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3,3'-dihydrofuran spiro-oxoindole derivative and preparation method and application thereof

A technology of dihydrofuran spiro and indole derivatives, which is applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve the problems of decreased reaction selectivity, irritating odor, inconvenient experimental operation, etc., and achieves atomic utilization. High yield, high yield and wide range of substrates

Active Publication Date: 2016-06-29
广东和博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this reaction is that α-isothiocyanate amide / ester / lactone generally has a pungent odor, which is not convenient for experimental operation
However, with this synthetic method, if triisopropylallylsilane is replaced with other allylsilanes, the proportion of isatin directly allylated products will increase, and the reaction selectivity will decrease.

Method used

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  • 3,3'-dihydrofuran spiro-oxoindole derivative and preparation method and application thereof
  • 3,3'-dihydrofuran spiro-oxoindole derivative and preparation method and application thereof
  • 3,3'-dihydrofuran spiro-oxoindole derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]Weigh 3-dicyanomethyleneoxindole (0.5 mmol) into a 50 mL eggplant-shaped bottle, and add 5 mL of commercially available reagent grade dichloromethane. Take another small bottle and add 5mL of water, weigh copper trifluoromethanesulfonate (0.05mmol), mix well, transfer to an eggplant-shaped bottle, and stir thoroughly. Weigh ethyl diazoacetate (2.0 mmol), add dichloromethane to make 4 mL mixed solution. The mixed solution was withdrawn with a 5 mL syringe, and injected into a mixed solution containing 3-dicyanomethyleneoxindole, copper trifluoromethanesulfonate, and dichloromethane through a peristaltic pump control. After stirring at room temperature for 1 hour, the layers were separated. The lower organic phase was collected and extracted three times with 15 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After filtration, a1 and a2 were separated by column chromatography (eluent:petroleum ether:ethyl acetate with ...

Embodiment 2

[0042] Weigh 5-methyl-3-dicyanomethyleneoxindole (0.5 mmol) into a 50 mL eggplant-shaped bottle, and add 5 mL of commercially available reagent grade dichloromethane. Take another small bottle and add 5mL of water, weigh copper trifluoromethanesulfonate (0.05mmol), mix well, transfer to an eggplant-shaped bottle, and stir thoroughly. Weigh ethyl diazoacetate (2.0 mmol), add dichloromethane to make 4 mL mixed solution. The mixed solution was withdrawn with a 5 mL syringe, and injected into a mixed solution containing 5-methyl-3-biscyanomethyleneoxindole, copper trifluoromethanesulfonate, and dichloromethane through a peristaltic pump. After stirring at room temperature for 1 hour, the mixture was allowed to stand still to separate layers. The lower organic phase was collected and extracted three times with 15 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After filtration, b1 and b2 were separated by column chromatography...

Embodiment 3

[0048] Weigh 5-methoxy-3-dicyanomethyleneoxindole (0.5 mmol) into a 50 mL eggplant-shaped bottle, and add 5 mL of commercially available reagent grade dichloromethane. Take another small bottle and add 5mL of water, weigh copper trifluoromethanesulfonate (0.05mmol), mix well, transfer to an eggplant-shaped bottle, and stir thoroughly. Weigh ethyl diazoacetate (2.0 mmol), add dichloromethane to make 4 mL mixed solution. The mixed solution was withdrawn with a 5 mL syringe, and injected into a mixed solution containing 5-methoxy-3-biscyanomethyleneoxindole, copper trifluoromethanesulfonate, and dichloromethane through a peristaltic pump. After stirring at room temperature for 1 hour, the mixture was allowed to stand still to separate layers. The lower organic phase was collected and extracted three times with 15 mL of ethyl acetate. The upper organic phases were combined and dried over anhydrous sodium sulfate. After filtration, c1 and c2 were separated by column chromatograp...

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Abstract

The invention discloses a 3,3'-dihydrofuran spiro-oxoindole derivative and a preparation method thereof. Cyano methylene oxoindole, water and diazonium are used as raw materials, a transition metal salt is used as a catalyst, dichloromethane and water are used as a mixed solvent, and the compound represented by the formula (I) is prepared by a one-step reaction. The invention also provides an application of the 3,3'-dihydrofuran spiro-oxoindole derivative in preparation of tumor suppressing drugs, and the 3,3'-dihydrofuran spiro-oxoindole derivative can be used as a potential bioactive skeleton. The high atom economic reaction is applied, the target product is prepared with high yield, and the method has the advantages of short synthetic route, green and environmental protection, simple operation and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method and application of 3,3'-dihydrofuran spiroepoxide indole derivatives. Background technique [0002] Oxindole spirocycle is a common structural unit in drug-like molecules, and exists in the molecular frameworks of various natural products including alkaloids. Such as anti-mitotic precursor strychnofoline, ML-219 and sodium ion channel blocker XEN907 and so on. [0003] [0004] Although its importance has attracted widespread attention from chemists, literature reports on the synthesis of the backbone of this class of compounds mainly focus on nitrogen-containing spirooxindole structures. Wang Rui's group at Lanzhou University used small organic molecules to catalyze the synthesis of 3,3'-pyrrolidone-oxindole (Angew. Chem. Int. Ed, 2011, 50, 9124-9127). The key technology of the route is to use methylene oxide indole as a substrat...

Claims

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Application Information

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IPC IPC(8): C07D491/107A61P35/00
Inventor 胡文浩滕胜寒史滔达魏雅洁
Owner 广东和博制药有限公司
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