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3-hydroxyl oxoindole compounds and asymmetric synthesis method thereof

A technology of hydroxyl oxidation and ketone compounds, applied in organic chemistry methods, organic chemistry, etc., to achieve the effects of low cost, specific reaction regioselectivity, and simple operation

Inactive Publication Date: 2018-11-13
WENZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the asymmetric synthesis of such compounds is mainly based on metal catalysis and ordinary Brönstedt base catalysis. The terminal methyl group and the 3-methylene group are both reactive sites that can participate in the reaction, and a single site with high regioselectivity to participate in the reaction has always been a challenging problem in the synthesis process

Method used

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  • 3-hydroxyl oxoindole compounds and asymmetric synthesis method thereof
  • 3-hydroxyl oxoindole compounds and asymmetric synthesis method thereof
  • 3-hydroxyl oxoindole compounds and asymmetric synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] R 1 for hydrogen, R 2 The molar ratio of benzyl isatin, 2-pentanone and catalyst amino acid salt is 1.0:5.0:0.2 Feed, substrate N-benzyl isatin 474mg (2mmol), 2-pentanone 860mg (10mmol), L-phenylalanine potassium salt 81.2mg (0.4mmol); The organic solvent is tetrahydrofuran 9.5g, and its total consumption is 20 times that of the substrate N-benzyl isatin. Under room temperature conditions, the reaction was completed after stirring for 36 hours.

[0038] After the reaction was completed, separation and purification were obtained, and after drying, a white solid was obtained, which was 264.9 mg of the 3-hydroxyoxindole target compound 1a, with a yield of 41%, an enantioselective excess of 67% ee, and a purity of 99.0%. The structure is:

[0039]

[0040] Data representation:

[0041] 1-benzyl-3-hydroxy-3-(2-oxopentyl)indolin-2-one(1a): 41% yield, 67% ee, HPLC DAICEL CHIRALPAK AD-H, 2-propanol / n-hexane=10 / 90 , flow rate=1.0mL / min, λ=254nm, retention time: 21.7min(m...

Embodiment 2

[0043] The substance ratio of N-benzyl isatin, 2-pentanone and catalyst amino acid salt is 1.0:5.0:0.2 Feeding, substrate N-benzyl isatin 474mg (2mmol), 2-pentanone 860mg (10mmol), 81.2 mg (0.4 mmol) of L-phenylalanine potassium salt; the organic solvent is 9.5 g of N,N-dimethylformamide, and the total amount used is 20 times that of the substrate N-benzyl isatin.

[0044] The rest was the same as in Example 1, and 200.3 mg of the target product 1a was obtained with a yield of 31%, an enantioselective excess of 53% ee, and a purity of 99.2%.

Embodiment 3

[0046]The substance ratio of N-benzyl isatin, 2-pentanone and catalyst amino acid salt is 1.0:5.0:0.2 Feeding, substrate N-benzyl isatin 474mg (2mmol), 2-pentanone 860mg (10mmol), L-phenylalanine potassium salt 81.2mg (0.4mmol); Organic solvent is toluene 9.5g, and its total consumption is 20 times of substrate N-benzyl isatin.

[0047] The rest were the same as in Example 1 to obtain 316.5 mg of the target product 1a with a yield of 49%, an enantioselective excess of 74% ee, and a purity of 99.6%.

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Abstract

The invention discloses 3-hydroxyl oxoindole compounds and an asymmetric synthesis method thereof. The method comprises the following steps: isatin compounds and 2-ketone compounds are served as raw materials and directly and fully react in an organic solvent in the presence of the salt of common natural amino acid as a catalyst; after the reaction, reaction liquid is separated and purified to obtain the 3-hydroxyl oxoindole compounds containing quaternary carbon and with high regioselectivity and high enantioselectivity. According to the 3-hydroxyl oxoindole compounds and the asymmetric synthesis method thereof disclosed by the invention, the salt of amino acid is adopted as a catalyst for the first time, and the addition of the isatin compounds and the 2-ketone compounds is promoted to obtain the end methyl reacting quaternary carbon-containing 3-hydroxyl oxoindole compounds with high regioselectivity, high yield and high stereoselectivity. The method has the following main beneficial effects: (1) the operation is simple; (2) the catalyst cost is low; (3) the regioselectivity is high, and the obtained single end methyl is an addition product participating in reaction; (4) the quaternary carbon-containing 3-hydroxyl oxoindole compounds can be quickly constructed; (5) the reaction yield and the stereoselectivity are high. Therefore, the method disclosed by the invention has relatively high basic research value and great social economic benefits.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a 3-hydroxyindole compound and an asymmetric synthesis method thereof. Background technique [0002] 3-Hydroxyindole compounds widely exist in many natural products and drug molecules, and are important intermediates in organic synthesis and drug development engineering. 3-Hydroxyindole compounds, especially chiral oxindole compounds containing a quaternary carbon center at the 3-position are the main skeletons of drugs such as dioxibrassinine and SM-130686. Therefore, it is of great significance to develop green and efficient strategies for the asymmetric synthesis of 3-hydroxyindoles. [0003] According to the existing reports, the construction of 3-hydroxyoxindole compounds, which are important organic synthesis intermediates and the core skeleton of many pharmaceutically active molecules, is achieved by the addition of the receptor of the oxindole skeleton and the carbonyl c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/38
CPCC07B2200/07C07D209/38
Inventor 李娟刘洪鑫蒋俊刘鹏吴铨铨
Owner WENZHOU UNIVERSITY
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