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Preparation method of 16a-prednisolone hydroxyacetate

A technology of prednisolone hydroxyacetate and prednisone hydroxyacetate is applied in the directions of steroids, organic chemistry, etc., can solve the problems of many side reactions in oxidation reaction, high impurity and low yield, etc., and achieves less impurities and higher yield. High, economical and environmentally friendly production process

Inactive Publication Date: 2019-04-05
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Preparation method of 16a-prednisolone hydroxyacetate
  • Preparation method of 16a-prednisolone hydroxyacetate

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Experimental program
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Embodiment 1

[0032] A. Preparation of oxides:

[0033] 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%;

[0034] B. Preparation of protection:

[0035] In a 1000ml three-neck flask, add 100g of the oxide pre...

Embodiment 2

[0042] A. Preparation of oxides:

[0043] 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%;

[0044] B. Preparation of protection:

[0045] In a 1000ml three-neck flask, add...

Embodiment 3

[0052] A. Preparation of oxides:

[0053]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%;

[0054] B. Preparation of protection:

[0055] In a 1000ml three-neck flask, add 100g of the oxide ...

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Abstract

Disclosed is a preparation method of 16a-prednisolone hydroxyacetate. The method comprises dissolving 17-prednison dehydroxylated acetate as the raw material into organic solvent, under catalysis of acids, oxidizing 16th and 17th double bonds through potassium permanganate to obtain an oxide, and dissolving the oxide into acetone for acid-catalyzed reaction to obtain a protector; dissolving the protector into organic solvent, adding in reducing agent to reduce 11th ketone, then directly adding in acid aqueous solution for hydrolysis and deprotection to obtain the 16a-prednisolone hydroxyacetate. Although the preparation method of the 16a-prednisolone hydroxyacetate adds the two reaction steps of protection and deprotection, every unit reaction is high in yield, the third and fourth reaction steps can be completed within on pot, so that the production operation can be simple and convenient, the production processes are economical and environmentally friendly, the problems of many side reactions and impurities and difficulty impurity refining of oxidation reaction in traditional production process can be greatly solved, the total synthesizing yield can be greatly increased, and compared with traditional production methods, the preparation method of the 16a-prednisolone hydroxyacetate can reduce the production cost 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 prednisolone hydroxyacetate. Background technique [0002] 16a-prednisolone hydroxyacetate (molecular formula C23H28O7), chemical name 11b, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione, 21 acetate, is a A key intermediate for the production of neide steroid adrenocorticotropic hormone drugs, using it as a raw material, one-step condensation reaction with acetone to produce desonide acetate, one-step condensation with n-butyraldehyde to produce budesonide acetate, its hydrolysis After that, desonide and budesonide were prepared respectively. The steroid adrenocorticotropic hormone drug of neide is a kind of potent local anti-inflammatory agent. For example, budesonide is mainly used for various rhinitis, acute and chronic bronchitis clinically. The treatment of many diseases, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0061
Inventor 甘红星胡爱国吴来喜
Owner HUNAN KEREY BIOTECH
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