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Method for preparing dehydrogenated intermediate product for aclomethasone dipropionate

A technology of aclomethasone dipropionate and intermediates, which is applied in the field of intermediate products after dehydrogenation for preparing aclomethasone dipropionate, can solve the problems of low total synthesis yield, long synthesis route, many side reactions and the like

Active Publication Date: 2019-04-19
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 dehydrogenated intermediate product for aclomethasone dipropionate
  • Method for preparing dehydrogenated intermediate product for aclomethasone dipropionate

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Experimental program
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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 conten...

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

Disclosed is a method for preparing a dehydrogenated intermediate product for aclomethasone dipropionate. The method comprises the steps that with 16a-methyl pihydrocortisone as a raw material, a crude dehydrogenated intermediate product for aclomethasone dipropionate is synthesized through a six-step reaction of 21-site propionic acid esterification, 7,11-site double-oxidation into diketone, 17-site propionic acid esterification, 3-site enolization etherification protection, 7,11-site diketone reduction and acid hydrolysis deprotection and 1-site DDQ dehydrogenation, then the dehydrogenated intermediate product for aclomethasone dipropionate is obtained through refining. By means of the method, with 16a-methyl pihydrocortisone as the raw material, the dehydrogenated intermediate product for aclomethasone dipropionate is synthesized through the six-step reaction; the process has the advantages of being short in synthesis route, economical, environmentally friendly, simple in productionoperation, high in product yield and the like; a solvent used in production can be recycled and applied, 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 a dehydrogenated intermediate product for 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-po...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 谢来宾胡爱国羊向新
Owner HUNAN KEREY BIOTECH
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