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A kind of preparation method of chiral spironaphthoquinopyranoxindole compound

An oxindole compound and a technology for the compound are applied in the field of preparation of chiral spironaphthoquinone and oxindole compounds, and can solve the problems of narrow substrate application range, harsh reaction conditions, high reaction temperature and the like, and achieve Excellent enantioselectivity, mild reaction conditions and high yield

Inactive Publication Date: 2015-09-23
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 isatin, malononitrile and 2-hydroxy-1, 4-naphthoquinone as raw materials under the condition of p-toluenesulfonic acid as catalyst and water as solvent, three components in one pot The racemic spironaphthoquinone-oxindole compound was synthesized by the method; however, the reaction needs to be carried out at 100°C, and the scope of applicable substrates is 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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  • A kind of preparation method of chiral spironaphthoquinopyranoxindole compound
  • A kind of preparation method of chiral spironaphthoquinopyranoxindole compound
  • A kind of preparation method of chiral spironaphthoquinopyranoxindole compound

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Experimental program
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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 spironaphthoquinone-pyranoxindole compound, which specifically uses the condensation product of isatin compound and malononitrile and 2-hydroxy-1,4-naphthoquinone compound as reactants , under the catalysis of dihydroquinine thiourea, the product was prepared in a solvent. This method has simple and easy raw materials, mild reaction conditions, simple and convenient post-treatment, wide range of applicable substrates, high enantioselectivity, and a yield of up to 99%. It is a new high-efficiency synthesis with important medicinal value and Method for the asymmetric synthesis of valuable chiral spironaphthoquinopyranoxindoles. The product prepared by the method can be used to prepare intermediates of chiral drugs, and has broad-spectrum 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 Patents(China)
IPC IPC(8): C07D491/107
CPCC07D491/107
Inventor 王兴旺潘锋锋
Owner SUZHOU UNIV