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A kind of iodine medium preparation method of chiral pyrazole spirofuran compound

A technology for pyrazole spirofuran and compounds, which is applied in the field of iodine medium preparation of chiral pyrazole spirofuran compounds, can solve the problems of increasing post-processing costs, etc., and achieve good reaction characteristics, mild reaction conditions, and good selectivity

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

This method requires the use of an equivalent amount of inorganic base and iodine element, which produces more inorganic salts and increases the post-processing cost.

Method used

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  • A kind of iodine medium preparation method of chiral pyrazole spirofuran compound
  • A kind of iodine medium preparation method of chiral pyrazole spirofuran compound
  • A kind of iodine medium preparation method of chiral pyrazole spirofuran compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: (2R,3S)-3'-methyl-3-nitromethyl-1'-phenyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1 'H)-ketone;

[0078]

[0079] (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, 0.0011g), solvent dichloromethane (1mL), after reacting at 25°C for 6h, a mixture containing intermediate compound 1-A was obtained;

[0080] (B) Remove the solvent from the mixture containing intermediate compound 1-A, add cuprous iodide (0.076g, 0.4mmol), lithium carbonate (0.4mmol, 0.0296g), solvent dichloromethane (1mL), 25°C After reacting for 8 hours, 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, 57%ee,>99:1dr) obtained by column chromatography separation and purifica...

Embodiment 2

[0081] Example 2: (2R,3S)-3'-ethyl-3-nitromethyl-1'-phenyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1 'H)-ketone;

[0082]

[0083] (A) Take 10mL clean small test tube, add o-hydroxynitroalkene (0.2mmol, 0.033g), 5-ethyl-2-phenyl-pyrazolone (0.2mmol, 0.0376g), chiral squaraine catalyst VI (0.02mmol, 0.0096g), solvent toluene (2mL), after reaction at 0°C for 24h, a mixture containing intermediate compound 2-A was obtained;

[0084] (B) Remove the solvent from the mixture containing intermediate compound 2-A, then add iodobenzene acetate (0.8mmol, 0.2576g), sodium carbonate (0.2mmol, 0.0212g), solvent toluene (2mL), and react at 25°C for 1h Finally, extract with ethyl acetate (3 × 10mL), the organic phase is desolvated under reduced pressure, use ethyl acetate:petroleum ether=1:10 mixed solvent as eluent; 200-300 mesh column chromatography silica gel is as filler, column The target product obtained by chromatographic separation and purification (0.0604g, 86%yield, 78%ee, >99:1...

Embodiment 3

[0085] Example 3: (2R,3S)-3-nitromethyl-1',3'-diphenyl-3H-spiro[benzofuran-2,4'-pyrazole]-5'(1'H )-ketone;

[0086]

[0087] (A) Take 10mL clean small test tube, add o-hydroxynitroalkene (0.2mmol, 0.033g), 2,5-diphenyl-pyrazolone (0.2mmol, 0.0472g), chiral squaraine catalyst VII ( 0.04mmol, 0.0246g), solvent ethyl acetate (3mL), after reaction at -20°C for 20h, a mixture containing intermediate compound 3-A was obtained;

[0088] (B) Remove the solvent from the mixture containing intermediate compound 3-A, then add hydrogen iodide (2mmol, 0.256g), potassium carbonate (0.1mmol, 0.0614g), solvent ethyl acetate (3mL), and react at 25°C After 2h, 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 (0.0599g, 75%yield, 84%ee, >99:1dr) obtained by column chromatography separation and purification, 1 H ...

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Abstract

The invention provides an iodine-mediated preparation method of chiral pyrazole spirofuran compounds shown in formula (I), the synthesis method is carried out as follows: the o-hydroxyl nitroalkene shown in formula (II) Compounds and pyrazolone compounds shown in formula (III), chiral squaraine catalysts, and organic solvents are mixed, and reacted at -60 to 60°C for 1 to 48 hours to obtain compounds shown in formula (IV). Add an iodine source additive and an alkali to the compound shown in (IV), react at -60 to 60°C for 1 to 48 hours, and the reaction solution is post-treated to obtain the chiral pyrazole spirofuran compound shown in the formula (I); the present invention The reaction conditions are mild, the product yield is high, and the selectivity is excellent.

Description

[0001] (1) Technical field [0002] The invention relates to an iodine-mediated preparation method of chiral pyrazole spirofuran compounds. [0003] (2) Background technology [0004] 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 inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/107B01J31/02
CPCB01J31/0244C07B2200/07C07D491/107
Inventor 许丹倩汤成科张晓龙夏爱宝
Owner ZHEJIANG UNIV OF TECH
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