CN104725461B - The preparation method of eplerenone - Google Patents
The preparation method of eplerenone Download PDFInfo
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- CN104725461B CN104725461B CN201510155345.9A CN201510155345A CN104725461B CN 104725461 B CN104725461 B CN 104725461B CN 201510155345 A CN201510155345 A CN 201510155345A CN 104725461 B CN104725461 B CN 104725461B
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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 field of medicaments, be specifically related to the preparation method of a kind of eplerenone.With 17 α pregnant steroid 4 alkene 7 α, 21 dicarboxylic acids 11 α, 17 β dihydroxy 3 oxo gamma lactone 7 methyl esters are initiation material, dehydration is there is under the effect of phosphorus pentachloride and boron trihalides, obtain the 17 pregnant steroids of α 4,9 (11) diene 7 α, 21 dicarboxylic acids 17 β hydroxyl 3 oxo gamma lactones, 7 methyl esters, the 17 pregnant steroids of α 4,9 (11) diene 7 α, 21 dicarboxylic acids 17 β hydroxyl 3 oxo gamma lactones, 7 methyl esters obtain eplerenone through epoxidation reaction.This preparation method has selectivity, decreases the generation of impurity, and products obtained therefrom quality is good, yield is high, and product purity reaches more than 99.5%；Raw material is easy to get, simple to operate, and reaction condition is gentle, it is easy to accomplish industrialized production.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the preparation method of a kind of eplerenone.
Background technology
Eplerenone obtains U.S. FDA approval on September 27th, 2002 with new molecular entity, on January 31st, 2004 in the U.S.
Initial Public Offering, trade name Inspra；Listing preparation is tablet, and specification is every 25mg, 50mg, 100mg.In moral
State, Britain and U.S.'s listing.Generic drug in 2008 gets the Green Light listing in the U.S..Domestic enterprise has started to by chemical drug 3.1 at present
Class is declared, and formulation has capsule and tablet.
Eplerenone by being combined the aldosterone blocked in renin-angiotensin-aldosterone system (RAAS) with aldosterone receptor
Effect, thus play the effect that reduces blood pressure.In 2003, U.S. FDA have approved again eplerenone treatment Acute myocardial stalk
The new indication of after death congestive heart failure, clinical research confirmation eplerenone is received for left ventricle after improving acute myocardial infarction AMI
Contracting dysfunction (cardiac ejection fraction≤40%) and have the survival rate of stable patient of congestive heart failure clinic foundation to have very
Good effect.Therefore, exploitation eplerenone oral formulations will provide for numerous doctors and patient behind Discussion on Chinese Listed and more preferably treat
Means, create considerable Social benefit and economic benefit.
17 beta-hydroxy-3-oxy-17 α-pregnant steroid-4,6-diene-21-carboxylic acid-gamma lactone (i.e. compound 8 is called for short canrenone) is to produce spiral shell
The intermediate of lactone, has the production history of many decades both at home and abroad, and technique is highly developed, and production cost is low, and at canrenone
Molecule introduces C-11 α hydroxyl and generates 11 Alpha-hydroxy-17 beta-hydroxy-3-oxy-17 α-pregnant steroid-4,6-diene-21-carboxylic acid-gamma lactone (i.e.
Compound 7, is called for short 11 Alpha-hydroxy canrenones) microorganism fungus kind, relatively conventional, productivity is high, so at numerous eplerenones
In synthesis document, mostly using 11-hydroxy-canrenone (compound 7) is initiation material or intermediate, and process route is as follows:
With 11-hydroxy-canrenone (compound 7) as initiation material, react with Cymag and obtain 5 ' R (5 ' α), 7 ' β-20 '-amino ten hexahydros
-11 ' beta-hydroxy-10 ' α, 13 ' alpha-alpha-dimethyls-3 ', 5-dioxo spiral shell [furans-2 (3H), 17 ' α (5 ' H)-[7,4] methane [4H] pentamethylene [α] are luxuriant and rich with fragrance]-5 '-
Nitrile (i.e. compound 6 is called for short enamine), enamine is converted into 4 ' S (4 ' α), 7 ' α-20 '-ten hexahydro-11 ' Alpha-hydroxies again with hydrochloric acid reaction
-10 ' β, 13 ' beta-dimethyls-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 is called for short diketone).Then, under the conditions of sodium methoxide, occur open loop to eliminate and react to obtain 17 α-pregnant steroid-4-alkene-7 α, 21-
Dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters (i.e. compound 4).
For the preparation of compound 2, the technique in existing document is: compound 4 first react with mesyl chloride and triethylamine make 17 α-
Hydroxyl-11 α-(methyl sulphonyl) epoxide-3-oxo pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-gamma lactone-7-methyl esters (i.e. compound 3), then
By methanesulfonates and formic acid, acetic anhydride and potassium formate or add thermal response with acetic acid and sodium acetate, be prepared into compound 2.
