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Pyranopyrazole acrylate derivative as well as preparation method and application thereof

A technology of pyranopyrazole acrylic acid and acrylic acid ester, which is applied in the application field of pyranopyrazole acrylic acid ester derivatives and the preparation of antitumor drugs, and achieves high chemical selectivity and regioselectivity, and easy-to-obtain raw materials , the effect of easy operation

Active Publication Date: 2021-06-11
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Pyranopyrazole acrylate derivative as well as preparation method and application thereof
  • Pyranopyrazole acrylate derivative as well as preparation method and application thereof
  • Pyranopyrazole acrylate derivative as well as preparation method and application thereof

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 pyran-pyrazole acrylate derivative as well as a preparation method and application thereof. The preparation method of the derivative comprises the following steps: mixing MBH carbonate containing quinoline heterocycle as shown in a formula (II), a pyrazolone derivative as shown in a formula (III) and a solvent, adding a chiral phosphine catalyst and alkali, and carrying out stirring reaction for 36-240 hours at -20 to 80 DEG C to prepare the pyranopyrazole acrylate derivative, that is, the 1,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-b]quinoline-4-acrylate derivative. The method has the advantages that raw materials are easy to obtain, operation is easy and convenient, and chemical selectivity and regioselectivity are high; the target compound has a good in-vitro proliferation inhibition effect on human colon cancer cells HT-29, human non-small cell lung cancer cells A549 and triple negative breast cancer cells MDA-MB-231. Thus, the method has high implementation value and application prospects.

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 Applications(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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