Method for preparing 16Alpha-hydroxyprednisolone

A method for preparing 16alpha-hydroxyprednisolone, wherein a synthetic route of the method is as follows:

• the method comprises the following steps:
• 1) an oxidation reaction:
• dissolving a compound (1) in an organic solvent A;
• adding an acid catalyst A, and cooling to −20° C. to −5° C. while stirring;
• adding a potassium permanganate aqueous solution and stirring for reaction;
• after the completion of the reaction, adding a sodium bisulfite aqueous solution;
• collecting a filtrate after filtration, and removing the organic solvent A by concentration;
• performing water precipitation, filtering and drying to obtain an intermediate (2), wherein the organic solvent A is one of acetone, butanone, and dichloromethane, and has a usage amount in volume of 30 to 50 times of the weight of the compound (1);
• the acid catalyst A is formic acid, oxalic acid, or glacial acetic acid, and has a usage amount of 1.5 to 2.5 times of the molar amount of the compound (1);
• the potassium
• permanganate aqueous solution has a mass concentration of 6% to 10%, and a usage amount of 1.1 to 1.5 times of the molar amount of the compound (1);
• and the sodium bisulfite aqueous solution has a mass concentration of 5% to 20%, and a usage amount of 1.5 to 2.5 times of the molar amount of the compound (1);
• 2) a bromo-hydroxylation reaction:
• dissolving the intermediate (2) in an organic solvent B;
• adding an acid catalyst B, and cooling to −10° C. to 5° C. while stirring;
• adding a brominating agent and stirring for reaction;
• after the completion of the reaction, adding a sodium sulfite solution;
• removing the organic solvent B by concentration;
• performing water precipitation, filtering and drying to obtain an intermediate (3), wherein the organic solvent B is one of acetone and butanone, and has a usage amount in volume of 20 to 40 times of the weight of the intermediate (2);
• the acid catalyst B is one of perchloric acid, fluoroboric acid, trifluoroacetic acid, and methanesulfonic acid, and has a mass concentration of 2% to 10%, and a usage amount of 0.3 to 0.5 times of the molar amount of the intermediate (2);
• the brominatinq agent is one of N-bromosuccinimide and dibromohydantoin, and has a usage amount of 1.8 to 2.5 times of the molar amount of the intermediate (2);
• and the sodium sulfite aqueous solution has a mass concentration of 5% to 20%, and a usage amount of 0.5 to 1.0 times of the molar amount of the intermediate (2);
• 3) a debromination reaction:
• dissolving the intermediate (3) in an organic solvent C;
• adding mercaptoacetic acid, and cooling to -5° C. to 15° C. while stirring;
• adding a hydrochloric acid solution of CrCl2 and stirring for reaction;
• after the completion of the reaction, performing water precipitation, filtering and drying to obtain an intermediate (4), wherein the organic solvent C is one of N,N-dimethylformamide and tetrahydrofuran, and has a usage amount in volume of 5 to 10 times of the weight of the intermediate (3);
• the mercaptoacetic acid has a usage amount of 4 to 10 times of the molar amount of the intermediate (3);
• and the hydrochloric acid solution of CrCl2 has a mass concentration of 30% to 50%, and a usage amount of 3 to 10 times of the molar amount of the intermediate (3);
• and
• 4) an alcoholysis reaction:
• dissolving the intermediate (4) in an organic solvent D;
• cooling to −10° C. to 10° C. while stirring;
• adding alkali liquor and stirring for reaction;
• after the completion of the reaction, neutralizing with acetic acid, and removing the organic solvent D by concentration;
• performing water precipitation, filtering;
• and drying to obtain a crude product;
• refining the crude product once with the organic solvent D to obtain the 16alpha-hydroxyprednisolone (5), wherein the organic solvent D is a mixture of dichloromethane and methanol/ethanol/propanol in a volume ratio of 1:1 to 3:1, and has a usage amount in volume of 15 to 30 times of the weight of the intermediate (4);
• the alkali liquor is one of a methanol solution of sodium hydroxide, a methanol solution of potassium hydroxide and a methanol solution of potassium carbonate, and has a mass concentration of 2% to 10%, and a usage amount of 0.4 to 0.9 times of the molar amount of the intermediate (4);
• and the acetic acid has a mass concentration of 5% to 50%, and a usage amount of 0.4 to 0.9 times of the molar amount of the intermediate (4).