New method for preparing eplerenone

A technology of eplerenone and androstenedione, which is applied in the field of preparation of new steroidal aldosterone receptor antagonist eplerenone, achieves the effect of cheap source, low cost and high yield

Inactive Publication Date: 2012-08-01
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a cheaper and more effective eplerenone preparation method in order to overcome the defects of the existing eplerenone preparation method

Method used

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  • New method for preparing eplerenone
  • New method for preparing eplerenone
  • New method for preparing eplerenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 4,9(11)-Androstadiene-3,17-dione (III)

[0039] Under nitrogen protection, add II (16.80g), benzene, BF 3 AcOH, reflux and stir for 30min, cool down in an ice-water bath, add water to quench the strong stirring, separate the liquids, wash the organic phase with water, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a tan solid (16.20 g).

Embodiment 2

[0041] 3-Ethoxy-3,5,9(11)-androstatriene-3,17-dione (IV)

[0042] Under nitrogen protection, add III (8.00g), THF, triethyl orthoformate, TsOH·H 2 O, stirred and reacted for 2h, added a small amount of triethylamine to the reaction solution, then added saturated aqueous sodium bicarbonate solution and stirred vigorously, extracted with ethyl acetate, washed the combined organic phase with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a reddish-brown solid (9.01g).

Embodiment 3

[0044] 3-keto-4,9(11)-diene-17β-hydroxypregna-21-carboxylate γ-lactone (V)

[0045] Install a dropping funnel and a nitrogen inlet tube on the 100mL three-necked bottle. Add 19 mL of dry dimethyl sulfoxide (DMSO) to the reaction flask, add 60% sodium hydride, and heat to 70° C. for 1 hour after the addition is complete. The cooled reaction solution was diluted with dry THF. Subsequently, the temperature of the reaction system was lowered to about -5°C, and then a solution of trimethylsulfide iodide dissolved in dry dimethyl sulfoxide was added dropwise. After stirring for a few minutes, a solution of 2.7 g of IV dissolved in THF was added dropwise. During the dropwise addition, keep the system temperature not higher than 0°C. After the dropwise addition was completed, the reaction was stirred at 0° C. for 2 hours and then raised to room temperature for 15 hours. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dr...

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Abstract

The invention provides a method for preparing a novel steroid aldosterone acceptor antagonist eplerenone. The method comprises the following steps: producing 9alpha-hydroxyandrostenedione (9alpha-OH-AD) through carrying out microbial conversion on a raw material androstenedione (4-AD), carrying out 17-keto epoxidation, condensation and carboxyl removal, introducing double bonds to 9(11) and 6(7), and carrying out 6(7) furanization, oxidation and esterification, and carrying out 9, 11 double bond epoxidation to generate eplerenone. The method which utilizes the cheap and easily available raw material and adopts a semisynthetic technology of microbial fermentation has the advantages of environmental protection, easy control of the operation, high yield, and low cost, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a novel steroidal aldosterone receptor antagonist eplerenone. Background technique [0002] Eplerenone (Eplerenone, formula I), its chemical name is 4-ene-9(11)α-epoxy-7α-methoxyformyl-3-ketone-androst-21,17-carboxylic acid ester. Its structural formula is as follows: [0003] [0004] Eplerenone is an oral highly selective aldosterone receptor antagonist, which can block the action of the renin-angiotensin-aldosterone system (RAAS), by competitively inhibiting the binding of aldosterone to mineralocorticoid receptors, antagonizing Aldosterone binds to mineralocorticoid receptors in epithelial (eg, kidney) and non-epithelial (eg, heart, blood vessels, and brain) tissues. Aldosterone induces renal sodium ion reabsorption by binding to mineralocorticoid receptors and possibly other mechanisms to increase blood pressure. Therefore, the main pharmacological effect of eplerenone is to reduce Na+ and fl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00
Inventor 方项张亚高崇谢军
Owner SHANGHAI SCIENPHARM CO LTD
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