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3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof

A technology for hydroxyindolinone and derivatives, which is applied in the field of 3-substituted-3-hydroxyindolinone derivatives and their preparation, can solve the problems of many reaction steps, complicated operations and the like, and achieves high selectivity, simple and safe operation , the effect of inhibiting cell growth

Inactive Publication Date: 2012-06-27
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention overcomes the defects of complex operations and many reaction steps in the preparation method of 3-substituted-3-oxindolinone derivatives in the prior art, and proposes a 3-substituted-3-oxindolinone Derivatives and their preparation methods and applications, the preparation method of the present invention has the beneficial effects of efficient atom economy, high selectivity, high yield, simple and safe operation, etc.

Method used

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  • 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof
  • 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof
  • 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] Dissolve 6-chloroisatin (0.28mmol), aniline (0.42mmol) and rhodium acetate (0.0028mmol) in 4mL of tetrahydrofuran to form a reaction system, and dissolve diazoacetanilide (0.42mmol) in 2mL of tetrahydrofuran to form a solution. The solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise into the reaction system within 1 hour using an automatic injection pump. After the sample injection was completed, the stirring reaction was continued at room temperature 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 (1-1). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain a pure product. Yield: 84%, dr value: 32:68.

[0056] 1 H-NMR (DMSO-d 6 , 400MHz): δ10.47(s, 1H), 9.65(s, 1H), 6.62-7.69(m, 14H), 5.73(d, 1H), 4.37(s, 1H).;

[0057] 13 C-NMR (DMSO-d 6 , 125MHz): δ177.2, 167.6, 147.9, 1...

Embodiment 2

[0059]

[0060] Dissolve 6-chloroisatin (0.28mmol), aniline (0.42mmol) and rhodium acetate (0.0028mmol) in 4mL tetrahydrofuran to form a reaction system, and dissolve diazoacetyl-p-methoxyaniline (0.42mmol) in 2mL tetrahydrofuran A solution was formed, and at normal temperature, a solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise to the reaction system within 1 hour by using an auto-sampling pump. After the sample injection was completed, the stirring reaction was continued at room temperature 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 (1-2). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain a pure product. Yield: 85%, dr value: 30:70.

[0061] 1 H-NMR (DMSO-d 6 , 400MHz): δ10.49(s, 1H), 10.15(s, 1H), 6.47-7.55(m, 12H), 6.47(s, 1H), 4.70(d, 1H), 4.34(d, 1H), 3.71(s, 3H).;

[0062...

Embodiment 3

[0064]

[0065] 6-chloroisatin (0.28mmol), aniline (0.42mmol) and rhodium acetate (0.0028mmol) were dissolved in 4mL tetrahydrofuran to form a reaction system, diazoacetyl n-propylamine (0.42mmol) was dissolved in 2mL tetrahydrofuran to form a solution, At normal temperature, a solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise into the reaction system within 1 hour by using an automatic injection pump. After the sample injection was completed, the stirring reaction was continued at room temperature 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 (1-3). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain a pure product. Yield: 66%, dr value: 27:73.

[0066] 1 H-NMR (DMSO-d 6 , 400MHz): δ10.43(s, 1H), 8.10(s, 1H), 6.58-7.35(m, 8H), 6.35(s, 1H), 4.73(d, 1H), 4.41(d, 1H), 2.89-3.09(m, 2H), 1...

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Abstract

The invention discloses 3-substituted-3-hydroxyindazolone derivatives, and a preparation method and application thereof. Isatin, amine and diazo compound are used as raw materials, rhodium acetate is used as a catalyst, and an organic solvent is used as a solvent, a one-step reaction is carried out to obtain the product 3-substituted-3-hydroxyindazolone derivatives. The preparation method disclosed by the invention has the advantages of high atom economical efficiency, high selectivity, high yield and the like, and is simple and safe to operate. The 3-substituted-3-hydroxyindazolone derivatives have bioactivity, and are applicable to preparing antineoplastic drugs.

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-3-oxindolinone derivative and its preparation method and application. Background technique [0002] The protein of the oncogene MDM2 can combine with the tumor suppressor protein p53 and inhibit the function of p53, and promote the degradation of p53. The overexpression of MDM2 is one of the important factors in the occurrence and development of tumors. According to the structure of MDM2-p53 complex, the development of anti-tumor drugs has a good prospect. [0003] There are many foreign documents reporting some small molecule MDM2-p53 inhibitors (J.Am.Chem.Soc.2008,130,12355-12369, Bioorg.Med.Chem.Lett.15,2005,1515-1520, J Med. Chem. 2006, 49, 3759-3762). 3-substituted-3-oxindolinone derivatives are the skeleton structures of some natural active compounds, and their structures are simila...

Claims

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Application Information

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IPC IPC(8): C07D209/38A61P35/00
Inventor 胡文浩厉铭郭鑫周静郭婧杨琍苹
Owner EAST CHINA NORMAL UNIVERSITY
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