methyl (1R,2S,9R,10R,11S,14R,15S,17S)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate

Base Information

• Chemical Name: methyl (1R,2S,9R,10R,11S,14R,15S,17S)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate
• CAS No.: 107724-20-9
• Molecular Formula: C24H30O6
• Molecular Weight: 414.499
• Hs Code.: 29322090
• European Community (EC) Number: 600-850-8
• Wikipedia: Eplerenone
• Mol file: 107724-20-9.mol

Synonyms:107724-20-9

Chemical Property of methyl (1R,2S,9R,10R,11S,14R,15S,17S)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate

Chemical Property:

• Appearance/Colour: White solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 241-243 °C
• Refractive Index: 1.587
• Boiling Point: 597.933 °C at 760 mmHg
• Flash Point: 259.474 °C
• PSA: 82.20000
• Density: 1.31 g/cm³
• LogP: 3.12450
• Storage Temp.: Store at RT
• Solubility.: DMSO: soluble2mg/mL, clear (warmed)
• XLogP3: 1.4
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 2
• Exact Mass: 414.20423867
• Heavy Atom Count: 30
• Complexity: 907

Purity/Quality:

99% HPLC ^*data from raw suppliers

Eplerenone ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC12CCC(=O)C=C1CC(C3C24C(O4)CC5(C3CCC56CCC(=O)O6)C)C(=O)OC
• Isomeric SMILES: C[C@]12CCC(=O)C=C1C[C@H]([C@@H]3[C@]24[C@@H](O4)C[C@]5([C@H]3CC[C@@]56CCC(=O)O6)C)C(=O)OC
• Recent EU Clinical Trials: Patiromer-facilitated, dose-escalation of mineralocorticoid antagonists for the management of worsening congestion in people with heart failure and hyperkalaemia.
• Description: Eplerenone is used alone or in combination with other medications to treat high blood pressure. Eplerenone is in a class of medications called mineralocorticoid receptor antagonists. It works by blocking the action of aldosterone, a natural substance in the body that raises blood pressure. Eplerenone is a mineralocorticoid receptor antagonist. It is selective for the mineralocorticoid receptor over glucocorticoid, androgen, progesterone, and estrogen receptors in radioligand binding assays (IC50s = 138, 6,920, 523, >10,000, and 5,702 nM, respectively). Eplerenone inhibits aldosterone-induced mineralocorticoid activity in a luciferase assay (IC50 = 122 nM). In vivo, eplerenone (100 mg/kg per day) reduces urinary albumin secretion and glomerulosclerosis in the Dahl salt-sensitive rat model of hypertension and nephropathy. It reduces myocardial IL-1β levels and collagen deposition, as well as improves left ventricular systolic dysfunction in a mouse model of acute myocardial infarction. Formulations containing eplerenone have been used in the treatment of hypertension and heart failure after myocardial infarction. Eplerenone derives its antihypertensive effect by blocking the binding of aldosterone at the mineralocorticoid receptor (MR). The drug, which was previously approved only for the oral treatment of hypertension, is now indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction ＜40%) and clinical evidence congestive heart failure (CHF) after an acute myocardial infarction. Aldosterone is a key hormone in the renin-angiotensin-aldosterone system (RAAS), which is of critical importance in the development and progression of hypertension, cardiac remodeling and other cardiovascular diseases. The purpose of RAAS is to control sodium, potassium, and fluid volume balance. Aldosterone binds to MRs in both epithelial (e.g. kidney) and nonepithelial (e.g. heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. The actions of aldosterone can be blocked by spironolactone (Aldactone ?), a relatively nonselective MR antagonist that has been used in clinical practice for many years. Eplerenone, a structural analog of spironolactone, is a highly selective MR antagonist, with significantly lower affinity for other nuclear receptors. It can be prepared by several related ways, with the key step being the introduction of 11-a-hydroxy group on the steroid scaffold via microbiological conversion. The presence of the 11-a-hydroxy group permits the derivation of the epoxy functionality found in eplerenone. Following oral administration, eplerenone is well absorbed and reaches peak plasma concentrations in～2 h. The bioavailability of eplerenone is 98% and it is cleared predominantly by CYP3A4 metabolism, with an elimination half-life of 4–6 h. Steady state is reached within two days. Eplerenone therapy is typically initiated with 25 mg once daily oral dosing and, if tolerated by the patient, titrated to 50 mg once daily. In a clinical study, eplerenone significantly reduced deaths in congestive heart failure patients after a heart attack, above and beyond standard therapy, including ACE inhibitors and β-blockers. The trial in more than 6600 hospitalized patients demonstrated a 15% reduction in the risk of death for eplerenone compared with placebo, in addition to standard treatment. The most commonly reported adverse events associated with eplerenone are hyperkalemia and increased creatine.
• Uses: Selective aldosterone receptor antagonist (SARA), structurally similar to Spiranolactone. Eplerenone is used alone or in combination with other medications to treat high blood pressure. Eplerenone is in a class of medications called mineralocorticoid receptor antagonists. It works by blocking the action of aldosterone, a natural substance in the body that raises blood pressure. Eplerenone is an aldosterone antagonist with an IC50 of 0.36 μM. It is used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it may be more specific for the mineralocorticoid receptor and is sp anticancer agent
• 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.

Technology Process of methyl (1R,2S,9R,10R,11S,14R,15S,17S)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate

There total 20 articles about methyl (1R,2S,9R,10R,11S,14R,15S,17S)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 98.0%

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)

Guidance literature:

With dipotassium hydrogenphosphate; trichloroacetamide; dihydrogen peroxide; In dichloromethane; at 0 - 15 ℃; for 24h; pH=9;

Reference yield: 82.0%

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

Guidance literature:

With dipotassium hydrogenphosphate; dihydrogen peroxide;

DOI:10.1055/s-2008-1032064

Reference yield: 27.1%

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)

Guidance literature:

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;

With hydrogenchloride; In methanol; water; Heating / reflux;

With dipotassium hydrogenphosphate; formic acid; dihydrogen peroxide; potassium formate; acetic anhydride; methanesulfonyl chloride; triethylamine; trichloroacetonitrile; more than 3 stages;

upstream raw materials:

17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester

Δ⁹⁽¹¹⁾-canrenone

C₂₃H₃₀O₄

17β-hydroxy-7α-cyano-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone

Refernces

• 1、 Dams, Iwona,Bia?ońska, Agata,Cmoch, Piotr,Krupa, Ma?gorzata,Pietraszek, Anita,Ostaszewska, Anna,Chodyński, Micha?. "Synthesis and physicochemical characterization of the process-related impurities of eplerenone, an antihypertensive drug". . . Retrieved 2017.
• 2、 -. "Preparation method of eplerenone with high efficiency and low pollution". Paragraph 0037; 0046-0047; 0048; 0057-0058; 0059; 0068-0069. . Retrieved 2020/11/10.