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Preparation method of high optical purity shikonin and alkannin, and derivatives thereof

A technology of optical purity and shikonin, applied in the field of medicine and chemical industry

Inactive Publication Date: 2012-04-04
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no report on the simultaneous preparation of shikonin and arcanin with high optical purity by the resolution method

Method used

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  • Preparation method of high optical purity shikonin and alkannin, and derivatives thereof
  • Preparation method of high optical purity shikonin and alkannin, and derivatives thereof
  • Preparation method of high optical purity shikonin and alkannin, and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Synthesis of ethyl 3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene)propionate (2)

[0061] Under the protection of nitrogen, 1 mol of ethyl bromoacetate was dropped into the tetrahydrofuran solution of activated zinc powder (2 mol). -2-Naphthaldehyde tetrahydrofuran solution, after addition, continue to reflux for 2 hours, cool, add 200ml of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.92mol 3-hydroxyl-3 -(1,4,5,8-Tetramethoxy-2-naphthalene) ethyl propionate, yield 92%. 1 H-NMR (300MHz, CDCl 3 ): d 1.27(t, J=8.1, 3H, -CH2 CO 2 CH 2 C H 3 ), 2.7-2.9(m, 2H, -C H 2 CO 2 CH 2 CH 3 ), 3.78(s, 3H, ArOC H 3 ), 3.90(s, 3H, ArOC H 3 ), 3.94(s, 3H, ArOC H 3 ), 3.96(s, 3H, ArOC H 3 ), 4.20(dd, J 1 =6.9,J 2 =13.8, 2H, -CH 2 CO 2 C H 2 CH 3 ), 5.61(m, 1H, -C H OHCH 2 -), 6.82(s, 2H, Ar H ), 7.08(s, 1H, Ar H ).

Embodiment 2

[0062] Example 2: Synthesis of 3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene)propionic acid (3)

[0063] Dissolve 0.5mol 3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene) ethyl propionate in methanol, add 100ml of 6M sodium hydroxide, reflux for 1h, add 6M Hydrochloric acid 100ml, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an equivalent amount of 3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene) Propionic acid was directly used in the next reaction without further purification. 1 H-NMR (300MHz, CDCl 3 ): d 2.90(m, 2H, -C H 2 CO 2 H), 3.76(s, 3H, ArOC H 3 ), 3.90(s, 9H, 3×ArOC H 3 ), 5.65(m, 1H, -C H OHCH 2 -), 6.81(s, 2H, Ar H ), 7.04(s, 1H, Ar H ).

Embodiment 3

[0064] Example 3: (R, S)-3-hydroxyl-3-(1,4,5,8-tetramethoxy-2-naphthalene)-N-(1-phenylethyl)-propionamide (4- 1) and (S,S)-3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene)-N-(1-phenylethyl)-propionamide (4-2 )Synthesis

[0065] 0.5mol 3-hydroxy-3-(1,4,5,8-tetramethoxy-2-naphthalene)propionic acid, 0.5mol (S)-α-methylbenzylamine, 0.55mol benzotriazole -1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and 1.1mol triethylamine were dissolved in 100ml of anhydrous N,N-dimethylformamide, stirred at room temperature for 2h, and N, N-dimethylformamide was added with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography to obtain 0.40 mol (R, S)-3-(tert-butyl Dimethylsilyloxy)-3-(1,4,5,8-tetramethoxy-2-naphthalene)-N-(1-phenylethyl)-propionamide (4-1), yield 40 %. [α] 20 D =1.975; 1 H-NMR (300MHz, CDCl 3 ): d 1.4...

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Abstract

The invention discloses a preparation method of high optical purity shikonin and alkannin, and derivatives thereof. According to the invention, an intermediate separation means is used to prepare the high optical purity shikonin and alkannin, and the derivatives thereof, wherein the intermediate separation is that an amide diastereomer is formed from a carboxyl-contained intermediate and chiral amine, and separation is carried out through column chromatography or a recrystallization process. The derivatives of shikonin and alkannin are tetramethoxylated derivatives with shikonin and alkannin as mother nuclei, dimethoxylated-2-sidechainisomer derivatives and dimethoxylated-6-sidechainisomer derivatives with shikonin and alkannin as mother nuclei, 1,4-diacetoxylated-5,8-dimethoxylated-2-sidechainisomer derivatives and 1,4-diacetoxylated-5,8-dimethoxylated-6-sidechainisomer derivatives with shikonin and alkannin as mother nuclei, and diacetoxylated-6-sidechainisomer derivatives and diacetoxylated-2-sidechainisomer derivatives with shikonin and alkannin as mother nuclei. The preparation method of the invention, which has the advantages of easily available raw material, low price and high yield of each step reaction, is suitable for the large scale preparation.

Description

technical field [0001] The present invention relates to a preparation method in the technical field of medicine and chemical industry, specifically, a method for preparing shikonin, arcanin and derivatives thereof with high optical purity through the splitting of intermediates and total synthesis. 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 ingredients in hard comfrey are shikonin (Shikonin, Ⅰ-1) and its derivatives, and soft comfrey contains alkannin (Alkannin, Ⅰ-2) and its derivatives, shikonin and aka Ning is enantiomer of each other, shikonin is in R configuration, and arcanin is in S configuration. They have been proven to have various biological activities such as ant...

Claims

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Application Information

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IPC IPC(8): C07C50/32C07C46/00C07C43/23C07C41/26C07C69/18C07C69/21C07C67/08
CPCY02P20/55
Inventor 李绍顺王汝冰
Owner SHANGHAI JIAO TONG UNIV
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