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Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof

A technology for nucleoside alkyl and derivatives, which is applied in the field of shikonin-naphthyme nucleoside oxyalkylation derivatives and its preparation, and can solve the problem that the synthesis route is long and unsuitable for the synthesis of shikonin-naphthyme nucleoxane Kylated derivatives and other issues

Inactive Publication Date: 2010-07-21
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] After searching the literature of the prior art, it was found that the Chinese invention patent application with the publication number CN1420111A disclosed a class of naphthalene derivatives and their preparation methods and uses, and reported the inhibitory effect and anti-tumor effect of this type of compound on telomerase , these compounds are acylated derivatives of the side chain hydroxyl of shikonin; patent application WO 97 / 03940 discloses a new class of 6-substituted 5,8-dioxo-1,4-naphthoquinone derivatives Anti-tumor effect, these compounds include 5,8-dioxoalkylated products, but the side chain is an alkyl chain different from shikonin; the Chinese invention patent application with publication number CN101139287 discloses the derivative of shikonin dimethyl ether However, these synthetic methods have long synthetic routes and are not suitable for the synthesis of some shikonin naphthalene oxyalkylated derivatives

Method used

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  • Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof
  • Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof
  • Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0108] Preparation of 1,4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)naphthalene (II-1)

[0109] Step 1, in a 25ml reaction bottle, add shikonin (144mg, 0.50mmol), dried potassium carbonate (690mg, 5.0mmol), DMF (15ml), KI (20mg), methyl iodide (0.16ml, 2.5mmol) . Under the protection of nitrogen, the reaction was carried out at room temperature (25°C) for 24h. After the reaction, dilute with water (10ml), extract with ethyl acetate (20ml×3), wash the extract with water (15ml×2), dry over anhydrous magnesium sulfate, filter, and concentrate to dryness to obtain 139mg of crude product, which was analyzed by PTLC Separation gave 121.0 mg of 5,8-dimethoxy-2-(1-hydroxyl-4-methyl-3-pentenyl)-1,4-naphthoquinone (VI-1) orange-red solid, yield was 76.6%. Melting point: 56~59℃, IR(KBr): 3457, 2930, 1652, 1571, 1475, 826cm -1 . 1 H NMR (300MHz, CDCl 3 , δppm): δ7.32(s, 2H, H Ar ), 6.79 (s, 1H, H quin ), 5.17(t, 1H, J=7.80Hz, CH=), 4.75(t, 1H, J=7.20Hz, CHO), 3.98(s, 6H, 2...

Embodiment 2

[0112] Preparation of 1,4,5,8-tetramethoxy-2-(1-acyloxy-4-methyl-3-pentenyl)naphthalene

[0113] Step one and step two are the same as embodiment 1;

[0114]Step 3, dissolve compound II-1 in dry dichloromethane, add 2 times molar amount of dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-dimethylaminopyridine (DMAP) and 2 times The amount of corresponding carboxylic acid was stirred at room temperature for 2 h. An appropriate amount of petroleum ether was added to the reaction liquid for filtration, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with petroleum ether: ethyl acetate (4 / 1, V / V) to obtain the ester derivative of II-1 things.

[0115] 40.2 mg of 1,4,5,8-tetramethoxy-2-(1-acetoxy-4-methyl-3-pentenyl)naphthalene (II-2) orange-red oily compound was obtained by the above method , and the yield was 71.9%. 1 H NMR (300MHz, CDCl 3 , δppm): δ6.87(s, 1H, H Ar ), 6.82(s, 2H, H Ar ), 6.3...

Embodiment 3

[0123] Preparation of 1,4,5,8-tetramethoxy-2-(1-alkoxy-4-methyl-3-pentenyl)naphthalene

[0124] Step one and step two are the same as embodiment 1;

[0125] Step 3, dissolve 1,4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)naphthalene (II-1) in dry N,N-bis Add 1.5 equivalents of NaH to methylformamide, stir thoroughly for 10 minutes, then add 1.1 equivalents of the corresponding bromoalkane, and stir at room temperature for 12 hours. Add 10ml of ethyl acetate to the reaction solution for dilution, then wash with water and saturated brine respectively, wash with anhydrous MgSO 4 After drying, ethyl acetate was distilled off under reduced pressure. The crude product was chromatographed on a silica gel column, eluting with ethyl acetate:petroleum ether (1:4) to obtain the ether derivative of II-1.

[0126] 41.4 mg of yellow oily 1,4,5,8-tetramethoxy-2-(1-methoxy-4-methyl-3-pentenyl)naphthalene (II-9) was obtained by the above method. The rate is 79.5%. 1 HNMR (300MHz, C...

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Abstract

The invention relates to an oxygen alkylated derivative of a parent nucleus of alkannin naphthazarin and a preparation method and application thereof. The structural formula of the oxygen alkylated derivative of the parent nucleus of alkannin naphthazarin is particularly shown as in the following formula, wherein R is H, alkane with 1-10 carbon atom(s), olefin, acrne or COR', R' is H, alkane with 1-10 carbon atom(s), olefin or acrne. The invention also relates to the application of the oxygen alkylated derivative of the parent nucleus of alkannin naphthazarin in preparation of anticancer drugs. The preparation method of the invention has the advantages of easily accessible raw materials, short synthetic route and high reaction yield, and the prepared compound can be used as a prodrug for treatment of malignant tumors.

Description

technical field [0001] The invention relates to a compound in the technical field of medicine and chemical engineering and its preparation method and application, in particular to a shikonin naphthalene oxyalkylated derivative and its preparation method and application. Background technique [0002] Comfrey is a commonly used clinical traditional Chinese medicine recorded in the Pharmacopoeia of the People's Republic of China. It can be divided into Lithospermumerythrohizon, also known as Northeast Comfrey and Soft Comfrey (A.euchroma Johnst), also known as Xinjiang Comfrey. The main active ingredients in hard comfrey are shikonin and its derivatives, while soft comfrey contains akanin and its derivatives, shikonin and akanin are enantiomers of each other, and shikonin is R Configuration, Akanin is S configuration. These ingredients all have antibacterial, anti-inflammatory, anti-cancer, and treatment of burns and scalds. The antitumor effect of shikonin has been confirmed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/06C07D307/68C07D307/24C07C69/618C07C69/533C07C69/675C07C69/21C07C67/08C07C43/23C07C41/01C07C41/16C07C43/215C07C46/00C07C50/32C07C69/18C07C67/297C07C69/30C07C69/78C07C69/612C07C69/92C07C69/734C07C201/12C07C205/57A61K31/216A61K31/22A61K31/235A61K31/09A61K31/122A61K31/341A61K31/357A61P35/00A61P35/02
CPCC07C41/16C07C69/18C07C69/30C07C69/533C07D307/68C07C69/92C07C69/616C07C205/57C07C50/32C07C69/21C07C67/297C07C69/675C07C69/56C07C43/23C07D307/24C07C69/78C07C69/33C07C41/01C07C69/734C07D493/06A61P35/00A61P35/02
Inventor 李绍顺周文
Owner SHANGHAI JIAO TONG UNIV
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