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

A technology for oxindolinone and its derivatives, which is applied in the field of 3-substituted-3-oxindolinone derivatives and its preparation, can solve the problems of many reaction steps and complicated operation, and achieve high selectivity, simple and safe operation , the effect of high yield

Inactive Publication Date: 2013-09-11
EAST CHINA NORMAL UNIV
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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 tetrahydrofuran to form a reaction system, and dissolve diazoacetanilide (0.42mmol) in 2mL tetrahydrofuran to form a solution, at room temperature Then, the solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise to the reaction system within 1 hour using an automatic sampling pump. After the injection was completed, the reaction was continued to be stirred 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 is shown in formula (1-1). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain 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...

Embodiment 2

[0059]

[0060] 6-Chloroisatin (0.28mmol), aniline (0.42mmol) and rhodium acetate (0.0028mmol) were dissolved in 4mL of tetrahydrofuran to form a reaction system, and diazoacetyl-p-methoxyaniline (0.42mmol) was dissolved in 2mL of tetrahydrofuran To form a solution, at room temperature, a solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise to the reaction system within 1 hour with an automatic sampling pump. After the injection was completed, the reaction was continued to be stirred 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 is shown in formula (1-2). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain 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).;

[...

Embodiment 3

[0064]

[0065] Dissolve 6-chloroisatin (0.28mmol), aniline (0.42mmol) and rhodium acetate (0.0028mmol) in 4mL tetrahydrofuran to form a reaction system, and dissolve diazoacetyl-n-propylamine (0.42mmol) in 2mL tetrahydrofuran to form a solution, At room temperature, a solution of diazoacetanilide dissolved in tetrahydrofuran was added dropwise to the reaction system within 1 hour using an automatic sampling pump. After the injection was completed, the reaction was continued to be stirred 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 is shown in formula (1-3). The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain 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), 1.29(m, 2H), 0.77(t, ...

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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 industry, and in particular relates to a 3-substituted-3-hydroxyindolinone derivative with biological activity and a preparation method and application thereof. Background technique [0002] The protein of the oncogene MDM2 can bind to the tumor suppressor protein p53 and inhibit the function of p53, promoting the degradation of p53. Overexpression of MDM2 is one of the important factors in tumorigenesis and progression. The development of antitumor drugs based on the structure of MDM2-p53 complex has a good prospect. [0003] Many foreign literatures have reported some small molecule MDM2-p53 inhibitors (J.Am.Chem.Soc.2008, 130, 12355-12369, Bioorg.Med.Chem.Lett.15, 2005, 1515-1520, J.Am.Chem.Soc.2008, 130, 12355-12369, . Med. Chem. 2006, 49, 3759-3762). 3-Substituted-3-hydroxyindolinone derivatives are the backbone structures of some natural active compounds, and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 UNIV
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