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Preparation method of hydrocortisone butyrate

A technology of hydrocortisone butyrate and hydrocortisone, which is applied in the directions of organic chemistry, steroids, etc., can solve the problems of relatively harsh temperature conditions, high price of -butyryl chloride, and increased difficulty in production management, etc. The equipment requirements are not high, it is conducive to environmental protection, and the effect of reducing the generation of waste acid water

Inactive Publication Date: 2015-02-18
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Butyryl chloride, the main raw material used in this process, is expensive, active in nature, and difficult to store for a long time, which increases production costs and increases the difficulty of production management; HCl is generated during the acylation reaction, polluting the on-site environment, and corroding production. Equipment; the hydrolysis reaction needs to be carried out under the condition of -15 ° C ~ 20 ° C, and the temperature conditions are relatively strict, which improves the equipment requirements

Method used

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  • Preparation method of hydrocortisone butyrate
  • Preparation method of hydrocortisone butyrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 160ml of dimethylformamide and 40g of hydrocortisone to the reaction bottle in turn, stir at room temperature to dissolve. Then the temperature was controlled to 20° C., 50 ml of triethyl orthobutyrate was added, and 1 g of p-toluenesulfonic acid was added, and the reaction was stirred for 3 hours. TLC showed the reaction was complete. Then slowly add the reaction solution into ice water pre-cooled to 0°C-5°C, after the addition, continue to stir at 0°C-5°C for 0.5 hours, let it stand for more than 2 hours, filter, wash with water until neutral and dry to obtain 50.8 g cyclic esters.

[0021] Add 10g of concentrated sulfuric acid with a mass percentage concentration ≥ 98% dropwise to 50ml of acetone for dilution, put it into 90g of 60-100 mesh silica gel, stir for 1 hour, evaporate the acetone under reduced pressure, and vacuum dry for 6 hours to obtain the desired solid acid.

[0022] Add 1500ml of methanol, 75ml of water and 50.8g of cyclic esters to the reactio...

Embodiment 2

[0024] Add 200ml of dimethylformamide and 40g of hydrocortisone to the reaction bottle in turn, stir at room temperature to dissolve. Then the temperature was controlled to 20° C., 60 ml of triethyl orthobutyrate was added, and 1 g of p-toluenesulfonic acid was added, and the reaction was stirred for 2.5 hours. TLC showed the reaction was complete. Then slowly add the reaction solution into ice water pre-cooled to 0°C-5°C, after the addition, continue to stir at 0°C-5°C for 0.5 hours, let it stand for more than 2 hours, filter, wash with water until neutral and dry to obtain 50.6 g cyclic esters.

[0025] Add 1500ml of methanol, 75ml of water and 50.6g of cyclic esters to the reaction flask in turn, stir at room temperature to dissolve. Then the temperature was lowered to 15°C, 12.5g of dry hydrogen catalytic resin was added, and the mixture was stirred and reacted at 15°C-20°C for 1.5 hours. Filtrate (the filter cake is rinsed with 50ml of methanol and continue to be recyc...

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Abstract

The invention relates to a preparation method of hydrocortisone butyrate. The preparation method comprises the steps of adding a raw material of hydrocortisone serving as a solvent into dimethylformamide, and generating macrolide under the catalysis action of p-toluenesulfonic acid and the action of triethyl orthobutyrate; dissolving the prepared macrolide into a methyl alcohol-water mixed solvent, and performing hydrolysis reaction under the catalysis action of solid strong acid to generate hydrocortisone butyrate. According to the preparation method, the common technical prejudice that the hydrolysis reaction is low in selectivity and large in byproduct proportion under a strong acid condition in the prior art is solved; the solid strong acid is used as a catalyst, so that production of a large amount of industrial waste acid water is avoided, and the phenomenon that the catalyst is difficult to separate when attached and wrapped in a product is avoided; the reaction conditions are mild; the catalyst can be repeatedly used; the quantity of byproducts is small; the requirement on equipment is low; the environmental protection is facilitated, and the cost is low; the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of hydrocortisone butyrate. Background technique [0002] The structural formula of hydrocortisone butyrate (11β, 17α, 21-trihydroxy-pregna-4ene-3,20-dione-17α-butyrate) is: [0003] [0004] Hydrocortisone butyrate belongs to the adrenal cortex hormone drug, which has various pharmacological effects such as anti-inflammation, anti-allergy and immune suppression, and is suitable for treating eczema, dermatitis, allergic skin diseases, etc. [0005] The existing preparation method of hydrocortisone butyrate is to generate 17α and 21-cyclic esters from hydrocortisone and corresponding orthobutyrate, and then hydrolyze under acidic conditions to restore the original hydroxyl group at the 21 position, thereby obtaining the product . The hydrolyzate obtained in the hydrolysis ring-opening reaction step not only contains the product 17 ester (hydro...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 廖俊曾建华冯旋李桂莲付林
Owner HUAZHONG PHARMA