For the process route in existing document, We conducted verification experimental verification.Result of the test shows: by compound 3 preparation
In the operation of compound 2, the impurity of generation is the most, and the selectivity of reaction is the most bad.Confirm after deliberation, the major impurity of generation
Have 9 α, 17-dihydroxy-3-oxo-17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids, double (gamma lactones) (i.e. compound 9 is called for short 7,9-lactone) and
17 beta-hydroxy-3-oxy-17 α-pregnant steroid-4,11 (12)-diene-7 α, 21-dicarboxylic acids-gamma lactones, (i.e. compound 10 is called for short 7-methyl esters
Δ11,12-alkene), its structure is as follows:
For the preparation of compound 2, document is also had to use one-step method.I.e. by 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 β-
Dihydroxy-3-oxo-gamma lactone-7-methyl esters (compound 4), uses the dehydration of phosphorus pentachloride one step to prepare 17 α-pregnant steroid-4,9 (11)-diene
-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound 2), but reaction temperature needs to control at-78 DEG C of bars
Under part, therefore this process route the most do not possess on a large scale, the condition of industrialized production.
At epoxidation process, i.e. by 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters
(compound 2) is prepared in the operation of eplerenone, and existing document is to use Tritox, dipotassium hydrogen phosphate and hydrogen peroxide.I
Be also carried out verification experimental verification, result of the test shows: reactant liquor color is partially deep, and then causes the outward appearance of finished product bad.
Summary of the invention
For the deficiencies in the prior art, it is an object of the invention to provide the preparation method of a kind of eplerenone, product yield is high, matter
Measure, it is easy to accomplish industrialized production.
The preparation method of eplerenone of the present invention, with 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxygen
Generation-gamma lactone-7-methyl esters (compound 4) is initiation material, and dehydration occurs under the effect of phosphorus pentachloride and boron trihalides,
Obtain 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters (compound 2), 17 α-pregnant steroid
-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters (compound 2) is through epoxidation reaction get Yi Pu
Profit ketone.Its course of reaction is:
Use phosphorus pentachloride and the boron trihalides as catalyst, it is to avoid the condition of ultralow temperature of prior art (-78 DEG C), prior
Be the addition of boron trihalides co-catalyst, improve the selectivity of reaction, decrease major impurity [7,9-lactones (compound 9) and
Δ11,12-alkene (compound 10)] generation.
Wherein,
The consumption of phosphorus pentachloride is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, and 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters (is changed
Compound 4) 0.5～2.0 times of quality.
The consumption of boron trihalides is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, and 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters (is changed
Compound 4) 0.2～1.0 times of quality.
Boron trihalides is boron chloride or boron trifluoride.
The solvent of dehydration is oxolane, and reaction temperature is 0～10 DEG C.
17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound 2) uses isopropyl
Alcohol refines.
The oxidant of epoxidation reaction is hydrogen peroxide, and Oxygen atom transfer agent is trichloroacetamide, and buffer is potassium acetate.
The consumption of trichloroacetamide is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters
0.5～3.0 times of (compound 2) quality, the consumption of potassium acetate is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 β-hydroxyls
Base-3-oxo-gamma lactone, 0.1～1.0 times of 7-methyl esters (compound 2) quality.
Use potassium acetate to make buffer, reaction system very slight color, and then to make the color and luster of finished product be white crystals, product matter
Measure, and, potassium acetate is as buffer environmental protection.
The solvent of epoxidation reaction is dichloromethane, and reaction temperature is 0～30 DEG C.
Eplerenone uses acetone or butanone to refine.
Compared with prior art, the method have the advantages that
(1) preparation method of the present invention has selectivity, decreases the generation of impurity, and products obtained therefrom quality is good, yield is high,
Product purity reaches more than 99.5%.
(2) present invention agents useful for same environmental protection in epoxidation process, environmental sound.
(3) preparation method of the present invention is simple to operate, and reaction condition is gentle, it is easy to accomplish industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described.
The all raw materials used in embodiment, in addition to specified otherwise, are commercial.
Embodiment 1
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone is prepared, 7-methyl esters (compound 2):
17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters is put in four mouthfuls of reaction bulbs
(compound 4) 20g and oxolane 150mL, is cooled to 10 DEG C, the dichloro of dropping boron chloride in stirring downhill reaction bottle
Dichloromethane 90mL (equivalent boron chloride 10.55g), drips off for 30 minutes.Then, reactant liquor is down to 10 DEG C, adds pentachloro-
Changing phosphorus 12g, continue stirring reaction, TLC detects response situation, disappears to raw material spot, stops reaction.
