CN104725461A - Preparation method of eplerenone - Google Patents
Preparation method of eplerenone Download PDFInfo
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- CN104725461A CN104725461A CN201510155345.9A CN201510155345A CN104725461A CN 104725461 A CN104725461 A CN 104725461A CN 201510155345 A CN201510155345 A CN 201510155345A CN 104725461 A CN104725461 A CN 104725461A
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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Abstract
The invention belongs to the medical field, and particularly relates to a preparation method of eplerenone. The preparation method comprises the following steps: in the presence of phosphorous pentachloride and boron trihalide, performing dehydration reaction on 17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid-11alpha,17beta-dihydroxy-3-oxo-gamma-lactone-7-methyl ester used as an initial raw material to obtain 17alpha-pregn-4,9(11)-diene-7alpha,21-dicarboxylic acid-17beta-hydroxyl-3-oxo-gamma-lactone and 7-methyl ester; and performing epoxidation reaction on the 17alpha-pregn-4,9(11)-diene-7alpha,21-dicarboxylic acid-17beta-hydroxyl-3-oxo-gamma-lactone and 7-methyl ester to obtain the eplerenone. The preparation method has specificity, and reduces generation of foreign matters; the obtained product is favorable in quality and high in yield, and the product purity is up to 99.5% or above; and the preparation method has the advantages of accessible raw materials, simple operation and mild reaction conditions, and is easy to implement industrial production.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of preparation method of eplerenone.
Background technology
Eplerenone obtains U.S. FDA approval on September 27th, 2002 with new molecular entity, on January 31st, 2004 in U.S.'s Initial Public Offering, and trade(brand)name Inspra; Listing preparation is tablet, and specification is every sheet 25mg, 50mg, 100mg.Now in Germany, UK and USA listing.Generic drug in 2008 to get the Green Light listing in the U.S..Current domestic enterprise has started to declare by chemical drug 3.1 class, and formulation has capsule and tablet.
Eplerenone by being combined the effect of the aldosterone blocked in renin-angiotensin-aldosterone system (RAAS) with aldosterone receptor, thus plays the effect reduced blood pressure.In 2003, U.S. FDA have approved again the new indication of congestive heart failure after eplerenone treatment acute myocardial infarction, and clinical research confirmation eplerenone is for Assessment of Left Ventricular Systolic Function abnormal (cardiac ejection fraction≤40%) after improving acute myocardial infarction and have the survival rate of the stable patient of the clinical foundation of congestive heart failure to have fine effect.Therefore, exploitation eplerenone oral preparations will provide more preferably treatment means for numerous doctors and patient behind Discussion on Chinese Listed, create considerable Social benefit and economic benefit.
17 beta-hydroxy-3-oxy--17 α-pregnant steroids-4, 6-diene-21-carboxylic acid-gamma lactone (i.e. compound 8, be called for short canrenone) be the intermediate producing spironolactone, the production history of existing many decades both at home and abroad, technique is very ripe, production cost is low, and in canrenone molecule, introduce C-11 α hydroxyl generate 11 Alpha-hydroxy-17 beta-hydroxy-3-oxy--17 α-pregnant steroids-4, 6-diene-21-carboxylic acid-gamma lactone (i.e. compound 7, be called for short 11 Alpha-hydroxy canrenones) microbial strains, more common, productive rate is high, so in numerous eplerenones synthesis document, mostly 11-hydroxy-canrenone (compound 7) is adopted to be starting raw material or intermediate, operational path is as follows:
With 11-hydroxy-canrenone (compound 7) for starting raw material, 5 ' R (5 ' α) is obtained by reacting with sodium cyanide, 7 ' β-20 '-amino 16 hydrogen-11 ' beta-hydroxy-10 ' α, 13 ' alpha-alpha-dimethyl-3 ', 5-dioxo spiral shell [furans-2 (3H), 17 ' α (5 ' H)-[7, 4] methane [4H] pentamethylene [α] is luxuriant and rich with fragrance]-5 '-nitrile (i.e. compound 6, be called for short enamine), enamine is converted into 4 ' S (4 ' α) again with hydrochloric acid reaction, 7 ' α-20 '-ten six hydrogen-11 ' Alpha-hydroxy-10 ' β, 13 ' beta-dimethyl--3 ', 5, 20 '-trioxy-spiral shell [furans-2 (3H), 17 ' β-[4, 7] methane [17H] pentamethylene [α] is luxuriant and rich with fragrance]-5 ' β (2 ' H)-nitrile (i.e. compound 5, be called for short diketone).Then, under sodium methylate condition, there is open loop eliminative reaction and obtain 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (i.e. compound 4).
