Method for preparing eplerenone

A technology of eplerenone and inhibitor is applied in the new preparation field of antihypertensive drug eplerenone, can solve the problems of controlling below 0.2%, unsuitable for large-scale production, not mentioned, etc., and the method is simple and feasible Effect

Active Publication Date: 2010-10-20
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In US6887991, there is no mention of how to purify and remove related impurities, while US2008 / 0234478A1 provides a clear method, that is, to form derivatives by acetic anhydride esterification, and then remove impurities by recrystallization, but the yield of this treatment method is only About 40%, and its single impurity is only controlled below 0.2%
Not suitable for large-scale production

Method used

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  • Method for preparing eplerenone
  • Method for preparing eplerenone
  • Method for preparing eplerenone

Examples

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Embodiment 1

[0034] In a 250ml three-necked bottle with mechanical stirring and a thermometer, add 200ml of dichloromethane, 8.5g of dipotassium hydrogen phosphate, 15ml of trichloroacetonitrile, 1.5g of urea, dropwise add 75g of 30% hydrogen peroxide at room temperature, and heat the mixture under reflux for 4 hours. Cool to 30°C, then add 17α-hydroxyl-3-keto-γ-lactone-pregna-4,9(11)-diene-7α,21-dicarboxylate (formula IV) 10g, at 35 Heat the reaction at ~40°C, and then add 2ml of trichloroacetonitrile after 12 hours until the reaction is complete as detected by TLC. Separate the organic layer, back-extract the aqueous layer with 20ml of dichloromethane, combine the dichloromethane layers, wash with 3% sodium metabisulfite until non-oxidizing, and then wash with 100ml of water, dry the organic layer under reduced pressure, add 60ml of acetone to crystallize and filter, The crude product of eplerenone was obtained, and then recrystallized with methyl ethyl ketone to obtain 8.7 g of finished...

Embodiment 2

[0036] In a 250ml three-necked bottle with mechanical stirring and a thermometer, add 200ml of dichloromethane, 8.5g of dipotassium hydrogen phosphate, 15ml of trichloroacetonitrile, 0.75g of urea, dropwise add 75g of 30% hydrogen peroxide at room temperature, and heat the mixture under reflux for 4 hours. Cool to 30°C, then add 17α-hydroxyl-3-keto-γ-lactone-pregna-4,9(11)-diene-7α,21-dicarboxylate (formula IV) 10g, at 35 Heat the reaction at ~40°C, and add 2ml of trichloroacetonitrile after 12 hours until the reaction is complete as detected by TLC. Separate the organic layer, back-extract the aqueous layer with 20ml of dichloromethane, combine the dichloromethane layers, wash with 3% sodium metabisulfite until non-oxidizing, and then wash with 100ml of water, dry the organic layer under reduced pressure, add 60ml of acetone to crystallize and filter, The crude product of eplerenone was obtained, and then recrystallized with acetone to obtain 7.6 g of finished eplerenone with...

Embodiment 3

[0038] Add 200ml of dichloromethane, 8.5g of dipotassium hydrogen phosphate, 15ml of trichloroacetonitrile, 1.5g of thiourea into a 250ml three-neck flask with mechanical stirring and a thermometer, add 75g of 30% hydrogen peroxide dropwise at room temperature, and heat the mixture under reflux for 4 hours , cooled to 30°C, then added 17α-hydroxyl-3-keto-γ-lactone-pregna-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester (formula IV) 10g, in Insulate the reaction at 35-40°C, and add 2ml of trichloroacetonitrile after 12 hours until the reaction is complete as detected by TLC. Separate the organic layer, back-extract the aqueous layer with 20ml of dichloromethane, combine the dichloromethane layers, wash with 3% sodium metabisulfite until non-oxidizing, and then wash with 100ml of water, dry the organic layer under reduced pressure, add 60ml of acetone to crystallize and filter, The crude product of eplerenone was obtained, and then recrystallized with butanone to obtain 8.2 g ...

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Abstract

The invention provides a method for preparing eplerenone, which comprises the following steps of: (1) in a solvent, in the presence of a secondary reaction inhibitor, in a buffer system of trichlormethyl eyanide, an oxidizing agent and phosphate, performing double bond selective epoxidation on 17 alpha-hydroxy-3-keto-gamma-lactone-pregna-4,9(11)-diene-7 alpha,21-dicarboxylicacid methyl ester IV to prepare crude eplerenone; and (2) recrystallizing the crude eplerenone to obtain quality eplerenone. The high-purity eplerenone can be prepared by the method, the purity reaches 99.5 percent, the yield reaches 87 percent, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a new preparation method of antihypertensive drug eplerenone. Background technique [0002] Eplerenone, English chemical name: [0003] (7α, 11α, 17α)-9, 11-epoxy-17-hydroxy-3-oxo-pregn-4-ene-7, 21-dicarboxylic acid, γ-lactone, 7-methyl ester, is an antihypertensive medicine. It is mainly used to treat heart failure after myocardial infarction caused by essential hypertension. Its mechanism of action is to block aldosterone in the renin-angiotensin-aldosterone system by binding to aldosterone receptors, thereby lowering blood pressure. [0004] [0005] Eplerenone [0006] The existing preparation method of eplerenone generally takes trienone (formula I) as raw material, reacts with diethylaluminum cyanide or sodium cyanide to generate 7-CN (formula II), and then obtains through reduction oxidation reaction 7-COOH (formula III), formula III is methylated to obtain formula IV, and the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00C07J21/00A61P9/12A61P9/04
CPCC07J71/0015C07J21/003A61P9/04A61P9/12
Inventor 褚定军洪香仙
Owner AURISCO PHARMACEUTICAL CO LTD
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