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Preparation method of chiral spiro naphthoquinone benzopyran hydroxyindole compound

A pyranoxindole compound and a compound technology are applied in the field of preparation of chiral spironaphthoquinopyranoxidole compounds, and can solve the problems of narrow substrate application range, harsh reaction conditions, narrow substrate range and the like, Achieve excellent enantioselectivity, mild reaction conditions, and a wide range of substrates

Inactive Publication Date: 2014-02-05
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In 2009, Bazgir, A. et al. used p-toluenesulfonic acid as catalyst and water as solvent to use isatin, malononitrile and 2-hydroxy -1, 4-Naphthoquinone as raw material, a three-component one-pot method was used to synthesize the racemic spironaphthoquinone-pyranoxindole compound; however, the reaction needs to be carried out at 100°C, and the scope of applicable substrates is relatively wide. Narrow (see: Ghahremanzadeh, R.; Amanpour, T.; Bazgir, A., J. Heterocycl. Chem. 2009, 46, 1266-1270 )
[0004] The prior art can prepare the racemate spironaphthoquinone-pyranoxindole compound, but because many natural products and drug intermediates are chiral molecules, and The prior art only provides the preparation of racemic products, and requires a relatively large amount of catalyst, and the reaction conditions are harsh, requiring a very high reaction temperature
In addition, the existing methods have a narrow range of substrates

Method used

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  • Preparation method of chiral spiro naphthoquinone benzopyran hydroxyindole compound
  • Preparation method of chiral spiro naphthoquinone benzopyran hydroxyindole compound
  • Preparation method of chiral spiro naphthoquinone benzopyran hydroxyindole compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Xiang Shengyou 3a (34.8 mg, 0.2 mmol), dihydroquinine thiourea Cat. 1n (3.0 mg, 0.005 mmol) Add 2 mL of ether to the reaction bottle, and then add 2a (39.0 mg, 0.2 mmol), stirred at room temperature for 48 hours (reaction detected by TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluent was ethyl acetate / petroleum ether=1 / 2, then two Chloromethane / methanol=40 / 1) to get the target product 4a (72.4 mg), the yield was 98%.

[0034] The target product was characterized and analyzed as follows: brown solid, 98% yield, 98% ee, [ α ] D 25 = -94.0 (c 0.50, CH 3 COCH 3 ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.91-7.77 (m, 3H), 7.59 (s, 2H), 7.28-7.15(m, 2H), 6.95-6.84(m, 2H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 182.0, 177.8, 176.5, 158.8, 150.6, 141.8, 135.0, 134.6, 130.7, 130.4, 129.1, 126.4, 126.2, 124.4, 122.2, 119.7, 117.2, 109.8, (IR) ν max / cm -1 ): 3417, 33...

Embodiment 2

[0036]

[0037] Xiang Shengyou 3a (34.8 mg, 0.2 mmol), dihydroquinine thiourea Cat. 1n (3.0 mg, 0.005 mmol) Add 2 mL of ether to the reaction bottle, and then add 2b (45.9 mg, 0.2 mmol), stirred at room temperature for 6 hours (reaction detected by TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluent was ethyl acetate / petroleum ether=1 / 2, then two Chloromethane / methanol=40 / 1) to get the target product 4b (79.9 mg), the yield was 99%.

[0038] The target product was characterized and analyzed as follows: brown solid, 99% yield, 91% ee, [ α ] D 25 = -39.0 (c 0.50, CH 3 COCH 3 ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.11-8.02 (m, 1H), 7.93-7.82 (m, 3H), 7.79 (s, 2H), 7.33-7.21 (m, 1H), 6.99-6.85 (m, 2H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 181.8, 176.7, 176.1, 159.7, 150.9, 143.8, 135.2, 134.8, 131.0, 130.2, 130.1, 129.7, 129.0, 126.3, 122.4, 116.7, 109.1, 48.5; IR (KBR) (KBR) (KBR) ν max / cm -1 ): ...

Embodiment 3

[0040]

[0041] Xiang Shengyou 3a (34.8 mg, 0.2 mmol), dihydroquinine thiourea Cat. 1n (3.0 mg, 0.005 mmol) Add 2 mL of ether to the reaction bottle, and then add 2c (54.8 mg, 0.2 mmol), stirred at room temperature for 12 hours (reaction detected by TLC), after the reaction was complete, the crude product was subjected to column chromatography (eluent was ethyl acetate / petroleum ether=1 / 2, then two Chloromethane / methanol=40 / 1) to get the target product 4c (87.8 mg), the yield was 98%.

[0042] The target product was characterized and analyzed as follows: brown solid, 98% yield, 90% ee, [ α ] D 25 = -10.0 (c 0.50, CH 3 COCH 3 ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.12-8.02 (m, 1H), 7.93-7.82 (m, 3H), 7.77 (s, 2H), 7.25-7.14 (m, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H); 13 C NMR (75 MHz, DMSO-d 6 ) δ 181.7, 176.6, 176.2, 159.7, 151.1, 144.1, 135.3, 134.9, 131.2, 130.5, 130.2, 130.1, 126.6, 126.3, 118.6, 116.7, 109.5, 49.7; ν ...

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Abstract

The invention discloses a preparation method of a chiral spiro naphthoquinone benzopyran hydroxyindole compound. The method comprises the following specific steps: reacting the condensation product of an isatin compound and propane dinitrile and a 2-hydroxyl-1,4-naphthoquinone compound in a solvent under the catalysis of quinine thiourea dihydride, thereby obtaining a product. According to the method, raw materials are simple and easily available, the reaction condition is mild, the post-treatment is simple and convenient, the applicative substrates are wide, the enantioselectivity is high, and the yield can reach 99%; therefore, the method is a novel method capable of efficiently synthesizing the chiral spiro naphthoquinone benzopyran hydroxyindole compound having important medicinal value and asymmetric synthesis value. The compound prepared by the method can be used for preparing intermediates of chiral drugs and has wide physiological and pharmacological activities.

Description

technical field [0001] The invention relates to the preparation of naphthoquinopyran organic compounds, in particular to a preparation method of chiral spironaphthoquinopyran oxindole compounds. Background technique [0002] Naphthoquinone structural compounds have been found to have broad-spectrum antibacterial and anticancer activities, and are the core fragments of many natural products and modern drugs, such as α -lapachone, β - Lappaquinone, metamycin, etc., are widely used in the treatment of various diseases. Indolinone is a nitrogen-containing aromatic heterocyclic organic compound with a bicyclic structure consisting of a benzene ring and a five-membered nitrogen heterocycle. It is an important pharmaceutical and pesticide intermediate. Indol-2-one derivatives are widely used as pharmacophore in medicine. The spironaphthoquinonepyranoxindole compound contains naphthoquinone, pyran and oxindole structural units, and is of great significance as a medicinal compound...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107
CPCC07D491/107
Inventor 王兴旺潘锋锋
Owner SUZHOU UNIV
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