Preparation method and application of 9-substituted dual functional group berberine derivative

A derivative, the technology of berberine, applied in the field of food and pharmacy, can solve the problems of low water solubility, low bioavailability and low fat solubility of berberine hydrochloride

Inactive Publication Date: 2016-10-26
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Berberine hydrochloride has little water solubility, even less fat solubility, and poor absorption in the gastrointestinal tract, resulting in low oral bioavailability, which affects its systemic therapeutic effect
Although

Method used

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  • Preparation method and application of 9-substituted dual functional group berberine derivative
  • Preparation method and application of 9-substituted dual functional group berberine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] a) Synthesis of Berberine

[0014] Add 7.4g of berberine to a 250mL round flask, heat for about 30min at a vacuum of 20-30mmHg, 190-200°C, the yellow solid gradually turns dark red, cool to room temperature in a vacuum desiccator, and purify by silica gel column chromatography , to obtain dark red powder 4.7g, yield 75%.

[0015] b) Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid-2-bromoethyl ester

[0016] Add 2-(4-chlorophenoxy)-2-methylpropionic acid (4.28g0.02mol) to a 100mL round bottom flask, add 10mL DMF to dissolve, stir at room temperature, add sodium hydroxide (0.96g, 0.024mol), Stir for 10 minutes, then add (7.5g, 0.04mol) 1,2-dibromoethane, raise the temperature to 70°C, stir for about 5 hours, follow the reaction by TLC, add 20ml of water after the reaction is complete, and extract with ethyl acetate 20mL*2 For the second time, the organic phases were combined, dried, filtered, concentrated under reduced pressure, purified by silica gel column chr...

Embodiment 2

[0020] a) Synthesis of Berberine

[0021] Same as a) in Example 1

[0022] b) Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid-3-bromopropyl ester

[0023] Add 2-(4-chlorophenoxy)-2-methylpropionic acid (4.28g, 0.02mol) to a 100mL round bottom flask, add 10mL DMF to dissolve, stir at room temperature, add sodium hydroxide (0.96g, 2.4mmol) , stirred for 10 minutes, then added (8g, 0.04mol) 1,3-dibromopropane, heated to 70°C, stirred for about 5 hours, followed by TLC. After the reaction was complete, 20ml of water was added, and the dibromopropane was extracted with 20mL*2 ethyl acetate. Once, the organic phases were combined, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 6 g of 2-(4-chlorophenoxy)-2-methylpropionic acid-3-bromopropyl, with a yield of 90% .

[0024] c) Synthesis of 9-(3-(2-(4-chlorophenoxy)-2-methylpropionic acid)propoxy)-O-berberine hydrobromide

[0025] Add berberine (3.2g, 1mol) to...

Embodiment 3

[0027] a) Synthesis of Berberine

[0028] Same as a) in Example 1

[0029] b) Synthesis of 2-(4-chlorophenoxy)-2-methylpropionic acid-4-bromobutyl

[0030] Add 2-(4-chlorophenoxy)-2-methylpropionic acid (4.3g, 0.02mmol) to a 100mL round bottom flask, add 10mL of DMF to dissolve, stir at room temperature, add sodium hydroxide (1g, 0.025mmol), Stir for 10 minutes, then add (8.6g, 0.04mol) 1,4-butylbromopropane, raise the temperature to 70°C, stir for about 5 hours, follow the reaction by TLC, add 20ml of water after the reaction is complete, and extract the disulfide with ethyl acetate 20mL*2 Once, the organic phases were combined, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 5.8 g of 2-(4-chlorophenoxy)-2-methylpropionic acid-4-bromobutyl, yield 83 %.

[0031] c) Synthesis of 9-(4-(2-(4-chlorophenoxy)-2-methylpropionic acid)butoxy)-O-berberine hydrobromide

[0032] Add berberine (3.2g, 1mol) to a 50mL round...

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PUM

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Abstract

The invention provides a synthetic method of a 9-substituted dual functional group berberine derivative, belonging to the field of chemical synthesis. Discovered by pharmacological experiments, the derivative has multiple values of medicinal activity, especially has easy absorbability which other medicines do not have, and concretely the derivative shows excellent effects on regulating the blood sugar and blood fat of rats with diabetes type 2 in animal experiments. The main effects of the 9-substituted dual functional group berberine derivative are embodied in improving orally administered glucose tolerance, promoting insulin secretion, improving insulin resistance, lowering the level of triglyceride and the like.

Description

technical field [0001] The invention relates to the technical field of food and pharmaceuticals, in particular to the application of berberine derivatives in the preparation of products for preventing or treating obesity and related diseases or symptoms. Background technique [0002] About 12 million people die of cardiovascular disease and cerebral apoplexy every year in the world, and atherosclerosis caused by hyperlipidemia is the main cause of coronary heart disease, hypertension and cerebrovascular disease. In 2002, the global annual sales of only atorvastatin (a blood lipid-lowering drug) was nearly 8 billion US dollars, becoming the world's best-selling drug that year. It can be seen that the research and development of blood lipid-lowering drugs has significant social benefits and market prospects. Fibrates significantly reduced elevated triglycerides (TG), elevated high-density lipoprotein cholesterol (HDL-Ch), reduced total cholesterol (TCh) and low-density lipopr...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P3/10A61P3/06A61P3/04
CPCC07D455/03
Inventor 何勇高永好吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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