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Chiral 3-indolyl-3,3'-disubstituted oxoindole compound and preparation method thereof

A technology of oxidizing indole and indolyl group, applied in the direction of organic chemistry method, organic chemistry, etc., can solve the problems of limiting the universality of the substrate, limiting the application of the reaction, low reaction yield and the like, achieving low catalyst dosage, Simple operation and good stereoselectivity

Active Publication Date: 2020-09-11
CHENGDU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The above synthetic route, the first route is an aryl substitution reaction, which must use fluorobenzene with a nitro group to react, which greatly limits the universality of the substrate , and the enantioselectivity of the reaction is moderate
The second route is the 1,3-alkyl transfer reaction catalyzed by chiral phosphoric acid. The substrate is not easy to obtain, and the R group is an electron-withdrawing substituent such as F, Cl, Br, I, COOEt, etc. The reaction effect is good, and The reaction yield is generally low (60-80%), which limits the application of the reaction
However, the asymmetric dearomatization reaction of 2-nitroindole catalyzed by small organic molecules has not been reported. Therefore, it has very high application value to explore the asymmetric dearomatization reaction of 2-nitroindole

Method used

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  • Chiral 3-indolyl-3,3'-disubstituted oxoindole compound and preparation method thereof
  • Chiral 3-indolyl-3,3'-disubstituted oxoindole compound and preparation method thereof
  • Chiral 3-indolyl-3,3'-disubstituted oxoindole compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Synthesis of Compound (III-a)

[0040]

[0041] Asymmetric synthesis of compound III-a:

[0042]Method 1: In a dry reaction tube, Chiral Catalyst A (0.02 mmol) was dissolved in 1 mL of toluene. 2-Nitroindole I-a (0.1 mmol) and 3-substituted oxindole II-a (0.12 mmol) were then added. The reaction mixture was stirred at room temperature for 2 days. Then 1 mL of dichloromethane and p-toluenesulfonic acid (0.12 mmol) were added to the reaction system, and the reaction was continued to be stirred at room temperature for 12 h. After the reaction is completed, the crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1~6:1) to obtain compound III-a. The yield was 90%, 6% ee.

[0043] Method 2: In a dry reaction tube, the chiral catalyst B (0.02 mmol) was dissolved in 1 mL of toluene. 2-Nitroindole I-a (0.1 mmol) and 3-substituted oxindole II-a (0.12 mmol) were then added. The reaction mixture was stirred at room ...

Embodiment 2

[0047] Example 2: Synthesis of Compound (III-b)

[0048]

[0049] Asymmetric synthesis of compound III-b: In a dry reaction tube, 50 mg of activated Molecular sieves and chiral catalyst D (0.02 mmol) were dissolved in 1 mL of toluene. After cooling to 0°C, 2-nitroindole I-a (0.1 mmol) and 3-substituted oxide indole II-b (0.12 mmol) were added. The reaction mixture was stirred at 0°C for 5 days. The reaction system was warmed to room temperature, 1 mL of dichloromethane and methanesulfonic acid (0.12 mmol) were added to the reaction system, and the reaction was continued to stir at room temperature for 15 h. After the reaction is completed, the crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1~6:1) to obtain compound III-b. White solid, 54.7 mg, 97% yield; 97% ee; [α] D 20 =+82.5(c 1.0, CH 2 Cl 2 ); m.p.261.8-262.7℃.Theee was determined by HPLC analysis using a ChiralpakAD-H column(70 / 30hexane / i-PrOH;flow rate:1.0mL / ...

Embodiment 3

[0050] Example 3: Synthesis of Compound (III-c)

[0051]

[0052] Asymmetric synthesis of compound III-c: In a dry reaction tube, 50 mg of activated Molecular sieves and chiral catalyst D (0.02 mmol) were dissolved in 1 mL of chlorobenzene. After cooling to 0°C, 2-nitroindole I-a (0.1 mmol) and 3-substituted oxide indole II-c (0.12 mmol) were added. The reaction mixture was stirred at 0°C for 5 days. The reaction system was raised to room temperature, 1 mL of chloroform and p-toluenesulfonic acid (0.12 mmol) were added to the reaction system, and the reaction was continued to stir at room temperature for 12 h. After the reaction is complete, the crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1~6:1) to obtain compound III-c. White solid, 52.8 mg, 91% yield; 92% ee; [α] D 20 =+87.3(c 1.0, CH 2 Cl 2 ); m.p.204.3-205.1℃.The ee was determined by HPLC analysis using a ChiralpakAD-H column(70 / 30hexane / i-PrOH;flowrate:1.0m...

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Abstract

The invention discloses a chiral 3-indolyl-3,3'-disubstituted oxoindole compound and a preparation method thereof and belongs to the field of organic chemical synthesis; the preparation method comprises the following steps: dissolving 2-nitroindole (I) and 3-substituted oxindole (II) in an organic solvent, adding a chiral catalyst, carrying out a stirring reaction at 0-25 DEG C for 5-7 days, adding a solvent and an organic acid into the reaction system after the reaction is completed, continuously carrying out a reaction on the reaction mixed solution at 0-25 DEG C for 10-15 h, and carrying out separation and purification. According to the preparation method disclosed by the invention, through asymmetric dearomatization / heavy aromatization reaction of 2-nitroindole, the preparation of chiral 3-indolyl-3'-alkyl oxindole and 3-indolyl-3'-aryl oxindole derivatives is realized; the compound is a key synthetic intermediate of cyclic tryptamine alkaloid, and can provide more candidate molecules for research and development of new drugs and screening of drugs. The preparation method disclosed by the invention has the advantages of novelty, simplicity, simplicity in operation, mild reaction conditions, high yield, high stereoselectivity and the like.

Description

technical field [0001] The present invention relates to the technical field of organic synthesis, in particular to a chiral 3-indolyl-3,3'-disubstituted oxindole compound and a preparation method thereof. Background technique [0002] Chiral 3,3'-disubstituted indole oxides are widely found in natural or non-natural biologically active molecules, and most of these molecules are found to have good biological activity, which is an important source for the development of new drugs , and is also an important intermediate in the synthesis of cyclic tryptamine alkaloids. Therefore, it is of great significance to construct such compounds through methodological studies. [0003] At present, there have been many reports on chiral 3,3'-disubstituted oxindole compounds and their preparation methods. For example, the Chinese patent application with the application number of 2017103594202 discloses a 3-indolyl-3,3 '-Disubstituted oxide indole compounds and preparation method. In this ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34C07D405/14
CPCC07D209/34C07D405/14C07B2200/07Y02P20/584
Inventor 袁伟成赵建强游勇王振华
Owner CHENGDU UNIV
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