3,3'-disubstituted-3-hydroxy bis-indolinone derivative and preparation method and application thereof

A kind of technology of hydroxybisindolone and derivatives, applied in 3 fields

Inactive Publication Date: 2012-07-04
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the reaction is 52-80%, and the diastereoselectivity is greater than 11:1, but the reaction requires a two-step reaction, and the aldol reaction occurs at a temperature of -78°C to -50°C, and the temperature is difficult to control. The required Boron trifluoride is 2.0 equivalents
[0004] The present invention overcomes the many reaction steps existing in the prior art 3,3'-disubstituted-3-hydroxybisindolinone preparation method, and the reaction temperature is difficult to control , the amount of required catalyst is high, and a method for preparing 3,3'-disubstituted-3-hydroxybisindolinone derivatives is proposed. The preparation method of the present invention has efficient atom economy, high selectivity, and high yield , simple and safe operation and other beneficial effects

Method used

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  • 3,3'-disubstituted-3-hydroxy bis-indolinone derivative and preparation method and application thereof
  • 3,3'-disubstituted-3-hydroxy bis-indolinone derivative and preparation method and application thereof
  • 3,3'-disubstituted-3-hydroxy bis-indolinone derivative and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045]Dissolve N-benzyl isatin (0.12 mmol) and rhodium acetate (0.0012 mmol) in 1 mL of tetrahydrofuran to form a reaction system, and dissolve N-methyldiazoacetanilide (0.24 mmol) in 1 mL of tetrahydrofuran to form a solution. A solution of N-methyldiazoacetanilide dissolved in tetrahydrofuran was added dropwise to the reaction system within 1 hour using an automatic injection pump. After the sample injection, continue to stir at room temperature for 0.5 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was shown in formula (1-1). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=15:1-4:1) to obtain a pure product. Yield: 66%, dr value: 92:8.

[0046] 1 H-NMR (CDCl 3 , 500MHz): δ 7.58 (d, J = 7.2 Hz, 1 H), 7.20-7.30 (m, 2 H), 7.10-7.18 (m, 2 H), 7.07-7.08 (m, 2 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.70 (t, J = 9.2 Hz, 1 H), 6.57-6.69 (m, 3 H), 6.2...

Embodiment 2

[0049]

[0050] Dissolve N-benzyl isatin (0.12 mmol) and rhodium acetate (0.0012 mmol) in 1 mL of toluene to form a reaction system, and dissolve N-methyldiazoacetanilide (0.24 mmol) in 1 mL of toluene to form a solution. A solution of N-methyldiazoacetanilide dissolved in toluene was added dropwise to the reaction system within 1 hour using an auto-sampling pump. After the sample injection, continue to stir at room temperature for 0.5 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product whose structure is shown in formula (1-2). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=15:1-4:1) to obtain a pure product. Yield: 60%, dr value: 90:10.

Embodiment 3

[0052]

[0053] Dissolve N-benzyl isatin (0.12 mmol) and rhodium acetate (0.0012 mmol) in 1 mL of dichloromethane to form a reaction system, and dissolve N-methyldiazoacetanilide (0.24 mmol) in 1 mL of dichloromethane to form a reaction system Solution, at room temperature, the solution of N-methyldiazoacetanilide dissolved in dichloromethane was added dropwise to the reaction system within 1 hour with an automatic injection pump. After the injection was completed, stirring was continued at room temperature for 0.5 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was shown in formula (1-3). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=15:1-4:1) to obtain a pure product. Yield: 68%, dr value: 80:20.

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Abstract

The invention discloses a 3,3'-disubstituted-3-hydroxy bis-indolinone derivative and a preparation method and an application thereof. In the preparation method for the 3,3'-disubstituted-3-hydroxy bisindole ketone derivative disclosed by the invention, a one-step reaction is carried out on isatin and a diazo compound serving as raw materials by taking rhodium acetate as a catalyst and taking an organic solvent as a solvent, so that a product, i.e., the 3,3'-disubstituted-3-hydroxy bisindole ketone derivative is obtained. The preparation method disclosed by the invention has the advantages of high atom economy, high selectivity, high yield and the like, and is easy and safe for operating. The 3,3'-disubstituted-3-hydroxy bisindole ketone derivative prepared with the method is a precursor compound of a series of multi-indole ring-fused alkaloids.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and in particular relates to a 3,3'-disubstituted-3-hydroxybisindolinone derivative of a polyindolo ring alkaloid precursor, a preparation method and application thereof. Background technique [0002] Some alkaloids with special structures, such as compounds containing polyindolo rings, are widely found in natural plants and have good biological activities (Angew. Chem. Int. Ed. 2003, 42, 2525). The structure of 3,3'-disubstituted-3-hydroxybisindolinone can synthesize alkaloid idiospermuline through a series of reactions (Angew.Chem.Int.Ed.2003,42,2525), which has important significance in biomedicine , has the biological activity of reducing the polarization of acetylcholine and inhibiting the transfer of acetylcholine in vivo (J.Nat.Prod.1995,58,1200-1208). The 3,3'-disubstituted-3-hydroxybisindolinone structure is used as a precursor for the synthesis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12A61K31/404A61P43/00
Inventor 胡文浩昝力厉铭周静张霞杨琍苹
Owner EAST CHINA NORMAL UNIV
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