Being cooled to 0 DEG C, be slowly added to deionized water 60mL, adition process controls reacting liquid temperature less than 20 DEG C.Stirring 10
After minute, add dichloromethane 250mL, continue stirring 10 minutes.Separatory, separates water layer, and dichloromethane layer washes with water successively
Wash 3 times, saturated aqueous common salt wash 2 times.Add anhydrous sodium sulfate to be dried 1 hour, press filtration, dichloromethane washing filter cake, dense
Contracting filtrate, obtains yellow oil.
In above-mentioned yellow oil, add isopropanol 40mL, after heating makes grease dissolve, be cooled to room temperature, separate out faint yellow
Solid.Then, it is cooled to 5 DEG C, filters after 1 hour, and wash filter cake with isopropanol.At 55 DEG C be dried 5 hours, obtain 17 α-
Pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters (compound 2) 13.6g, yield 71.0%,
Content 96.0%.
(2) eplerenone is prepared:
In four mouthfuls of reaction bulbs, add dichloromethane 250mL, under stirring, add 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxyls
Acid-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 16g and potassium acetate 4g, stirring makes it
Dissolve.Then being cooled to 0 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Drip complete, be warming up to 12 DEG C,
Continuing stirring reaction, TLC detects response situation, disappears to raw material spot, stops reaction.
Stratification, water layer dichloromethane extracts (50mL × 2), and combined dichloromethane layer uses 3% sodium hydrogensulfite successively
Solution (25mL × 2), cold 1N NaOH, 3% watery hydrochloric acid, water and saturated aqueous common salt washing, add anhydrous Na2SO4It is dried 1
Hour, suction filtration removes filter cake, concentrates filtrate, obtains white solid.
Adding acetone 160mL in above-mentioned white solid, stirring intensification makes solid dissolve.After solid is the most molten, normal pressure concentrates,
After steaming the acetone of 55%, stop concentrating.Stirring is naturally cooling to 25 DEG C, filters after being cooled to 5 DEG C of holdings 1 hour with brine ice,
And wash filter cake with acetone.It is dried 4 hours at 90 DEG C, obtains eplerenone 19.4g, yield 83.6%, content 99.5%.
Embodiment 2
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone is prepared, 7-methyl esters (compound 2):
17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters is put in four mouthfuls of reaction bulbs
(compound 4) 20g and oxolane 150mL, is cooled to 0 DEG C, the diethyl ether solution (folding of stirring lower inwardly dropping boron trifluoride
Close boron trifluoride 6.2g) 25mL.Drip complete, reacting liquid temperature is down to 0 DEG C, add phosphorus pentachloride 30g, continue stirring
10 minutes, TLC detected response situation, disappeared to raw material spot, stopped reaction.
Reaction terminates, and is cooled to 0 DEG C, is slowly added to deionized water 60mL, and adition process controls reacting liquid temperature less than 20 DEG C.
After stirring 10 minutes, add dichloromethane 250mL, continue stirring 10 minutes.Then separating water layer, dichloromethane layer is successively
Wash with water 3 times, saturated aqueous common salt wash 2 times.Add anhydrous sodium sulfate to be dried 1 hour, press filtration, wash with dichloromethane
Filter cake, concentrated filtrate, obtain yellow oil.
Adding isopropanol 40mL in above-mentioned yellow oil, heating makes grease dissolve, and stops heating, naturally cools to room temperature,
Separate out faint yellow solid.It is cooled to 5 DEG C, filters after 1 hour, and wash filter cake with isopropanol.It is dried 5 hours at 55 DEG C,
17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters (compound 2) 17.4g, yield
90.9%, content 98.0%.
(2) eplerenone is prepared:
In four mouthfuls of reaction bulbs, add dichloromethane 250mL, under stirring, add 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxyls
Acid-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 30g and potassium acetate 15g, stirring makes it
Dissolve.Then being cooled to 20 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Drip complete, be warming up to 27 DEG C,
Continuing stirring reaction, TLC detects response situation, disappears to raw material spot, stops reaction.
Stratification, water layer dichloromethane extracts (50mL × 2), and combined dichloromethane layer uses 3% sodium hydrogensulfite successively
Solution (25mL × 2), cold 1N NaOH, 3% watery hydrochloric acid, water and saturated aqueous common salt washing, add anhydrous Na2SO4It is dried
1 hour, suction filtration removed filter cake, concentrates filtrate, obtains white solid.
