107724-20-9

Basic information

• Product Name: Eplerenone
• Synonyms: pregn-4-ene-7,21-dicarboxylic acid 9,11-epoxy-17-hydroxy-3-oxo gamma-lactone methyl ester;EPLERENONE 98%;EPLERENONE USP STANDARD;Elperenone;EplerenoneC24H3006;pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo, γ-lactone, methyl ester (7 α, 11 α, 17 α);EPLERENONE AND N-1 INTERMEDIATE;epoxymexrenone
• CAS NO: 107724-20-9
• Molecular Formula: C₂₄H₃₀O₆
• Molecular Weight: 414.49
• EINECS: 1308068-626-2
• Product Categories: Antihypertensive;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Steroid and Hormone;Inspra;Cardiovascular APIs
• Mol File: 107724-20-9.mol

Chemical Properties

• Melting Point: 241-243°C
• Boiling Point: 597.933 °C at 760 mmHg
• Flash Point: 259.474 °C
• Appearance: white to beige/
• Density: 1.31 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.587
• Storage Temp.: Store at RT
• Solubility: DMSO: soluble2mg/mL, clear (warmed)
• Merck: 14,3625
• CAS DataBase Reference: Eplerenone(CAS DataBase Reference)
• NIST Chemistry Reference: Eplerenone(107724-20-9)
• EPA Substance Registry System: Eplerenone(107724-20-9)

Safety Data

• RIDADR: 3077
• WGK Germany: 3
• Hazardous Substances Data: 107724-20-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Eplerenone is used as an antihypertensive agent for the treatment of high blood pressure. It is used alone or in combination with other medications to manage hypertension by blocking the action of aldosterone.
Used in Cardiology:
Eplerenone is used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone but may be more specific for the mineralocorticoid receptor, making it a preferred choice in certain cases.
Used in Oncology:
Eplerenone is also used as an anticancer agent, exhibiting potential benefits in cancer treatment.
Chemical Properties:
Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility being essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.
Brand Name:
Inspra (Searle) is the brand name under which Eplerenone is marketed.

Pharmacodynamics

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

Biological activity

Eplerenone belongs to a class of drugs called aldosterone antagonists. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions. Eplerenone works by interfering with the activity of a steroid in your body called aldosterone. Aldosterone acts to increase the amount of sodium and water you retain. This increased sodium and water can cause high blood pressure, which can in turn cause heart failure.

Interactions

Eplerenone is primarily metabolized by the cytochrome P450 enzyme CYP3A4. Thus the potential exists for adverse drug interactions with other drugs that induce or inhibit CYP3A4. Specifically, the concomitant use of the CYP3A4 potent inhibitors ketoconazole and itraconazole is contraindicated. Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. Other drugs that increase potassium concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes, potassium supplements and other potassium-sparing diuretics.

Mechanism of action

Aldosterone,with many physiological and pathological effects, can cause central blood pressure and endothelial injury (catecholamines enhance its role), reduce heart rate variability, induce ventricular arrhythmias, and promote retention of sodium, potassium and magnesium loss, promote myocardial fibrosis, necrosis and inflammation, damage the fibrinolytic system. Angiotensin converting enzyme inhibitors (also called angiotensin converting enzyme inhibitors, referred to as ACEI) and angiotensin Ⅱ receptor antagonist ARB aldosterone can inhibit the secretion of adrenaline, but after a period of treatment.The release of aldosterone was restored,which may even exceed the baseline plasma concentration levels. Despite adequate treatment of ACEI and ARB, aldosterone-induced damage can still happen, so it is necessary to use aldosterone receptor antagonists in the treatment of hypertension. Clinical studies have shown that patients who are not satisfied with the efficacy of ACEI or ARB therapy can add eplerenone along with the treatment. Non-selective aldosterone receptor antagonist spironolactone can reduce mortality in patients with congestive heart failure, However, the side effects of male hyperplasia and other diseases associated with sex hormones have limited its application in the treatment of hypertension.

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, altered renal function, and increased creatinine concentration.

References

https://en.wikipedia.org/wiki/Eplerenone https://medlineplus.gov/druginfo/meds/a603004.html http://www.rxlist.com/inspra-drug.htm

Originator

Ciba-Geigy (Novartis) (US)

Biological Activity

Selective mineralocorticoid (aldosterone) receptor antagonist (IC 50 = 360 nM). Displays > 27-fold selectivity over androgen, progesterone and estrogen receptors (IC 50 > 10 μ M). Orally active antihypertensive in vivo .

