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Danshensu derivatives and synthesis method and application thereof

A technology of danshensu derivatives and compounds, which is applied in the field of drug synthesis, and can solve problems such as unsuitable chiral resolution and chemical synthesis of d-danshensu and its derivatives that have not yet been seen.

Active Publication Date: 2009-12-23
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since there are two phenolic hydroxyl groups that are easily oxidized in the structure of Danshensu, it is not suitable to use the direct resolution method to perform chiral resolution of Danshensu racemate to obtain natural D-danshensu
Therefore, so far, there are no reports about the chemical synthesis of d-danshensu and its derivatives

Method used

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  • Danshensu derivatives and synthesis method and application thereof
  • Danshensu derivatives and synthesis method and application thereof
  • Danshensu derivatives and synthesis method and application thereof

Examples

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preparation example Construction

[0033] The preparation method of the present invention can be further embodied as follows with a representative compound preparation process:

[0034] Examples 1-6 of the present invention describe in detail the preparation of compounds 1-6 according to the method of scheme 1.

[0035] Examples 7-15 of the present invention describe in detail the preparation of compounds 7-14 according to the method of scheme 2.

Embodiment 1

[0036] Embodiment 1 According to flow process 1, when R is acetyl group,

[0037]

[0038] Synthesis of (Z)-2-acetylamino-3-(3,4-diacetoxyphenyl)acrylic acid (1):

[0039] Add 3,4-dihydroxybenzaldehyde 10.8g, 0.078mol and 30mL of anhydrous acetic anhydride, 32.4g, 0.319mol, anhydrous sodium acetate 6.4g, 0.078mol in a 250mL eggplant-shaped bottle, and react at room temperature for 3 hours to Petroleum ether / ethyl acetate (V / V=2:1) ​​was the developing solvent, and TLC showed that the raw material point (R f =0.3) disappear and new point appears (R f =0.4), continue to add N-acetylglycine 9.2g in the reaction solution, 0.0789mol, heat to 100 ℃ and react for 2 hours, TLC shows the R of the product point f value is still 0.4, stop the reaction, the reaction solution is poured into 400mL cold water, overnight, a yellow solid precipitates, the solid is filtered and dissolved in ethyl acetate for recrystallization to obtain compound (1)(Z)-2-acetamido- 3-(3,4-diacetoxyphenyl)a...

Embodiment 2

[0040] Embodiment 2: Synthesis of (Z)-3-(3,4-dihydroxyphenyl)-2-hydroxyacrylic acid (2)

[0041] Add compound 1 (1g, 0.016mol) to 250mL eggplant-shaped bottle, add 9% hydrochloric acid 40mL, react under reflux conditions for 6 hours, the reaction solution is deep red, and chloroform / methanol / acetic acid (V / V / V=18 : 3: 1) as developing solvent, TLC showed raw material point (R f =0.9) disappear, there are new points (R f= 0.5) to generate, after dipping in phosphomolybdic acid, the new point can be baked into dark blue color, but the raw point cannot be baked in color, stop the reaction, wait for the reaction solution to cool, extract with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate, filter , and evaporated to dryness under reduced pressure to obtain a dark red solid, which was washed with a small amount of water to obtain 0.53 g of a pale yellow solid of compound (2)(Z)-3-(3,4-dihydroxyphenyl)-2-hydroxyacrylic acid, with a yield of 87%. mp179-181℃ (...

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Abstract

The invention belongs to the field of medicament synthesis, and relates to Danshensu derivatives with a structure in the following formula, a synthesis method thereof, and application thereof in pharmacy. The synthesis method adopts a chiral synthesis method to synthesize the Danshensu derivatives with stable structures in high yield, in particular derivatives of dextrorotatory Danshensu with high optical purity. Through experiments of animal models with hypoxic myocardial cells, results show that the Danshensu derivatives can reduce LDH leakage of the hypoxic myocardial cells, improve the activity of hyperoxide dismutase in the cells, inhibit generation of a product of lipid peroxidation, promote the expression of anti-apoptotic gene bcl-2 mRNA and inhibit the expression of pro-apoptosisgene bax mRNA and apoptotic gene caspase-3mRNA; and the results prove that the Danshensu derivatives have an effect of protecting hypoxic cardiac muscle and can be used for preparing medicaments for treating ischemic heart disease.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and specifically relates to a synthesis method of a danshensu derivative and an application in pharmacy. technical background [0002] Traditional Chinese medicine has a long history in our country and has a history of thousands of years. Its main advantage is that it has less toxic and side effects. The development of traditional Chinese medicine is limited. Therefore, the preparation of active ingredient monomers of traditional Chinese medicine and the synthesis and semi-synthesis of chemical drugs and salt-forming derivatives with natural active ingredients as lead compounds, that is, the modernization of traditional Chinese medicine, have become the main direction of modern Chinese medicine research. Danshensu is a main active ingredient in the traditional Chinese medicine Salvia miltiorrhiza. Its chemical name is: D-(+)-β-3,4-dihydroxyphenyl lactic acid. Pharmacological experiments have sho...

Claims

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Application Information

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IPC IPC(8): C07C69/73C07D317/60A61K31/216A61K31/36A61P9/10
Inventor 朱依谆王洋董村南
Owner FUDAN UNIV
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