Method for preparing 16a-hydroxyl prednisolone product

Abstract

The invention provides a method for preparing a 16a-hydroxyl prednisolone product. The method comprises the steps: firstly, subjecting 17a-deshydroxy prednisolone acetate, which serves as a starting raw material, and organic peroxy acid to an epoxidation reaction at 16,17 sites in a first organic solvent, so as to prepare epoxide; subjecting the epoxide and glacial acetic acid to a ring-opening reaction under the catalysis of an acid catalyst in a second organic solvent, so as to prepare 16a,21-diacetoxyl prednisolone; then, dissolving the 16a,21-diacetoxyl prednisolone in a third organic solvent, and hydrolyzing acetate of two positions under the catalysis of a solid-phase alkali catalyst, so as to prepare 16a-hydroxyl prednisolone; finally, subjecting the crude 16a-hydroxyl prednisoloneobtained through solid-phase alkali-catalyzed hydrolysis to heated refluxing, decoloring and recrystallization by low carbon alcohols of C4 or less, thereby obtaining the 16a-hydroxyl prednisolone product. The 16a-hydroxyl prednisolone is prepared by the efficient, environment-friendly and cheap method.

Description

technical field

[0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically refers to a preparation method of a 16a-hydroxyprednisolone product. Background technique

[0002] 16a-hydroxyprednisolone (molecular formula C 21 h 28 o 6 ), chemically named 11b, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione, is a key intermediate in the production of nedadrenoid steroid adrenocorticotropic hormone drugs , using it as a raw material, one-step condensation reaction with acetone can produce desonide, and one-step condensation reaction with n-butyraldehyde can produce budesonide. For example, budesonide is mainly used clinically for the treatment of many diseases such as various rhinitis, acute and chronic bronchitis, etc., with low side effects, good effect and broad market prospect. The traditional production method of 16a-hydroxyprednisolone is to use prednisolone as raw material, through 17,21-position diesterizati...

Examples

Embodiment 1

[0043] Step A---preparation of epoxy:

[0044] In a 3000ml three-necked flask, add 100g of starting materials 17a-prednisolone dehydrogenacetate, 1000ml of ethyl acetate, stir at room temperature to completely dissolve the solid, and add dropwise 40g of ophthalmic acid at 25-30°C The peracid solution made of oxybenzoic acid and 500ml ethyl acetate is dropped in about 2-2.5 hours, and then kept at 25-30°C for 6-12 hours, TLC confirms the end point of the reaction, and the reaction is complete Finally, add a mixed solution of 400ml 5% sodium hydroxide and 100ml 10% sodium sulfite to neutralize and destroy the acid produced by the reaction and excess peroxyacid, then concentrate under reduced pressure below 50°C to recover 90-95% ethyl acetate ester, then lowered to room temperature, added 500ml of tap water, stirred and analyzed for 3-4 hours, filtered, the filtrate was discharged into the wastewater treatment tank, the filter cake was washed with water, and dried below 60°C to ...

Embodiment 2

[0053] Step A: Preparation of epoxy:

[0054] In a 3000ml three-necked flask, add 100g of starting material 17a-prednisolone dehydroxyacetate, 1000ml of chloroform, stir at room temperature to completely dissolve the solid, and add 40g of m-chloroperoxy The peracid solution made of benzoic acid and 500ml ethyl acetate was dropped in about 2-2.5 hours, and then kept at 25-30°C for 6-12 hours, and the end point of the reaction was confirmed by TLC. After the reaction, add Mixed solution of 400ml 5% sodium hydroxide and 100ml 10% sodium sulfite to neutralize and destroy the acid and excess peroxyacid, then concentrate under reduced pressure below 50°C to recover 90-95% chloroform and ethyl acetate The mixed solvent was lowered to room temperature, added 500ml of tap water, stirred and analyzed for 3-4 hours, filtered, the filtrate was discharged into the waste water treatment tank, the filter cake was washed with water, and dried below 60°C to obtain 16,17a-epoxyprednilacetate S...

