3-amino-3-hydroxymethyloxindole derivative as well as preparation method and application thereof

Abstract

The invention discloses a 3-amino-3-hydroxymethyloxindole derivative shown as a formula (I) and a preparation method thereof. The 3-amino-3-hydroxymethyloxindole derivative is obtained by taking 3-diazooxindole, aniline and formaldehyde as raw materials, taking rhodium acetate as a catalyst and taking an organic solvent as a solvent through a one-step reaction. The preparation method disclosed by the invention can be used for constructing a compound with a plurality of functional groups in one step, and has the characteristics of high flexibility, high selectivity, efficient atom economy, high yield and simplicity and safety in operation and the like. The invention further discloses an inhibition effect of the 3-amino-3-hydroxymethyloxindole derivative shown as the formula (I) on proliferation of five types of tumor cells including human osteosarcoma cells (SJSA-1), human colorectal cancer cells (HCT-116), hepatocellular carcinoma cells (BEL7402), human oral epidermoid carcinoma cells (KB) and human T-cell leukemia cells (Jurkat).

Description

technical field

[0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to a 3-amino-3-hydroxymethyloxindole derivative and its application. Background technique

[0002] Many natural products and active compounds contain 3-aminoindole structure, so the preparation of 3-aminoindole 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 the characteristics of cell differentiation . World Chinese Journal of Digestion 2006,14(13):1262-1266 reported that AG-041R can inhibit the proliferation activity of MKN-45 cells. J.Org.Chem.2012,77,3589-3594 also reported that 3-aminooxindole derivative SSR-149415 can be used to treat anxiety and depression.

[0003] Therefore, efficient synthesis of such compounds has very important theoretical and...

Examples

Embodiment 1

[0054] Embodiment 1 prepares compound Ia of the present invention

[0055] Dissolve 2,6-dichloroaniline (0.1mmol), formaldehyde (0.6mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-formaldehyde A solution of 3-diazo-2-oxindole (0.1 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system in 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 a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to obtain pure product Ia. Yield: 78%. See Table 1.

[0056]

[0057] Characterization of 3-amino-3-hydroxymethyloxindole derivative Ia:

[0058] 1 H NMR (400MHz, CDCl 3 )δ7.26(d, J=6.5Hz, 1H), 7.11(d, J=8.0Hz, 2H), 6.86–6.73(m, 3H), 6.68(d, J=7.3Hz, 1H), 5.22( s, 1H), 3.9...

Embodiment 2-22

[0060] Embodiment 2-22 prepares compound (Ib~Iv)

[0061] Embodiment 2-22 preparation process is the same as embodiment 1. See Table 1 for the changes of substituents, compound numbers, yields, etc. during the reaction.

[0062] Table 1

[0063]

[0064]

[0065] The characterization of product 3-amino-3-hydroxymethyloxindole derivatives Ib~IV is as follows:

[0066] Characterization of Ib:

[0067] 1 H NMR (400MHz, CDCl 3 )δ7.40–7.27(m,5H),7.15(td,J=7.8,1.0Hz,1H),7.09(d,J=8.0Hz,2H),6.78(dt,J=12.4,4.1Hz,3H ),6.69–6.59(m,1H),5.27(s,1H),5.04(d,J=15.4Hz,1H),4.82(d,J=15.4Hz,1H),3.97(t,J=10.9Hz ,1H),3.87(dd,J=11.3,3.0Hz,1H),3.15(dd,J=10.4,3.1Hz,1H).

[0068] 13 C NMR (100MHz, CDCl 3 )δ178.1, 143.0, 140.0, 135.5, 129.7, 129.4, 128.8, 128.1, 127.9, 127.8, 125.8, 124.1, 123.7, 122.3, 109.6, 69.8, 66.5, 44.1.

[0069] Characterization of Ic:

[0070] 1 H NMR (400MHz, CDCl 3 )δ7.39–7.27(m, 6H), 7.14(d, J=8.0Hz, 2H), 6.83(t, J=8.0Hz, 1H), 6.78(d, J=1.8Hz, 1H), 6.64( d...

Embodiment 23

[0129] Example 23 3-Amino-3-Hydroxymethyloxindole Derivatives Effects on Human Osteosarcoma Cells (SJSA-1), Human Colorectal Cancer Cells (HCT-116), Human Liver Cancer Cells (BEL7402), Human Oral Epidermoid Carcinoma Cells (KB) and human T-cell leukemia cells (Jurkat) the inhibitory effect on the proliferation of five tumor cells.

[0130] The present invention adopts CCK-8 method to measure the effect of 3-amino-3-hydroxymethyloxindole derivatives described in embodiment 1-22 (Ia-Iv) on human osteosarcoma cells (SJSA-1), human colorectal cancer Cells (HCT-116), human liver cancer cells (BEL7402), human oral epidermoid carcinoma cells (KB) and human T-cell leukemia cells (Jurkat) five tumor cell proliferation inhibitory effects.