Biochem/physiol Actions

Eplerenone is an aldosterone antagonist more specific for the mineralocorticoid receptor than spironolactone (S3378), having lower affinity for progesterone, androgen, and glucocorticoid receptors.

Clinical Use

A newer drug, eplerenone, has a structure similar to that of spironolactone and a similar mechanism of action. It was initially approved for use in the treatment of hypertension but it can now be used in the treatment of patients with left ventricular systolic dysfunction and congestive heart failure after myocardial infarction.

Drug interactions

Potentially hazardous interactions with other drugsACE inhibitors or AT-II antagonists: enhanced hypotensive effect; risk of severe hyperkalaemia.Anti-arrhythmics: concentration increased by amiodarone - reduce eplerenone dose.amiodarone - reduce eplerenone dose. Antibacterials: concentration increased by clarithromycin and telithromycin - avoid; concentration increased by erythromycin - reduce eplerenone dose; concentration reduced by rifampicin - avoid; avoid with lymecycline; increased risk of hyperkalaemia with trimethoprim.Antidepressants: concentration reduced by St John’s wort - avoid; increased risk of postural hypotension with tricyclics; enhanced hypotensive effect with MAOIs.Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, phenytoin, phenobarbital and primidone - avoid.Antifungals: concentration increased by itraconazole and ketoconazole - avoid; concentration increased by fluconazole - reduce eplerenone dose.Antihypertensives: enhanced hypotensive effect, increased risk of first dose hypotensive effect with post-synaptic alpha-blockers.Antivirals: concentration increased by ritonavir - avoid; concentration increased by saquinavir - reduce eplerenone doseCiclosporin: increased risk of hyperkalaemia and nephrotoxicityCytotoxics: increased risk of nephrotoxicity and ototoxicity with platinum compounds.NSAIDs: increased risk of hyperkalaemia (especially with indometacin); increased risk of nephrotoxicity; antagonism of diuretic effect.Potassium salts: increased risk of hyperkalaemia.Lithium: reduced lithium excretion - avoidTacrolimus: increased risk of hyperkalaemia and nephrotoxicity.CYP3A4 inhibitors: Do not exceed a dose of 25 mg daily for eplerenone.CYP3A4 inducers: reduced eplerenone concentration - avoid.

Metabolism

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma. Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and faeces. Following a single oral dose of radiolabelled drug, approximately 32% of the dose was excreted in the faeces and approximately 67% was excreted in the urine

InChI:InChI=1/C24H30O6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19H,4-9,11-12H2,1-3H3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1

Synthetic route

17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4) → eplerenone (107724-20-9)

Conditions	Yield
With dipotassium hydrogenphosphate; trichloroacetamide; dihydrogen peroxide In dichloromethane at 0 - 15℃; for 24h; pH=9;	98%
With trichloroacetamide; dihydrogen peroxide; potassium acetate In dichloromethane at 10 - 15℃; for 0.75h; Temperature;	91.3%
With potassium phosphate; trichloroacetamide; dihydrogen peroxide In dichloromethane at 20℃;	85.3%

methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone (192704-58-8) → eplerenone (107724-20-9)

Conditions	Yield
With dipotassium hydrogenphosphate; dihydrogen peroxide	82%
Multi-step reaction with 2 steps 1: potassium formate; formic acid / acetic anhydride / 100 °C 2: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme

methanol (67-56-1) + 4'S(4'α),7'α-hexadecahydro-11'α-hydroxy-10'β,13'β-dimethyl-3',5,20'-trioxospiro[furan-2(3H),17'β-[4,7]metheno(17H)cyclopenta[a]phenanthrene]-5'β(2'H)-carbonitrile (192704-54-4) + sodium methylate (124-41-4) → eplerenone (107724-20-9)

