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2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof

A synthetic method, the technology of indoledione, which is applied in the field of medicine, can solve the problems of difficult synthesis of raw materials, narrow application range of substrates, and low yield.

Inactive Publication Date: 2017-02-22
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the methods for synthesizing N-alkenyl nitrones mainly include: multi-step synthesis of nitroalkenes (S.E.Denmark, J.I.Montgomery, J.Org.Chem.2006, 71, 6211), copper-mediated coupling reaction (D.L. Mo, D.A.Wink, L.L.Anderson, Org.Lett.2012, 14, 5180), 1,4-conjugated elimination of halogenated oximes (R.E.Michael, K.M.Chando, T.Sammakia, J.Org.Chem.2015, 80 , 6930) etc., but these reactions all have the deficiencies such as raw material is difficult to synthesize, and productive rate is low, and the scope of application of substrate is narrow etc.

Method used

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  • 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof
  • 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof
  • 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Synthesize the 2,3-indoledione-3-N-enylnitrone derivatives of the present invention according to the following synthetic route.

[0077]

[0078] Put 2,3-indoledione-3-oxime substrate 1 (0.3mmol) and alkenyl boronic acid 2 (0.9mmol) in a reaction tube, add 3mL of methanol, stir the reaction at 25°C for 5-20h, spin Remove the solvent, add water (10mL) to the resulting reactant, extract with dichloromethane (2×10mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and separate by silica gel column chromatography (petroleum ether / Ethyl acetate=10:1~1:1, volume ratio), the target product 3 was obtained. The different target products and their characterization are as follows:

[0079] 3aa: Orange-red solid, 68mg, 93% yield; mp 170-171℃. 1 H NMR (400MHz, DMSO–d 6 ):δ10.94(s,1H),8.78(dt,J=13.2,1.4Hz,1H),8.22(d,J=7.6Hz,1H),7.34(t,J=7.7Hz,1H),7.02 (t,J=7.7Hz,1H),6.95-6.85(m,2H),2.27(q,J=7.3Hz,2H),1.49-1.41...

Embodiment 2

[0116] Synthesize the 2,3-indoledione-3-N-enylnitrone derivatives of the present invention according to the following synthetic route.

[0117]

[0118] Put 2,3-indoledione-3-oxime substrate 1 (0.3mmol), alkenyl boronic acid 2 (0.9mmol), cuprous bromide (0.3mmol), triethylamine (3mmol) in the reaction tube , add 3mL of 1,2-dichloroethane, stir the reaction at 60°C for 5-20h, remove the solvent from the reactant under reduced pressure, and separate by silica gel column chromatography (dichloromethane / methanol=100:1~10:1, volume ratio), the target product 3 was obtained. The different target products and their characterization are as follows:

[0119] 3al: Orange-red solid, 52mg, 76% yield; mp 144-145℃. 1 H NMR (500MHz, DMSO–d 6 ): δ10.94(s, 1H), 8.37(d, J=7.6Hz, 1H), 7.55(t, J=7.7Hz, 1H), 7.21(t, J=7.6Hz, 1H), 7.06(d ,J=7.8Hz,1H),6.31(d,J=7.7Hz,1H),2.89(d,J=5.9Hz,2H),2.69(m,2H),2.27-2.19(m,2H); 13 C NMR (125MHz, DMSO–d 6 ): δ160.6, 146.9, 141.2, 135.0, 132.8, 128.6, 12...

experiment example 1

[0133] Experimental Example 1: The 2,3-indoledione-3-N-enylnitrone derivatives of the present invention were tested for their inhibitory activity against various human tumor strains in vitro:

[0134] (1) Cell culture: MGC-803, HepG2, NCI-H460, 7702 cells were cultured in DMEM containing 10% (volume ratio) fetal bovine serum and 1% (volume ratio) double antibody (containing penicillin and streptomycin) Medium, at a temperature of 37°C, 5% CO 2 and 95% air incubator, and change the medium every other day. After the cells were confluent, they were passaged and frozen.

[0135] (2) Seed plate: Take cells in the logarithmic growth phase, remove the old medium, wash twice with PBS, digest the cells with trypsin, add new medium after the cells become round, stop the digestion of the cells and pipette the suspended cells to prepare into a single cell suspension. Take an appropriate amount of cell suspension, add a certain amount of medium to dilute, inoculate into a 96-well plate,...

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Abstract

The invention discloses a 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and a synthesis method and application thereof. The derivative has the structure shown in the formula (I). The synthesis method includes the steps that a 2,3-indolinone-3-oxime derivative shown in the formula (II), cyclopropyboronic acid shown in the formula (III), copper salt and alkaline matter are obtained and placed in organic solvent and react under the condition that oxygen exists, and a target crude product is prepared. The synthesis method of the derivative is simple and easy to control, the period is short, the yield is high, part of compounds in the derivative have remarkable anti-tumor activity, and a lead compound is provided for developing new anti-tumor medicine. Please see the compounds of the structures shown in the formula (I), the formula (II) and the formula (III) in the description.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a 2,3-indoledione-3-N-enylnitrone derivative and its synthesis method and application. Background technique [0002] Nitrones are a very important class of organic synthons, important pharmacophore in drug molecules, important physiologically active units, and have important applications in anti-tumor, anti-cancer and other aspects. [0003] N-alkenylnitrones have attracted increasing attention in organic synthesis due to their high reactivity and diverse transformations. However, N-alkenyl nitrones have always been a difficult point in organic synthesis, and many international research groups are devoted to research in this direction. At present, the methods for synthesizing N-alkenyl nitrones mainly include: multi-step synthesis of nitroalkenes (S.E.Denmark, J.I.Montgomery, J.Org.Chem.2006, 71, 6211), copper-mediated coupling reaction (D.L. Mo, D.A.Wink, L.L.Anderson, Org.Le...

Claims

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Application Information

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IPC IPC(8): C07D209/40C07D405/12A61K31/404A61P35/00
CPCC07D209/40C07D405/12
Inventor 莫冬亮陈春华马小盼刘凤萍潘毓敏苏桂发
Owner GUANGXI NORMAL UNIV
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