For the preparation of compound 2; technique in existing document is: compound 4 first reacts with methylsulfonyl chloride and triethylamine makes 17 Alpha-hydroxy-11 α-pregnant steroid of (methyl sulphonyl) oxygen base-3-oxo-4-alkene-7 α; 21-dicarboxylic acid-gamma lactone-7-methyl esters (i.e. compound 3); then by methanesulfonates and formic acid, diacetyl oxide and potassium formiate or with acetic acid and sodium acetate reacting by heating, be prepared into compound 2.
For the operational path in existing document, We conducted verification experimental verification.Test-results shows: prepared in the operation of compound 2 by compound 3, the impurity of generation is very many, and the selectivity of reaction is very bad.Confirm after deliberation, the major impurity produced has 9 α, 17-dihydroxyl-3-oxo-17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid, two (gamma lactone) (i.e. compound 9, be called for short 7,9-lactone) and 17 beta-hydroxy-3-oxy--17 α-pregnant steroid-4,11 (12)-diene-7 α, 21-dicarboxylic acid-gamma lactone, (i.e. compound 10 is called for short Δ to 7-methyl esters
11,12-alkene), its structure is as follows:
For the preparation of compound 2, document is also had to adopt single stage method.Namely by 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4), phosphorus pentachloride one step Dehydration is adopted to obtain 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2), but temperature of reaction needs to control under-78 DEG C of conditions, therefore this operational path do not possess on a large scale yet, the condition of suitability for industrialized production.
At epoxidation process, namely by 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) is prepared in the operation of eplerenone, and existing document adopts Trichloroacetonitrile, dipotassium hydrogen phosphate and hydrogen peroxide.We have also carried out verification experimental verification, and test-results shows: reaction solution color is partially dark, and then causes the outward appearance of finished product bad.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of preparation method of eplerenone, product yield is high, quality good, be easy to realize suitability for industrialized production.
The preparation method of eplerenone of the present invention, with 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) is starting raw material, dehydration reaction is there is under the effect of phosphorus pentachloride and boron trihalides, obtain 17 α-pregnant steroid-4, 9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2), 17 α-pregnant steroid-4, 9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) obtains eplerenone through epoxidation reaction.Its reaction process is:
Adopt phosphorus pentachloride and boron trihalides as catalyzer, avoid the condition of ultralow temperature (-78 DEG C) of prior art, the more important thing is adding of boron trihalides promotor, improve the selectivity of reaction, decrease major impurity [7,9-lactone (compound 9) and Δ
11,12-alkene (compound 10)] generation.
Wherein,
The consumption of phosphorus pentachloride is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid-11 α, 0.5 ~ 2.0 times of 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) quality.
The consumption of boron trihalides is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid-11 α, 0.2 ~ 1.0 times of 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) quality.
Boron trihalides is boron trichloride or boron trifluoride.
The solvent of dehydration reaction is tetrahydrofuran (THF), and temperature of reaction is 0 ~ 10 DEG C.
17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) adopts Virahol to refine.
The oxygenant of epoxidation reaction is hydrogen peroxide, and Oxygen atom transfer agent is trichloroacetamide, and buffer reagent is potassium acetate.
The consumption of trichloroacetamide is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 0.5 ~ 3.0 times of 7-methyl esters (compound 2) quality, the consumption of potassium acetate is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 0.1 ~ 1.0 times of 7-methyl esters (compound 2) quality.
Adopt potassium acetate to make buffer reagent, reaction system very slight color, and then make the color and luster of finished product be white crystals, good product quality, and potassium acetate is as buffer reagent environmental protection.
