Method of synthesizing 25-hydroxy cholesterol

Patent metadata

Field	Value
Publication number	US-9802977-B2
Application number	US-201515329255-A
Country	US
Kind code	B2
Filing date	May 22, 2015
Priority date	Jul 30, 2014
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

The present invention discloses a method for synthesizing 25-hydroxy cholesterol. The method is as below: subjecting 24-dehydrocholesterol derivative as a raw material, which undergoes an addition reaction with a hydroxyl containing reagent in an organic solvent under catalysis, and then hydrolyzing the reaction product and separating to obtain 25-hydroxy cholesterol. The present invention adopts hydroxyl containing reagents such as water, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, p-methyl benzoic acid to replace the commonly used extremely toxic reagents such as Cr reagent, Hg reagent and polyfluorinated acetone in the prior art. The raw materials of the present invention are easily available, and have low effect on environment. The operation and post treatment are convenient. Moreover, the method has the advantages of mild reaction conditions, simple operation, good selectivity, high efficiency, high yield, simple post treatment, easy product separation, less three wastes and easy industrialization.

First claim

What is claimed is:

1. A method for synthesizing 25-hydroxy cholesterol, comprising: adding a 24-dehydrocholesterol derivative and a hydroxyl containing reagent to an organic solvent and react at −40° C.-150° C. for 1-40 hours in the presence of a catalyst; after completing the reaction, hydrolyzing with alkali, and then separating the reaction solution to obtain 25-hydroxy cholesterol, wherein the structural formulas of the 25-hydroxy cholesterol, the 24-dehydrocholesterol derivative and the hydroxyl containing reagent are shown in formula (I), formula (II) and formula (III) respectively:

the R1 in formula (II) is the same as the R2 in formula (III), which is H or C1-C12 acyl group,
wherein the hydroxyl containing reagent is one of water, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid and p-methyl benzoic acid or a mixture thereof at any ratio,
wherein the catalyst is one of sulfuric acid, phosphoric acid, p-toluenesulfonic acid, sodium bisulfate, potassium bisulfate, phosphorus pentoxide, aluminum trichloride, titanium tetrachloride, ferric trichloride, nickel chloride, cobalt chloride, zinc chloride, magnesium chloride, calcium chloride, aluminum tribromide, ferric tribromide, zinc bromide, magnesium bromide, magnesium iodide, scandium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, iridium methanesulfonate, neodymium trifluoromethanesulfonate, samarium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, gallium trifluoromethanesulfonate, copper trifluoromethanesulfonate, gold trifluoromethanesulfonate, silver trifluoromethanesulfonate or indium trifluoromethanesulfonate.

2. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the mole ratio of the 24-dehydrocholesterol derivative to the hydroxyl containing reagent to the catalyst is 1:(1-100):(0.01-1).

3. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the organic solvent is one or a mixture of two or more of toluene, xylene, chlorobenzene, dichloromethane, chloroform, dichloroethane, ethyl acetate, acetone, butanone and cyclohexanone at any ratio.

4. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the reaction temperature is 50° C.-80° C. and the reaction time is 5-8 hours.

5. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the alkali is sodium hydroxide or potassium hydroxide.

6. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the hydrolysis temperature is 50° C.-80° C. and the hydrolysis time is 1-2 hours.

7. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the mole ratio of the 24-dehydrocholesterol derivative to the hydroxyl containing reagent to the catalyst is 1:(5-10):(0.01-0.1).

8. The method for synthesizing 25-hydroxy cholesterol according to claim 1 , wherein the method is performed based on the following steps: dissolving the 24-dehydrocholesterol derivative in the organic solvent at room temperature; adding the hydroxyl containing reagent and the catalyst; stirring the mixture to react at −40° C.-150° C. for 1-40 hours; after completing the reaction, adding water for layering to remove the aqueous phase; adding aqueous alkali solution to the organic phase to keep the pH of the system at 12; warming the mixture to 50° C.-80° C. and stirring the mixture to react for 1-2 hours; after the reaction, separating the mixture to remove the aqueous phase, and washing the organic phase with water again; after drying with anhydrous sodium sulfate, filtering and concentrating to obtain a yellowish crude product; and then re-crystallizing the product with ethyl acetate/petroleum ether to obtain the 25-hydroxy cholesterol.

Assignees

• Univ Zhejiang Technology
• Zhejiang Garden Biochemical High-Tech Co Ltd
• Hangzhou Xiasha Biochemical Tech Co Ltd

Inventors

• Jin Can
• Su Weike
• Wang Ziqiang
• Liu Jiangang
• Sun Bin
• Xu Wenhao

Classifications

• C07J9/00 Primary

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title