3-substituted indolone derivative and preparation method and application thereof

A technology of derivatives and indolinones, which is applied in the field of 3-substituted indolinone derivatives and their preparation, can solve the problems of limited scope of application of substrates, low diastereoselectivity and enantioselectivity, and difficulty in obtaining Issues such as high diastereoselectivity and highly enantioselective products

Inactive Publication Date: 2014-04-16
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, there are relatively few reports on asymmetric Mannich reactions, and it is difficult to obtain high diastereoselectivity and high enantioselectivity products.
[0004] The present invention overcomes the defects such as low diastereoselectivity and enantioselectivity in the preparation method of prior art 3-substituted indolinone derivatives, and the scope of substrate application is not wide, and proposes a 3-substituted indolinone derivative. Substituted indolinone derivatives and their preparation methods and applications, the preparation method of the present invention has efficient atom economy, high selectivity, high yield, wide application range of substrates, high diastereoselectivity and enantioselectivity and simple operation Beneficial effects such as safety

Method used

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  • 3-substituted indolone derivative and preparation method and application thereof
  • 3-substituted indolone derivative and preparation method and application thereof
  • 3-substituted indolone derivative and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064]

[0065] Dissolve imine (0.1mmol), chiral phosphoric acid (0.01mmol) and rhodium acetate (0.002mmol) in 1mL of dichloromethane to form a reaction system, and dissolve diazo compound (0.2mmol) in 1mL of dichloromethane to form a solution , At -20°C, the solution of the diazo compound dissolved in dichloromethane was added dropwise to the reaction system within 1 hour using an autosampler pump. After the injection was completed, the reaction was continued to stir at -20°C for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-1). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-6:1) to obtain a pure product. Yield: 72%, dr: 99:1, ee 97%.

[0066] In this embodiment, R in the structural formula of the chiral phosphoric acid is a triphenylsilyl group.

[0067] 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 7.25 (d, J = 7.5Hz, 1H), 7.19 (...

Embodiment 2

[0069]

[0070] Dissolve imine (0.1mmol), chiral phosphoric acid (0.01mmol) and rhodium acetate (0.002mmol) in 1mL of dichloromethane to form a reaction system, and dissolve diazo compound (0.2mmol) in 1mL of dichloromethane to form a solution , At -20°C, the solution of the diazo compound dissolved in dichloromethane was added dropwise to the reaction system within 1 hour using an autosampler pump. After the injection was completed, the reaction was continued to stir at -20°C for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-2). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-6:1) to obtain a pure product. Yield: 70%, dr: 99:1, ee 97%.

[0071] In this embodiment, R in the structural formula of the chiral phosphoric acid is a triphenylsilyl group.

[0072] 1 H NMR (CDCl 3 , 400MHz): δ (ppm) 7.23 (d, J = 7.1Hz, 1H), 7.19 (...

Embodiment 3

[0074]

[0075] Dissolve imine (0.1mmol), chiral phosphoric acid (0.01mmol) and rhodium acetate (0.002mmol) in 1mL of dichloromethane to form a reaction system, and dissolve diazo compound (0.2mmol) in 1mL of dichloromethane to form a solution , At -20°C, the solution of the diazo compound dissolved in dichloromethane was added dropwise to the reaction system within 1 hour using an autosampler pump. After the injection was completed, the reaction was continued to stir at -20°C for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-3). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-6:1) to obtain a pure product. Yield: 57%, dr: 99:1, ee 95%.

[0076] In this embodiment, R in the structural formula of the chiral phosphoric acid is a triphenylsilyl group.

[0077] 1 H NMR (CDCl 3 , 400MHz): δ(ppm) 7.29-7.26(m, 2H), 7.19(t, J=7.6H...

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Abstract

The invention discloses a preparation method for 3-substituted indolone derivative. The preparation method comprises the steps of: using imine and diazo compound as materials, rhodium acetate and chiral phosphoric acid as catalysts and organic solvent as solvent, performing one-step reaction to acquire the 3-substituted indolone derivative. The preparation method has the advantages of high-efficiency atom economy, high selectivity, high yield, simple and safe operation and the like. With high diastereomeric selectivity and enantioselectivity, and bioactivity, the 3-substituted indolone derivative prepared by the method is applicable to the preparation application of anti-tumour medicines.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and in particular relates to a biologically active 3-substituted indolinone derivative and its preparation method and application. Background technique [0002] Chiral indolinone compounds widely exist in natural compounds and drug molecules. Due to their special physiological activities, the synthesis of such compounds is one of the important fields of organic chemistry research, especially asymmetric synthesis is more challenging. [0003] There are multiple methods for the synthesis of chiral indolinones reported in the literature, mainly focusing on the asymmetric addition reaction to prochiral indole (Chem.Sci., 2011, 2, 2035; Chen, Chem.Comm., 2009, 11, 3955; Org. Lett., 2009, 11, 3874). Among them, there are relatively few reports on asymmetric Mannich reactions, and it is also difficult to obtain products with high diastereoselectivity and high e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34A61P35/00
Inventor 胡文浩厉铭昝力周静张霞杨琍苹
Owner EAST CHINA NORMAL UNIV
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