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Preparation method of betamethasone 17 alpha-propionate

A technology of betamethasone and propionate is applied in the preparation of intermediates, the field of preparation of betamethasone 17α-propionate, and can solve the problems of unrecovered organic solvent, incompatible with energy saving and environmental protection, and many reaction steps, etc. Achieve the effect of guaranteed quality yield, improved production process economy and low cost

Inactive Publication Date: 2019-07-12
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the method for obtaining betamethasone 17α-propionate announced in the above information, dioxane and dimethylformamide are used as solvents, the solvents have certain toxicity, and there are many reaction steps, which require multiple discharges and feeds. , the overall yield is low, a large amount of waste water is produced, the environmental pollution is serious, and it cannot meet the current environmental protection requirements. Using 2-methyltetrahydrofuran as a solvent is expensive, and the two-step yield of cyclic ester and ring-opening acidolysis is also low.
Compared with the aforementioned process, it has been greatly improved, but there are still many problems, such as cumbersome steps, complicated post-processing, and unrecovered organic solvents, etc., which do not meet the concept of energy saving, environmental protection, and green development.

Method used

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  • Preparation method of betamethasone 17 alpha-propionate
  • Preparation method of betamethasone 17 alpha-propionate
  • Preparation method of betamethasone 17 alpha-propionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A. Under nitrogen protection, add 200ml tetrahydrofuran and 1.6ml triethyl orthopropionate into the reaction flask, add 20g betamethasone, stir to dissolve, cool down to below 15°C, add 0.8g p-toluenesulfonic acid, control Temperature 15 ℃ ~ 20 ℃, heat preservation reaction for 2 hours;

[0022] B, TLC detects that raw material betamethasone reacts completely. Cool down to 10-15°C, slowly add aluminum trichloride solution (1.5g of aluminum trichloride) dropwise to the reaction solution, keep the temperature at 10-15°C, keep warm for about 1.5 hours, after the dropwise addition, keep warm reaction. The temperature is 25°C-30°C, and the reaction time is 15 hours;

[0023] C. TLC detects that the reaction of the raw material betamethasone-17-21 cyclic ester is complete, control the temperature at about 50°C, and the vacuum degree is not less than 0.06Mpa, concentrate under reduced pressure to produce 190ml of tetrahydrofuran, and precipitate a white solid, then add 100ml...

Embodiment 2

[0025] A. Under nitrogen protection, add 200ml tetrahydrofuran and 1.4ml triethyl orthopropionate into the reaction flask, add 20g betamethasone, stir to dissolve, cool down to below 15°C, add 0.6g p-toluenesulfonic acid, control Temperature 15 ℃ ~ 20 ℃, heat preservation reaction for 3 hours;

[0026] B, TLC detects that raw material betamethasone reacts completely. Cool down to 10-15°C, slowly add aluminum trichloride solution (1.3g of aluminum trichloride) dropwise to the reaction solution, keep the temperature at 10-15°C, keep warm and drop for about 1.5 hours, after the dropwise addition, keep warm reaction. The temperature is 25°C-30°C, and the reaction time is 18 hours.

[0027] C. TLC detects that the reaction of the raw material betamethasone-17-21 cyclic ester is complete, control the temperature at about 50°C, and the vacuum degree is not less than 0.06Mpa, concentrate under reduced pressure to produce 191ml of tetrahydrofuran, and precipitate a white solid, then ...

Embodiment 3

[0029] A. Under nitrogen protection, add 150ml tetrahydrofuran and 1.8ml triethyl orthopropionate into the reaction flask, add 20g betamethasone, stir to dissolve, cool down to below 15°C, add 0.8g p-toluenesulfonic acid, control Temperature 15℃~20℃, heat preservation reaction for 1.5 hours;

[0030] B, TLC detects that raw material betamethasone reacts completely. Cool down to 10-15°C, slowly add aluminum trichloride solution (aluminum trichloride 1.7g) dropwise to the reaction solution, keep the temperature at 10-15°C, keep warm and drop for about 1.5 hours, after the dropwise addition, keep warm reaction. The temperature is 25°C-30°C, and the reaction time is 13 hours.

[0031]C. TLC detects that the reaction of the raw material betamethasone-17-21 cyclic ester is complete, control the temperature at about 50°C, and the vacuum degree is not less than 0.06Mpa, concentrate under reduced pressure to produce 190ml of tetrahydrofuran, and precipitate a white solid, then add 15...

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Abstract

The invention provides a preparation method of betamethasone 17 alpha-propionate. According to the preparation method, betamethasone is subjected to a reaction with triethyl orthopropionate, the reaction is performed in a tetrahydrofuran solvent, further, p-toluenesulfonic acid is adopted as a catalyst, after the reaction is finished, an aluminum trichloride solution is dropwise added to the samesolvent system directly without discharging, a thermal insulation reaction is performed after the solution is dropwise added, and betamethasone 17 alpha-propionate is obtained with a post-treatment process. According to the preparation method of betamethasone 17 alpha-propionate, preparation process is simplified, yield is increased and purity is improved while the problem that dioxane, dimethylformamide or another solvent is adopted as the reaction solvent of betamethasone 17 alpha-propionate is solved.

Description

technical field [0001] The invention relates to a preparation method of an intermediate in the production of betamethasone dipropionate, in particular to a preparation method of betamethasone 17α-propionate, belonging to the field of medicinal chemistry. Background technique [0002] (betamethasone dipropionate)Also known as betamethasone dipropionateThe chemical name is 11β,17α,21-trihydroxy-16β-methyl-9α-fluoro-pregna-1,4-diene-3,20- Diketone-17, 21-dipropionate, compared with other steroid drugs, has two propionate groups added to its structure, so it has greater fat solubility, excellent skin penetration performance, and long maintenance time Etc. Clinically, it is mainly used to treat skin inflammation and pruritus, such as neurodermatitis, contact dermatitis, seborrheic dermatitis, eczema, localized pruritus, discoid lupus erythematosus, etc. The structural formula of betamethasone dipropionate is as follows: [0003] [0004] Betamethasone 17α-propionate is an...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 孟栋梁王海波黄燕鸽李合兴陈玉真
Owner HENAN LIHUA PHARMA
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