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Preparation method and application of 9-position substituted di-functional-group berberine derivatives

A derivative, the technology of berberine, which is applied in the field of food and pharmaceuticals, can solve the problems of low fat solubility, poor absorption in the gastrointestinal tract, and affecting the therapeutic effect of the whole body.

Active Publication Date: 2016-11-09
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 nicotinic acid and berberine have many similar pharmacological activities, their clinical use is limited to a certain extent due to their low bioavailability. And the method of exerting the synergistic effect of the two will have very important clinical significance

Method used

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  • Preparation method and application of 9-position substituted di-functional-group berberine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] a) Synthesis of Berberine

[0013] Add 7.4g of berberine to a 250mL round flask, heat at 190-200°C for about 30min at a vacuum of 20-30mmHg, the yellow solid gradually turns dark red, cool to room temperature in a vacuum desiccator, and purify by silica gel column chromatography. Obtained 4.7 g of dark red powder with a yield of 75%.

[0014] b) Synthesis of 2-bromoethyl nicotinate

[0015] Add 2.46g (0.02mol) of nicotinic acid to a 25mL round bottom flask, add 10mL of DMF to dissolve, stir at room temperature, add 0.96g (0.024mmol) of sodium hydroxide, stir for 10min, then add 7.4g (0.04mol) of 1,2-di Ethyl bromide, heat up to 70°C, stir and react for about 5 hours, follow the reaction by TLC, add 20ml of water after the reaction is complete, extract twice with ethyl acetate 20mL*2, combine the organic phases, dry, filter, concentrate under reduced pressure, and use a silica gel column Purified by chromatography to obtain 4.1 g of 2-bromoethyl nicotinate with a yield...

Embodiment 2

[0019] a) Synthesis of Berberine

[0020] Same as a) in Example 1

[0021] b) Synthesis of 3-bromopropyl nicotinate

[0022] Add 2.5g (0.02mol) of nicotinic acid to a 25mL round bottom flask, add 10mL of DMF to dissolve, stir at room temperature, add 1g (0.025mol) of sodium hydroxide, stir for 10min, then add 8g (0.04mol) of 1,3-dibromopropane , heated to 70°C, stirred for about 5 hours, TLC followed the reaction, added 15ml of water after the reaction was complete, extracted twice with dichloromethane 20mL*2, combined the organic phases, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography , 4.3 g of 3-bromopropyl nicotinic acid ester was obtained, and the yield was 88%.

[0023] c) Synthesis of 9-(3-(nicotinoyl)oxypropyl)-O-berberine hydrobromide

[0024] Add berbererythine (3.2g, 0.01mol) in 50mL round bottom flask, after 5ml DMF is dissolved, add 80% sodium hydrogen (0.3g, 0.01mol), then add 3-bromopropylnicotinate (2.4g...

Embodiment 3

[0026] a) Synthesis of Berberine

[0027] Same as a) in Example 1

[0028] b) Synthesis of 4-bromobutyl nicotinate

[0029] Add 2.5g (0.02mol) of nicotinic acid to a 25mL round bottom flask, add 10mL of DMF to dissolve, stir at room temperature, add 1g (0.025mol) of sodium hydroxide, stir for 10min, then add 8.6g (0.04mol) of 1,4-butyl bromide Propane, heat up to 70°C, stir and react for about 5 hours, follow the reaction by TLC, add 20ml of water after the reaction is complete, extract twice with ethyl acetate 20mL*2, combine the organic phases, dry, filter, concentrate under reduced pressure, and perform silica gel column chromatography After purification, 4.4 mg of 4-bromobutylnicotinate was obtained, with a yield of 85%.

[0030] c) Synthesis of 9-(4-(nicotinoyl)oxybutyl)-O-berberine hydrobromide

[0031] Add berberyrine (3.2g, 0.01mol) in 50mL round bottom flask, after 5ml DMF is dissolved, add 80% sodium hydrogen (0.3g, 0.01mol), then add 4-bromobutylnicotinate (2.6g ...

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Abstract

The invention provides a synthetic method of 9-position substituted di-functional-group berberine derivatives, and belongs to the field of drug synthesis. A pharmacological experiment proves that the derivatives have the drug activities of various values and have the absorbable performance which the other drugs do not have, and particularly the derivatives have the excellent effects of adjusting blood glucose and blood fat of rats suffering from type-II diabetes. The derivatives have the main effects that the oral glucose tolerance can be improved, insulin secretion can be promoted, insulin resistance can be improved, and the amount of triglyceride can be lowered.

Description

technical field [0001] The invention relates to the technical field of food and pharmaceuticals, in particular to the application of niacin 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. Nicotinic acid is converted into nicotinamide in the body, and then forms nicotinamide adenine dinucleotide (coenzyme I) and nicotinamide adenine dinucleotide phosphate (coe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61K31/4375A61P3/10A61P3/06A61P3/08
CPCC07D455/03
Inventor 何勇高永好吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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