Chiral spiro oxindole dihydropyran derivative and synthesizing method thereof

A technology of spirocyclic oxindole dihydropyran derivatives and synthetic methods, applied in the field of chiral spirocyclic oxindole dihydropyran derivatives and their catalytic synthesis, achieving high yield and chemoselectivity Good, handles simple effects

Active Publication Date: 2017-09-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, the synthesis method of compounds containing acetal structure is relatively common, but the synthesis method of spiro-oxindole dihydropyran acetal compounds based on oxindole structure is rarely reported.

Method used

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  • Chiral spiro oxindole dihydropyran derivative and synthesizing method thereof
  • Chiral spiro oxindole dihydropyran derivative and synthesizing method thereof
  • Chiral spiro oxindole dihydropyran derivative and synthesizing method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031]

[0032] Under nitrogen atmosphere, Cu(OTf) 2 (0.9 mg, 0.0025 mmol, 2.5 mol%), L (1.84 mg, 0.0025 mmol, 2.5 mol%) were placed in anhydrous benzotrifluoride (1 mL), stirred at room temperature for 1 hour, and reactant 1a (25.9 mg, 0.1 mmol) and 2b (16.8 mg, 0.2 mmol, 2 equiv), reacted at room temperature for 24 hours until the substrate 1a disappeared, and the reaction system was directly separated by petroleum ether / ethyl acetate (3 / 1) column chromatography to obtain 32.2 mg White solid 3ab, white solid, 94% yield, 161–162 °C.

[0033] The product 3ab was analyzed and the results were as follows: >99:1 dr , 94% ee [Daicel Chiralcel AD-H, hexanes / i -PrOH = 80 / 20, flow rate: 1.0 mL·min –1 , λ = 254.4 nm, t (major)=12.087, t (minor)= 15.133]; [ α ]25 D = 148.9 (c 0.14, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (td, J = 7.6, 1.7 Hz, 1H), 7.16 – 7.02 (m, 2H), 6.84 (d, J =7.8 Hz, 1H), 5.67 (s, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.23 (qq, J = 7.5, 3.7Hz, 2...

Embodiment 2

[0036]

[0037] Under nitrogen atmosphere, Cu(OTf) 2 (1.8 mg, 0.005 mmol, 5 mol%), L (3.69 mg, 0.005 mmol, 5 mol%) were placed in anhydrous benzotrifluoride (1 mL), stirred at room temperature for 1 hour, and reactant 1b (24.5 mg, 0.1mmol) and 2b (33.6 mg, 0.4 mmol, 4 equiv), reacted at room temperature for 24 hours until the substrate 1b disappeared, and the reaction system was directly separated by petroleum ether / ethyl acetate (3 / 1) column chromatography to obtain 29.9 mg White solid 3bb, white solid, 91% yield, 140–141 °C.

[0038] Product 3bb is analyzed, and the results are as follows: 96:4 dr , 93% ee [Daicel Chiralcel AD-H, hexanes / i -PrOH = 80 / 20, flow rate: 1.0mL min –1 , λ = 254.4 nm, t (major)=13.307, t (minor)= 18.928]; [ α ]25 D = 191.7 (c 0.1, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (td, J = 7.5, 1.8 Hz, 1H), 7.16 – 7.06 (m, 2H), 6.85 (d, J =7.8 Hz, 1H), 5.70 (s, 1H), 5.63 (d, J = 8.9 Hz, 1H), 4.09 (dd, J = 11.8, 4.6Hz, 1H), 3.80 (s, 3...

Embodiment 3

[0041]

[0042] Under nitrogen atmosphere, Cu(OTf) 2 (0.9 mg, 0.0025 mmol, 2.5 mol%), L (1.84 mg, 0.0025 mmol, 2.5 mol%) were placed in anhydrous benzotrifluoride (1 mL), stirred at room temperature for 1 hour, and reactant 1c (28.9 mg, 0.1 mmol) and 2b (16.8 mg, 0.2 mmol, 2 equiv), reacted at room temperature for 24 hours until the substrate 1c disappeared, and the reaction system was directly separated by petroleum ether / ethyl acetate (3 / 1) column chromatography to obtain 34.6 mg White solid 3cb, white solid, 93% yield, 63–64 °C.

[0043] The product 3cb was analyzed and the results were as follows: >99:1 dr , 93% ee [Daicel Chiralcel AD-H, hexanes / i -PrOH = 80 / 20, flow rate: 1.0 mL·min –1 , λ = 254.4 nm, t (major)=10.943, t (minor)= 12.549]; [ α ]25 D = 185 (c 0.16, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 7.18 – 7.08 (m, 2H), 7.04 (d, J = 7.9 Hz, 1H), 5.69(d, J = 1.6 Hz, 1H), 5.59 (dd, J = 9.0, 1.6 Hz, 1H), 5.21 – 4.99 (m, 2H),4.25 (qq, J ...

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Abstract

The invention discloses a synthesizing method of a chiral spiro oxindole dihydropyran derivative. The synthesizing method comprises the following steps of using dihydropyran (pyran) and isatin-derived beta,gamma-unsaturated alpha-keto ester as reaction matters; under the existence of a chiral (Box) / Cu(II) complex, synthesizing in a benzotrifluoride solvent to obtain a product. The synthesizing method disclosed by the invention has the advantages that the raw materials are simple, the obtaining is easy, the reaction condition is mild, the post-treatment is simple and convenient, the applicable substrate range is broad, the yield is high, and the enantioselectivity and non-enantioselectivity are high; the synthesized product has potential medical value.

Description

technical field [0001] The invention relates to the synthesis of spirocyclic oxindole compounds, in particular to chiral spirocyclic oxindole dihydropyran derivatives and a catalytic synthesis method thereof. Background technique [0002] Five-membered and six-membered oxygen-containing heterocyclic rings such as pyran, dihydropyran, tetrahydropyran and tetrahydrofuran are important structural units and widely exist in a variety of biologically active drug molecules and natural product molecules. Many pharmaceutical molecules synthesized or extracted from marine organisms have one or more oxygen-containing heterocyclic structural units. Moreover, it has been proved by experiments that various physiological and pharmacological activities of such molecules are often attributed to the five-membered or six-membered oxygen-containing heterocyclic structural units in the molecular structure. In addition, the cyclic acetal structure often has good physiological activity due to its...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20
CPCC07B2200/07C07D491/20
Inventor 王兴旺李乃凯
Owner SUZHOU UNIV
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