Embodiment 3

[0063] Step A---preparation of epoxy:

[0064] In a 3000ml three-necked flask, add 100g of starting materials 17a-prednisolone dehydrogenacetate, 1000ml of DME, stir at room temperature to completely dissolve the solid, and add dropwise a solution containing 40g of peracetic acid and 500ml of DME at 25-30°C. The prepared peracid solution was dripped in about 2-2.5 hours, and then continued to keep warm at 25-30°C for 6-12 hours after the dripping, and TLC confirmed the reaction end point. After the reaction, add 400ml of 5% sodium hydroxide and 100ml of a mixed solution made of 10% sodium sulfite to neutralize and destroy the acid and excess peroxyacid produced by the reaction, then concentrate under reduced pressure below 50°C to recover 90-95% DME solvent, then lower it to room temperature, add 500ml of tap water, Stir and analyze in water for 3-4 hours, filter, discharge the filtrate into the waste water treatment tank, wash the filter cake with water, and dry below 60°C to...

technical field

[0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically refers to a preparation method of a 16a-hydroxyprednisolone product. Background technique

[0002] 16a-hydroxyprednisolone (molecular formula C 21 h 28 o 6 ), chemically named 11b, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione, is a key intermediate in the production of nedadrenoid steroid adrenocorticotropic hormone drugs , using it as a raw material, one-step condensation reaction with acetone can produce desonide, and one-step condensation reaction with n-butyraldehyde can produce budesonide. For example, budesonide is mainly used clinically for the treatment of many diseases such as various rhinitis, acute and chronic bronchitis, etc., with low side effects, good effect and broad market prospect. The traditional production method of 16a-hydroxyprednisolone is to use prednisolone as raw material, through 17,21-position diesterizati...

Examples

Embodiment 1

[0043] Step A---preparation of epoxy:

[0044] In a 3000ml three-necked flask, add 100g of starting materials 17a-prednisolone dehydrogenacetate, 1000ml of ethyl acetate, stir at room temperature to completely dissolve the solid, and add dropwise 40g of ophthalmic acid at 25-30°C The peracid solution made of oxybenzoic acid and 500ml ethyl acetate is dropped in about 2-2.5 hours, and then kept at 25-30°C for 6-12 hours, TLC confirms the end point of the reaction, and the reaction is complete Finally, add a mixed solution of 400ml 5% sodium hydroxide and 100ml 10% sodium sulfite to neutralize and destroy the acid produced by the reaction and excess peroxyacid, then concentrate under reduced pressure below 50°C to recover 90-95% ethyl acetate ester, then lowered to room temperature, added 500ml of tap water, stirred and analyzed for 3-4 hours, filtered, the filtrate was discharged into the wastewater treatment tank, the filter cake was washed with water, and dried below 60°C to ...

Embodiment 2

[0053] Step A: Preparation of epoxy:

[0054] In a 3000ml three-necked flask, add 100g of starting material 17a-prednisolone dehydroxyacetate, 1000ml of chloroform, stir at room temperature to completely dissolve the solid, and add 40g of m-chloroperoxy The peracid solution made of benzoic acid and 500ml ethyl acetate was dropped in about 2-2.5 hours, and then kept at 25-30°C for 6-12 hours, and the end point of the reaction was confirmed by TLC. After the reaction, add Mixed solution of 400ml 5% sodium hydroxide and 100ml 10% sodium sulfite to neutralize and destroy the acid and excess peroxyacid, then concentrate under reduced pressure below 50°C to recover 90-95% chloroform and ethyl acetate The mixed solvent was lowered to room temperature, added 500ml of tap water, stirred and analyzed for 3-4 hours, filtered, the filtrate was discharged into the waste water treatment tank, the filter cake was washed with water, and dried below 60°C to obtain 16,17a-epoxyprednilacetate S...

Embodiment 3

[0063] Step A---preparation of epoxy:

[0064] In a 3000ml three-necked flask, add 100g of starting materials 17a-prednisolone dehydrogenacetate, 1000ml of DME, stir at room temperature to completely dissolve the solid, and add dropwise a solution containing 40g of peracetic acid and 500ml of DME at 25-30°C. The prepared peracid solution was dripped in about 2-2.5 hours, and then continued to keep warm at 25-30°C for 6-12 hours after the dripping, and TLC confirmed the reaction end point. After the reaction, add 400ml of 5% sodium hydroxide and 100ml of a mixed solution made of 10% sodium sulfite to neutralize and destroy the acid and excess peroxyacid produced by the reaction, then concentrate under reduced pressure below 50°C to recover 90-95% DME solvent, then lower it to room temperature, add 500ml of tap water, Stir and analyze in water for 3-4 hours, filter, discharge the filtrate into the waste water treatment tank, wash the filter cake with water, and dry below 60°C to...

Images