Method for preparing beclomethasone dipropionate product

A technology of aclomethasone dipropionate and products, applied in the field of preparing aclomethasone dipropionate products, can solve the problems of low total synthesis yield, long synthesis route, many side reactions and the like

Active Publication Date: 2019-04-23
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic method has a long synthetic route, and the total synthetic yield is only 2.678%, especially in the last step of 6,7-position HCl gas addition reaction, the synthetic yield is less than 20%. Due to the low synthetic total yield, multi-step synthetic chemical reactions There are many side reactions, the amount of impuritie

Method used

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  • Method for preparing beclomethasone dipropionate product
  • Method for preparing beclomethasone dipropionate product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] A. Preparation of esterified product: In a 1000ml three-necked flask, add 100g16a-methyl epihydrocortisone, 200ml propionic acid, 40g propionic anhydride, 5g p-toluenesulfonic acid, react at 20~25°C for 6~8 hours, TLC confirms the end point of the reaction. After the reaction is completed, slowly add the reaction solution dropwise to a 5000ml three-neck flask containing 2000ml molar concentration of 5% sodium hydroxide solution, stir and crystallize at 0~5°C for 4~5 hours, filter, The filtrate is discharged into the wastewater treatment tank, and the filter cake is added to 600ml of ethanol aqueous solution with a molar concentration of 20%, stirred at 30-35°C for 5-6 hours, then cooled to 0-5°C, stirred and crystallized for 5-6 hours, filtered , the filtrate was used in the next batch of refining process, the filter cake was washed and dried to obtain the esterified product: 112g of 16a-methyl epihydrocortisone-21 propionate, the HPLC content was 97.4%, and the weight y...

Embodiment 2

[0056] A. Preparation of esterified product: In a 1000ml three-neck flask, add 100g16a-methyl epihydrocortisone, 500ml chloroform, 40g propionic anhydride, 8g p-toluenesulfonic acid, react at 20~25°C for 6~8 hours, TLC Confirm the end point of the reaction. After the reaction is completed, slowly add 20ml of sodium hydroxide solution with a molar concentration of 50% dropwise. After water separation, concentrate under reduced pressure to recover 90-95% chloroform, then add 500ml of pure water, and stir at 0-5°C. Crystallize for 4-5 hours, filter, and discharge the filtrate into the wastewater treatment tank, add the filter cake to 600ml of ethanol aqueous solution with a molar concentration of 20%, stir at 30-35°C for 5-6 hours, then cool down to 0-5°C and stir Crystallize for 5-6 hours, filter, and use the filtrate in the next batch of refining process, wash the filter cake, and dry to obtain esterified product: 109.5 g of 16a-methyl-epihydrocortisone-21 propionate, HPLC conte...

Embodiment 3

[0064] A. Preparation of esterified product: In a 1000ml three-necked flask, add 100g16a-methyl epihydrocortisone, 500ml toluene, 40g propionic anhydride, 6g trifluoroacetic acid, react at 20~25°C for 6~8 hours, confirm by TLC At the end of the reaction, after the reaction, slowly add 20ml of sodium hydroxide solution with a molar concentration of 50% dropwise, after water separation, concentrate under reduced pressure to recover 90-95% toluene, then add 500ml of pure water, stir and crystallize at 0-5°C After 4 to 5 hours, filter, and the filtrate is discharged into the waste water treatment tank, and the filter cake is added to 600ml of ethanol aqueous solution with a molar concentration of 20%, stirred at 30 to 35°C for 5 to 6 hours, then cooled to 0 to 5°C, stirred and analyzed. crystallized for 5-6 hours, filtered, and the filtrate was used in the next batch of refining process, the filter cake was washed and dried to obtain esterified product: 106.8g of 16a-methyl-epihydr...

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Abstract

The invention discloses a method for preparing a beclomethasone dipropionate product. The method includes taking 16a-methylepihydrocortisone as a raw material, preforming a seven-step reaction to synthesize a crude product through esterification of 21-position propionic acid, double oxidation of 7-position and 11-position diketones, esterification of 17-position propionic acid, etherification protection of 3-position enolization, reduction of 7-position and 11-position diketones and acid hydrolysis deprotection, dehydrogenation of 1-position DDQ and substitution of 7-position chlorine; and refining to obtain the beclomethasone dipropionate product. According to the method, 16a-methylepihydrocortisone is taken as a raw material, and beclomethasone dipropionate is synthesized through the seven-step reaction, compared with the traditional method, the process has the advantages of short synthesis route, economical and environment-friendly process, simple and convenient production operation, high product yield and the like; when the method is used for producing beclomethasone dipropionate, the total synthesis yield is increased to 32-35% from the original 2.678%, and the production costis lower than 20% of the traditional method; and solvents used in production can be recycled and reused, and industrial production is easy to implement.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drugs, and in particular relates to a method for preparing alclomethasone dipropionate. Background technique [0002] Alclomethasone dipropionate (molecular formula C 28 h 37 ClO 7 ), with the chemical name 7a-chloro-16a-methyl-11-hydroxy-pregna-1,4-diene-3,20-dione-17,21-dipropionate, is a potent steroid Corticosteroid drugs have potent local anti-inflammatory, antipruritic and vasoconstrictive effects. They are mainly used clinically for the treatment of eczema, atopic dermatitis, psoriasis, and other skin diseases. They have low side effects and good effects. Broad prospects. The traditional production method of aclomethasone dipropionate is to use dexamethasone defluroacetate as raw material, dehydrogenate at 6-position of DDQ, hydrolyze with base catalyzed at 21-position, cyclic esterify with triethyl orthopropionate at 17 and 21-position, and acid catalyze Cyclic ester hy...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 羊向新左前进吴来喜
Owner HUNAN KEREY BIOTECH
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