The solvent of epoxidation reaction is methylene dichloride, and temperature of reaction is 0 ~ 30 DEG C.
Eplerenone adopts acetone or butanone to refine.
Compared with prior art, the present invention has following beneficial effect:
(1) preparation method of the present invention has specificity, decreases the generation of impurity, and products obtained therefrom quality is good, yield is high, and product purity reaches more than 99.5%.
(2) the present invention's agents useful for same environmental protection in epoxidation process, environmental sound.
(3) preparation method of the present invention is simple to operate, and reaction conditions is gentle, is easy to realize suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
The all raw materials used in embodiment, except specified otherwise, are commercial.
Embodiment 1
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α is prepared, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2):
17 α-pregnant steroid-4-alkene-7 α is dropped in four mouthfuls of reaction flasks, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) 20g and tetrahydrofuran (THF) 150mL, be cooled to 10 DEG C, stir the dichloromethane solution 90mL (amounting to boron trichloride 10.55g) dripping boron trichloride in downhill reaction bottle, within 30 minutes, drip off.Then, reaction solution is down to 10 DEG C, adds phosphorus pentachloride 12g, continue stirring reaction, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Be cooled to 0 DEG C, slowly add deionized water 60mL, adition process controls reacting liquid temperature and is no more than 20 DEG C.Stir after 10 minutes, add methylene dichloride 250mL, continue stirring 10 minutes.Separatory, point water-yielding stratum, dichloromethane layer washes 3 times, saturated common salt water washing 2 times successively with water.Add anhydrous sodium sulfate drying 1 hour, press filtration, washed with dichloromethane filter cake, concentrated filtrate, obtains yellow oil.
In above-mentioned yellow oil, add Virahol 40mL, heating is cooled to room temperature after oily matter is dissolved, and separates out faint yellow solid.Then, be cooled to 5 DEG C, filter after 1 hour, and use washed with isopropyl alcohol filter cake.At 55 DEG C, drying 5 hours, obtains 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 13.6g, yield 71.0%, content 96.0%.
(2) eplerenone is prepared:
Methylene dichloride 250mL is added in four mouthfuls of reaction flasks, 17 α-pregnant steroid-4 is added again under stirring, 9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 16g and Potassium ethanoate 4g, stir and make it dissolve.Then be cooled to 0 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Dropwise, be warming up to 12 DEG C, continue stirring reaction, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Stratification, water layer is with dichloromethane extraction (50mL × 2), and combined dichloromethane layer, uses 3% sodium sulfite solution (25mL × 2), cold 1N sodium hydroxide, 3% dilute hydrochloric acid, water and saturated common salt water washing successively, add anhydrous Na
2sO
4dry 1 hour, suction filtration removing filter cake, concentrated filtrate, obtains white solid.
In above-mentioned white solid, add acetone 160mL, stir intensification and make dissolution of solid.After solid is entirely molten, normal pressure concentrates, and after steaming the acetone of 55%, stops concentrated.Stir Temperature fall to 25 DEG C, be cooled to 5 DEG C of maintenances with icy salt solution and filter after 1 hour, and use washing with acetone filter cake.At 90 DEG C, drying 4 hours, obtains eplerenone 19.4g, yield 83.6%, content 99.5%.
Embodiment 2
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α is prepared, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2):
17 α-pregnant steroid-4-alkene-7 α is dropped in four mouthfuls of reaction flasks, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) 20g and tetrahydrofuran (THF) 150mL, be cooled to 0 DEG C, stir lower diethyl ether solution (the amounting to boron trifluoride 6.2g) 25mL inwardly dripping boron trifluoride.Dropwise, reacting liquid temperature is down to 0 DEG C, add phosphorus pentachloride 30g, continue stirring 10 minutes, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Reaction terminates, and is cooled to 0 DEG C, slowly adds deionized water 60mL, and adition process controls reacting liquid temperature and is no more than 20 DEG C.Stir after 10 minutes, add methylene dichloride 250mL, continue stirring 10 minutes.Then divide water-yielding stratum, dichloromethane layer washes 3 times, saturated common salt water washing 2 times successively with water.Add anhydrous sodium sulfate drying 1 hour, press filtration, use washed with dichloromethane filter cake, concentrated filtrate, obtain yellow oil.
