Preparation method of chiral hexahydropyrroloindole compound

A technology of hexahydropyrrole and indole, applied in the direction of organic chemistry, etc., to achieve the effect of less reaction steps, high yield and stereoselectivity, and easy availability of reaction raw materials

Inactive Publication Date: 2015-07-29
ANHUI NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The construction of chiral hexahydropyrrolo[2,3-b]indole ring structures by catalytic asymmetric Lewis acid-catalyzed [3+2] cyclization has not been reported so far

Method used

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  • Preparation method of chiral hexahydropyrroloindole compound
  • Preparation method of chiral hexahydropyrroloindole compound
  • Preparation method of chiral hexahydropyrroloindole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Under argon atmosphere, add copper tetraacetonitrile boron tetrafluoride (0.0025mmol), (R)-XylBINAP (0.0015mmol) and dry m-xylene (0.25mL) successively into a dry Schlenk tube, and stir at room temperature for 20 minutes Then add 1,3-dimethylindole (0.05mmol dissolved in 0.25mL dry m-xylene) and 2-phenyl-N-p-toluenesulfonyl aziridine (0.11mmol) successively, and then stir at 15°C The reaction was carried out for 12 hours (monitored by TLC). After the reaction, a saturated aqueous sodium bicarbonate solution (5 mL) was added to terminate the reaction, extracted with ethyl acetate (5 mL×3), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was passed through 1 According to H NMR analysis, the ratio of diastereoisomers dr>20:1, using petroleum ether: ethyl acetate = 20:1 mixed solvent (containing 0.5v% triethylamine) as developing solvent, separated by column chromatography Product (20.3 mg, yield: ...

Embodiment 2

[0035] Under argon atmosphere, add copper tetraacetonitrile boron tetrafluoride (0.0025mmol), (R)-XylBINAP (0.0015mmol) and dry m-xylene (0.25mL) successively into a dry Schlenk tube, and stir at room temperature for 20 minutes Then, 1,3-dimethylindole (0.05mmol dissolved in 0.25mL dry m-xylene) and 2-(4-fluorophenyl)-N-p-toluenesulfonyl aziridine (0.11mmol) were added successively to complete Then the reaction was stirred at 15°C for 18 hours (monitored by TLC). After the reaction, a saturated aqueous sodium bicarbonate solution (5 mL) was added to terminate the reaction, extracted with ethyl acetate (5 mL×3), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was passed through 1 According to H NMR analysis, the ratio of diastereoisomers dr>20:1, using petroleum ether: ethyl acetate = 20:1 mixed solvent (containing 0.5v% triethylamine) as developing solvent, separated by column chromatography Product (...

Embodiment 3

[0039] Under argon atmosphere, add copper tetraacetonitrile boron tetrafluoride (0.0025mmol), (R)-XylBINAP (0.0015mmol) and dry m-xylene (0.25mL) successively into a dry Schlenk tube, and stir at room temperature for 20 minutes Then, 1,3-dimethylindole (0.05mmol dissolved in 0.25mL dry m-xylene) and 2-(4-chlorophenyl)-N-p-toluenesulfonyl aziridine (0.11mmol) were added successively to complete Then the reaction was stirred at 15°C for 32 hours (monitored by TLC). After the reaction, a saturated aqueous sodium bicarbonate solution (5 mL) was added to terminate the reaction, extracted with ethyl acetate (5 mL×3), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was passed through 1 According to H NMR analysis, the ratio of diastereoisomers dr>20:1, using petroleum ether: ethyl acetate = 20:1 mixed solvent (containing 0.5v% triethylamine) as developing solvent, separated by column chromatography Product (...

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Abstract

The invention relates to a preparation method of a chiral hexahydropyrroloindole compound. A catalytic amount of cuprous salt and chiral diphosphine ligand are first stirred to react in organic solvent under argon atmosphere and room temperature for 20 minutes, and are then sequentially added with C(3)/C(2)-substituted indole and substituted N-sulphonyl ethylene imine to react under certain temperature, and thereby the chiral hexahydropyrroloindole compound is obtained. The reaction process is tracked by thin-layer chromatography (TLC), ethyl acetate is adopted for extraction, anhydrous sodium sulfate is adopted for drying, pressure is reduced to remove solvent, so that a crude product is obtained, mixed solvent in which the volume ratio of petroleum ether containing 0.5v percent of triethylamine and ethyl acetate is 10 to 40:1 is adopted as developing solvent, the product is obtained by column chromatography separation, the enantiomeric excess of the product is determined by high-performance liquid chromatography on a chiral chromatographic column, and the molar ratio of the cuprous salt, the chiral diphosphine ligand, the C(3)-substituted indole and the substituted N-sulphonyl ethylene imine is 5:3:100:220. Compared with the prior art, the method can prepare the chiral hexahydropyrroloindole compound with a catalytic asymmetric [3+2] cycloaddition method, and has the following characteristics: the reaction materials are simple and easy to obtain, the reaction conditions are mild, product structure types are rich, and yield and stereoselectivity are high.

Description

technical field [0001] The invention relates to a preparation method of chiral hexahydropyrroloindole compounds, in particular to a class of chiral hexahydropyrrolo[2,3-b]indole compounds and a preparation method thereof. Background technique [0002] Chiral hexahydropyrrolo[2,3-b]indole ring system has many important biological activities and medicinal value. For example, the acetyl or butyrylcholinesterase inhibitor (-)-physostigmine (physostigmine), which is clinically used to treat glaucoma, and its artificially synthesized analogues (-)-phenserine and (+)-phenserine are also It was once or is being used in clinical treatment trials of Alzheimer's disease (A.M.Lilja, Y.Luo, Q.-s.Yu, J. Y. Zhou, A.M. Marini, A. Marutle, A. Nordberg, N.H. Greig, PLoS One, 2013, 8, e54887). Therefore, the research on efficient and selective construction methods of such structures has always been a research hotspot in the field of asymmetric catalysis. [0003] Structurally speaking, the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 柴卓朱佑民王绍武杨培俊杨高升
Owner ANHUI NORMAL UNIV
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