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Method for preparing alclometasone dipropionate by using etherified intermediate

A technology of aclomethasone dipropionate and intermediates, which is applied in the field of preparation of steroid hormone drugs, can solve the problems of long synthesis route, low synthesis yield, many side reactions, etc., and achieves simple production and operation, economical and environmentally friendly process , the effect of short synthetic route

Active Publication Date: 2019-05-24
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 impurities produced is large, the refining and purification is difficult, and there are many three wastes produced at the same time, and it is not easy to handle, and it is easy to pollute the environment, which makes the production cost and market price of aclomethasone dipropionate very high, which aggravates this type of patients. drug burden

Method used

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  • Method for preparing alclometasone dipropionate by using etherified intermediate
  • Method for preparing alclometasone dipropionate by using etherified intermediate

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Experimental program
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Effect test

Embodiment 1

[0031] 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

[0039] 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

[0047] 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 provides a method for preparing alclometasone dipropionate by using an etherified intermediate. According to the method, the etherified intermediate 3-vinyl alcohol ether-16a-methyl-17a,21-bipropionyloxy-pregna-3,5-diene-7,11,20-triketone serves as the raw material and is reduced with 7-site and 11-site diketone and subjected to three reactions including acid hydrolysis deprotection,1-site DDQ dehydrogenation and 7-site chlorine substitution, and then alclometasone dipropionate is synthesized. According to the method, the etherified intermediate 3-vinyl alcohol ether-16a-methyl-17a,21-bipropionyloxy-pregna-3,5-diene-7,11,20-triketone serves as the raw material, alclometasone dipropionate is synthesized through three steps of reactions, compared with a traditional method using de-fluorated dexamethasone acetate as the raw material, the technology has the advantages that a synthetic route is short, the process is economical and environmentally friendly, the production operation is simple and convenient and the product yield is high; solvents used during production can be recycled, 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 from an etherified intermediate. 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, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 羊向新左前进吴来喜
Owner HUNAN KEREY BIOTECH
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