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Method for synthesizing flavone alkyl phosphate compound and application thereof in cholesterol esterase inhibitor medicine

A technology for flavonoid phosphate and compound, which is applied to the synthesis of flavonoid phosphate alkyl ester compounds and the application field of cholesterol esterase inhibitor drugs, can solve the problems of low solubility, difficult phosphorylation reaction and the like, and achieves conversion efficiency High, good economic and social benefits, obvious catalytic effect

Inactive Publication Date: 2011-02-16
HUNAN AGRICULTURAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Traditional methods mostly use CCl 4 Phosphates are synthesized as solvents, but flavonoids are in CCl 4 Medium solubility is usually very low, the phosphorylation reaction of flavonoids in CCl 4 Difficult to carry out in

Method used

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  • Method for synthesizing flavone alkyl phosphate compound and application thereof in cholesterol esterase inhibitor medicine
  • Method for synthesizing flavone alkyl phosphate compound and application thereof in cholesterol esterase inhibitor medicine
  • Method for synthesizing flavone alkyl phosphate compound and application thereof in cholesterol esterase inhibitor medicine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] Weigh 1a (715.6mg, 2.5mmol), DMAP (1.8326g, 15mmol) in a dry 150mL round bottom flask, add THF (30.0mL) under stirring, and slowly add Et 3 N (2.80 mL, 20 mmol). Measure CIP(O)(OEt) 2 (2.5883g, 15mmol), diluted with THF (20.0mL), reacted at room temperature for 24h. Add about 1 times the total volume of the reaction system with ethyl acetate to dilute, then wash with 0.5 mol / L HCl, 5% (w / v) potassium carbonate solution, saturated sodium chloride solution, and water respectively. The ethyl acetate layer (product layer) was dried with anhydrous sodium sulfate, and then concentrated and dried under reduced pressure to obtain 1.8753 g of a yellow liquid with a yield of 90.3%. According to NMR, MS, IR, and UV spectroscopic analysis, the product was 2a.

Embodiment 2

[0041]

[0042] Under nitrogen protection, 1b (302.1 mg, 1.0 mmol), DMAP (1.2217 g, 10.0 mmol) were added to a dry 50 mL round bottom flask. Add HMPA (10.0mL) under stirring, and slowly add Et 2 NH (1.1mL, 10.7mmol), measure ClP(O)(OEt) 2 (1.7255g, 10.0mmol), diluted with 5.0mL HMPA, reacted at 0°C for more than 40h, diluted with ethyl acetate, passed through 0.5mol / L HCl solution, 5% (w / v) K 2 CO 3 After washing with aqueous solution, saturated NaCl aqueous solution and water, add anhydrous NaCl 2 SO 4 Dry, filter, and evaporate the solvent under reduced pressure to obtain 817.3 mg of yellow viscous liquid with a yield of 83.2%. According to NMR, MS, IR, and UV spectroscopic analysis, the product is 2b.

Embodiment 3

[0044]

[0045] Under nitrogen protection, 1c (635.6mg, 2.5mmol), DMAP (0.9163g, 7.5mmol) were added to a dry 150mL round bottom flask, DMSO (30.0mL) was added under stirring, and pyridine (0.61 mL, 7.5mmol), measure ClP(O)(OEt) 2 (1.2941g, 7.5mmol), diluted with DMSO (20.0mL), reacted at 120°C for 2h, diluted with ethyl acetate, passed through 0.5mol / L HCl solution, 5% (w / v) K 2 CO 3 After washing with aqueous solution, saturated NaCl aqueous solution and water, add anhydrous NaCl 2 SO 4 Dry, filter, and evaporate the solvent under reduced pressure to obtain a yellow radial solid. This product is treated with anhydrous ether / n-hexane to obtain 1.1344 g of a light yellow (near white) solid, with a yield of 86.2%. NMR, MS, IR, and UV spectra Analysis, the product was 2c.

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Abstract

The invention relates to a method for synthesizing a flavone alkyl phosphate compound and application thereof in a cholesterol esterase inhibitor, which overcomes the disadvantages of the traditional method that CCl4 is used as a solvent for synthesizing organic phosphate, while flavone usually has a low solubility in CCl4 and thus is difficult to carry out a phosphorylation reaction in CCl4. In the method, DMSO (Dimethylsulfoxide), DMF (Dimethyl Formamide), acetonitrile, diethyl ether, dioxane, THF (Tetrahydrofuran), and the like, which have stronger polarity are used as solvents, and flavone has high solubility in the solvents; nitrogenous bases, such as triethylamine, diethylamine, pyridine, and the like, are used as alkali reagents; ClPO (OEt)2 (Diethyl Chlorophosphate) is used as a phosphorus esterification reagent; and DMAP (Dimethylaminopyridine) is used as a catalyst. Thus, the method has the advantages of high compounding reaction speed, mild reaction conditions, high chemical selectivity, high reaction efficiency and higher yield of a flavone phosphate compound with a novel structure. The new compound has the advantages of simple separation and purification method, high currency and low production cost, and the conditions required in the whole process from synthesis to separation and purification are suitable for condition requirements on production in a large scale. The new synthesized compound can be applied to preparing the cholesterol esterase inhibitor with a high activity, and the active IC50 of the cholesterol esterase inhibitor is within 3.76-390nM and shows a very obvious structure-activity relationship.

Description

technical field [0001] The invention relates to a synthesis method of a flavonoid phosphate compound and its application in cholesterol esterase inhibitor drugs. Background technique [0002] Structural modification of natural active substances is one of the main directions in the research and development of new drugs and new active compounds. Flavonoids are a kind of widely distributed secondary metabolites, which have many physiological functions and medicinal value, such as anti-oxidation, anti-aging, anti-tumor, anti-bacterial, anti-HIV virus and so on. At present, flavonoids have become an important treasure house for the development of herbal medicines, providing a rich source of lead substances for the development of new drugs. Using natural flavonoids as lead compounds to carry out structural transformation and synthesis of new drugs has attracted extensive attention from domestic and foreign scholars. Hotspots in the development of drug-like compounds. [0003] Ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/655A61K31/665A61P3/06
Inventor 彭国平
Owner HUNAN AGRICULTURAL UNIV
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