Conditions	Yield
Stage #1: methanol; 4'S(4'α),7'α-hexadecahydro-11'α-hydroxy-10'β,13'β-dimethyl-3',5,20'-trioxospiro[furan-2(3H),17'β-[4,7]metheno(17H)cyclopenta[a]phenanthrene]-5'β(2'H)-carbonitrile; sodium methylate for 20.25h; Heating / reflux; Stage #2: With hydrogenchloride In methanol; water Heating / reflux; Stage #3: With dipotassium hydrogenphosphate; formic acid; dihydrogen peroxide; potassium formate; acetic anhydride; methanesulfonyl chloride; triethylamine; trichloroacetonitrile more than 3 stages;	27.1%
Stage #1: methanol; 4'S(4'α),7'α-hexadecahydro-11'α-hydroxy-10'β,13'β-dimethyl-3',5,20'-trioxospiro[furan-2(3H),17'β-[4,7]metheno(17H)cyclopenta[a]phenanthrene]-5'β(2'H)-carbonitrile; sodium methylate at 67℃; for 16 - 20h; Stage #2: With methanesulfonyl chloride; triethylamine In dichloromethane at 0℃; for 0.75h; Stage #3: With dipotassium hydrogenphosphate; formic acid; dihydrogen peroxide; potassium formate; acetic anhydride; trichloroacetonitrile more than 3 stages;	7.2 g

methanol (67-56-1) + C24H27NO5 → eplerenone (107724-20-9)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene for 24h; Heating / reflux;	20%

Δ9(11)-canrenone (95716-71-5) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 82 g / AlEt3 / hexane; tetrahydrofuran / 0.5 h / Heating 2: 6.9 g / DIBAH / 1,2-dimethoxy-ethane; hexane / 2 h / 5 °C 3: 6.6 g / aq. CrO3, H2SO4 / acetone / 0.5 h / 5 °C 4: 2.7 g / CH2Cl2; diethyl ether / 0.17 h 5: 71.6 percent / aq. H2O2, (CCl3CO)2O / CH2Cl2 / 1.5 h / below 4 deg C View Scheme
Multi-step reaction with 5 steps 1.1: boron trifluoride diethyl etherate / tetrahydrofuran / -10 °C 2.1: N-Bromosuccinimide; potassium carbonate / tetrahydrofuran; water / 35 °C 3.1: ozone / dichloromethane; isopropyl alcohol / -20 °C 3.2: 20 °C 4.1: potassium hydrogencarbonate / tetrahydrofuran / 10 °C 5.1: dipotassium hydrogenphosphate; 2-chloro-2,2-difluoroacetamide; dihydrogen peroxide / toluene / 55 °C View Scheme

C23H30O4 (188988-15-0) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 6.6 g / aq. CrO3, H2SO4 / acetone / 0.5 h / 5 °C 2: 2.7 g / CH2Cl2; diethyl ether / 0.17 h 3: 71.6 percent / aq. H2O2, (CCl3CO)2O / CH2Cl2 / 1.5 h / below 4 deg C View Scheme

17β-hydroxy-7α-cyano-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone (95716-72-6) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 6.9 g / DIBAH / 1,2-dimethoxy-ethane; hexane / 2 h / 5 °C 2: 6.6 g / aq. CrO3, H2SO4 / acetone / 0.5 h / 5 °C 3: 2.7 g / CH2Cl2; diethyl ether / 0.17 h 4: 71.6 percent / aq. H2O2, (CCl3CO)2O / CH2Cl2 / 1.5 h / below 4 deg C View Scheme

17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone (95716-74-8) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.7 g / CH2Cl2; diethyl ether / 0.17 h 2: 71.6 percent / aq. H2O2, (CCl3CO)2O / CH2Cl2 / 1.5 h / below 4 deg C View Scheme

methanol (67-56-1) + C24H27NO5 + sodium methylate (124-41-4) → eplerenone (107724-20-9)

Conditions	Yield
for 23.5h; Heating / reflux;

17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4) → 7-methyl hydrogen 17-hydroxy-3,12-dioxo-17α-pregna-4,9(11)-diene-7α,21-dicarboxylate, γ-lactone + 7-methyl hydrogen 12α,17-dihydroxy-3-oxo-17α-pregna-4,9(11)-diene-7α,21-dicarboxylate, γ-lactone + 7-methyl hydrogen 4α,5α:9α,11α-diepoxy,17-hydroxy-3-oxo-17α-pregnane-7α,21-dicarboxylate, γ-lactone + 7-methyl hydrogen 9α,11β,17-trihydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylate, γ-lactone + eplerenone (107724-20-9)

Conditions	Yield
With dipotassium hydrogenphosphate; dihydrogen peroxide; trichloroacetonitrile In dichloromethane; water at 8 - 10℃; for 23h;	A n/a B 123 mg C n/a D 46.7 mg E 3.16 g

C23H28O6 → eplerenone (107724-20-9)

