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Method for synthesizing alkannin dimethyl ether derivative

A technology of shikonin dimethyl ether and synthesis method, which is applied in the field of synthesis of shikonin dimethyl ether derivatives and can solve problems such as incompatibility

Inactive Publication Date: 2008-03-12
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also not suitable for the synthesis of derivatives such as ethers, thioethers, and thioesters with side chain hydroxyl groups

Method used

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  • Method for synthesizing alkannin dimethyl ether derivative
  • Method for synthesizing alkannin dimethyl ether derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] cyclized shikonin 2

[0025] Weigh 100 mg (0.347 mmol) of shikonin 1, dissolve it in 10 ml of anhydrous dichloromethane, and add 5 equivalents of tin tetrachloride. Under the protection of nitrogen, the reaction was carried out at room temperature for 0.5 hours. Add dichloromethane to dilute the reaction solution, wash with water and saturated brine several times, anhydrous MgSO 4 Dry, filter, and evaporate dichloromethane under reduced pressure. The crude product was chromatographed on a silica gel column, eluting with ethyl acetate:petroleum ether (1:15) to obtain 98.3 mg of the red target compound, with a yield of 98.3%. [α] D =+179.1° (C=0.01, CHCl 3 ), mp79-80℃, 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 12.53 (s, 1H, OH Ar ), 12.52 (s, 1H, OH Ar ), 7.23~7.19 (m, 3H, CH Ar ), 5.17 (dd, J=6.3, 5.7H Z , 1H, C H OH), 2.66-2.62 (m, 1H, CH 2 ), 1.90-1.89 (m, 1H, CH 2 ), 1.90~1.89 (m, 1H, CH 2 ), 1.88-1.74 (m, 1H, CH 2 ), 1.38 (s, 3H, CH 3 ), 1.35 (s, 3H, =CH 3...

Embodiment 2

[0027] tetraoxomethyl cyclized shikonin 3

[0028] Under nitrogen protection, 100 mg (0.347 mmol) of cyclized shikonin 2 was dissolved in 4 ml of water / tetrahydrofuran (1:4), and 5 times equivalents of sodium hydroxide, 10 equivalents of sodium hydroxide, and 10 equivalents of Dimethyl sulfate, stir well. After half an hour, reflux for 36 hours, cool to room temperature, add dichloromethane to the reaction solution, wash the dichloromethane layer with water and saturated brine, and anhydrous MgSO 4 After drying, dichloromethane was evaporated under reduced pressure. The resulting crude product was chromatographed on a silica gel column, eluting with ethyl acetate:petroleum ether (1:4) to obtain 95.6 mg of a light yellow oily compound, with a yield of 80.3%. 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 7.12 (s, 1H, CH Ar ), 6.80 (s, 2H, CH Ar ), 5.52 (m, 1H, C H OH), 3.99(s, 3H, -OCH 3 ), 3.95(s, 3H.-OCH 3 ), 3.93(s, 3H.-OCH 3 ), 3.75(s, 3H.-OCH 3 ), 2.54-2.48 (m, 1H, CH 2 ),...

Embodiment 3

[0030] 1,4,5,8-tetramethoxy-2-(1’,4’-diacetyl-4’-methyl-3’-pentane)-naphthalene 4

[0031] Under the protection of nitrogen, 100 mg (0.291 mmol) of tetraoxomethyl cyclized shikonin 3 was dissolved in 2 ml of dichloromethane, 2 ml of acetic anhydride and an equivalent p-toluenesulfonic acid monohydrate were added, and at -10°C, React for 24 hours. , dilute the reaction solution with ethyl acetate, wash with 5% aqueous sodium bicarbonate solution, water, and saturated brine, respectively, and evaporate the solvent under reduced pressure to obtain a crude product. By silica gel column chromatography, eluting with ethyl acetate:petroleum ether (1:3), 111.2 mg of the target compound was obtained as light yellow oil, with a yield of 85.5%. 1 HNMR (300MHz, CDCl 3 ), δ (ppm): 6.85 (s, 1H, H Ar ), 6.83(s, 2H, H Ar )6.32(t, 1H, J=7.8Hz, OCH-), 3.94~3.84(s, 12H, 4XOCH 3 ), 2.12(s, 3H, OAc) 1.93~1.71(m, 5H, OAc, CH 2 ), 1.41 (s, 3H, CH 3 ), 1.39 (s, 3H, -CH 3 ).

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Abstract

The present invention is a synthesis method of the shikonin dimethyl ester derivative in the pharmaceutical and chemical technological field. The synthesis method of the second-level side-chain isomer and the sixth-level side-chain isomer of the shikonin dimethyl ester of the present invention uses the shikonin as the raw material; the shikonin is first cyclized; then the cyclized shikomin is in the tetramethyl and ring-opening reaction; in the process, the absolute configuration of the shikonin is maintained; then the esterification or etherification is done; at last, the methyls are selectively doffed to get the target compound. The reagent in each step of the reaction is easy to get; the conditions are mild; the collection rates of the reaction all surpass 65 percent; the total collection rate is 33.2 percent (calculated by the shikonin). The reaction process has no racemic reaction.

Description

technical field [0001] The invention relates to a method in the technical field of medicine and chemical engineering, in particular to a method for synthesizing shikonin dimethyl ether derivatives. Background technique [0002] Lithospermum erythrohizon is a commonly used clinical traditional Chinese medicine recorded in the Pharmacopoeia of the People's Republic of China. Its main active ingredient is shikonin and its derivatives, which have antibacterial, anti-inflammatory, anti-cancer, and treatment of burns and scalds. However, the toxic side effects and hydrophobicity of shikonin limit its clinical application. The naphthalene (5,8-dihydroxy-1,4-naphthoquinone) structure of the mother nucleus of shikonin and its derivatives may be one of the causes of toxic side effects. The methylation of the naphthalene nuclei of shikonin and its derivatives can reduce the cytotoxicity and increase the water solubility. [0003] After searching the literature of the prior art, it w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/21C07C67/00C07D307/68
Inventor 李绍顺周文徐德锋赵爱宏
Owner SHANGHAI JIAO TONG UNIV
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