Asymmetric synthesis method of chiral benzofuran spirooxindole compound

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: 2018-12-28
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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  • Asymmetric synthesis method of chiral benzofuran spirooxindole compound
  • Asymmetric synthesis method of chiral benzofuran spirooxindole compound
  • Asymmetric synthesis method of chiral benzofuran spirooxindole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: (2R,3S)-3-(nitromethyl)-2'-oxa-3H-spiro[benzofuran-2,3'-indoline]-1'-tert-butyl ester ;

[0065]

[0066] (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;

[0067] (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

[0068] Example 2: (2R,3S)-7-methoxy-3-(nitromethyl)-2'-oxa-3H-spiro[benzofuran-2,3'-indoline]- 1'-tert-butyl ester;

[0069]

[0070] (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;

[0071] (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

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

[0073]

[0074] (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;

[0075] (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 spirooxindole compound as shown in a formula (I). The synthesis method is performed through the following steps of mixing ao-hydroxy nitroolefin compound as shown in the formula (II), with an oxoindole compound as shown in a formula (III), a chiral hydrogen key catalyst and an organic solvent, and performing a reaction at minus 40-60 DEG C for 1-240h so as to obtain a compound as shown in the formula (IV); and adding an iodine source additive and an oxidizer to the compound as shown in the formula (IV), performing areaction at minus 40-60 DEG C for 1-48h, and performing after-treatment on reaction liquid so as to obtain the chiral benzofuran spirooxindole compound as shown in the formula (I). According to the asymmetric synthesis method disclosed by the invention, the reaction condition is mild, the yield of products is high, and the selectivity is excellent. (As shown in the description).

Description

(1) Technical field [0001] The invention relates to an asymmetric synthesis method of chiral benzofuran spirooxindole compounds. (2) Background technology [0002] 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 cruciferous pl...

Claims

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Application Information

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Patent Type & Authority Applications(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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