Adding butanone 160mL in above-mentioned white solid, stirring intensification makes solid dissolve.After solid is the most molten, normal pressure concentrates,
After steaming the butanone of 55%, stop concentrating.Stirring is naturally cooling to 20 DEG C, filters after being cooled to 0 DEG C of holding 1 hour with brine ice,
And wash filter cake with butanone.It is dried 4 hours at 90 DEG C, obtains eplerenone 18.7g, yield 89.9%, content 99.6%.
Embodiment 3
(1) 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound are prepared
2):
17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters is put in four mouthfuls of reaction bulbs
(compound 4) 20g and oxolane 150mL, is cooled to 5 DEG C, the lower dichloromethane solution inwardly dripping boron chloride of stirring
(equivalent boron chloride 16.0g) 136mL.Drip complete, reacting liquid temperature is down to 5 DEG C, add phosphorus pentachloride 16g, continue
Continuous stirring 10 minutes, TLC detects response situation, disappears to raw material spot, stops reaction.
Reaction terminates, and is cooled to 0 DEG C, is slowly added to deionized water 60mL, and adition process controls reacting liquid temperature less than 20 DEG C.
After stirring 10 minutes, add dichloromethane 250mL, continue stirring 10 minutes.Then separating water layer, dichloromethane layer is successively
Wash with water 3 times, saturated aqueous common salt wash 2 times.Adding anhydrous sodium sulfate to be dried 1 hour, press filtration, with appropriate dichloromethane
Alkane washing filter cake, concentrated filtrate, obtain yellow oil.
Adding isopropanol 40mL in above-mentioned yellow oil, heating makes grease dissolve, and stops heating, naturally cools to room temperature,
Separate out faint yellow solid.It is cooled to 5 DEG C, filters after 1 hour, and wash filter cake with isopropanol.It is dried 5 hours at 55 DEG C,
17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters (compound 2) 14.1g, yield
73.6%, content 96.4%.
(2) eplerenone is prepared:
In four mouthfuls of reaction bulbs, add dichloromethane 250mL, under stirring, add 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxyls
Acid-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters (compound 2) 20g, trichloroacetamide 48g and potassium acetate 18g, stirring makes it
Dissolve.Then being cooled to 10 DEG C, drip 30% hydrogen peroxide 160mL, 45min adds.Drip complete, be warming up to 15 DEG C,
Continuing stirring reaction, TLC detects response situation, disappears to raw material spot, stops reaction.
Stratification, water layer dichloromethane extracts (50mL × 2), and combined dichloromethane layer is molten with 3% sodium hydrogensulfite successively
Liquid (25mL × 2), cold 1N NaOH, 3% watery hydrochloric acid, water and saturated aqueous common salt washing, add anhydrous Na2SO4It is dried 1 little
Time, suction filtration removes filter cake, concentrates filtrate, obtain white solid.
Adding butanone 160mL in above-mentioned white solid, stirring intensification makes solid dissolve.After solid is the most molten, normal pressure concentrates,
After steaming the butanone of 55%, stop concentrating.Stirring is naturally cooling to 20 DEG C, filters after being cooled to 0 DEG C of holding 1 hour with brine ice,
And wash filter cake with butanone.It is dried 4 hours at 90 DEG C, obtains eplerenone 19.0g, yield 91.3%, content 99.7%.
Claims (8)
1. the preparation method of an eplerenone, it is characterized in that: with 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters is initiation material, dehydration 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 acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters, 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactone, 7-methyl esters obtains eplerenone through epoxidation reaction；
Wherein:
The consumption of boron trihalides is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 0.2～1.0 times of 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters quality；
The oxidant of epoxidation reaction is hydrogen peroxide, and Oxygen atom transfer agent is trichloroacetamide, and buffer is potassium acetate.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: the consumption of phosphorus pentachloride is 17 α-pregnant steroid-4-alkene-7 α, 21-dicarboxylic acids-11 α, 0.5～2.0 times of 17 beta-dihydroxy-3-oxos-gamma lactone-7-methyl esters quality.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: boron trihalides is boron chloride or boron trifluoride.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: the solvent of dehydration is oxolane, and reaction temperature is 0～10 DEG C.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-gamma lactones, 7-methyl esters uses isopropanol to refine.
The preparation method of eplerenone the most according to claim 1, it is characterized in that: the consumption of trichloroacetamide is 17 α-pregnant steroid-4,9 (11)-diene-7 α, 21-dicarboxylic acids-17 beta-hydroxy-3-oxys-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 acids-17 beta-hydroxy-3-oxys-gamma lactone, 0.1～1.0 times of 7-methyl esters quality.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: the solvent of epoxidation reaction is dichloromethane, and reaction temperature is 0～30 DEG C.
The preparation method of eplerenone the most according to claim 1, it is characterised in that: eplerenone uses acetone or butanone to refine.
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| 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 |
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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 |
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