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Series catalytic preparation method of chiral pyrazospirofurin compound

A technology for the preparation of pyrazole spirofuran and catalysis, which is applied in the direction of organic chemistry methods and organic chemistry, and can solve problems such as complex processes and excessive amounts

Active Publication Date: 2018-12-14
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method needs excessive inorganic base and chlorosuccinimide, and the reaction needs to be carried out step by step, and the process is complex

Method used

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  • Series catalytic preparation method of chiral pyrazospirofurin compound
  • Series catalytic preparation method of chiral pyrazospirofurin compound
  • Series catalytic preparation method of chiral pyrazospirofurin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1: (2S,3R)-3'-methyl-3-nitromethyl-1'-phenyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1 'H)-ketone;

[0091]

[0092] (A) Take 10mL clean small test tube, add o-hydroxynitroalkene (0.2mmol, 0.033g), 5-methyl-2-phenyl-pyrazolone (0.2mmol, 0.0348g), chiral squaraine catalyst V (0.002mmol, 0.0012g), solvent dichloromethane (1mL), after reacting at 25°C for 6h, a mixture containing intermediate compound 1-A was obtained;

[0093] (B) Remove the solvent from the mixture containing intermediate compound 1-A, add cuprous iodide (0.076g, 0.4mmol), 30% hydrogen peroxide solution (0.4mmol, 0.0453g), solvent dichloromethane (1mL), After reacting at 25°C for 8h, 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 (0.0593g, 88%yield, 92%ee,>99:1dr) obtained by column chromatography separation an...

Embodiment 2

[0094] Example 2: (2S,3R)-3'-ethyl-3-nitromethyl-1'-phenyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1 'H)-ketone;

[0095]

[0096] (A) Take a 10mL clean small test tube, add o-hydroxynitroolefin (0.2mmol, 0.033g), 5-ethyl-2-phenyl-pyrazolone (0.2mmol, 0.0376g), chiral squaraine catalyst VI (0.02mmol, 0.0093g), solvent toluene (2mL), after reaction at 25°C for 48h, a mixture containing intermediate compound 2-A was obtained;

[0097] (B) The mixture containing intermediate compound 2-A was desolvated, then added iodobenzene acetate (0.8mmol, 0.2576g), 70% hydroperoxide tert-butanol aqueous solution (0.2mmol, 0.0257g), solvent toluene ( 2mL), after reacting at 25°C for 48h, extracted with ethyl acetate (3×10mL), and the organic phase was precipitated under reduced pressure, using 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 (0.0604g, 86%yield, 92%ee,>99:1dr) obtained by col...

Embodiment 3

[0098] Example 3: (2S,3R)-3-nitromethyl-1'-phenyl-3'-propyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1 'H)-ketone;

[0099]

[0100] (A) Take 10mL clean small test tube, add o-hydroxynitroalkene (0.2mmol, 0.033g), 5-propyl-2-phenyl-pyrazolone (2mmol, 0.404g), chiral squaraine catalyst VII (0.01mmol, 0.0060g), solvent acetonitrile (4mL), after reacting at 40°C for 1h, a mixture containing intermediate compound 3-A was obtained;

[0101] (B) Remove the solvent from the mixture containing intermediate compound 3-A, then add tetrabutylammonium iodide (0.5mmol, 0.1845g), 85% m-chloroperbenzoic acid solution (2mmol, 0.407g), solvent Acetonitrile (4mL), after reacting at 40°C for 2h, extracted with ethyl acetate (3×10mL), the organic phase was precipitated under reduced pressure, using ethyl acetate:petroleum ether=1:10 mixed solvent as eluent; 200-300 The column chromatography silica gel is used as filler, and the target product (0.0593g, 81%yield, 92%ee,>99:1dr) obtained by colum...

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Abstract

The invention provides a series catalytic preparation method of a chiral pyrazospirofurin compound represented by the formula (I). The synthesis method is carried out according to the following steps:mixing an O-hydroxy nitroolefin compound represented by the formula (II) with a pyrazolone compound represented by the formula (III), a chiral squaric acid catalyst and an organic solvent, and carrying out a reaction for 1 to 48 h at the temperature of -20 to 60 DEG C, to obtain a compound represented by the formula (IV); and adding an iodine source additive and an oxidant to the compound represented by the formula (IV), carrying out a reaction for 1 to 48 h at the temperature of -20 to 60 DEG C, and post-treating the reaction liquid to obtain the chiral pyrazospirofurin compound representedby the formula (I). The reaction conditions are mild, the yield of the product is high and the selectivity is excellent. The prepared chiral pyrazospirofurin compound has chirality, and the skeleton structure has novelty.

Description

(1) Technical field [0001] The invention relates to a tandem catalytic preparation method of chiral pyrazole spirofuran compounds. (2) Background technology [0002] Chiral pyrazole spirocyclic compounds exist in a large number of biologically active natural products and clinical medicines, which have a wide range of biological activities, such as antipyretic, neuroprotective, anti-analgesic, anti-bacterial, anti-fungal, anti-inflammatory, anti-tumor effects. The common structures of chiral pyrazole spirocyclic compounds include pyrazole spirocyclopentane, pyrazole spirocyclohexane, pyrazole spirocyclohexanone, pyrazole spirocyclohexenone, etc., such as: the scientific name is 4-(3 ,4-dimethoxyphenyl)-2-(1-(5-hydroxy-2-methylbenzoyl)-4-piperidinyl)-2,3-diazaspiro[4.4]nonane - Compound A of 3-en-1-one and scientific name N-(3-isobutyl-4-oxa-2,3-diazaspiro[4.5]dec-1-en-8-yl Compound B of )-4-(1H-pyrazol-1-yl)benzenesulfonamide is a phosphodiesterase PDE4 inhibitor, a drug c...

Claims

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Application Information

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IPC IPC(8): C07D491/107
CPCC07B2200/07C07D491/107
Inventor 夏爱宝汤成科许丹倩
Owner ZHEJIANG UNIV OF TECH
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