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Novel preparation method of 16 alpha-hydroxyprednisolone

A technology of hydroxyprednisolone and hydroxyprednisolone acetate, applied in the directions of steroids, organic chemistry, etc., can solve the problems of many side reactions of oxidation reaction, high impurity and low yield, etc., and achieves less impurities and high yield. High, improve the effect of total yield

Inactive Publication Date: 2019-04-19
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Therefore, the present invention aims at the problems of many side reactions of oxidation reaction and low yield of impurities in the traditional 16a-hydroxyprednisolone and 16a-hydroxyprednisolone acetate production process, in order to prepare 16a-hydroxyprednisolone efficiently and environmentally friendly Songlong and 16a-hydroxyacetate prednisolone, in the present invention, adopt earlier to prepare 16a-hydroxyacetate prednisolone with specific method first, then obtain by the method for alkaline hydrolysis of 16a-hydroxyacetate prednisolone under specific conditions 16a-Hydroxyprednisolone

Method used

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  • Novel preparation method of 16 alpha-hydroxyprednisolone

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Experimental program
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Embodiment 1

[0037] A. Preparation of oxides:

[0038] In a 5000ml three-necked flask, add 100g of 17-dehydroxyacetate prednisone, 2000ml of acetone, 12.5g of 80% formic acid, stir to dissolve the solid completely, control the temperature to 20-25°C, and add 900g of 5% dropwise within 1-1.5 hours Potassium permanganate aqueous solution, after dripping, react at 20-25°C for 1-2 hours, TLC controls the reaction end point, after the reaction, 90-95% of the solvent acetone is recovered by vacuum distillation below 35°C for the next Batch oxidation reaction, the residue was cooled to room temperature, added 1000ml of pure water for water analysis, filtered to obtain the oxide: crude product of 16a-hydroxyacetate prednisone; the crude product was recrystallized with 1000ml of 50% alcohol aqueous solution to obtain 16a-hydroxyacetate Nisone 93.8g, HPLC content 97.5%, weight yield about 93.8%;

[0039] B. Preparation of protection:

[0040] In a 1000ml three-neck flask, add 100g of the oxide pre...

Embodiment 2

[0047] A. Preparation of oxides:

[0048] In a 5000ml three-necked flask, add 100g of 17-dehydroxyacetate prednisone, 1500ml of chloroform, 15g of 20% phosphoric acid, stir to dissolve the solid completely, control the temperature to 20-25°C, and add 1500g of 3% phosphoric acid dropwise within 1-1.5 hours Potassium permanganate aqueous solution, after dripping, react at 20-25°C for 1-2 hours, TLC controls the reaction end point, after the reaction, recover 90-95% of the solvent chloroform by vacuum distillation below 35°C for the next batch Oxidation reaction, the residue was cooled to room temperature, added 1000ml of pure water for water analysis, filtered to obtain the oxide: 16a-hydroxyprednisone acetate crude product; the crude product was recrystallized with 1000ml50% alcohol aqueous solution to obtain 16a-hydroxyprednisone acetate Pine 91.6g, HPLC content 98.0%, weight yield about 91.6%;

[0049] B. Preparation of protection:

[0050] In a 1000ml three-neck flask, add...

Embodiment 3

[0057] A. Preparation of oxides:

[0058] In a 5000ml three-neck flask, add 100g of 17-dehydroxyprednisone acetate, 1500ml of DME, 50g of 20% acetic acid, stir to dissolve the solid completely, control the temperature to 20-25°C, and dropwise add 900g of 5% acetic acid within 1-1.5 hours Potassium manganate aqueous solution, after dripping, react at 20-25°C for another 1-2 hours, TLC controls the reaction end point, after the reaction, 90-95% of the solvent DME is recovered by vacuum distillation below 35°C for the next batch oxidation Reaction, the residue is cooled to room temperature, add 1000ml pure water for water analysis, filter to obtain the oxide compound: 16a-hydroxy prednisone acetate crude product; the crude product is recrystallized with 1000ml50% alcohol aqueous solution to obtain 16a-hydroxy prednisone acetate 92.5g, HPLC content 97.6%, weight yield about 92.5%;

[0059] B. Preparation of protection:

[0060] In a 1000ml three-neck flask, add 100g of the oxide...

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Abstract

A novel preparation method of 16 alpha-hydroxyprednisolone comprises the following steps: dissolving 17-prednisone dehydroxyacetate as a raw material in an organic solvent, oxidizing a 16-position double bond and a 17-position double bond with potassium permanganate under acid catalysis to obtain an oxide, dissolving the obtained oxide in the organic solvent, adding acetone, and carrying out acidcatalysis reaction to obtain a protective substance; then dissolving the protective substance in an organic solvent, adding a reducing agent to reduce the 11-position ketone, and directly adding an acid aqueous solution to perform hydrolysis and deprotection after the reduction reaction to obtain the 16 alpha-hydroxyprednisolone, and dissolving 16 alpha -hydroxyacetate in an organic solvent, hydrolyzing 21-position acetic ester under the catalysis of solid-phase base to obtain 16 alpha -hydroxyprednisolone. Although two steps of the protection reaction and deprotection reaction are added, thereaction yield of each step unit is high, and the operation is simple and convenient, and the process is economical and environment-friendly, and the total synthesis yield is greatly improved; and compared with the traditional production method, the preparation cost of the method is reduced by 20-25%.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically relates to a key intermediate 16a- Preparation technology of hydroxyprednisolone. Background technique [0002] 16a-Hydroxyprednisolone (molecular formula C21H28O6), chemical name 11b,16a,17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione, is a kind of nedide The key intermediate of steroidal adrenocorticotropic hormone drugs, using it as a raw material, one-step condensation reaction with acetone to produce desonide, and one-step condensation reaction with n-butyraldehyde to prepare budesonide, neide-like steroidal adrenocorticotropic hormone drugs It is a class of potent local anti-inflammatory agents, such as budesonide, which 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0092
Inventor 吴来喜胡爱国羊向新
Owner HUNAN KEREY BIOTECH
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