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Method for preparing hydrocortisone

A technology of hydrocortisone and hydrocortisone acetate, applied in the directions of organic chemistry, steroids, etc., can solve the problem of inability to improve the primary mass yield of the crude product directly precipitated, time-consuming concentration and evaporation of the solvent, difficulty in crystallization of the product, etc. problems, to avoid the phenomenon of foam overflow, novel process route, and simplify the post-processing operation process.

Inactive Publication Date: 2016-03-02
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The deprotection step of the 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; in the post-reaction treatment process, since the reaction product is basically dissolved in the acidic solvent system, the crystallization of the product is difficult, The operation method of multiple extractions with a large amount of solvent is required, the solvent consumption is large, and the concentration and evaporation of the solvent takes a long time, which greatly increases the production cost
The applicant of the present invention explores according to the patented process, and the crude product of hydrocortisone can be precipitated in the deprotection reaction process, but the mass yield of the crude product directly precipitated is only 30% to 35%. The method of sodium aqueous solution can not improve the primary mass yield of directly precipitated crude product. Only after multiple extractions with solvents are used, the total mass yield of crude product can be increased to 60% to 65%.
[0008] In the process route of preparing hydrocortisone from cortisone acetate in the prior art, the deprotection reaction process generally has the disadvantages of poor reaction selectivity, difficult product crystallization, multiple extractions with solvents to ensure the yield, and high production costs.

Method used

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  • Method for preparing hydrocortisone
  • Method for preparing hydrocortisone
  • Method for preparing hydrocortisone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Add 900ml of acetone, 30g of hydrocortisone intermediate reduction product, 12g of sodium acetate, 45ml of acetic anhydride, and 9ml of acetic acid to the reaction flask in sequence, and react at reflux at elevated temperature for 5 hours. TLC showed that the reaction was complete, and most of the solvent was recovered by distillation under normal pressure, and the solvent was evaporated under reduced pressure. The temperature was lowered to below 5°C. After stirring for 30 minutes, it was allowed to stand for more than 2 hours, filtered and dried to obtain 31.3 g of esterified compound.

[0040] Put 30g of the esterified product into a solution made up of 210ml of 36% hydrochloric acid, 390ml of water and 15ml of chloroform, and stir at 25℃~30℃ for 30 minutes to dissolve. The temperature is lowered, and a solution prepared by 15g sodium nitrite and 150ml water is added dropwise at 5℃~10℃. After the addition, continue to react at 5°C to 10°C for 2 hours. TLC shows that th...

Embodiment 2

[0043] 900ml of acetone, 30g of hydrocortisone intermediate reductant, 15g of potassium acetate, 51ml of acetic anhydride, and 9ml of acetic acid were added to the reaction flask in sequence, and the reaction was heated and refluxed for 6 hours. TLC showed that the reaction was complete, and most of the solvent was recovered by distillation under normal pressure, and the solvent was evaporated under reduced pressure. The temperature was lowered to below 5°C. After stirring for 30 minutes, it was allowed to stand for more than 2 hours, filtered and dried to obtain 31.5 g of esterified compound.

[0044] Put 30g of the esterified product into a solution made up of 210ml of 36% hydrochloric acid, 390ml of water and 15ml of chloroform, and stir at 25℃~30℃ for 30 minutes to dissolve. The temperature is lowered, and a solution prepared by 15g sodium nitrite and 150ml water is added dropwise at 5℃~10℃. After the addition, continue to react at 5°C to 10°C for 2 hours. TLC shows that the...

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Abstract

The invention relates to a method for preparing hydrocortisone. The method includes: subjecting a cortisone acetate raw material to sites No. 3,20-keto protective reaction, site No.11-keto reduction reaction, site No.21-hydroxy esterification reaction, sites No. 3,20-ketone deprotection reaction, and site No. 21-acetate hydrolysis to obtain hydrocortisone. The method provides a new synthetic route containing esterification and deprotection in order, greatly improves the reaction selectivity, easily separates deprotection reaction products and avoids the posttreatment of tedious several times of extraction of a large amount of solvents in the traditional deprotection reaction process, and also avoids the side reaction caused by quenching reaction in the posttreatment of the traditional process; and the ester hydrolysis reaction is carried out under protection of inert gases in a mixed solvent, so as to avoid by-products produced in the hydrolysis reaction. The process route of the invention is novel, simple for operation, low in production cost, and applicable to industrial scale production.

Description

Technical field [0001] The invention belongs to the field of chemical pharmacy, and specifically relates to a preparation method of hydrocortisone. Background technique [0002] The structural formula of hydrocortisone (11β, 17α, 21-trihydroxy-pregna-4ene-3,20-dione) is: [0003] . [0004] Hydrocortisone belongs to the adrenal cortex hormone drug, which has various pharmacological effects such as anti-inflammatory, immunosuppressive, anti-toxic and anti-shock. The 11β-hydroxyl group in the structure of steroids is a necessary group for anti-inflammatory drugs. How to introduce 11β-hydroxyl group during the preparation of hydrocortisone is a key step of the whole process. The existing processes mainly include microbial transformation and chemical methods. Two kinds. Absidia is widely used as an oxidizing strain in China, and 11β-hydroxyl is introduced into the substrate RSA through one-step microbial transformation. This process has the disadvantages of low conversion rate, many...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 廖俊付林曾建华李桂莲徐明琴刘玉亭
Owner HUAZHONG PHARMA
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