In above-mentioned yellow oil, add Virahol 40mL, heating makes oily matter dissolve, and stops heating, naturally cools to room temperature, separates out faint yellow solid.Be cooled to 5 DEG C, filter after 1 hour, and use washed with isopropyl alcohol filter cake.At 55 DEG C, drying 5 hours, obtains 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 17.4g, yield 90.9%, content 98.0%.
(2) eplerenone is prepared:
Methylene dichloride 250mL is added in four mouthfuls of reaction flasks, 17 α-pregnant steroid-4 is added again under stirring, 9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 30g and Potassium ethanoate 15g, stir and make it dissolve.Then be cooled to 20 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Dropwise, be warming up to 27 DEG C, continue stirring reaction, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Stratification, water layer is with dichloromethane extraction (50mL × 2), and combined dichloromethane layer, uses 3% sodium sulfite solution (25mL × 2), cold 1N sodium hydroxide, 3% dilute hydrochloric acid, water and saturated common salt water washing successively, add anhydrous Na
2sO
4dry 1 hour, suction filtration removing filter cake, concentrated filtrate, obtains white solid.
In above-mentioned white solid, add butanone 160mL, stir intensification and make dissolution of solid.After solid is entirely molten, normal pressure concentrates, and after steaming the butanone of 55%, stops concentrated.Stir Temperature fall to 20 DEG C, be cooled to 0 DEG C of maintenance with icy salt solution and filter after 1 hour, and use butanone washing leaching cake.At 90 DEG C, drying 4 hours, obtains eplerenone 18.7g, yield 89.9%, content 99.6%.
Embodiment 3
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α is prepared, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2):
17 α-pregnant steroid-4-alkene-7 α is dropped in four mouthfuls of reaction flasks, 21-dicarboxylic acid-11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters (compound 4) 20g and tetrahydrofuran (THF) 150mL, be cooled to 5 DEG C, stir lower dichloromethane solution (the amounting to boron trichloride 16.0g) 136mL inwardly dripping boron trichloride.Dropwise, reacting liquid temperature is down to 5 DEG C, add phosphorus pentachloride 16g, continue stirring 10 minutes, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Reaction terminates, and is cooled to 0 DEG C, slowly adds deionized water 60mL, and adition process controls reacting liquid temperature and is no more than 20 DEG C.Stir after 10 minutes, add methylene dichloride 250mL, continue stirring 10 minutes.Then divide water-yielding stratum, dichloromethane layer washes 3 times, saturated common salt water washing 2 times successively with water.Add anhydrous sodium sulfate drying 1 hour, press filtration, with appropriate washed with dichloromethane filter cake, concentrated filtrate, obtains yellow oil.
In above-mentioned yellow oil, add Virahol 40mL, heating makes oily matter dissolve, and stops heating, naturally cools to room temperature, separates out faint yellow solid.Be cooled to 5 DEG C, filter after 1 hour, and use washed with isopropyl alcohol filter cake.At 55 DEG C, drying 5 hours, obtains 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 14.1g, yield 73.6%, content 96.4%.
(2) eplerenone is prepared:
Methylene dichloride 250mL is added in four mouthfuls of reaction flasks, 17 α-pregnant steroid-4 is added again under stirring, 9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 48g and Potassium ethanoate 18g, stir and make it dissolve.Then be cooled to 10 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Dropwise, be warming up to 15 DEG C, continue stirring reaction, TLC detection reaction situation, disappear to raw material spot, stopped reaction.
Stratification, water layer is with dichloromethane extraction (50mL × 2), and combined dichloromethane layer, uses 3% sodium sulfite solution (25mL × 2), cold 1N sodium hydroxide, 3% dilute hydrochloric acid, water and saturated common salt water washing successively, add anhydrous Na
2sO
4dry 1 hour, suction filtration removing filter cake, concentrated filtrate, obtains white solid.
