Preparation method of hydrocortisone

A hydrocortisone and ketone-based technology, which is applied in the direction of organic chemistry and steroids, can solve the problems of polluting the site environment, restricting applications, and damaging the health of operators, so as to reduce production costs, increase process yields, The effect of shortening the generation cycle

Inactive Publication Date: 2015-02-04
HUAZHONG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The deprotection step of this technical route has the following disadvantages: the selectivity of the deprotection reaction is poor, and the reaction produces a large amount of impurities, resulting in an extremely low deprotection yield; the deprotection reagent—sodium nitrite is a substance that is highly toxic and can cause cancer, and its use pollutes the The on-site environment damages the health of the operators; in the post-reaction treatment process, due to the difficulty in crystallizing the product, it is necessary to use a large amount of solvent for multiple extractions, which greatly increases the production cost
Chinese patent CN102827231 adopts a heterogeneous system reaction in the deprotection reaction, which can directly precipitate the material, saves the extraction step, and correspondingly improves the yield, but the process still needs to react under the action of toxic substance sodium nitrite, which is unavoidable It will affect the selectivity of the deprotection reaction, pollute the field environment and damage the health of operators
After cortisone acetate is hydrolyzed to obtain cortisone, the same difficulty is still encountered in the reaction of ketal protection, and the required 3- and 20-position bis-ketals cannot be obtained.
Since the 20-position ketone group is difficult to react completely in the ketal protection, the application of the ketal protection method in the preparation of hydrocortisone from cortisone acetate is limited.

Method used

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  • Preparation method of hydrocortisone
  • Preparation method of hydrocortisone
  • Preparation method of hydrocortisone

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Add 120ml of glacial acetic acid, 280ml of water and 30g of cortisone acetate to the reaction flask in turn, and stir for 10 minutes. Add 18 g of methyl carbazate, and stir and react at 25°C to 30°C for 5 hours. TLC showed that the reaction was complete, and the temperature was lowered to 0°C to 5°C and stirred for 0.5 hours, allowed to stand for more than 2 hours, filtered, washed with water until neutral and dried to obtain 38.6g of methylhydrazine base.

[0027] Add 300ml of methanol, 0.4g of sodium hydroxide dissolved in 60ml of water, and 20g of methylhydrazine to the reaction flask in turn, and stir for 10 minutes. Cool down, and add 5 g of sodium borohydride five times at 10° C. to 15° C., with an interval of 30 minutes each time. After the addition was completed, the reaction was continued at 10°C to 15°C for 8 hours. TLC showed that the reaction was complete, lower the temperature to below 5°C, add dropwise glacial acetic acid to adjust the pH value to 6.5-7....

Embodiment 2

[0030] Add 120ml of glacial acetic acid, 280ml of water and 30g of cortisone acetate to the reaction flask in turn, and stir for 10 minutes. Add 19.5 g of ethyl carbazate, and stir and react at 25°C to 30°C for 6 hours. TLC showed that the reaction was complete, and the temperature was lowered to 0°C to 5°C and stirred for 0.5 hours, allowed to stand for more than 2 hours, filtered, washed with water until neutral and dried to obtain 40.6 g of ethylhydrazine.

[0031] Add 300ml of methanol, 0.4g of sodium hydroxide dissolved in 60ml of water, and 20g of ethylhydrazine to the reaction flask in turn, and stir for 10 minutes. Cool down, and add 6 g of potassium borohydride five times at 10°C to 15°C, with an interval of 30 minutes each time. After the addition was complete, the reaction was continued at 10°C to 15°C for 9 hours. TLC showed that the reaction was complete, lower the temperature to below 5°C, add dropwise glacial acetic acid to adjust the pH value to 6.5-7.0, conc...

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Abstract

The invention relates to a preparation method of hydrocortisone. The preparation method comprises the following steps: by taking cortisone acetate as a raw material and orderly carrying out a 3-site / 20-site keto protection reaction, a 11-site keto reduction reaction and a 3-site / 20-site keto deprotection reaction to obtain the hydrocortisone. The preparation method of the hydrocortisone has the advantages that the use of a toxic carcinogenic reagent in a traditional process is avoided, the selectivity of the reactions are greatly improved, meanwhile, the after-treatment mode of multiple extraction by use of a large amount of solvent is avoided, and the production cost is low; as a result, the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of hydrocortisone. Background technique [0002] The structural formula of hydrocortisone (11β, 17α, 21-trihydroxy-pregn-4-ene-3,20-dione) is: [0003] [0004] Hydrocortisone belongs to the adrenal cortex hormone drug, which has various pharmacological effects such as anti-inflammation, immunosuppression, anti-drug and anti-shock. The 11β-hydroxyl group in the structure of steroids is an essential group for anti-inflammatory drugs. How to introduce the 11β-hydroxyl group in the preparation process of hydrocortisone is a key step in the whole process. The existing processes mainly include microbial transformation and chemical methods. two kinds. Domestically, Agsidiaceae is widely used as the oxidative strain, and 11β-hydroxyl is introduced into the substrate RSA through one-step microbial transformation. This process has defects such as low...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 廖俊曾建华魏旭力冯旋付林
Owner HUAZHONG PHARMA
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