Naphthazarin nucleus oxialkyl and acyl substituted alkannin derivative, its preparation and application thereof

A kind of nucleooxyalkyl, acyl substitution technology, applied in the field of chiral natural products

Inactive Publication Date: 2012-07-11
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The applicant previously invented the preparation method of chiral shikonin and arcanin (application number: 20110209290.7) and shikonin racemate (authorization number: ZL200510025243.1), and applied for a series of shikonin naphthalene Oxyalkylated derivatives of the parent nucleus (application number: 201010046435.2, 201010209926.3), but except for a few compound intermediates in the preparation process, no other arcanin derivatives are involved

Method used

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  • Naphthazarin nucleus oxialkyl and acyl substituted alkannin derivative, its preparation and application thereof
  • Naphthazarin nucleus oxialkyl and acyl substituted alkannin derivative, its preparation and application thereof
  • Naphthazarin nucleus oxialkyl and acyl substituted alkannin derivative, its preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Compound (s)-2-(1-acetoxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (II-1), (s)-2 -(1-acetoxy-4-methyl-3-pentenyl)-5,8-dimethoxy-1,4-naphthoquinone (III-1) and (s)-6-(1- Preparation of Acetoxy-4-methyl-3-pentenyl)-5,8-dimethoxy-1,4-naphthoquinone (IV-1)

[0048] (s)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (1,4,5,8-O-tetramethyl Arkanin) was dissolved in anhydrous dichloromethane, and 1.5 equivalents of acetic anhydride, 2 equivalents of triethylamine, and a catalytic amount of DMAP were added at 0-5°C, stirred at room temperature for 15-30 minutes, and extracted with dichloromethane. Dry over anhydrous sodium sulfate, concentrate and column chromatography to obtain compound II-1 as a yellow oil. Yield 96%, 1 H NMR (300MHz, CDCl 3 ): δ=6.87(s, 1H, H Ar ), 6.82(s, 2H, H Ar ), 6.34(dd, 1H, J=4.2, 6.0Hz, -CH-), 6.15(t, 1H, J=4.5Hz, -CH=), 3.93(s, 6H, 2×-OCH 3 ), 3.86(s, 3H, -OCH 3 ), 3.83 (s, 3H, -OCH 3 ), 2.54-2.95 (m, 2H, -CH ...

Embodiment 2

[0053] Compound (s)-2-[1-(3-methyl-but-2-enoyloxy)-4-methyl-pent-3-enyl]-1,4,5,8-tetramethoxy Base naphthalene (II-2), (s)-2-[1-(3-methyl-but-2-enoyloxy)-4-methyl-pent-3-enyl]-5,8- Dimethoxy-1,4-naphthoquinone (III-2) and (s)-6-[1-(3-methyl-but-2-enoyloxy)-4-methyl-pent-3 Preparation of -alkenyl]-5,8-dimethoxy-1,4-naphthoquinone (IV-2)

[0054] Dissolve (s)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene in anhydrous dichloromethane at 0-5 ℃ respectively add 1.5 equivalents of β, β-dimethacrylic acid, 2.5 equivalents of DCC, and catalytic amount of DMAP, stir at room temperature for 2-4 hours, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate and perform column chromatography , to obtain yellow oil compound II-2 respectively. Yield 71%, 1 HNMR (300MHz, CDCl 3 ): δ=6.63(s, 1H, H Ar ), 6.52(s, 2H, H Ar ), 5.52(m, 1H, -COCH=), 5.30(s, 1H, -CH-), 5.22(s, 1H, -CH 2 CH=), 3.88(s, 6H, 2×-OCH 3 ), 3.84 (s, 3H, -OCH 3 ), 3.76 (s, 3...

Embodiment 3

[0059] Compound (s)-2-[1-(3-methyl-3-hydroxy-butyryloxy)-4-methyl-pent-3-enyl]-1,4,5,8-tetramethoxy Naphthalene (II-3), (s)-2-[1-(3-methyl-3-hydroxy-butyryloxy)-4-methyl-pent-3-enyl]-5,8- Dimethoxy-1,4-naphthoquinone (III-2) and (s)-6-[1-(3-methyl-3-hydroxy-butyryloxy)-4-methyl-penta-3 Preparation of -alkenyl]-5,8-dimethoxy-1,4-naphthoquinone (IV-3)

[0060] Dissolve (s)-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene in anhydrous dichloromethane at 0-5 ℃ were added corresponding 1.5 equivalents of β-hydroxyisovaleric acid, 2.5 equivalents of DCC, and a catalytic amount of DMAP, stirred at room temperature for 1-2 h, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated and then column chromatographed. Compound II-3 was obtained as yellow oil. Yield 62%, 1 H NMR (300MHz, CDCl 3 ): δ=6.88(s, 1H, H Ar ), 6.84(s, 2H, H Ar ), 6.09(dd, 1H, J=2.7, 5.4Hz, -CH-), 6.15(t, 1H, J=4.5Hz, -CH=), 3.93(s, 6H, 2×-OCH 3 ), 3.86(s, 3H, -OCH ...

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Abstract

The invention discloses a naphthazarin nucleus oxialkyl and acyl substituted alkannin derivative, its preparation and an application thereof. The activity of the compound provided by the invention is equivalent to or better than that of a corresponding alkannin nucleus oxialkyl and substituted derivative. By the use of the derivative, cytotoxicity of some compounds is reduced or disappears, and the animal body shows a certain effect of inhibiting tumor growth through an antitumor test. The derivative can be used as an antitumor drug or prodrug to treat malignant tumor. Simultaneously, the preparation method provided by the invention has advantages of easily-obtained raw materials, short synthesis route and high optical purity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method and a medical application of a series of chiral natural product alkaninaxime parent nucleus oxyalkyl and acyl substituted derivatives with antitumor activity. Background technique [0002] Comfrey is a commonly used clinical traditional Chinese medicine recorded in the Pharmacopoeia of the People's Republic of China. Comfrey can be divided into hard comfrey (also known as northeast comfrey, Lithospermum erythrohizon) and soft comfrey (also known as Xinjiang comfrey, A.euchroma Johnst). The main active ingredient in hard comfrey is shikonin (Shikonin) and its derivatives, and soft comfrey contains alkannin (Alkannin) and its derivatives, and shikonin and alkannin are enantiomers of each other , shikonin is in the R configuration, and akanin is in the S configuration. They have been proven to have various biological activities such as anti-inflam...

Claims

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Application Information

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IPC IPC(8): C07C50/32C07C46/00C07C69/035C07C67/08C07C67/24C07C67/39C07C229/12C07C227/04A61K31/122A61K31/222A61K31/223A61P35/00
Inventor 李绍顺王汝冰周文郑小刚朱梦媛
Owner SHANGHAI JIAO TONG UNIV
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