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A kind of pyranopyrazole acrylate derivative and its preparation method and application

A technology of pyranopyrazole acrylic acid and its derivatives, which is applied in the field of medicine and chemical industry, and achieves great implementation value and application prospect, high chemoselectivity and regioselectivity, and good effect of inhibiting proliferation in vitro

Active Publication Date: 2022-04-01
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, chiral organic small molecules are used to catalyze the asymmetric [3+3] cycloaddition of pyrazolone derivatives and MBH carbonate containing quinoline heterocycles to construct 1,4-dihydropyrazolo with potential physiological activity. [4',3':5,6]pyrano[2,3-b]quinoline-4-acrylate derivatives are rarely reported

Method used

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  • A kind of pyranopyrazole acrylate derivative and its preparation method and application
  • A kind of pyranopyrazole acrylate derivative and its preparation method and application
  • A kind of pyranopyrazole acrylate derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: (R)-2-(3-methyl-1-phenyl-1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b The preparation of ] quinoline-4-yl) methyl acrylate (I-1)

[0022]

[0023] Add MBH carbonate IIa (226 mg, 0.6 mmol), pyrazolone derivative IIIa (87 mg, 0.5 mmol), sodium carbonate (53 mg, 0.5 mmol) and o-dichlorobenzene (2.5 mL) into a dry Shrek tube ( 15 mL), add chiral phosphine catalyst P3 (15 mg, 0.025 mmol), stir at 40 °C for 72 hours, concentrate under reduced pressure to recover the solvent, and separate by column chromatography (petroleum ether / ethyl acetate=3 / 1, v / v) To obtain light yellow solid I-1, 166.7mg, yield 84%, ee value 93%.

[0024] Structural characterization of I-1: m.p.: 129-130°C; 1 H NMR (400MHz, CDCl 3 )δ8.18(s,1H),7.97(d,J=8.4Hz,1H),7.91(d,J=7.6Hz,2H),7.76(d,J=8.0Hz,1H),7.71–7.66( m,1H),7.52–7.45(m,3H),7.32–7.27(m,1H),6.38(s,1H),5.87(s,1H),5.30(s,1H),3.64(s,3H) ,2.22(s,3H). 13 C NMR (100MHz, CDCl 3 )δ165.9, 155.2, 146.8, 145.9, 145.4, 142.0, 139.3, 137...

Embodiment 2

[0025] Example 2: (R)-2-(3-methyl-1-phenyl-1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b The preparation of ] quinoline-4-yl) methyl acrylate (I-1)

[0026] Add MBH carbonate IIa (226 mg, 0.6 mmol), pyrazolone derivative IIIa (87 mg, 0.5 mmol), sodium carbonate (53 mg, 0.5 mmol) and toluene (2.5 mL) into a dry Shrek tube (15 mL) , add chiral phosphine catalyst P1 (55.7mg, 0.1mmol), stir at 25°C for 96 hours, concentrate under reduced pressure to recover the solvent, and separate by column chromatography (petroleum ether / ethyl acetate=3 / 1, v / v) , to obtain light yellow solid I-1, 99.3mg, yield 50%, ee value 98%.

Embodiment 3

[0027] Example 3: (R)-2-(3-methyl-1-phenyl-1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b The preparation of ] quinoline-4-yl) methyl acrylate (I-1)

[0028] Add MBH carbonate IIa (226 mg, 0.6 mmol), pyrazolone derivative IIIa (87 mg, 0.5 mmol), sodium carbonate (53 mg, 0.5 mmol) and toluene (2.5 mL) into a dry Shrek tube (15 mL) , add chiral phosphine catalyst P2 (65.3mg, 0.1mmol), stir at 25°C for 96 hours, concentrate under reduced pressure to recover the solvent, and separate by column chromatography (petroleum ether / ethyl acetate=3 / 1, v / v) , to obtain light yellow solid I-1, 109.2mg, yield 55%, ee value 98%.

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Abstract

The invention discloses a pyranopyrazole acrylate derivative, a preparation method and application thereof. The preparation method of this type of derivative is as follows: the MBH carbonate containing quinoline heterocycle as shown in formula (II), the pyrazolone derivative shown in formula (III) are mixed with solvent, add chiral phosphine catalyst and The base is stirred and reacted to prepare the pyranopyrazole acrylate derivatives shown in the formula (I). The method of the present invention has the characteristics of easy-to-obtain raw materials, simple and convenient operation, high chemical selectivity and regioselectivity, and the target compound is effective against human colon cancer cell HT-29, human non-small cell lung cancer cell A549, and triple-negative breast cancer cell MDA-MB-231. It has better effect of inhibiting proliferation in vitro, therefore, the method of the present invention has great implementation value and application prospect.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a pyranopyrazole acrylate derivative, that is, 1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3 -b] quinoline-4-acrylic acid ester derivatives and their preparation methods and their application in the preparation of antitumor drugs. Background technique [0002] Pyranopyrazole structure is an important class of heterocyclic skeleton, and its derivatives have a wide range of biological and pharmacological activities. For example, compound 1 shown in formula (1) has antiplatelet effect (Org.Lett.2016,18,556-559.), compound 2 shown in formula (2) has anti-inflammatory activity (J.Org.Chem.2016, 81,4340-4346.), compound 3 shown in formula (3) is an adenosine receptor antagonist for the treatment of Parkinson's (J.Org.Chem.2017,82,2926-2934.), formula (4) The shown compound 4 containing spirooxindole furopyrazolone structure has antitumor activity against U937 and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/147A61P35/00
CPCC07D491/147A61P35/00
Inventor 钟为慧邵炳宣肖霄凌飞
Owner ZHEJIANG UNIV OF TECH
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