[0131] Firstly, the activity of 22 compounds against the proliferation of SJSA-1 cells was determined, and then the compound with the best proliferation activity was selected, and its inhibitory activity against HCT-116 cells, BEL7402 cells, KB cells...

technical field

[0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to a 3-amino-3-hydroxymethyloxindole derivative and its application. Background technique

[0002] Many natural products and active compounds contain 3-aminoindole structure, so the preparation of 3-aminoindole 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 the characteristics of cell differentiation . World Chinese Journal of Digestion 2006,14(13):1262-1266 reported that AG-041R can inhibit the proliferation activity of MKN-45 cells. J.Org.Chem.2012,77,3589-3594 also reported that 3-aminooxindole derivative SSR-149415 can be used to treat anxiety and depression.

[0003] Therefore, efficient synthesis of such compounds has very important theoretical and...

Examples

Embodiment 1

[0054] Embodiment 1 prepares compound Ia of the present invention

[0055] Dissolve 2,6-dichloroaniline (0.1mmol), formaldehyde (0.6mmol) and rhodium acetate (0.001mmol) in 1mL ethyl acetate to form a reaction system, keep the temperature at 60°C, and use an automatic injection pump to inject 1-formaldehyde A solution of 3-diazo-2-oxindole (0.1 mmol) dissolved in 1 mL of ethyl acetate was added to the reaction system in 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 a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to obtain pure product Ia. Yield: 78%. See Table 1.

[0056]

[0057] Characterization of 3-amino-3-hydroxymethyloxindole derivative Ia:

[0058] 1 H NMR (400MHz, CDCl 3 )δ7.26(d, J=6.5Hz, 1H), 7.11(d, J=8.0Hz, 2H), 6.86–6.73(m, 3H), 6.68(d, J=7.3Hz, 1H), 5.22( s, 1H), 3.9...

Embodiment 2-22

[0060] Embodiment 2-22 prepares compound (Ib~Iv)

[0061] Embodiment 2-22 preparation process is the same as embodiment 1. See Table 1 for the changes of substituents, compound numbers, yields, etc. during the reaction.

[0062] Table 1

[0063]

[0064]

[0065] The characterization of product 3-amino-3-hydroxymethyloxindole derivatives Ib~IV is as follows:

[0066] Characterization of Ib:

[0067] 1 H NMR (400MHz, CDCl 3 )δ7.40–7.27(m,5H),7.15(td,J=7.8,1.0Hz,1H),7.09(d,J=8.0Hz,2H),6.78(dt,J=12.4,4.1Hz,3H ),6.69–6.59(m,1H),5.27(s,1H),5.04(d,J=15.4Hz,1H),4.82(d,J=15.4Hz,1H),3.97(t,J=10.9Hz ,1H),3.87(dd,J=11.3,3.0Hz,1H),3.15(dd,J=10.4,3.1Hz,1H).

[0068] 13 C NMR (100MHz, CDCl 3 )δ178.1, 143.0, 140.0, 135.5, 129.7, 129.4, 128.8, 128.1, 127.9, 127.8, 125.8, 124.1, 123.7, 122.3, 109.6, 69.8, 66.5, 44.1.

[0069] Characterization of Ic:

[0070] 1 H NMR (400MHz, CDCl 3 )δ7.39–7.27(m, 6H), 7.14(d, J=8.0Hz, 2H), 6.83(t, J=8.0Hz, 1H), 6.78(d, J=1.8Hz, 1H), 6.64( d...

Embodiment 23

[0129] Example 23 3-Amino-3-Hydroxymethyloxindole Derivatives Effects on Human Osteosarcoma Cells (SJSA-1), Human Colorectal Cancer Cells (HCT-116), Human Liver Cancer Cells (BEL7402), Human Oral Epidermoid Carcinoma Cells (KB) and human T-cell leukemia cells (Jurkat) the inhibitory effect on the proliferation of five tumor cells.

[0130] The present invention adopts CCK-8 method to measure the effect of 3-amino-3-hydroxymethyloxindole derivatives described in embodiment 1-22 (Ia-Iv) on human osteosarcoma cells (SJSA-1), human colorectal cancer Cells (HCT-116), human liver cancer cells (BEL7402), human oral epidermoid carcinoma cells (KB) and human T-cell leukemia cells (Jurkat) five tumor cell proliferation inhibitory effects.

[0131] Firstly, the activity of 22 compounds against the proliferation of SJSA-1 cells was determined, and then the compound with the best proliferation activity was selected, and its inhibitory activity against HCT-116 cells, BEL7402 cells, KB cells...

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