A kind of method for preparing aclomethasone dipropionate

A technology of aclomethasone dipropionate and propionate, which is applied in the field of preparation of steroid hormone drugs, can solve the problems of excessive three wastes, long synthesis route, aggravating the burden of medication for patients and the like

Active Publication Date: 2020-08-11
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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  • A kind of method for preparing aclomethasone dipropionate
  • A kind of method for preparing aclomethasone dipropionate

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Comparison scheme
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Embodiment 1

[0047] 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

[0055] 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

[0063] 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. According to the method, alclometasone dipropionate is synthesized by the following seven reaction steps: esterification of 16a-methyl epihydrocortisone as a raw material with propionic acid at position 21; double-oxidization at positions 7 and 11 to obtain diketone; esterification with propionic acid at position 17; enolization and etherification protection at position 3; reduction and acid hydrolysis for deprotection with diketone at positions 7 and 11; dehydrogenation with DDQ (Dichlorodicyanobenzoquinone) at position1; and chlorine substitution at position 7. According to the method for preparing alclometasone dipropionate, the alclometasone dipropionate is synthesized by taking 16a-methyl epihydrocortisone as the raw material through seven steps; compared with a convention method with dexamethasone fluoroacetate as the raw material, the process has the advantages of short synthetic route and economy and environmental protection, simple production and operation, high product yield and the like; in the alclometasone dipropionate produced with the method, the total synthetic yield is increased from original 2.678% to 32-35%, the production cost is less than 20% of that of the traditional method; the solvent used in production can be recycled and reused; the 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 吴来喜胡爱国羊向新
Owner HUNAN KEREY BIOTECH
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