Synthetic method of 17beta-cyano-17alpha-hydroxy-9-dehydroandrostenedione

Abstract

The invention discloses a synthesis method of 17 [beta]-cyano-17 [alpha]-hydroxy-9-dehydroandrostenedione, which comprises the following steps: (1) dissolving 9-hydroxyandrostane-4-ene-3, 17-dione and a cyaniding reagent in an organic solvent, and carrying out a cyanation reaction in a tubular reactor R1 filled with strongly basic ion exchange resin; (2) carrying out dehydration reaction on the obtained cyanation reaction feed liquid in a tubular reactor R2 filled with strongly acidic ion exchange resin; and (3) carrying out post-treatment on the feed liquid after the dehydration reaction, so as to obtain the product 17 [beta]-cyano-17 [alpha]-hydroxy-9-dehydroandrostenedione. The method has the advantages that the online reaction amount is small, the safety is high, continuous and automatic production is easy to realize, and the like; the repeated utilization rate of ion exchange resin in the tubular reactor is high, so that the process cost is reduced; the use of inorganic acid and inorganic base is eliminated from the source, the three wastes of the process are reduced, and the environment-friendly requirement is met. The reaction formula is as follows:

Description

technical field [0001] The invention relates to a method for synthesizing 17β-cyano-17α-hydroxyl-9-dehydroandrostenedione, a key intermediate of hydrocortisone. Background technique [0002] 17β-cyano-17α-hydroxy-9-dehydroandrostenedione is an important intermediate in the synthesis of steroid hormone drug hydrocortisone. Hydrocortisone has important pharmacological activities, such as anti-inflammatory, anti-viral, anti-allergic, anti-shock, etc. It is widely used clinically in the treatment of diseases such as adrenal insufficiency, rheumatoid arthritis, gout, and dermatitis. [0003] At present, the synthesis of 17β-cyano-17α-hydroxy-9-dehydroandrostenedione is mainly through the dehydration reaction under acid catalysis and the cyanation reaction under base catalysis, using 9-hydroxyandrostenedione as raw material. Realize (CN201410747239.5, CN201610204515.2, CN201811395764.X, CN201410707307.5 etc.); adopt the above-mentioned preparation 17β-cyano-17α-hydroxyl-9-dehydro...

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Problems solved by technology

[0003] At present, the synthesis of 17β-cyano-17α-hydroxy-9-dehydroandrostenedione is mainly through dehydration reaction under acid catalysis and cyanation reaction under base catalysis, using 9-hydroxyandrostenedione as raw material. Realize (CN201410747239.5, CN201610204515.2, CN201811395764.X, CN201410707307.5 etc.); Adopt above-mentioned preparation 17β-cyano-17α-hydroxyl-9-dehydroandrostenedione, mainly have the following problems: (1) in Carried out under the traditional tank reaction conditions, the material backmixing is serious, the selectivity and repeatability are poor, and the yield is low;

[0004] (2) The amount of alkaline and acidic reagents is large, the cyanide-containing wastewater is difficult to treat, the organic solvent is difficult to recycle, and the environmental protection hazards are large; (3) The online reaction material of the kettle reaction is large, the selectivity of the cyanation reaction is poor, and the traditional kettle reaction Side reactions such as condensation are prone to occur during the formula reaction

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