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Preparation method of 16alpha-hydroxyprednisolone

A technology of hydroxyprednisolone and prednisone acetate, which is applied in the field of chemical synthesis of pharmaceutical intermediates, can solve the problems of difficulty in intermediate control, high production cost, and high equipment requirements, and achieves reduced side reactions, short reaction steps, and reduced The effect of production costs

Active Publication Date: 2015-01-07
江西赣亮医药原料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This method has high requirements for equipment in the industrial process production process. In order to reduce the 11-position carbonyl group and protect the 20-position and 3-position carbonyl groups at the same time, the steps are relatively cumbersome, the products in the reaction process are complicated, and the intermediate control is difficult. Nitrogen dioxide, a major and important air pollutant, has disadvantages such as low yield and high production cost

Method used

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  • Preparation method of 16alpha-hydroxyprednisolone
  • Preparation method of 16alpha-hydroxyprednisolone
  • Preparation method of 16alpha-hydroxyprednisolone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Put 100g of prednisone acetate, 500ml of chloroform, 250ml of acetic anhydride and 5g of p-toluenesulfonic acid into the three-necked reaction flask, stir and heat up to reflux, keep it warm for 14-16h, after the reaction is completed, cool down to about 25°C, add 200ml of water dropwise Terminate the reaction, concentrate to dryness under reduced pressure, add 1000ml of water, stir for 30min, filter and wash with water until neutral, and dry to obtain 109g of compound II, namely 1,4,-diene-3,11,20-trione pregna-17α ,21-Diacetate; weight yield: about 109%, HPLC content: 99%.

[0030] Add 250ml of methanol, 250ml of dichloromethane, 50g of compound II, and 30g of anhydrous zinc chloride into the three-necked reaction flask, dissolve completely under stirring, cool down to about 10-15°C, and slowly add potassium borohydride to the reaction solution in batches The solid is 8g, after the reaction is completed, add glacial acetic acid to adjust the pH to 6~7, stir for 10 min...

Embodiment 2

[0035] Put 100g of prednisone acetate, 600ml of dichloroethane, 250ml of propionic anhydride and 4ml of concentrated sulfuric acid into the three-necked reaction bottle, stir and heat up to 80°C, keep it warm for 14-16h, after the reaction is complete, cool down to about 25°C, add 200ml of water dropwise to stop Reaction, concentrated under reduced pressure to gradually dryness, added 1000ml of water, stirred for 30min, filtered and washed with water until neutral, and dried to obtain 115g of compound II, namely 1,4,-diene-3,11,20-trione pregna-17α, -Propionate-21-acetate; weight yield: about 115%, HPLC content: 99%.

[0036] Add 350ml of ethanol, 250ml of chloroform, 50g of compound II, and 30g of anhydrous magnesium chloride into the three-necked reaction flask, dissolve completely under stirring, cool down to about 10-15°C, and slowly add potassium acetylborohydride to the reaction solution in batches The solid is 16g, after the reaction is completed, add glacial acetic aci...

Embodiment 3

[0041] Put 100g of prednisone acetate, 500ml of dichloromethane, 250ml of acetyl chloride and 100ml of pyridine into the three-necked reaction bottle, stir and heat up to 40°C, keep it warm for 2-4 hours, after the reaction is complete, cool down to about 25°C, add 100ml of water dropwise to terminate the reaction , concentrated to dryness under reduced pressure, added 1000ml of water, stirred for 30min, filtered and washed until neutral, and dried to obtain 109g of compound II, that is, 1,4,-diene-3,11,20-triketone pregna-17α,21 - diacetate; weight yield: about 109%, HPLC content: 99%.

[0042] Add 250ml of anhydrous methanol, 250ml of dichloromethane, 50g of compound II, and 30g of anhydrous nickel chloride into the three-necked reaction flask, dissolve completely under stirring, cool down to about -10~-5°C, and slowly pour into the reaction solution in batches Add 4g of solid lithium aluminum hydride, after the reaction is complete, add glacial acetic acid to adjust the pH ...

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Abstract

The invention discloses a preparation method of 16alpha-hydroxyprednisolone, which comprises the following steps: by using a compound I prednisone acetate as an initial raw material, carrying out esterification reaction, reduction reaction, elimination reaction, oxidation reaction and hydrolysis reaction to obtain the end product VI 11beta,16alpha,17alpha,21-tetrahydroxyprogsteroid-1,4-diene-3,20-dione, i.e. 16alpha-hydroxyprednisolone. By using the cheaper initial raw material, the method has the advantages of shorter reaction steps, feasible reaction steps, higher yield and higher economy and safety for production, and is more suitable for industrial production. The method avoids using the traditional virulent product for bis-hydroxy oxidation, enhances the reaction safety and operability, simplifies the multiple protection and deprotection operation steps, greatly shortens the synthesis route, lowers the production cost, basically prevents the three-site carbonyl groups from being simultaneously reduced in the reduction process, greatly reduces the side reactions, and enhances the yield and quality of the reduction reaction.

Description

technical field [0001] The invention relates to a chemical synthesis method of a drug intermediate, in particular to a preparation method of 16α-hydroxyprednisolone. Background technique [0002] 16α-hydroxyprednisolone, English name 16alpha-hydroxyprednisolone, chemical name: 11β, 16α, 17α, 21-tetrahydroxypregna-1,4-diene-3,20-dione, is halogen-free The important pharmaceutical intermediates of adrenal cortex hormone drugs are the basic raw materials for the manufacture of desonide, budesonide, ciclesonide and triamcinolone acetonide for the treatment of bronchial inflammation and asthma drugs, and the market prospect is very broad. [0003] The preparation method of compound 16α-hydroxyprednisolone, the current preparation process mainly contains two kinds, one method uses prednisolone as the starting raw material, through multi-step reactions such as cyclic ester, hydrolysis, acylation, elimination and oxidation In this method, the price of the starting material predniso...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0061
Inventor 杨坤何辉贤蒋华容张沙田应正平蒋青锋
Owner 江西赣亮医药原料有限公司
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