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A kind of asymmetric synthesis method of chiral benzofuran spiro indole oxide compounds

A technology of benzofuran spiro and oxindole, applied in asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve the problems of multiple metal wastes and inorganic salts, increased synthesis costs, and poor atom economy. Achieve good reaction characteristics, mild reaction conditions, and simple operation

Active Publication Date: 2021-04-06
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the one hand, the synthesis method reported by Shi's research group requires the use of a large amount of heavy metal silver oxide (silver oxide) and a large amount of inorganic base as an acid-binding agent (dipotassium hydrogen phosphate), which makes the process produce a lot of heavy metal waste. Compounds and inorganic salts, poor atom economy, high cost of post-processing
On the other hand, the chlorinated oxindole involved in this method needs to be chlorinated first, which increases the synthesis cost

Method used

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  • A kind of asymmetric synthesis method of chiral benzofuran spiro indole oxide compounds
  • A kind of asymmetric synthesis method of chiral benzofuran spiro indole oxide compounds
  • A kind of asymmetric synthesis method of chiral benzofuran spiro indole oxide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: (2R,3S)-3-(nitromethyl)-2'-oxa-3H-spiro[benzofuran-2,3'-indoline]-1'-tert-butyl ester ;

[0069]

[0070] (A) Take a 10mL clean small test tube, add o-hydroxynitroalkene (0.2mmol, 0.033g), N-Boc protected oxindole (0.2mmol, 0.0932g), organic hydrogen bond catalyst V (0.002mmol, 0.0013g) , solvent acetonitrile (0.5mL), after reacting at 0°C for 24h, a mixture containing intermediate compound 1-A was obtained;

[0071] (B) After removing the solvent from the mixture containing intermediate compound 1-A, add cuprous iodide (0.04mmol, 0.0076g), 85% m-chloroperoxybenzoic acid solid (2mmol, 0.407g), solvent acetonitrile ( 1mL), after reacting at 60°C for 1h, extract with ethyl acetate (3×10mL), desolvate the organic phase under reduced pressure, use ethyl acetate:petroleum ether=1:10 mixed solvent as eluent; 200-300 mesh column Chromatographic silica gel is used as filler, and the target product (0.0341g, 43%yield, 82%ee, >99:1dr) obtained by column chromatogr...

Embodiment 2

[0072] Example 2: (2R,3S)-7-methoxy-3-(nitromethyl)-2'-oxa-3H-spiro[benzofuran-2,3'-indoline]- 1'-tert-butyl ester;

[0073]

[0074] (A) Take 10mL clean small test tube, add 3-methoxy substituted o-hydroxyl nitroalkene (0.2mmol, 0.039g), N-Boc protected oxindole (2mmol, 0.466g), organic hydrogen bond catalyst VI ( 0.04mmol, 0.0101g), solvent tetrahydrofuran (1mL), after reacting at 60°C for 1h, a mixture containing intermediate compound 2-A was obtained;

[0075] (B) After removing the solvent from the mixture containing intermediate compound 2-A, potassium iodide (0.2mmol, 0.076g), 70% aqueous tert-butanol hydroperoxide (2mmol, 0.257g), solvent tetrahydrofuran (1mL) were added, After reacting at 25°C for 6h, extract with ethyl acetate (3×10mL), and desolvate the organic phase under reduced pressure, use ethyl acetate:petroleum ether=1:10 mixed solvent as eluent; 200-300 mesh column chromatography silica gel As filler, the target product (0.0596g, 70%yield, 47%ee, >99:1d...

Embodiment 3

[0076] Example 3: (2R,3S)-7-ethoxy-3-(nitromethyl)-2'-oxa-3H-spiro[benzofuran-2,3'-indoline]- 1'-tert-butyl ester;

[0077]

[0078] (A) Take a 10mL clean small test tube, add 3-ethoxy substituted o-hydroxynitroalkene (0.2mmol, 0.042g), N-Boc protected oxindole (1mmol, 0.233g), organic hydrogen bond catalyst VII ( 0.02mmol, 0.0129g), solvent ethyl acetate (2mL), after reacting at -40°C for 240h, a mixture containing intermediate compound 3-A was obtained;

[0079] (B) After removing the solvent from the mixture containing intermediate compound 3-A, tetrabutylammonium iodide (0.05mmol, 0.0185g), 5% sodium hypochlorite aqueous solution (1mmol, 1.5g), solvent ethyl acetate (4mL ), after reacting for 6h at 25°C, extract with ethyl acetate (3×10mL), and desolvate the organic phase under reduced pressure, use ethyl acetate:petroleum ether=1:10 mixed solvent as eluent; 200-300 mesh column layer Silica gel was used as filler, and the target product (0.0598g, 68%yield, 99%ee, >99:...

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Abstract

The invention provides an asymmetric synthesis method of a chiral benzofuran spiro indole compound represented by formula (I), and the synthesis method is carried out according to the following steps: The nitroalkene compound is mixed with the oxidized indole compound represented by the formula (III), a chiral hydrogen bond catalyst, and an organic solvent, and the reaction is carried out at ‑40~60° C. for 1~240h to obtain the compound represented by the formula (IV), Add iodine source additive and oxidant to the compound represented by formula (IV), react at -40~60°C for 1~48h, the reaction solution is post-treated to obtain the chiral benzofuran spiro indole represented by formula (I) compound; the reaction conditions of the present invention are mild, the product yield is high, and the selectivity is excellent.

Description

[0001] (1) Technical field [0002] The invention relates to an asymmetric synthesis method of chiral benzofuran spirooxindole compounds. [0003] (2) Background technology [0004] Chiral spirooxindole compounds exist in a large number of biologically active natural products and clinical medicines, which have a wide range of biological activities. Indole, pyrazoline spirooxindole, isoxazoline spirooxindole, etc., such as: Compound A, a Chinese herbal medicine alkaloid named (-)-Horsfiline, exists in Phoebe genus Schima, mainly used In terms of pain relief and sedation; Tan et al. reported that Compound B has a good inhibitory effect on the growth of human breast cancer cells. Further mechanistic studies have found that Compound B mainly inhibits the step-by-step phosphorylation in the signaling pathway of mitogen-activated protein kinase. Proliferation of human cancer cell lines (acute leukemia T cell line, human breast cancer cell line and HeLa cell line) by the antitoxin of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/107C07B53/00
CPCC07B53/00C07B2200/07C07D491/107
Inventor 夏爱宝汤成科许丹倩
Owner ZHEJIANG UNIV OF TECH
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