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One-pot preparation method of clobetasol propionate intermediate

A technology for clobetasol propionate and intermediates, which is applied in the field of one-pot preparation of clobetasol propionate intermediates, can solve problems not involved in process improvement of betamethasone-17-propionate, and achieve shortening The effect of production cycle, saving raw and auxiliary materials, and reducing production cost

Inactive Publication Date: 2016-06-08
SHANDONG TAIHUA BIO & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chinese patents, application numbers 200610053511.5 and 201010152502.8 involve process optimization of chlorination reaction and final product purification, but do not involve process improvement of betamethasone-17-propionate

Method used

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  • One-pot preparation method of clobetasol propionate intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0026] Add 50mL of 2-Me-THF to a 250mL three-neck round bottom flask, start stirring, add 20g of betamethasone, wash the bottle wall with 10mL of 2-Me-THF, control the temperature at 25°C~30°C, and add 13.47g of triethyl orthopropionate , 4.82g p-toluenesulfonic acid monohydrate, heat preservation reaction 3h, TLC detection reaction is complete. Add 30% sodium sulfite aqueous solution to terminate the reaction, adjust the pH to 7~8, concentrate under reduced pressure at 40°C until there is almost no 2-Me-THF; wash into 100mL water for water analysis, suction filter after 0.5h, wash with 1000mL water, and dry at 80°C Betamethasone-17-propionate. After constant weight, detection: HPLC content: 98.08%, maximum simple impurity: 0.89%, raw material point: 0.27%, mass yield 113.5%.

example 2

[0028] Add 150mL of ethyl acetate to a 250mL three-neck round bottom flask, start stirring, add 20g of betamethasone, wash the bottle wall with 10mL of ethyl acetate, control the temperature at 35°C~40°C, add 10.26g of trimethyl orthopropionate, 3.51 g of p-toluenesulfonic acid, incubated for 3 hours, and TLC detected that the reaction was complete. Add 40% sodium bicarbonate aqueous solution to terminate the reaction, adjust the pH to 7~8, concentrate under reduced pressure at 40°C until almost no ethyl acetate is present; pour into 100mL water for water analysis, suction filter after 0.5h, wash with 1000mL water, and dry at 80°C Betamethasone-17-propionate. After constant weight, detection: HPLC content: 97.32%, maximum simple impurity: 1.27%, raw material point: 0.32%, mass yield 113.3%.

example 3

[0030] Add 110mL of methyl tert-butyl ether into a 250mL three-necked round-bottomed flask, start stirring, add 20g of betamethasone, wash the bottle wall with 10mL of methyl tert-butyl ether, control the temperature at 30°C~35°C, and add 20.51g of propane Acetate trimethyl ester, 1g sulfuric acid, heat preservation reaction 3h, TLC detects that the reaction is complete. Add 20% potassium carbonate aqueous solution to terminate the reaction, adjust the pH to 7~8, concentrate under reduced pressure at 40°C until almost no methyl tert-butyl ether is present; pour into 100mL water for water analysis, suction filter after 0.5h, wash with 1000mL water, and wash with water for 80 °C drying to obtain betamethasone-17-propionate. After constant weight, detection: HPLC content: 97.53%, maximum simple impurity: 1.02%, raw material point: 0.38%, mass yield 112.7%.

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Abstract

The invention discloses an improved production technology of a clobetasol propionate intermediate (betamethasone-17-propionate). Two steps namely cyclo-esterification and hydrolysis in the conventional technology are merged into one step. By merging the steps, the procedure and production period are shortened, the product purity and yield are increased, the energy consumption is reduced, the raw materials and auxiliary materials are saved; the environment pollution is reduced, and the production cost is reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to the improvement of a production process of a clobetasol propionate intermediate, in particular to a one-pot method for preparing the clobetasol propionate intermediate. Background technique [0002] Clobetasol Propionate (Clobetasol Propionate, structural formula 1), is a potent halogen-containing adrenal glucocorticoid drug, externally used for chronic eczema, neurodermatitis, psoriasis, palmoplantar pustulosis, lichen planus, discoid erythema Lupus and other pruritic and non-infectious inflammatory skin diseases. The anti-inflammatory effect is about 112 times that of hydrocortisone, and the systemic adverse reactions are 3 times that of fluocinolone. It has an anhydrous sodium retention effect and can promote the excretion of sodium and potassium to a certain extent. [0003] [0004] The classic method of producing clobetasol propionate both at home and abroad is to take ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 赵振国王娟韩明
Owner SHANDONG TAIHUA BIO & TECH
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