Method for preparing hydrocortisone

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...

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.

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