3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof

A technology of indole derivatives and oxyindole, which is applied in the fields of drug combination, organic chemistry, and pharmaceutical formulations, can solve problems such as special structure, complicated operation, and harsh reaction conditions, and achieve high flexibility, simple and safe operation, and high efficiency. selective effect

Active Publication Date: 2015-07-15
广东和博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the 3-amino-3-hydroxymethyloxindole derivative provided by this patent has a special structure, it is difficult to synthesize this type of compound by traditional methods, and there is no report of this type of compound at present; the 3 provided by this patent -Hydroxy-3-hydroxymethyl oxindole derivatives are brand new compounds, although some 3-hydroxy-3-hydroxymethyl oxindole derivatives can be derived from the literature Nat.Med.2009, 15, 750-756 , but the reaction conditions of this method are harsh and the operation is complicated

Method used

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  • 3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof
  • 3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof
  • 3-amino-3-hydroxymethyl oxoindole and 3-hydroxyl-3-hydroxymethyl oxoindole derivative, and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] Dissolve 2,6-dichloroaniline (0.1mmol), formaldehyde (0.6mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl A solution of 3-diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was Compound 1 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 94%

[0049] 1 H NMR (400MHz, CDCl 3 )δ7.40-7.27 (m, 5H), 7.15 (td, 1H), 7.09 (d, 2H), 6.78 (dt, 3H), 6.69-6.59 (m, 1H), 5.27 (s, 1H), 5.04 (d, 1H), 4.82(d, 1H), 3.97(t, 1H), 3.87(dd, 1H), 3.15(dd, 1H);

[0050] 13 C NMR (100MHz, CDCl ...

Embodiment 2

[0052]

[0053] Dissolve aniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an autosampler pump to inject 1-benzyl-3-diazo - A solution of 2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the compound 2 whose structure was shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 42%

[0054] 1 H NMR (400MHz, CDCl 3 )δ7.40-7.16(m, 8H), 7.06(t, 1H), 6.95(t, 2H), 6.84(d, 1H), 6.70(t, 1H), 6.27(d, 2H), 5.18(s , 1H), 5.11(d, 1H), 4.76(d, 1H), 3.92(t, 1H), 3.75-3.64(m, 1H), 3.12(d, 1H);

[0055] 13 C NMR (100MHz, CDCl 3 )δ 178.04, 145.5...

Embodiment 3

[0057]

[0058] Dissolve 4-chloroaniline (0.10mmol), formaldehyde (0.60mmol) and rhodium acetate (0.001mmol) in 1mL of ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-benzyl-3 - A solution of diazo-2-oxindole (0.10 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system within 1 hour. After the injection was completed, the reaction was continued to stir at 60° C. for 1 hour. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, the structure of which was compound 3 shown above. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain a pure product. Yield: 89%

[0059] 1 H NMR (400MHz, CDCl 3 )δ7.60(dd, 4H), 7.26-7.22(m, 1H), 7.22-7.16(m, 2H), 7.06(t, 1H), 6.88(t, 2H), 6.84(d, 1H), 6.24 -6.12(m, 2H), 5.24(s, 1H), 5.09(d, 1H), 4.73(d, 1H), 3.97-3.82(m, 1H), 3.75-3.66(m, 1H), 3.46(d ,1H); ...

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Abstract

The invention discloses preparation methods of 3-amino-3-hydroxymethyl oxoindole and a 3-hydroxyl-3-hydroxymethyl oxoindole derivative; with 3-diazonium oxoindole, aniline and formaldehyde or 3-diazonium oxoindole, water and formaldehyde as raw materials, with rhodium acetate as a catalyst and an organic solvent as a solvent, and through a one-step reaction, the product 3-amino-3-hydroxymethyl oxoindole and the 3-hydroxyl-3-hydroxymethyl oxoindole derivative are obtained. The preparation methods have the advantages of high-efficiency atomic economy, high selectivity and the like, and the operation is simple, safe and reliable. The 3-amino-3-hydroxymethyl oxoindole and the 3-hydroxyl-3-hydroxymethyl oxoindole derivative have anti-cancer activity and contain important natural product and active pharmaceutical molecular intermediate skeletons, and have broad application prospects in the field of medicine and chemical industry.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis and chemical engineering, and in particular relates to a preparation method of 3-amino-3-hydroxymethyl oxindole and 3-hydroxy-3-hydroxymethyl oxindole derivatives. Background technique [0002] Many natural products and active compounds contain 3-aminoindole and 3-hydroxyindole structures, so the preparation of 3-aminoindole and 3-hydroxyindole derivatives is of great significance. For example: J.Org.Chem.2012, 77, 3589-3594 pointed out that 3-aminoindole derivative AG-041R can stimulate chondrocyte proliferation and synthesis of cartilage-specific extracellular matrix in vitro without changing differentiated features. World Chinese Journal of Digestion 2006, 14(13): 1262-1266 reported that AG-041R has the activity of inhibiting the proliferation of MKN-45 cells. J.Org.Chem.2012, 77, 3589-3594 also reported that 3-aminoindole derivative SSR-149415 can be used to treat anxiety and depressi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40C07D209/38A61K31/404A61P35/00
CPCC07D209/38C07D209/40
Inventor 胡文浩汪成进邢栋车久威王冬伟
Owner 广东和博制药有限公司
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