A kind of berberine linoleic acid conjugate and its preparation method and application

A technology of berberine linoleic acid and conjugates, which is applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems of berberine compound structure instability, etc., to maintain anti-inflammatory and antioxidant properties, Good inhibitory activity and enhanced cell membrane permeability

Active Publication Date: 2021-03-12
BIOLOGY INST OF SHANDONG ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the problem that the structure of existing berberine compounds is unstable and can be decomposed in a weak acid or weak base environment, on the premise of ensuring a stable structure, the development of anti-tumor activity is good, the therapeutic effect on tumor cells is obvious, and oral A berberine antitumor drug with high absorption efficiency, the purpose of the present invention is to provide a berberine linoleic acid conjugate and its preparation method and application

Method used

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  • A kind of berberine linoleic acid conjugate and its preparation method and application
  • A kind of berberine linoleic acid conjugate and its preparation method and application
  • A kind of berberine linoleic acid conjugate and its preparation method and application

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preparation example Construction

[0060] The present invention also includes the preparation method of berberine linoleic acid conjugate, and the reaction equation is:

[0061]

[0062]

[0063] The preparation method comprises the following steps:

[0064] ① Preparation of the second berberine derivative:

[0065] Dissolve berberine in the first solvent, start stirring, add dibromocompound at 0-30°C, react to 50-90°C, stir for 3-10 hours to obtain a yellow turbid liquid, stop the reaction, Cool the reaction solution to 0-30°C, filter with suction, wash the filter cake with acetonitrile, and dry to obtain the first berberine derivative;

[0066] Dissolve the obtained first berberine derivative in the second solvent, add ammonia water and solid ammonium chloride successively under stirring, heat up to 50-80°C, stir and react for 10-48 hours, stop the reaction, and cool down to 0-30°C , adding dichloromethane for extraction, the organic phase is distilled off under reduced pressure to remove the solvent,...

Embodiment 1

[0090]

[0091] Preparation of 9-O-(2-aminoethyl)berberine hydrochloride: Weigh berberine (714 g, 2 mol) and dissolve it in 10 L of acetonitrile. Stirring was started, and 1,2-dibromoethane (1878 g, 10 mol) was added at 0-5°C. The temperature of the reaction solution was raised to 70°C, and the reaction was stirred at constant temperature for 3 hours to obtain a yellow turbid solution. Stop the reaction, lower the reaction solution to 25-30°C, filter with suction, wash the filter cake with acetonitrile, and dry to obtain a yellow powdery solid; dissolve the obtained yellow powdery solid in 5L of methanol, start stirring, add 5L of 25% ammonia water, Ammonium chloride solid (107 g, 2 mol) was then added. The temperature of the reaction solution was raised to 50° C., and the reaction was stirred at a constant temperature for 48 hours. At this time, the reaction was stopped, the reaction solution was cooled to room temperature, and 5 L of dichloromethane was added for extract...

Embodiment 2

[0097]

[0098] Preparation of 9-O-(6-aminohexyl) berberine hydrochloride: weigh berberine (357 g, 1.0 mol) and dissolve it in 4 L of acetonitrile. Start stirring, and add 1,6-dibromohexane (1220 g, 5 mol) at 20-25°C. The temperature of the reaction solution was raised to 70°C, and the reaction was stirred at constant temperature for 8 hours to obtain a yellow turbid solution. The reaction was stopped, the reaction solution was lowered to room temperature, suction filtered, the filter cake was washed with acetonitrile, and dried to obtain a yellow powdery solid, the solid was dissolved in 8L of methanol, the stirring was started, 4L of 25% ammonia was added, and then ammonium chloride solid ( 53 g, 1 mol). The temperature of the reaction solution was raised to 65° C., and the reaction was stirred at a constant temperature for 18 hours. At this time, the reaction was stopped, and the reaction solution was cooled to room temperature, and 5 L of dichloromethane was added for ...

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Abstract

The invention discloses a berberine linoleic acid conjugate, and a preparation method and application thereof. According to the invention, berberine is connected with linoleic acid through an amido bond connected with an alkyl group or through an amido bond connected with polyethylene glycol, the structure of the berberine linoleic acid conjugate is more stable than the structure of a conventionalberberine connected through a drug ester bond under physiological conditions; the berberine linoleic acid conjugate cannot be hydrolyzed in a weak acid or weak base environment, can be more easily made into various conventional preparations and is wide in application range; since the lipophilic linoleic acid is introduced, the cell membrane permeability of the berberine can be enhanced, and therefore, the pharmacological activity of the berberine is enhanced; the berberine linoleic acid conjugate can inhibit tumor growth by inducing formation of lipid peroxide, regulating lipid metabolism andthe like; and compared with a traditional single-target antitumor drug, the berberine linoleic acid conjugate is better in activity, has a very good inhibition effect on tumor cells, and can have better antitumor activity at a low dosage.

Description

technical field [0001] The invention relates to the technical fields of organic chemical synthesis and pharmaceutical engineering, in particular to a berberine linoleic acid conjugate and its preparation method and application. Background technique [0002] Berberine is a well-defined natural product extracted from Coptis chinensis. It is widely used in the treatment of dysentery, gastrointestinal diseases and other diseases in my country. It has certain anti-inflammatory, antioxidant and anti-tumor activities. Berberine acts on inflammatory cells to change the microenvironment in which tumor cells survive. At the same time, it removes free radicals around tumor cells through anti-oxidation, enhances the immunity of patients, and has a certain adjuvant therapeutic effect on tumors. However, because the antitumor activity of berberine itself is not high, the therapeutic effect on tumor cells is not ideal, and the oral absorption efficiency is very low. use. Therefore, modif...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/14A61P35/00
CPCA61P35/00C07D491/14
Inventor 王利振刘可春王荣春靳梦李晓彬陈锡强张姗姗张轩铭
Owner BIOLOGY INST OF SHANDONG ACAD OF SCI
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