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Preparation method of intermediate for preparing eplerenone

A technology for eplerenone and intermediates, which is applied in the field of preparation of intermediates for eplerenone, can solve problems such as being unsuitable for industrial production, and achieve the effects of avoiding product purification difficulties, simple method and improved yield.

Active Publication Date: 2008-02-13
湖南玉新药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The product must be obtained by column chromatography, so it is not suitable for industrial production

Method used

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  • Preparation method of intermediate for preparing eplerenone
  • Preparation method of intermediate for preparing eplerenone
  • Preparation method of intermediate for preparing eplerenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of 17β-hydroxy-7α-vinyl-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone:

[0032] Add anhydrous tetrahydrofuran 100mL, cuprous chloride (Fw: 99.01, 0.01g, 10mmol) in a dry 250mL three-neck flask equipped with a magnetic stirrer, a thermometer, and a constant pressure dropping funnel in sequence, and lower the temperature to -20°C. The tetrahydrofuran solution (2M, 50mL) of alkenylmagnesium chloride was slowly added dropwise to the system, and the dropwise addition was completed in about 5 minutes. After the dropwise addition was completed, the system was stirred at -20°C for 2 minutes, and then Δ 9(11) Kanrenone (Fw: 338.19, 3.38 g, 10 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, and transferred to a constant pressure dropping funnel. Decrease the temperature of the system to -50°C, and the Δ 9(11) - The kanrenone tetrahydrofuran solution was slowly added dropwise to the system, the reaction temperature was controlled at -50°C, an...

Embodiment 2

[0035] Preparation of 17β-hydroxy-7α-vinyl-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone:

[0036] Add anhydrous diethyl ether 100mL, anhydrous copper acetate (Fw: 181.63, 0.018g, 10mmol) in a dry 250mL three-necked flask equipped with a magnetic stirrer, a thermometer, and a constant pressure dropping funnel in sequence, and maintain the temperature at 20°C. Alkenylmagnesium chloride tetrahydrofuran solution (2M, 60mL) was added to the system all at once. After the dropwise addition was completed, the system was stirred at 20°C for 5 minutes, and then Δ 9(11 )-Kanrenone (Fw: 338.19, 3.38g, 10mmol) was dissolved in 15mL of anhydrous ether, and transferred to a constant pressure dropping funnel. Decrease the temperature of the system to 0°C, and the Δ 9(11) - The ether solution of kanrenone was slowly added dropwise to the system, the reaction temperature was controlled at 0°C, and the dropwise addition was completed in about 5 minutes. After the dropwise addit...

Embodiment 3

[0039] Preparation of 17β-hydroxy-7α-carboxy-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone:

[0040] The 17β-hydroxyl-7α-vinyl-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone (Fw: 366.49, 10g , 27.3mmol), dissolved in 100mL of dichloromethane, then the system temperature was lowered to -78°C, the mixed gas of ozone and oxygen was slowly introduced into the system, and the reaction temperature was kept at -78°C. After the system turns blue, stop the introduction of ozone. Then the temperature of the system was raised to -10°C, and peracetic acid (Fw: 76.05, 3.11g, 41.0mmol) was diluted in 10mL of dichloromethane, and then slowly added dropwise to the system, the temperature was kept at -3°C, about 30 Minutes dropwise completed. After the dropwise addition was complete, the system was warmed up to room temperature, and stirring was continued for 20 hours. Subsequently, saturated sodium thiosulfate aqueous solution was added dropwise to the system unt...

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Abstract

The invention provides a preparation method of the 17 beta- hydroxy-7alpha-carboxyl-3- oxo-17alpha-pregna-4, 9(11)-diene-21-carboxylic acid-gamma-lactone; the starting material of the invention is delta9 (11)- risperidone; with the use of the CuB or CuB2, the starting material reacts with the alkenyl halogenated magnesium; then with the solvent, the mixture of the ozone and oxygen takes part in the reaction; the peracid is added in, then the target product can be collected from the reaction products. The invention can get the product of the higher purity with a higher collection rate and a higher selectivity; the method is simple and safe; the purification is convenient; the invention greatly lowers the production cost. The environmental pollution is little and thus the invention facilitates the implementation of the industrialization.

Description

technical field [0001] The invention relates to an important intermediate for preparing eplerenone 17β-hydroxyl-7α-carboxy-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone Methods. Background technique [0002] English common name of eplerenone: Eplerenone; English chemical name: 9(11)α-epoxy-17β-hydroxy-7α-carbomethoxy-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (Formula 1). [0003] Eplerenone is mainly used for heart failure after myocardial infarction in essential hypertension, and its main mechanism of action is to block aldosterone in the renin-angiotensin-aldosterone system (RAAS) by binding to aldosterone receptors. Thereby play the role of lowering blood pressure. It can be esterified and epoxidized from 17β-hydroxy-7α-carboxy-3-oxo-17α-pregna-4,9(11)-diene-21-carboxylic acid-γ-lactone (Formula 2) obtained by a two-step reaction. [0004] [0005] At present, existing technologies, such as U.S. Patent US6180780, provide a method for preparing ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/34C07D307/94
Inventor 刘喜荣申玉良谢来宾何辉贤
Owner 湖南玉新药业有限公司
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