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A chiral spiro-oxindole dihydropyran derivative and its synthesis method

A spirocyclic oxindole dihydropyran derivative and technology for a synthesis method are applied in the field of chiral spirocyclic oxindole dihydropyran derivatives and their catalytic synthesis, and achieve high yield, enantioselectivity and Excellent diastereoselectivity and high compatibility

Active Publication Date: 2019-04-05
SUZHOU UNIV
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  • Abstract
  • Description
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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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  • A chiral spiro-oxindole dihydropyran derivative and its synthesis method
  • A chiral spiro-oxindole dihydropyran derivative and its synthesis method
  • A chiral spiro-oxindole dihydropyran derivative and its synthesis method

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Experimental program
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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, 0.1 mmol) 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: 1.0 mL·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,...

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 synthesis method of chiral spiro-oxindole dihydropyran derivatives, specifically, dihydrofuran (pyran) and isatin derivatives β , gamma -Unsaturated α The -ketoester is a reactant, and under the catalysis of a chiral (Box) / Cu(II) complex, the product is synthesized in a trifluorotoluene solvent. The method disclosed by the invention has simple and easy raw materials, mild reaction conditions, simple and convenient post-treatment, wide range of applicable substrates, high yield, high enantioselectivity and diastereoselectivity; the product synthesized thereby has potential medicinal 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 Patents(China)
IPC IPC(8): C07D491/20
CPCC07B2200/07C07D491/20
Inventor 王兴旺李乃凯
Owner SUZHOU UNIV
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