Method for preparing drospirenone intermediate 3beta,5-dihydroxy-15beta,16beta-methylene-5beta-androst-6-en-17-one

A technology of methylene androster and hydroxy androster, applied in the field of medicinal chemistry, can solve the problems of environmental pollution, high equipment investment cost and high technical difficulty

Inactive Publication Date: 2008-02-20
王爱玲 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The production of drospirenone intermediate by this method has high technical difficulty, high equipment investment cost, and the waste fermentation liquid pollutes the environment.
Domestic literature (Zhou Zhi et al., Synthetic Chemistry, Volume 12, 499-501) introduces the 7-position CrO 3 - Oxidation of pyridine, and then reduction with lithium tri-tert-butoxy aluminum hydride to obtain the 7-hydroxyl compound, and then react to obtain 3β, 5-dihydroxy-15β, 16β-methylene-5β-androst-6-ene-17 -ketone, compared with the present invention, the previous synthetic method has increased reaction steps, and synthetic yield also correspondingly descends

Method used

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  • Method for preparing drospirenone intermediate 3beta,5-dihydroxy-15beta,16beta-methylene-5beta-androst-6-en-17-one
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  • Method for preparing drospirenone intermediate 3beta,5-dihydroxy-15beta,16beta-methylene-5beta-androst-6-en-17-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、3

[0072] The preparation of embodiment 1,3β-acetoxy-17-ethylenedioxy-androst-5-ene (q01)

[0073] Add 62.5g of dehydroepiandrosterone acetate, 35.75ml of ethylene glycol, 0.125g of p-toluenesulfonic acid, and 90.0ml of triethyl orthoformate into a four-neck flask, heat to 90°C and reflux for about 1 hour Afterwards, dot plate tracking to determine the end point of the reaction. The solvent was distilled off until the temperature rose to 110°C. The hot solution was poured into 700 ml of methanol preheated and added with 10 ml of pyridine, and stirred for 0.5 hours. Add 200ml of water, cool down to room temperature, suction filter, wash with water, and dry to obtain 69.0g of 3β-acetoxy-17-ethylenedioxyandrost-5-ene. The melting point is 140-142°C.

Embodiment 2、3

[0074] Example 2, Preparation of 3β-acetoxy-16α-bromo-17-ethylenedioxyandrost-5-ene (q02)

[0075] In a four-necked reaction flask, add 112.5ml of tetrahydrofuran, add 37.5g of 3β-acetoxy-17-ethylenedioxyandrost-5-ene (q01), stir and dissolve, add 75g of perbromopyridinium salt and 112ml In the solution prepared in tetrahydrofuran, stir the reaction for 2 hours, keeping the reaction temperature at 20°C. Spot the plate to trace the reaction end point, add 225ml of water to dilute, and distill off tetrahydrofuran under reduced pressure. Suction filtration, washing with water, recrystallization with 85% ethanol after drying the filter cake to obtain 41.0 g of 3β-acetoxy-16α-bromo-17-ethylenedioxyandrost-5-ene. Melting point: 176-179°C.

Embodiment 3

[0076] Embodiment 3, the preparation of 3β-hydroxyl-17-ethylenedioxy-androst-5,15-diene (q03)

[0077] Add 240ml of dimethyl sulfoxide and 19.0g of 3β-acetoxy-16α-bromo-17-ethylenedioxyandrost-5-ene (q02) into the four-necked reaction flask, stir and dissolve, then add 11.0g of t- Potassium butoxide was reacted at 40°C for 20 hours under the protection of nitrogen, poured into 2000ml of anhydrous ether, stirred well, separated into layers, separated the organic phase and concentrated to dryness under reduced pressure, and recrystallized with 85% ethanol , to obtain 13.2 g of 3β-hydroxy-17-ethylenedioxyandrosta-5,15-diene. The melting point is 157-162°C.

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Abstract

The invention provides a method for preparing an intermediate of eplerenone 3 Beta, 5- dihydroxy-15 Beta, 16 Beta-methylene-5 Beta-androstane-6-alkene-17-ketone (q10) from dehydroepiandrosterone acetate.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to Drospirenone (Drospirenone, 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-carboxylide) Preparation method of important intermediate 3β, 5-dihydroxy-15β, 16β-methylene-5β-androst-6-en-17-one. Background technique [0002] Drospirenone can be used as a steroidal active substance as a raw material for high-efficiency non-toxic contraceptives. The important intermediate 3β, 5-dihydroxy-15β, 16β-methylene-5β-androst-6-en-17-one in the preparation process of drospirenone is prepared by fermentation method in EP51143 and USP4435327. body, and then prepared by synthetic method. Among them, USP4435327 uses dehydroepiandrosterone as a raw material to generate 3β, 7α, 15α-trihydroxy-5-androsten-17 ketone through biotransformation, and then reacts in 7 steps to obtain 3β, 5-dihydroxy-15β, 16β- Methylene-5β-androst-6-en-17-one. The...

Claims

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Application Information

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IPC IPC(8): C07J53/00C07J71/00
Inventor 王爱玲郁春辉潘正官张秋华
Owner 王爱玲
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