In above-mentioned white solid, add butanone 160mL, stir intensification and make dissolution of solid.After solid is entirely molten, normal pressure concentrates, and after steaming the butanone of 55%, stops concentrated.Stir Temperature fall to 20 DEG C, be cooled to 0 DEG C of maintenance with icy salt solution and filter after 1 hour, and use butanone washing leaching cake.At 90 DEG C, drying 4 hours, obtains eplerenone 19.0g, yield 91.3%, content 99.7%.
Claims (10)
1. a preparation method for eplerenone, is characterized in that: with 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid
11 α, 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters is starting raw material, under the effect of phosphorus pentachloride and boron trihalides, there is dehydration reaction, obtain 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters, 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 7-methyl esters obtains eplerenone through epoxidation reaction.
2. the preparation method of eplerenone according to claim 1, is characterized in that: the consumption of phosphorus pentachloride is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid
11 α, 0.5 ~ 2.0 times of 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters quality.
3. the preparation method of eplerenone according to claim 1, is characterized in that: the consumption of boron trihalides is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acid
11 α, 0.2 ~ 1.0 times of 17 beta-dihydroxyl-3-oxos-gamma lactone-7-methyl esters quality.
4. the preparation method of the eplerenone according to claim 1 or 3, is characterized in that: boron trihalides is boron trichloride or boron trifluoride.
5. the preparation method of eplerenone according to claim 1, is characterized in that: the solvent of dehydration reaction is tetrahydrofuran (THF), and temperature of reaction is 0 ~ 10 DEG C.
6. the preparation method of eplerenone according to claim 1, is characterized in that: 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, and 7-methyl esters adopts Virahol to refine.
7. the preparation method of eplerenone according to claim 1, is characterized in that: the oxygenant of epoxidation reaction is hydrogen peroxide, and Oxygen atom transfer agent is trichloroacetamide, and buffer reagent is potassium acetate.
8. the preparation method of eplerenone according to claim 7, it is characterized in that: the consumption of trichloroacetamide is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 0.5 ~ 3.0 times of 7-methyl esters quality, the consumption of potassium acetate is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acid-17 beta-hydroxy-3-oxy-s-gamma lactone, 0.1 ~ 1.0 times of 7-methyl esters quality.
9. the preparation method of eplerenone according to claim 1, is characterized in that: the solvent of epoxidation reaction is methylene dichloride, and temperature of reaction is 0 ~ 30 DEG C.
10. the preparation method of eplerenone according to claim 1, is characterized in that: eplerenone adopts acetone or butanone to refine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294805A (en) * | 2015-09-22 | 2016-02-03 | 江苏佳尔科药业集团有限公司 | Preparation method for eplerenone intermediate |
| CN110698529A (en) * | 2019-11-19 | 2020-01-17 | 湖南新合新生物医药有限公司 | Preparation method of eplerenone intermediate △ 9,11 alkenyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006032970A2 (en) * | 2004-09-09 | 2006-03-30 | Pharmacia Corporation | PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS |
| CN101967171A (en) * | 2010-09-24 | 2011-02-09 | 岳阳环宇药业有限公司 | Hydroxy removing process for eplerenone intermediate |
| CN103087139A (en) * | 2011-11-08 | 2013-05-08 | 中国科学院上海药物研究所 | Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof |
-
2015
- 2015-04-02 CN CN201510155345.9A patent/CN104725461B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006032970A2 (en) * | 2004-09-09 | 2006-03-30 | Pharmacia Corporation | PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS |
| CN101967171A (en) * | 2010-09-24 | 2011-02-09 | 岳阳环宇药业有限公司 | Hydroxy removing process for eplerenone intermediate |
| CN103087139A (en) * | 2011-11-08 | 2013-05-08 | 中国科学院上海药物研究所 | Canrenone derivative steroid compound, preparation method and application in eplerenone preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294805A (en) * | 2015-09-22 | 2016-02-03 | 江苏佳尔科药业集团有限公司 | Preparation method for eplerenone intermediate |
| CN110698529A (en) * | 2019-11-19 | 2020-01-17 | 湖南新合新生物医药有限公司 | Preparation method of eplerenone intermediate △ 9,11 alkenyl ester |
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