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Method for synthesizing eplerenone

A technology of eplerenone and ketone group is applied in the field of synthesizing steroidal antihypertensive drug eplerenone, and can solve the problems of high market price of canrenone, difficult process control, low reaction yield and the like, Achieve the effect of large industrial production value, easy control of process operation and high yield

Inactive Publication Date: 2008-12-10
JIANGSU CHUANGUO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above synthetic routes all use canrenone as the starting material, and the commercial price of canrenone is relatively expensive.
And above-mentioned synthesis method all is to introduce the lactone ring at position 17 first, and the lactone ring is all unstable under acidic and alkaline reaction conditions, easily causes reaction yield to be low, and process operation is difficult to control

Method used

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  • Method for synthesizing eplerenone
  • Method for synthesizing eplerenone
  • Method for synthesizing eplerenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 4-ene-11α-hydroxy-3,17-dione-androstane (II)

[0046] Under argon protection, 10.0 g of epicortisol was added to 400 ml of ethyl acetate, 40.0 g of manganese dioxide was added, and the mixture was heated to reflux for 3 hours. Filter while hot. After the filter cake was washed with 30 ml of ethyl acetate, 60 ml of ethyl acetate was added and the mixture was stirred and refluxed for 30 minutes. repeat. The obtained filtrates were combined and concentrated to dryness under reduced pressure to obtain 6.4 g of pale yellow crude product. The crude product was refluxed for half an hour by adding 10 ml of methanol, and crystallized by freezing. Filter and dry to obtain 5.0 g of product (II).

Embodiment 2

[0048] 3-Ethoxy-3,5(6)-diene-11α-hydroxy-17-one-androstane(III)

[0049] Under argon protection, 10.0 g of the compound of formula II was dissolved in 350 ml of dioxane, and then 34 ml of triethyl orthoformate, 0.6 g of p-toluenesulfonic acid and 10 ml of absolute ethanol were sequentially added. The reaction temperature was raised to 40°C, and the reaction was incubated for 1.5 hours. Followed by TLC (cyclohexane:ethyl acetate=3:1) until the reaction was complete, 140ml of saturated NaHCO was added rapidly 3 The solution terminates the reaction, the reaction solution is poured into 1 L of water, 300 ml of dichloromethane is added, stirred and left to separate layers. The separated aqueous phase was extracted with dichloromethane (50 x 3) to no product. The organic layers were combined, washed with saturated NaCl until neutral, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was concentrated to dryness to give a yellow solid. The crude product was purified by rec...

Embodiment 3

[0051] 4,6-Diene-11α-hydroxy-3,17-dione-androsta(IV)

[0052] 10.0 g of the compound of formula III was dissolved in 70 ml of acetone, stirred, and heated to 30-35°C. After all the solids were dissolved, 25 ml of water was added to separate out the solids, the temperature was lowered to 25-30° C., the reaction system was protected by argon gas, 8.0 g of tetrachlorobenzoquinone was added in the dark, and the reaction was maintained for about 1.5 hours. After the reaction was completed, it was poured into 210 ml of 10% NaOH solution and stirred for 0.5 hour. filter. The filter cake was washed with 50 ml of dichloromethane. The filtrates were combined and extracted with dichloromethane (50 ml x 4). The dichloromethane layer was successively washed with saturated Na 2 8 2 O 3 Aqueous solution and water wash. Anhydrous Na 2 SO 4 dry. filter. The filtrate was concentrated to dryness to obtain a yellow crude product. The crude product was purified with isopropyl ether to ...

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Abstract

The invention discloses a new method for synthesizing steroid drug eplerenone. A surface cortisol as a byproduct of hydrocortisone is used as a raw material to oxide 17-side chain into ketone; 5, 6-double bond is introduced by 3-one protection; 7-ester group is introduced by cyaniding; 11-hydroxy is eliminated and 9,11-double bond is introduced; 17-ketone group is subjected to epoxidation, condensation and decarboxylation; and finally, the 9,11-double bond is epoxidated to produce the eplerenone. The method has raw materials with cheap prices and available sources, the easy control of process operation, high yield and low cost and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a method for synthesizing steroid antihypertensive drug eplerenone. Background technique [0002] The chemical name of eplerenone is 4-ene-9α, 11α-epoxy 7α-methoxycarbonyl-3-keto-androst-21,17-carboxylic acid lactone, and the structural formula is as follows: [0003] [0004] Eplerenone is a selective aldosterone receptor antagonist (Aldosterone antagonist), which has the advantages of strong selectivity to aldosterone receptor, good antihypertensive effect, long-lasting effect, etc., and can reverse or reduce many adverse effects of aldosterone on cardiovascular . The current preparations of eplerenone include eplerenone tablets developed by Pfizer / Pharmacia, trade name Inspra, this product has a lower affinity for androgen and progesterone receptors than spironolactone, and has a negative impact on testicular function, ovulation or target Organ weight has no o...

Claims

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Application Information

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IPC IPC(8): C07J71/00C07J21/00
Inventor 李金亮赵楠
Owner JIANGSU CHUANGUO PHARMA CO LTD
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