11β,17β-dihydroxy-7α-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (1398078-03-9) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid / N,N-dimethyl-formamide / 0.5 h / 45 °C 1.2: 4 h 2.1: potassium carbonate / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0 °C 4.1: potassium formate; formic acid / acetic anhydride / 100 °C 5.1: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium nitrite / N,N-dimethyl-formamide / 1.5 h / 45 °C 1.2: 4 h 2.1: potassium carbonate / acetone / 0 - 20 °C 3.1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 4.1: acetic anhydride; potassium formate; formic acid / 19 h / 70 - 100 °C / Inert atmosphere 5.1: dipotassium hydrogenphosphate; dihydrogen peroxide; trichloroacetamide / dichloromethane / 24 h / 0 - 15 °C / pH 9 View Scheme

11β,17β-dihydroxy-7β-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (1398078-09-5) → eplerenone (107724-20-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: potassium carbonate; benzalkonium chloride; nitromethane / N,N-dimethyl-formamide / 48 h / 90 °C 2.1: acetic acid / N,N-dimethyl-formamide / 0.5 h / 45 °C 2.2: 4 h 3.1: potassium carbonate / 0 - 20 °C 4.1: triethylamine / dichloromethane / 0 °C 5.1: potassium formate; formic acid / acetic anhydride / 100 °C 6.1: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme

11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (192704-56-6) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 °C 2: potassium formate; formic acid / acetic anhydride / 100 °C 3: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: sulfuryl dichloride; 1H-imidazole / tetrahydrofuran / 1.5 h / -10 - 20 °C 2: trichloroacetamide; disodium hydrogenphosphate; dihydrogen peroxide / dichloromethane / 18 h / 15 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 2: acetic anhydride; potassium formate; formic acid / 19 h / 70 - 100 °C / Inert atmosphere 3: dipotassium hydrogenphosphate; dihydrogen peroxide; trichloroacetamide / dichloromethane / 24 h / 0 - 15 °C / pH 9 View Scheme

9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid γ-lactone (209253-72-5) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / 0 - 20 °C 2: triethylamine / dichloromethane / 0 °C 3: potassium formate; formic acid / acetic anhydride / 100 °C 4: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 0 - 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C 3: acetic anhydride; potassium formate; formic acid / 19 h / 70 - 100 °C / Inert atmosphere 4: dipotassium hydrogenphosphate; dihydrogen peroxide; trichloroacetamide / dichloromethane / 24 h / 0 - 15 °C / pH 9 View Scheme

11α-hydroxyl canrenone (192569-17-8) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate; benzalkonium chloride / N,N-dimethyl-formamide / 48 h / 90 °C 2.1: acetic acid / N,N-dimethyl-formamide / 0.5 h / 45 °C 2.2: 4 h 3.1: potassium carbonate / 0 - 20 °C 4.1: triethylamine / dichloromethane / 0 °C 5.1: potassium formate; formic acid / acetic anhydride / 100 °C 6.1: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 °C 2.1: acetic acid / N,N-dimethyl-formamide / 0.5 h / 45 °C 2.2: 4 h 3.1: potassium carbonate / 0 - 20 °C 4.1: triethylamine / dichloromethane / 0 °C 5.1: potassium formate; formic acid / acetic anhydride / 100 °C 6.1: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 20 °C 2.1: potassium carbonate; benzalkonium chloride; nitromethane / N,N-dimethyl-formamide / 48 h / 90 °C 3.1: acetic acid / N,N-dimethyl-formamide / 0.5 h / 45 °C 3.2: 4 h 4.1: potassium carbonate / 0 - 20 °C 5.1: triethylamine / dichloromethane / 0 °C 6.1: potassium formate; formic acid / acetic anhydride / 100 °C 7.1: trichloroacetamide; dihydrogen peroxide; dipotassium hydrogenphosphate / dichloromethane / 10 - 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate; benzalkonium chloride / N,N-dimethyl-formamide / 48 h / 90 - 100 °C 2.1: sodium nitrite / N,N-dimethyl-formamide / 1.5 h / 45 °C 2.2: 4 h 3.1: potassium carbonate / acetone / 0 - 20 °C 4.1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 5.1: acetic anhydride; potassium formate; formic acid / 19 h / 70 - 100 °C / Inert atmosphere 6.1: dipotassium hydrogenphosphate; dihydrogen peroxide; trichloroacetamide / dichloromethane / 24 h / 0 - 15 °C / pH 9 View Scheme

