Preparation method of eplerenone

A technology of eplerenone and oxo generation, which is applied in the field of medicine, can solve the problems of poor appearance of the final product and dark color of the reaction solution, and achieve the effects of easy industrial production, good product quality and mild reaction conditions

Active Publication Date: 2016-08-17
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

We have also conducted experiments to verify that the test results show that the color of the reaction solution is darker, which leads to poor appearance of the final product

Method used

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  • Preparation method of eplerenone
  • Preparation method of eplerenone
  • Preparation method of eplerenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Preparation of 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone, 7-methyl ester (compound 2):

[0035] Put 20g of 17α-pregn-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone-7-methyl ester (compound 4) into the four-necked reaction flask and tetrahydrofuran 150mL, lower the temperature to 10°C, add 90mL of boron trichloride in dichloromethane solution (equivalent to 10.55g of boron trichloride) dropwise into the reaction flask under stirring, and drop it in 30 minutes. Then, the reaction solution was lowered to 10° C., 12 g of phosphorus pentachloride was added, and the reaction was continued with stirring. The reaction was detected by TLC until the spots of the raw materials disappeared, and the reaction was stopped.

[0036] Cool down to 0°C, slowly add 60 mL of deionized water, and control the temperature of the reaction solution during the addition process to not exceed 20°C. After stirring for 10 minutes, 250 mL of d...

Embodiment 2

[0043] (1) Preparation of 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone, 7-methyl ester (compound 2):

[0044] Put 20g of 17α-pregn-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone-7-methyl ester (compound 4) into the four-necked reaction flask and 150 mL of tetrahydrofuran, cooled to 0°C, and 25 mL of boron trifluoride ether solution (equivalent to 6.2 g of boron trifluoride) was added dropwise with stirring. After the dropwise addition, the temperature of the reaction solution was lowered to 0° C., 30 g of phosphorus pentachloride was added, and the stirring was continued for 10 minutes. The reaction was detected by TLC until the spots of the raw materials disappeared, and the reaction was stopped.

[0045] After the reaction was completed, the temperature was lowered to 0°C, and 60 mL of deionized water was slowly added, and the temperature of the reaction solution was controlled not to exceed 20°C during the addition process....

Embodiment 3

[0052] (1) Preparation of 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone, 7-methyl ester (compound 2):

[0053] Put 20g of 17α-pregn-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone-7-methyl ester (compound 4) into the four-necked reaction flask and 150 mL of tetrahydrofuran, cooled to 5°C, and 136 mL of boron trichloride in dichloromethane solution (equivalent to 16.0 g of boron trichloride) was added dropwise with stirring. After the dropwise addition, the temperature of the reaction solution was lowered to 5° C., 16 g of phosphorus pentachloride was added, and the stirring was continued for 10 minutes. The reaction was detected by TLC until the spots of the raw materials disappeared, and the reaction was stopped.

[0054] After the reaction was completed, the temperature was lowered to 0°C, and 60 mL of deionized water was slowly added, and the temperature of the reaction solution was controlled not to exceed 20°C during the ad...

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Abstract

The invention belongs to the field of medicine, and in particular relates to a preparation method of eplerenone. Starting from 17α-pregna-4-ene-7α, 21-dicarboxylic acid-11α, 17β-dihydroxy-3-oxo-γ-lactone-7-methyl ester as starting materials, phosphorus pentachloride and Dehydration reaction occurs under the action of boron trihalide to obtain 17α-pregna-4,9(11)-diene-7α, 21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone, 7- Methyl ester, 17α-pregna-4,9(11)-diene-7α, 21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone, 7-methyl ester obtained by epoxidation Eplerenone. The preparation method has specificity, reduces the generation of impurities, and the obtained product has good quality and high yield, and the product purity reaches over 99.5%. The raw material is easy to obtain, the operation is simple, the reaction condition is mild, and industrial production is easy to realize.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of eplerenone. Background technique [0002] Eplerenone was approved by the U.S. FDA on September 27, 2002 as a new molecular entity, and was first listed in the U.S. on January 31, 2004, under the trade name Inspra; the listed preparations are tablets, and the specifications are 25mg and 50mg per tablet , 100 mg. Available now in Germany, UK and US. In 2008, the generic drug was approved for marketing in the United States. At present, domestic enterprises have begun to declare according to the 3.1 category of chemical drugs, and the dosage forms include capsules and tablets. [0003] Eplerenone blocks the action of aldosterone in the renin-angiotensin-aldosterone system (RAAS) by binding to aldosterone receptors, thereby exerting the effect of lowering blood pressure. In 2003, the U.S. FDA approved the new indication of eplerenone for the treatment of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00
CPCC07J71/0015
Inventor 商艳梅宋广慧郑忠辉徐玲
Owner SHANDONG XINHUA PHARMA CO LTD
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