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Preparation method of leonurine and aspirin conjugate

A technology for aspirin and leonurine, which is applied in the field of preparation of leonurine and its analogs and aspirin conjugates, can solve the problems of low esterification reaction yield, difficulty in operation, poor solubility of leonurine and the like, saves raw materials, shortens The effect of reaction time

Inactive Publication Date: 2018-02-27
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Studies have disclosed a variety of methods for the synthesis of motherwortine. Currently, the more commonly used synthetic routes include: using syringic acid and S-methylthiourea as starting materials, and preparing motherwort by acetylation, esterification, amidation, and hydrogenation reduction. Alkali, the disadvantage of its existence is: the yield of esterification reaction is low, the reaction catalyst is difficult to remove, and there is difficulty in purification; and temperature requirements are high, the acylating reagent used in the preparation process needs to be under anhydrous and oxygen-free conditions, and the operation has certain difficulties, etc.

Method used

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  • Preparation method of leonurine and aspirin conjugate
  • Preparation method of leonurine and aspirin conjugate
  • Preparation method of leonurine and aspirin conjugate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthesis (3) of embodiment 1 acetylated syringic acid

[0035]

[0036] Using acetic anhydride (Ac 2 )O as an acylating agent, controlling the reaction time can make the productive rate reach more than 90%; the specific operation is: 100ml three-necked flask, add N2 protection, syringic acid (19.8g, 0.1mol) is added in 100ml dichloromethane, slowly drop Add 30ml (0.2mol) of triethylamine, slowly add 15ml (0.15mol) of acetic anhydride dropwise after all the samples are dissolved, monitor the progress of the reaction by TLC, after 12 hours of reaction, concentrate the reaction solution to 30ml by vacuum filtration and rotary evaporation, dropwise add 1N concentrated hydrochloric acid until the pH was 5, a large amount of white crystals were sucked out at this time, and the crude product of acetosyringic acid (22.7 g, 95%) was obtained by suction filtration and drying;

[0037] [In this example, 1N hydrochloric acid can be used to adjust the pH to 3, and then use ...

Embodiment 2B

[0038] The synthesis (1) of embodiment 2 Boc protection guanidino groups

[0039]

[0040] Dissolve S-methylisothiouronium sulfate (6.95g, 0.025mol) in 50ml of water, add 13.8ml (0.1mol) of triethylamine, after the sample is completely dissolved, to obtain solvent I, take (Boc)2O(21.8 g, 0.1mol) was dissolved in 10ml tetrahydrofuran, slowly added dropwise to solvent I, and 0.05g DMAP was added to the mixed solvent, reacted for 96h, and TLC monitored the reaction progress. Place DCM and water in a separatory funnel and extract 3 times, collect the DCM layer and concentrate to obtain a crude product, purify by silica gel column chromatography, and elute with petroleum ether: ethyl acetate (40:1) to obtain Boc-protected S-methyl isosulfide Urea (6.5 g, 91%).

Embodiment 34

[0041] The synthesis of embodiment 34-guanidinobutanol (2)

[0042]

[0043] Dissolve Boc-protected S-methylisothiourea (14.5 g, 0.05 mol) in anhydrous DMF, stir at room temperature for 1 h, and place the reaction vessel in a cold well (-5°C) after it is completely dissolved. Add 4-aminobutanol (6.75g, 0.075mo) at the bottom, take it out after 10min and react at room temperature for 3h, monitor the progress of the reaction by TLC, after the raw material point of S-methylisothiourea disappears, spin the reaction solution and place it in a separatory funnel DCM and water were extracted three times, and the concentrated DCM layer was collected and purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (1:1) to obtain 4-guanidinobutanol (11.77 g, 71%).

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Abstract

The present invention is a pharmaceutical chemistry field, which involves the synthesis method of pupic mycaocyric aspirin.The present invention starts with clove acid, S 以 methyl sulfur sulfur, and aspirin as the starting raw material.The combination of amine, 4‑ 基 pyridine, and 4‑ methyl benzene sulfonic acid is used as a contraction catalyst to connect three fragments. Totorohide is protected to obtain a target compound.The method of the present invention is simple and mild, and the process is simple. It can increase the income of the alkaline products in the middle of the mother grass.The level has good antioxidant and anti -apoptosis effects, and has an exact effect on myocardial cells.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a conjugate of natural alkaloid leonurine and a non-steroidal anti-inflammatory drug aspirin, in particular to a preparation method of a conjugate of leonurine and its analogues and aspirin. Background technique [0002] In the prior art, Dongkai Leonurine is a specific alkaloid in Lamiaceae plant Leonurus, and relevant studies have shown that it has the ability to inhibit external Ca 2+ Influx and Ca 2+ Release and improve hemorheology, anti-oxidation, anti-apoptosis and other cardioprotective effects, and can promote the release of NO in vivo and in vitro. [0003] It is known that aspirin, also known as acetylsalicylic acid, is a common drug used clinically for analgesia and anti-inflammation. In recent years, studies have shown that aspirin can inhibit platelet aggregation, and has certain preventive and therapeutic effects on ischemic heart disease and angina pectoris. It ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C277/08C07C279/08C07C275/10C07C273/18C07C235/52C07C231/12A61P39/06A61P9/00
Inventor 朱依谆古险峰高欢
Owner FUDAN UNIV