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Preparation method of clobetasol and preparation method of clobetasol propionate

A technology of clobetasol propionate, clobetasol propionate, applied in the directions of steroids, organic chemistry, etc., can solve the problems of large solvent pollution, many side reactions, difficult to recover, etc., to shorten the synthesis route and reduce the production cost , the effect of production economy

Inactive Publication Date: 2015-03-04
江西赣亮医药原料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The starting material betamethasone of these two methods is expensive, and multi-step reaction has been carried out for the upper 21-position chlorine, and there are many influencing factors and many side reactions produced
Moreover, the solvent used is highly polluted and difficult to recycle

Method used

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  • Preparation method of clobetasol and preparation method of clobetasol propionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Take a three-necked reaction flask, pass through nitrogen protection, add 100g of compound I, namely 1,4,9(11)-trienandrost-3,17-dione, add 400ml THF, cool the system to 0°C, and then add 60ml oxalic acid Diethyl ester and 30g of sodium methoxide were stirred at a temperature of 0-5°C for 1 h, then 20 g of anhydrous potassium carbonate and 28 ml of methyl iodide were added, and the temperature was raised to reflux for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure to nearly dryness. Add 400ml of anhydrous methanol, cool down to 0-5°C; then add 12g of sodium methoxide, stir at 0-5°C for 2 hours, and take a sample to check that there is no intermediate. Adjust the pH to 7-8 with glacial acetic acid, add 2000ml of water, control the temperature of the system at 0-5°C and stir for 2 hours, filter with suction, wash the filter cake with water until neutral, and dry to obtain 95g of compound II, namely 16β-methyl-1,4 , 9(11)-triene ...

Embodiment 2

[0040] Take a three-necked reaction flask, pass through nitrogen protection, add 100g of compound I, namely 1,4,9(11)-triene androst-3,17-dione, add 600ml of dioxane, cool the system to 0°C, and then Add 60ml of diethyl oxalate and 40g of sodium ethoxide, control the temperature at 0-5°C and stir for 1 hour, then add 20g of anhydrous potassium carbonate, pass in 60g of methyl bromide, raise the temperature to 60-70°C and react for 10 hours, after the reaction is complete, concentrate under reduced pressure to near dryness . Add 400ml of anhydrous methanol, cool down to 0-5°C; then add 14g of sodium ethoxide, stir at 0-5°C for 2 hours, and take a sample to check that there is no intermediate. Adjust the pH to 7-8 with glacial acetic acid, add 2000ml of water, control the temperature of the system at 0-5°C and stir for 2 hours, filter with suction, wash the filter cake with water until neutral, and dry to obtain 93g of compound II, namely 16β-methyl-1,4 , 9(11)-triene androst-3...

Embodiment 3

[0048] Take a three-necked reaction flask, pass through nitrogen protection, add 100g of compound I, namely 1,4,9(11)-triene androst-3,17-dione, add 700ml of dichloromethane, cool the system to 0°C, and then add 60ml of diethyl oxalate and 50g of potassium tert-butoxide, stirred at 0-5°C for 1 hour, then added 20g of anhydrous potassium carbonate, introduced 50g of methyl chloride, raised the temperature to 40-45°C for 30 hours, after the reaction was completed, concentrated under reduced pressure to nearly dry. Add 400ml of anhydrous methanol, cool down to 0-5°C; then add 16g of potassium tert-butoxide, stir at 0-5°C for 2 hours, and take a sample to check that there is no intermediate. Adjust the pH to 7-8 with glacial acetic acid, add 2000ml of water, control the temperature of the system at 0-5°C and stir for 2 hours, filter with suction, wash the filter cake with water until neutral, and dry to obtain 90g of compound II, namely 16β-methyl-1,4 , 9(11)-triene androst-3,17-...

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Abstract

The invention discloses a preparation method of clobetasol and the preparation method of clobetasol propionate. The preparation method of the clobetasol comprises the following steps: by taking a compound I, namely 1,4,9(11)-triene androstane-3,17-diketone as an initial raw material, performing a methylation reaction, a cyan substitution reaction, a siloxy protection reaction, an intramolecular nucleophilic substitution reaction, a bromoepoxy reaction and a fluorination reaction to prepare a compound VII which is clobetasol. The compound VII is subjected to a propyl esterification reaction to prepare a compound VIII which is clobetasol propionate. According to the preparation method disclosed by the invention, since relatively basic initial raw materials which are cheap are used, each step of reaction is relatively easy to implement and high yield is achieved; the operation of multi-step protection and deprotection is simplified; moreover, 21 sites of fluorine are directly arranged in one step during arrangement of a side chain, and multiple steps of reaction for arranging the 21 sites of fluorine in the prior art are directly avoided, so that the synthetic route is greatly shortened, the total yield is increased, the product quality is improved and the production cost is greatly lowered.

Description

technical field [0001] The invention relates to a chemical synthesis method of medicine, in particular to a preparation method of clobetasol and a preparation method of clobetasol propionate. Background technique [0002] Clobetasol Propionate, also known as Clobetasol Propionate, also known as Clobetasol Propionate, Temeifu, English name Clobetasol Propionate, chemical name: 21-chloro-9-fluoro-11β-hydroxy-17-propionate-16β-formazan Pregnant-1,4-diene-3,20-dione, its structural formula is as follows: [0003] [0004] Clobetasol propionate is a synthetic high-efficiency topical glucocorticoid drug. It has strong anti-inflammatory, anti-itching and capillary constriction effects, and its anti-inflammatory effect is about 112.5 times that of hydrocortisone, 2.3 times that of betamethasone sodium phosphate, and 18.7 times that of fluocinolone. At the same time, it has the effect of inhibiting cell mitosis, and can effectively penetrate into the stratum corneum of the skin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
CPCC07J7/0085
Inventor 杨坤应正平蒋青锋何辉贤
Owner 江西赣亮医药原料有限公司
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