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Method for synthesizing stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone

A technology for the synthesis of stanozolol and its synthesis method, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of similar product polarity, influence on product purity, difficulty in removal, etc., and achieve the advantages of short route, easy control of production process and low production cost Effect

Pending Publication Date: 2019-03-08
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the case of 17-position acidolysis and 3-keto-ene etherification deprotection at the same time, the next step of catalytic hydrogenation reaction is easy to introduce a The isomeric impurity of 5βH structure, which is extremely similar to the polarity of the product and difficult to remove, thus ultimately affecting the purity of the product

Method used

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  • Method for synthesizing stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone
  • Method for synthesizing stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone
  • Method for synthesizing stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1. Preparation of compound 5-androstene-3,17-diethylene glycol ketal

[0035] Add 20g of 4-androstenedione, 100ml of dichloromethane, 30ml of trimethyl orthoformate, 40ml of ethylene glycol and 1g of p-toluenesulfonic acid into the reaction bottle, stir well and keep warm at 30°C to 35°C for 10 hours to react; After the reaction is complete, lower the temperature to below 5°C, add triethylamine dropwise to adjust the pH value to 7.0-7.5, and stir for 30 minutes after addition; evaporate all solvents under reduced pressure, entrain with 20ml of methanol, and concentrate under reduced pressure to a paste. Add 20ml of methanol and reflux for 30 minutes; cool down to below 5°C, filter and dry to obtain 24.8g of 5-androstene-3,17-diethylene glycol ketal;

[0036] 2. Preparation of compound 5α-androstane-3,17-dione

[0037] Add 20g of 5-androstene-3,17-diethylene glycol ketal and 400ml of ethanol to the reaction flask, stir well, add potassium hydroxide ethanol solution drop...

Embodiment 2

[0045] 1. Preparation of compound 5-androstene-3,17-diethylene glycol ketal

[0046] Add 20g of 4-androstenedione, 80ml of chloroform, 40ml of triethyl orthoformate, 60ml of ethylene glycol and 2g of pyridine hydrochloride into the reaction flask, stir evenly and keep warm at 30°C to 35°C for 9 hours to react; After completion, lower the temperature to below 5°C, add triethylamine dropwise to adjust the pH value to 7.0-7.5, and stir for 30 minutes after addition; evaporate all solvents under reduced pressure, entrain with 20ml methanol, concentrate under reduced pressure to paste, add 20ml Methanol was refluxed for 30 minutes; the temperature was lowered to below 5°C, filtered and dried to obtain 24.2g of 5-androstene-3,17-diethylene glycol ketal;

[0047] 2. Preparation of compound 5α-androstane-3,17-dione

[0048] Add 20g of 5-androstene-3,17-diethylene glycol ketal and 300ml of methanol into the reaction flask, stir evenly, add methanol solution of sodium hydroxide dropwis...

Embodiment 3

[0056] 1. Preparation of compound 5-androstene-3,17-diethylene glycol ketal

[0057] Add 20g of 4-androstenedione, 120ml of dichloromethane, 60ml of triethyl orthoformate, 60ml of ethylene glycol and 1g of p-toluenesulfonic acid into the reaction flask, stir evenly and keep warm at 30°C to 35°C for 9 hours for reaction; After the reaction is complete, lower the temperature to below 5°C, add triethylamine dropwise to adjust the pH value to 7.0-7.5, and stir for 30 minutes after addition; evaporate all solvents under reduced pressure, entrain with 20ml of methanol, and concentrate under reduced pressure to a paste. Add 20ml of methanol and reflux for 30 minutes; cool down to below 5°C, filter and dry to obtain 25.1g of 5-androstene-3,17-diethylene glycol ketal;

[0058] 2. Preparation of compound 5α-androstane-3,17-dione

[0059] Add 20g of 5-androstene-3,17-diethylene glycol ketal and 300ml of methanol into the reaction flask, stir evenly, add potassium hydroxide ethanol solut...

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Abstract

The invention provides a method for synthesizing a stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone. The method comprises the following steps: taking 4-androstenedione as a raw material, carrying out 3-site and 17-site keto-double-ketal, 5-site ethylenic bond catalytic hydrogenation and 3-site and 17-site double-ketal hydrolysis to prepare a compound 5alpha-androstane-3,17-diketone; then carrying out 3-site keto-double-etherification and 17-site Grignard addition, and finally carrying out hydrolysis to prepare the compound androstane-17alpha-methyl-17beta-hydroxyl-3-ketone, wherein the HPLC (High Performance Liquid Chromatography) purity of the compound is 99.0% or greater. The method provided by the invention is short in route, easy in production process control,environmentally-friendly, low in production cost and applicable to industrial large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing a stanozolol intermediate androst-17α-methyl-17β-hydroxyl-3-one. Background technique [0002] The structural formula of stanozolol (17-methyl-2'H-5α-androst-2-ene-[3,2-c]pyrazol-17β-ol) is: [0003] [0004] Stanozolol is an anabolic steroid drug, which can promote protein synthesis, inhibit protein dysgenesis, reduce blood cholesterol and triacylglycerol, promote calcium and phosphorus deposition, and relieve bone marrow suppression. The traditional synthesis process of stanozolol intermediate androst-17α-methyl-17β-hydroxy-3-one uses diosgenin as raw material, and undergoes reactions such as ring opening, acylation, oxidation, hydrolysis, and elimination to obtain diene , dienes undergo oximation, Beckmann rearrangement, acid hydrolysis, alkali hydrolysis, catalytic hydrogenation and other reactions to obtain epiandrostero...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0037
Inventor 廖俊曾建华刘玉亭王勇付林魏旭力
Owner HUAZHONG PHARMA
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