Preparation method of betamethasone dipropionate

A technology of betamethasone dipropionate and propionic anhydride, applied in the directions of steroids, organic chemistry, etc., can solve the problems of high price of 2-methyltetrahydrofuran, unsuitable for commercial production, unable to meet environmental protection requirements, etc. The effect of strong impurity capacity, moderate reaction temperature and convenient feeding

Pending Publication Date: 2021-05-28
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After the reaction, a large amount of waste liquid is produced, which seriously pollutes the environment and cannot meet the current environmental protection requirements, and 2-methyltetrahydrofuran is expensive
Refining with ethyl acetate / petroleum ether has poor impurity removal effect and low yield, so it is not suitable for commercial production

Method used

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  • Preparation method of betamethasone dipropionate
  • Preparation method of betamethasone dipropionate
  • Preparation method of betamethasone dipropionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0044] The preparation of embodiment 1 betamethasone dipropionate

[0045] Under nitrogen protection, dichloromethane (14.4kg) was added into the reaction kettle, stirring was started, and betamethasone-17-propionate (compound of formula II, 0.90kg, 2.0mol, 1.0eq), DMAP (catalyst) ( 61.3 g, 0.5 mol, 0.25 eq). Cool down to 0-10°C, add propionic anhydride (313g, 2.4mol, 1.2eq) and dichloromethane (1.197kg) solution, react for 3-5 hours, add water (4.5kg) to quench, let stand to separate , the aqueous layer was discarded, the organic layer was washed 3 times with water, dried with anhydrous sodium sulfate (0.27kg), filtered, and the filtrate was collected, concentrated under reduced pressure (temperature 40°C ~ 50°C, vacuum degree -0.05Mpa ~ -0.10Mpa) After concentrating to a small amount of liquid remaining, add n-hexane (0.594kg), and continue to concentrate to stop flow; add dichloromethane (2.68kg), absolute ethanol (50.4ml), heat to dissolve, add dropwise n-hexane (2.66kg),...

Embodiment 2 2

[0047] The preparation of embodiment 2 betamethasone dipropionate

[0048] Under the protection of nitrogen, add dichloromethane (493ml) into the reaction kettle, start stirring, add betamethasone-17-propionate (compound of formula II, 44.85g, 0.1mol, 1.0eq), DMAP (1.2g, 0.01 mol, 0.1 eq). Cool down to 15-25°C, add a solution of propionic anhydride (15.6g, 0.12mol, 1.2eq) and dichloromethane (45ml), react for 3-5 hours, add water (250ml) to quench, stand to separate layers, The aqueous layer was discarded, the organic layer was washed 3 times with water, dried by adding anhydrous sodium sulfate (25g), filtered, and the filtrate was collected, concentrated under reduced pressure (temperature 40℃~50℃, vacuum degree -0.05Mpa~-0.10Mpa), concentrated After a small amount of liquid remained, add n-hexane (50ml) and continue to concentrate to stop flow, then add n-hexane (50ml) and concentrate to stop flow; add dichloromethane (101ml) and absolute ethanol (2.5ml), heat to dissolve, ...

Embodiment 3 2

[0050] The preparation of embodiment 3 betamethasone dipropionate

[0051] Under the protection of nitrogen, add dichloromethane (493ml) into the reaction kettle, start stirring, add betamethasone-17-propionate (compound of formula II, 44.85g, 0.1mol, 1.0eq), DMAP (6.1g, 0.05 mol, 0.5eq). Cool down to -10-0°C, add propionic anhydride (15.6g, 0.12mol, 1.2eq) and dichloromethane (45ml) solution, react for 3-5 hours, add water (250ml) to quench, let stand and separate , the aqueous layer was discarded, the organic layer was washed 3 times with water, dried with anhydrous sodium sulfate (25g), filtered, and the filtrate was collected, concentrated under reduced pressure (temperature 40°C ~ 50°C, vacuum -0.05Mpa ~ -0.10Mpa), After concentrating to a small amount of liquid, add n-hexane (50ml) and continue to concentrate until the flow is cut off, then add n-hexane (50ml) and concentrate to stop the flow; add dichloromethane (101ml) and absolute ethanol (2.5ml) and heat to dissolve...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of betamethasone dipropionate. According to the method, betamethason-17-propionate is taken as a raw material, propionic anhydride is taken as a raw material, under the condition that 4-dimethylaminopyridine is taken as a catalyst, betamethasone dipropionate is generated through reaction, and high-purity betamethasone dipropionate is obtained through refining by adopting absolute ethyl alcohol, dichloromethane and normal hexane. The preparation process is simple, the reaction temperature is moderate, and ultralow-temperature or high-temperature reaction is avoided; the solvent or reagent used in the preparation is cheap and easy to obtain, convenient to charge and easy to transport and store; the method has the advantages of small dosage of reaction catalyst, high yield, less generated waste liquid, environmental friendliness and suitability for commercial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of betamethasone dipropionate. Background technique [0002] Betamethasone Dipropionate (Betamethasone Dipropionate) is also known as betamethasone dipropionate, the chemical name is 16β-methyl-11β,17α,21-trihydroxy-9α-fluoropregna-1,4-diene- 3,20-Diketo-17,21-dipropionate, a prodrug of the glucocorticoid drug betamethasone. Clinically, it is mainly used to treat skin inflammation and pruritus. The structural formula of betamethasone dipropionate is shown in formula I: [0003] [0004] The traditional synthetic method of betamethasone dipropionate is to obtain betamethasone-17,21-orthopropionate cyclic ester by cyclization reaction of betamethasone and triethyl orthopropionate, and then selectively hydrolyze the 21-position to obtain betamethasone 17-propionate, the last 21-hydroxyl group is propionylated to obtain the target pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 何志红何超陈頔
Owner CHONGQING HUABANGSHENGKAI PHARM
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