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Preparation method of danazol

A danazol and reaction technology, which is applied in the field of preparation of danazol, can solve the problems of reduced safety, hidden dangers, and excessively long routes, and achieves the effects of short reaction time, high reaction efficiency and short reaction steps.

Active Publication Date: 2019-03-26
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the above-mentioned method has the following disadvantages: 1, the route is too long, the whole preparation step has 5 steps, and the protection and deprotection of the 3-position are used, the method is loaded down with trivial details, and the efficiency is low; 2, in the ethynylation reaction, the easy Inflammable and explosive dangerous acetylene gas, the safety is greatly reduced, and there may be hidden dangers in the process of industrial production and preparation

Method used

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preparation example Construction

[0033] A preparation method of danazol is prepared by using androstenedione as a starting material through 2-methine hydroxylation reaction, 17-carbonyl ethynylation reaction and oximation reaction.

[0034] The preparation method of a kind of danazol provided by the present invention has changed the complicated problem of danazol reaction process in the prior art, androstenedione is used as the starting material, and the 2-methine hydroxylation reaction and the 17-position Danazol can be prepared by carbonyl acetylation and oximation, and the 2-methine hydroxylation and 17-carbonyl acetylation are completed in one step. The method has the advantages of safety, short reaction steps, high yield, high reaction efficiency, etc., does not use flammable and explosive acetylene gas with great safety hazards in the reaction, and uses acetylene magnesium bromide and ethynyl magnesium chloride instead of potassium alkynyl. safer. At the same time, the reaction that originally required...

Embodiment 1

[0057] (1) Synthesis of 17-position carbonyl ethynylation and 2-methine hydroxylation products

[0058] Add androstenedione (18g, 0.063mol) into 80mL of anhydrous tetrahydrofuran, heat up to 35-45°C and stir to dissolve, cool down to 0-10°C, slowly add acetylene magnesium bromide (190mL, specification 0.5M in THF) dropwise , after the dropwise reaction was completed, the reaction was kept for 3 hours, and then ethyl formate (25 g, 0.337 mol) was added, the temperature was raised to 15-20° C., and the reaction was kept for 5 hours. After the reaction, add the reaction material into 400mL water for water analysis, filter, and cool the filtrate to about 0°C, adjust the pH=1-2 to acidify and precipitate, filter, wash with water until neutral, and dry to obtain the 17-position carbonyl acetylation and the 2-position methylene hydroxy Compound 18g.

[0059] Result: The yield is 85%, mp182~185℃.

[0060] (2) Synthesis of Danazol

[0061] The 17-carbonyl ethynylation and 2-methyne ...

Embodiment 2

[0064] (1) Synthesis of 17-position carbonyl ethynylation and 2-methine hydroxylation products

[0065] Add androstenedione (27g, 0.095mol) into 120mL of anhydrous tetrahydrofuran, heat up to 35-45°C and stir to dissolve, cool down to 0-10°C, slowly add acetylene magnesium bromide (300mL, specification 0.5M in THF) dropwise , after the dropwise reaction was completed, the reaction was kept for 3 hours, and then ethyl formate (40 g, 0.539 mol) was added, the temperature was raised to 15-20° C., and the reaction was kept for 5 hours. After the reaction, add the reaction material to 600mL water for water analysis, filter, and cool the filtrate to about 0°C, adjust the pH=1-2 to acidify and precipitate, filter, wash with water until neutral, and dry to obtain the 17-position carbonyl acetylation and the 2-position methylene hydroxy Compound 28g.

[0066] Results: Yield 88%, mp 183-186°C.

[0067] (2) Synthesis of Danazol:

[0068] The 17 carbonyl ethynylation and 2 methylene hy...

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Abstract

The invention provides a preparation method of danazol. According to the preparation method of the danazol, androstenedione is used as an initial raw material, through 2-position secondary hydroxymethylation reaction, 17-position carbonyl ethinylation reaction and oximation reaction, the danazol can be prepared, and the 2-position secondary hydroxymethylation reaction and the 17-position carbonylethinylation reaction are completed in one step. The preparation method of the danazol has the advantages of being safe, short in reaction step, high in yield, efficient in reaction and the like, andin the reaction, no flammable and combustible acetylene gas with huge potential safety hazards is used, so that preparation in which potassiumacetylide is replaced by ethynylmagnesium bromide is safer. Meanwhile, the reaction which needs to be completed in four steps before is completed in one step, the reaction is more efficient, meanwhile, operation is simple, and reaction time is short.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical engineering, in particular to a preparation method of danazol. Background technique [0002] Danazol is a synthetic steroidal heterocyclic compound, that is, a derivative of the androgen 17a-ethynyl testosterone is a weak androgen, has anti-gonadotropic and mild androgenic effects, and can promote endometriosis Degeneration and improvement of symptoms can also make some infertility patients conceive. For the treatment of endometriosis, it can also be used for the treatment of fibrocystic breast disease, spontaneous thrombocytopenic purpura, hereditary angioedema, systemic lupus erythematosus, gynecomastia, and precocious puberty. [0003] For the preparation of danazol, the latest published patent CN201410281920 introduces the latest improved danazol preparation method. The method uses androstenedione as a starting material, and undergoes etherification of enol at 3, ethynylation o...

Claims

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Application Information

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IPC IPC(8): C07J71/00
CPCC07J71/0063
Inventor 吴为贲
Owner JIANGSU LIANHUAN PHARMA
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