9(11)-encanrenone (41850-21-9) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: boron trifluoride diethyl etherate / acetonitrile / 4 h / -25 - -20 °C / Inert atmosphere 2: potassium carbonate; 5,5-dibromohydantoin / tetrahydrofuran; water / 20 °C / Inert atmosphere 3: ozone / -50 °C 4: trichloroacetamide; potassium phosphate; dihydrogen peroxide / dichloromethane / 20 °C View Scheme

17β-hydroxy-7α-(5'-methyl-2'-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone (610785-40-5) → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate; 5,5-dibromohydantoin / tetrahydrofuran; water / 20 °C / Inert atmosphere 2: ozone / -50 °C 3: trichloroacetamide; potassium phosphate; dihydrogen peroxide / dichloromethane / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide; potassium carbonate / tetrahydrofuran; water / 35 °C 2.1: ozone / dichloromethane; isopropyl alcohol / -20 °C 2.2: 20 °C 3.1: potassium hydrogencarbonate / tetrahydrofuran / 10 °C 4.1: dipotassium hydrogenphosphate; 2-chloro-2,2-difluoroacetamide; dihydrogen peroxide / toluene / 55 °C View Scheme

7a-(1,4-dicarbonylpentenyl)-9(11)-encanrenone → eplerenone (107724-20-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ozone / dichloromethane; isopropyl alcohol / -20 °C 1.2: 20 °C 2.1: potassium hydrogencarbonate / tetrahydrofuran / 10 °C 3.1: dipotassium hydrogenphosphate; 2-chloro-2,2-difluoroacetamide; dihydrogen peroxide / toluene / 55 °C View Scheme

eplerenone (107724-20-9) → 9,11α-epoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, γ-lactone

Conditions	Yield
Stage #1: eplerenone With sodium hydroxide In water; acetonitrile at 25 - 90℃; for 66.67h; Heating / reflux; Stage #2: With sulfuric acid In water; acetonitrile	67%
Multi-step reaction with 2 steps 1: lithium hydroxide / water / 48 h 2: hydrogenchloride / water View Scheme

eplerenone (107724-20-9) → 9,11α-epoxy-7β-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone + 9,11α-epoxy-7-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone

Conditions	Yield
With sodium methylate In methanol for 24h; Reflux;	A 49% B 0.55 g

eplerenone (107724-20-9) → 9,11α-epoxy,17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, dipotassium salt

Conditions	Yield
With potassium hydroxide In 1,4-dioxane; water at 25 - 70℃; for 6h;	0.55 g

eplerenone (107724-20-9) → 9,11α-epoxy,17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, disodium salt

Conditions	Yield
With sodium hydroxide In methanol; water at 70℃; for 0.666667h;

eplerenone (107724-20-9) → 9,11α-epoxy-7β-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone

Conditions	Yield
With sodium methylate In methanol at 50 - 65℃; for 16.5h; Heating / reflux;	400 mg

orthoformic acid triethyl ester (122-51-0) + eplerenone (107724-20-9) → 7-methyl hydrogen 9,11α-epoxy-3-ethoxy-17-hydroxy-17α-pregn-4-ene-7α,21-dicarboxylate, γ-lactone

Conditions	Yield
Stage #1: orthoformic acid triethyl ester; eplerenone; toluene-4-sulfonic acid In ethanol at 20℃; for 0.5h; Stage #2: With pyridine; sodium acetate In ethanol	33.8 g

eplerenone (107724-20-9) → C47H42O10 (1621954-04-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium hydroxide / water / 48 h 2: hydrogenchloride / water 3: dmap; dicyclohexyl-carbodiimide View Scheme

eplerenone (107724-20-9) → C23H30O7 (1621954-05-9)

Conditions	Yield
With lithium hydroxide In water for 48h;

Upstream product

• 188988-15-0 C₂₃H₃₀O₄ 
• 95716-70-4 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester 
• 67-56-1 methanol 
• 192704-58-8 methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone 
• 610785-40-5 17β-hydroxy-7α-(5'-methyl-2'-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone 
• 41850-21-9 9⁽¹¹⁾-encanrenone 
• 192569-17-8 11α-hydroxyl canrenone 
• 209253-72-5 9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid γ-lactone 
• 192704-56-6 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone 
• 1398078-09-5 11β,17β-dihydroxy-7β-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone 
• 1398078-03-9 11β,17β-dihydroxy-7α-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone 
• 124-41-4 sodium methylate 
• 192704-54-4 4'S(4'α),7'α-hexadecahydro-11'α-hydroxy-10'β,13'β-dimethyl-3',5,20'-trioxospiro[furan-2(3H),17'β-[4,7]metheno(17H)cyclopenta[a]phenanthrene]-5'β(2'H)-carbonitrile 
• 95716-74-8 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone 

Relevant articles and documents

A diastereoselective synthesis of 7α-nitromethyl steroid derivative and its use for an efficient synthesis of eplerenone

A novel and efficient method of stereoselectively introducing α-nitromethyl group to C-7 position of 11α-hydroxyl canrenone 4 was described. In addition, this method was successfully applied in a total synthesis of Eplerenone 8. The route was characteristic of simple operation, moderate reaction conditions with 5 steps and 55% total yield, at the same time, without any expensive or toxic reagent in use.

