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Chiral amino indoline derivative as well as preparation method and application thereof

A technology of aminoindoline and derivatives, which is applied in the direction of drug combination, pharmaceutical formula, organic active ingredients, etc., can solve the problems of expensive and harsh reaction conditions, and achieve simple preparation steps, mild conditions, and high enantioselectivity Effect

Pending Publication Date: 2022-07-22
HUAZHONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem solved by the present invention is: to provide a chiral aminoindoline derivative and its preparation method and use, the chiral aminoindoline derivative has pharmaceutical activity or can be used to prepare chiral aminoindoline derivatives with pharmaceutical activity The precursor of indoline derivatives has simple preparation steps and mild conditions, and solves the technical problems of expensive synthesis catalysts and harsh reaction conditions of chiral aminoindoline derivatives in the prior art

Method used

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  • Chiral amino indoline derivative as well as preparation method and application thereof
  • Chiral amino indoline derivative as well as preparation method and application thereof
  • Chiral amino indoline derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of compound I-1:

[0048]

[0049] As shown in Reaction A, at room temperature, copper sulfate (0.01 mmol, 10 mol%) was mixed with ligand L 1 (0.012 mmol, 12 mol%) was dissolved in 3 mL of methanol and stirred under argon for 15 minutes. Then add base B 3 (0.2 mmol, 2.0 equiv.), stirring was continued for 15 minutes, followed by the addition of ethynyl benzoxazinone III (0.1 mmol, 1.0 equiv, where R 1 is -Ts, where R 2 for -ch3 , R 4 For H) and amine source IV (0.2mmol, 2.0equiv, R 3 For fluorenyl-Flu), the reaction mixture was continued to react at 30 ° C until the reaction was completed by TLC detection, using column chromatography gradient elution, with petroleum ether-ethyl acetate (V 石油醚 / V 乙酸乙酯 From 15:1 to 8:1) as a gradient elution solvent, the target product of formula I-1 was obtained in a yield of 86%.

[0050] Reaction formula A:

[0051]

[0052] Structural characterization data of product I-1: 1 H NMR (400MHz, CDCl 3 )δ(ppm)=8.1...

Embodiment 2

[0056] Preparation of compound I-2

[0057]

[0058] The reaction formula is shown in formula A. At room temperature, copper sulfate (0.01 mmol, 10 mol%) and ligand V (0.012 mmol, 12 mol%) were dissolved in 3 mL of methanol, and stirred for 15 minutes under argon protection. Then base B3 (0.2 mmol, 2.0 equiv.) was added, stirring was continued for 15 minutes, followed by addition of ethynyl benzoxazinone II (0.1 mmol, 1.0 equiv, where R 1 for -ts,r 2 for -ch 3 , R 4 6-F) and amine source IV (0.2mmol, 2.0equiv, R 3 For fluorenyl-Flu), the reaction mixture was continued to react at 30 ° C until the reaction was completed by TLC detection, using column chromatography gradient elution, with petroleum ether-ethyl acetate (V 石油醚 / V 乙酸乙酯 From 15:1 to 8:1) as a gradient elution solvent, the target product of formula I-2 was obtained in 88% yield.

[0059] Structural characterization data for product I-2: 1 H NMR (400MHz, CDCl 3 )δ(ppm)=8.05(dd,J=9.1,4.4Hz,1H),7.57-7.47(m,4H...

Embodiment 3

[0062] Preparation of compound I-3

[0063]

[0064] Copper sulfate (0.01 mmol, 10 mol %) and ligand V (0.012 mmol, 12 mol %) were dissolved in 3 mL of methanol at room temperature and stirred under argon for 15 minutes. Then base B3 (0.2 mmol, 2.0 equiv.) was added, stirring was continued for 15 minutes, followed by addition of ethynyl benzoxazinone II (0.1 mmol, 1.0 equiv, where R 1 For p-toluenesulfonyl-Ts, R 2 for -ch 3 , R 4 6-Br) and amine source IV (0.2mmol, 2.0equiv, R 3 For fluorenyl-Flu), the reaction mixture was continued to react at 30 ° C until the reaction was completed by TLC detection, using column chromatography gradient elution, with petroleum ether-ethyl acetate (V 石油醚 / V 乙酸乙酯 From 15:1 to 8:1) as a gradient elution solvent, the target product of formula I-3 was obtained in 83% yield.

[0065] Product structure characterization data: 1 H NMR (400MHz, CDCl 3 )δ(ppm)=7.97(d,J=8.7Hz,1H),7.60-7.42(m,6H),7.34-7.13(m,5H),7.02(m,J=7.5,1.2Hz,1H), 6.66(d,...

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Abstract

The invention relates to a chiral aminoindoline derivative and a preparation method and application thereof.The chiral aminoindoline derivative has pharmaceutical activity or can be used for preparing a chiral aminoindoline derivative precursor with pharmaceutical activity, the preparation steps are simple, the conditions are mild, and the chiral aminoindoline derivative is suitable for industrial production. The technical problems that in the prior art, a chiral amino indoline derivative synthesis catalyst is expensive, and reaction conditions are harsh are solved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a chiral aminoindoline derivative and a preparation method and application thereof. Background technique [0002] Chiral 3-aminoindoline derivatives are a class of molecular skeletons containing indoline structures, which are widely distributed in natural products and are widely used in medicine, organic chemical synthesis and other fields. For example: For example: Cipargamin compounds are a class of compounds with antimalarial activity and meet the criteria required for antimalarial drug candidates. AG-041R is a gastrin / CCK-B receptor antagonist, SSR-149415 is a drug currently in clinical trials for the treatment of anxiety and depression, compounds containing a 3-aminoindoline backbone are very useful , to develop more 3-aminoindoline derivatives with medicinal activity and their efficient synthesis methods, which has aroused the research interest of mor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40C07D409/12A61K31/404A61P35/00
CPCC07D209/40C07D409/12A61P35/00C07B2200/07Y02P20/55
Inventor 陆良秋王宝成熊芬娅曲宝乐肖文精
Owner HUAZHONG NORMAL UNIV
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