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Preparation method of compound 19-desmethyl-4-androstene-3,17 diketone

The technology of a compound and androstene, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as limiting the scope of use of hypochlorite oxidants, difficulty in storage and transportation of hypochlorite solution, and the process formula is easily affected by weather conditions. Storage and transportation, good stability, and the effect of improving product quality and yield

Active Publication Date: 2011-01-19
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hypochlorite solution is easy to decompose under the action of light and heat, which makes the storage and transportation of hypochlorite solution difficult, and the process formula is easily affected by weather conditions, which greatly limits the use of hypochlorite as an oxidant scope

Method used

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  • Preparation method of compound 19-desmethyl-4-androstene-3,17 diketone
  • Preparation method of compound 19-desmethyl-4-androstene-3,17 diketone
  • Preparation method of compound 19-desmethyl-4-androstene-3,17 diketone

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preparation example Construction

[0040] The preparation method of compound 19-desmethyl-4-androstene-3,17-dione (I) of the present invention uses compound 5α-chloro-3β-hydroxyl-6β, 19β-epoxy-androstene-17- Ketone (Ⅱ) is raw material, comprises the following steps:

[0041] The first step, the oxidation reaction:

[0042]Compound 5α-chloro-3β-hydroxyl-6β, 19β-epoxy-androst-17-one (Ⅱ) is added to haloalkane, alkaline buffer solution is added, and catalytic amount of 2,2,6,6-tetramethyl Piperidine-N-oxide (TEMPO), adjust the temperature to 5-15°C, add N-halogenated amide oxidant, stir and react at 5-15°C for 4-6 hours; after the reaction, add a reducing agent to quench the oxidation , separate layers, wash the organic layer until clean, separate the layers, concentrate the organic layer under reduced pressure, add acetone to take out the halogenated alkanes, add water, concentrate until there is no acetone smell, cool to 5-10 ° C, filter, wash until neutral, and obtain compound 5α -Chloro-6β,19β-epoxy-androst-...

Embodiment 1

[0062] The preparation process of compound 19-hydroxyl-4-androstene-3,17-dione (Ⅴ):

[0063] (1) Oxidation reaction: In the reaction bottle, put the compound 5α-chloro-3β-hydroxy-6β, 19β-epoxy-androst-17-one (II) 100g, dichloromethane 1000ml, stir to dissolve, add sodium carbonate - Sodium bicarbonate solution 1000ml, add 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) 0.93g, adjust the temperature to 5~10℃, add 50g dichlorodimethylhydantoin, Stir and react at 5 to 10°C for 6 hours; after the reaction is complete, add sodium metabisulfite to quench the oxidation, separate layers, wash the organic layer until clean, separate layers, concentrate the organic layer under reduced pressure, add acetone to take out dichloromethane, add water, and concentrate to No acetone smell, cool to 5-10°C, filter, wash until neutral to obtain compound 5α-chloro-6β, 19β-epoxy-androst-3,17-dione (Ⅲ) wet product;

[0064] (2) Elimination, reduction, and ring-opening reactions: In the reaction bottle...

Embodiment 2

[0066] The preparation process of compound 19-hydroxyl-4-androstene-3,17-dione (Ⅴ):

[0067] (1) Oxidation reaction: In the reaction bottle, put the compound 5α-chloro-3β-hydroxy-6β, 19β-epoxy-androst-17-one (II) 100g, chloroform 1000ml, stir to dissolve, add potassium carbonate - Potassium bicarbonate solution 1000ml, add 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) 1.0g, adjust the temperature to 10~15℃, add dibromodimethylhydantoin 100g, Stir and react at 10-15°C for 4 hours; after the reaction, add sodium bisulfite to quench the oxidative property, separate layers, wash the organic layer until clean, separate layers, concentrate the organic layer under reduced pressure, add acetone to take out chloroform, add water, Concentrate until there is no acetone smell, cool to 5-10°C, filter, and wash until neutral to obtain the wet product of compound 5α-chloro-6β, 19β-epoxy-androst-3,17-dione (Ⅲ);

[0068] (2) Elimination, reduction, and ring-opening reactions: In the reaction ...

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Abstract

The invention discloses a preparation method of a compound 19-desmethyl-4-androstene-3,17 diketone, comprises the following step of by taking compounds of 5alpha-chloro-3beta-hydroxy-6beta and 19beta-epoxy-androstane-17-ketone as raw materials, and carrying out oxidation reaction on the compounds of 5alpha-chloro-3beta-hydroxy-6beta and 19beta-epoxy-androstane-17-ketone as well as an intermediate compound 19-hydroxy-4-androstene-3,17-diketone with N-halogenated amide oxidant in a mixed solution of an organic solvent and an alkaline buffer solution in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine-N-oxide (TENPO) in the mild condition. In the two steps of oxidation reaction, the catalytic amount of 2,2,6,6-tetramethylpiperidine-N-oxide and the N-halogenated amide oxidant are both adopted to replace a mixed solution of chromium trioxide, sulfuric acid and water. In the oxidation method, without using the chromium trioxide, the use of carcinogenic substances are avoided being used, limitation by environmental protection is avoided and a great amount of wastes containing heavy metals in preparation are avoided being generated and accumulated, thereby no money and labor is consumed for removing the wastes.

Description

technical field [0001] The invention relates to a chemical synthesis method of medicine, in particular to a preparation method of compound 19-desmethyl-4-androstene-3,17-dione. Background technique [0002] Compound 19-desmethyl-4-androstene-3,17-dione (I) is an important intermediate of the steroidal contraceptive norethindrone series products. Its former intermediate compound 19-hydroxy-4-androstene-3,17-dione (Ⅴ) is also a steroidal anti-early pregnancy drug mifepristone (RU-486) ​​and cymipristone, nandrolone series , Estrogen series and other products are important intermediates. [0003] For the preparation of compound 19-desmethyl-4-androstene-3,17-dione (I), most of the manufacturers currently follow the "National Compilation of Raw Materials" (State Administration of Medicine, 1980) ) Norethindrone process production. Part of the process describes five steps of oxidation, elimination, reduction and ring opening, oxidation, and elimination using the compound 5α-ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
Inventor 方伟明
Owner ZHEJIANG XIANJU PHARMA
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