).

Embodiment 3

[0024] Example 32-((2-phenyl-1H-indol-3-yl)thio)benzo[d]thiazole

[0025]

[0026] In a 25mL three-neck flask, add B-1 (268mg, 1mmol), and then add Cs 2 CO 3 (652mg, 2mmol), benzothiazole disulfide (166mg, 0.5mmol), L-proline (34.5mg, 0.3mmol), cuprous iodide (19mg, 0.1mmol), phenylacetylene (102mg, 1mmol), 5mL of DMF, under the protection of nitrogen, react in an oil bath at 100°C for 24h, add 5mL of water after cooling, extract with 5mL of ethyl acetate each time, after repeating four times, the extract is washed with saturated saline, anhydrous sodium sulfate After drying and filtering, the liquid was distilled under reduced pressure, and the distillate was separated through a silica gel column (eluent: petroleum ether: ethyl acetate = 10:1) to obtain 272.4 mg of a light yellow solid with a yield of 76%.

[0027] 1 HNMR (500MHz, CDCl 3 )δ10.63(s,1H),7.81(s,1H),7.55(s,1H),7.47(s,3H),7.39(s,2H),7.30(s,6H).

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Abstract

The invention provides a preparation method for polysubstituted indole derivatives. The preparation method comprises employing alkynyl-terminated hydrocarbon, a halogenated aniline derivative and a disulfide as initial raw materials, using an amino acid as an additive and a copper salt as a catalyst, performing a coupling-tandem one-pot reaction in an organic solvent under an alkali-added condition, so as to obtain the corresponding polysubstituted indole derivative, wherein the catalyst is CuX, and X is iodine or bromine. According to the technical scheme, the method for synthesizing the polysubstituted indole derivatives through one-pot process is developed on the basis of a method for synthesizing 2-substituted indole through copper catalysis. The method does not employ an expensive palladium catalyst easily polluting environment. The method enables alkynyl-terminated hydrocarbon, one halogenated aniline derivative and one disulfide to have the coupling-tandem one-pot reaction under a relatively mild condition, is simple in technology and strong in operationality, and possesses industrial application prospect.

Description

technical field [0001] The invention belongs to the field of chemical industry and relates to a preparation method of multi-substituted indole derivatives. Background technique [0002] Multi-substituted indole is an important class of organic compounds, because indole skeleton compounds widely exist in natural products and biologically active compounds, and are important intermediates for drug development and synthesis. Among the many synthetic strategies and methods of indole ring skeleton construction, a step-by-step method is basically adopted, that is, the 2-substituted indole is first synthesized by noble metal palladium-catalyzed Sonogashira coupling reaction, and then derivatized at the 3-position of indole. However, due to the relatively expensive palladium catalyst and serious environmental pollution, in the past few years, some relatively mild methods of synthesizing 2-substituted indoles by adding ligands using Cu as a catalyst have been greatly developed. ((a) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/30C07D417/12
CPCC07D209/30C07D417/12
Inventor 刘烽张奕潘仙华陈晓云
Owner 北京普诺旺康医药科技有限公司
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