Synthesis and physicochemical characterization of the process-related impurities of eplerenone, an antihypertensive drug

Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α) -9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone.

Preparation method of eplerenone with high efficiency and low pollution

The invention discloses a preparation method of eplerenone with high efficiency and low pollution, and belongs to the technical field of preparation and processing of steroid hormone drugs. The methodcomprises the steps: by taking a compound I, namely delta 9,11-canrenone, as an initial raw material, carrying out 7-furyl addition, furyl ring opening and lactonization cyclization reaction to obtain 5,7-lactone, and carrying out ring opening methylation and 9,11-double bond epoxidation reaction to obtain the eplerenone. According to the method, raw materials and reagents are cheap and easy to obtain, and the method has extremely high market competitiveness in equipment investment and production cost; reagents used in the method are low in environmental pollution, and particularly cyano-containing high-toxicity compounds are not used, so that the method is greener and more environment-friendly; the production process is easy to control, high in yield, low in cost and suitable for industrial production.

Method for synthesizing 7a-methyl formate-9(11)-encanrenone

The invention discloses a method for synthesizing 7a-methyl formate-9(11)-encanrenone. The method comprises the following steps: reacting 9(11)-encanrenone used as a raw material with 2-methylfuran atfirst, performing ring opening by using dibromohydantoin, rearranging, ozonizing, adding a metal reducing agent to methanol or a mixed solution of methanol and other solvent, and performing reducingesterification to directly obtain the 7a-methyl formate-9(11)-encanrenone. The method has the advantages of operation step simplification, high yield, simplicity in operation, few three wastes, and suitableness for industrial production.

A steroid compound derivative having, its preparation process and its use in the preparation of Eplerenone

The invention relates to a canrenone derivative steroid compound, a preparation method and an application in the medicine field, and particularly relates to 7alpha-nitro methyl-11alpha,17beta-dihydroxy-3-oxo-17alpha-pregna-4-ene-21-carboxylic acid-gamma-lactone (a compound shown in formula 2), a preparation method and an application in eplerenone preparation. The key steps of the invention are that nitromethane is used as a nucleophilic reagent; the alpha-nitro methyl group is introduced to the C-7 position stereoselectively so as to further construct a carboxylic acid methyl ester structure with a C-7alpha position configuration of eplerenone; the method of the invention has the characteristics of short steps, mild conditions, and low cost.

Process for the preparation of Eplerenone

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.

A chemobiological synthesis of eplerenone

This paper will describe an approach to the synthesis of eplerenone, which is being marketed for the treatment of hypertension. The synthesis begins with DHEA available from wild yams and uses a combination of microbiological and chemical transformations to build eplerenone. Georg Thieme Verlag Stuttgart.

IMPROVED PROCESS FOR THE PREPARATION OF 9,11 EPOXY STEROIDS

Processes are described for epoxidation reactions. In particular, the process comprises the conversion of a steroid substrate having an olefinic unsaturation in the steroid nucleus to a structure comprising a 9,11-epoxy substituent by reaction of the substrate with a peroxide compound in the presence of a peroxide activator. The epoxidation processes described are conducted at relatively low hydrogen peroxide to steroid substrate ratio. Several optional process modifications are described.

Processes for preparing C-7 substituted steroids

This invention relates to processes for the preparation of novel 7-carboxy substituted steroid compounds of Formula I,

Processes for preparation of 3-keto-7alpha-alkoxycarbonyl-delta-4,5- steroids and intermediates useful therein

Multiple novel reaction schemes, novel process steps and novel intermediates are provided for the synthesis of epoxymexrenone and other compounds of Formula I wherein:-A-A- represents the group -CHR4-CHR5- or -CR4=CR5- R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, varyloxy;R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxyalkyl radical;-B-B- represents the group -CHR6-CHR7- or an alpha- or beta- oriented group: where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; andR8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.