95716-70-4

Basic information

• Product Name: (7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester
• Synonyms: Pregna-4,9(11)-Diene-7-21-Dicarboxylic Acid,17-Hydroxy-3-Oxo,Gamma-Lactone,Methylestor,(7a,17a)-;EPLERENONE INTERMEDIATE;PREGNA-4,9(11)-DIENE-7,21-CARBOXYLICACID,17-HDROXY-3-OXO-G-LACTONE,METHYL ESTER(7A,17A);6,pregnane 4,9(11)-7 alpha diene,21-dicarboxylic acid,17-hydroxy-3-ketone,-butyrolectone,methylester cas:(intermediate of eplerenone);(7A,17A)-17-HYDROXY-3-OXO-PREGNA-4,9(11)-DIENE-7,21-DICARBOXYLICACID G-LACTONE METHYL ESTER;PREGN-4(5)9(11)-DIENE-7,21-DICARBOXYLICACID,17-HYDROXY-3-OXO-,GAMMA-LACTONE;Pregna-4,9(11)-diene-7,21-dicarboxylic acid, 17-hydroxy-3-oxo-, g-lactone, methyl ester, (7a,17a)-;6,PREGNANE 4,9(11)-7 ALPHA DIENE,21-DICARBOXYLIC ACID,17-HYDROXY-3-KETONE,-BUTYROLECTONE,METHYLESTER
• CAS NO: 95716-70-4
• Molecular Formula: C₂₄H₃₀O₅
• Molecular Weight: 398.496
• Product Categories: (intermediate of eplerenone);Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids
• Mol File: 95716-70-4.mol

Chemical Properties

• Boiling Point: 580.2 °C at 760 mmHg
• Flash Point: 251.7 °C
• Appearance: /
• Density: 1.24 g/cm³
• Refractive Index: 1.576
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Acetone (Slightly), Chloroform (Slightly), Dichloromethane (Slightly), Methanol
• CAS DataBase Reference: (7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester(95716-70-4)
• EPA Substance Registry System: (7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester(95716-70-4)

Safety Data

• Hazardous Substances Data: 95716-70-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
(7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester is used as an intermediate in the preparation of Eplerenone and its derivatives. Eplerenone is a selective aldosterone receptor antagonist used for the treatment of hypertension, heart failure, and diabetic nephropathy. The unique structure of this compound allows for the development of new drugs with improved therapeutic properties and reduced side effects.
Used in Medicinal Chemistry Research:
As a key intermediate, (7a,17a)-17-Hydroxy-3-oxo-pregna-4,9(11)-diene-7,21-dicarboxylicacid g-lactone methyl ester is utilized in the synthesis of novel steroidal compounds with potential applications in various therapeutic areas. Researchers can modify its structure to create new molecules with enhanced biological activities, selectivity, and pharmacokinetic profiles, contributing to the advancement of drug discovery and development.

InChI:InChI=1/C24H30O5/c1-22-8-4-15(25)12-14(22)13-16(21(27)28-3)20-17(22)5-9-23(2)18(20)6-10-24(23)11-7-19(26)29-24/h5,12,16,18,20H,4,6-11,13H2,1-3H3/t16-,18?,20?,22+,23+,24-/m1/s1

Synthetic route

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

Conditions	Yield
With phosphorus pentachloride; boron trifluoride diethyl etherate In tetrahydrofuran at 0℃; for 0.166667h; Reagent/catalyst; Temperature;	90.9%

11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (192704-56-6) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
With hexafluoropropene-diethylamine adduct; diethyl-(pentafluoro-propenyl)-amine In chloroform at 30℃; for 30h; Solvent; Temperature; Reagent/catalyst;	90%
Stage #1: 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone With methanesulfonyl chloride; triethylamine In dichloromethane at 5℃; for 1h; Stage #2: With formic acid; potassium formate; acetic anhydride at 70 - 95℃; for 5 - 9h;	77%
With 1H-imidazole; sulfuryl dichloride In tetrahydrofuran at -10 - 20℃; for 1.5h;	71%

methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone (192704-58-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
With formic acid; potassium formate; acetic anhydride at 70 - 100℃; for 19h; Inert atmosphere;	80%
With formic acid; potassium formate; acetic anhydride at 70 - 105℃; for 6.5h;	1.9 g
Stage #1: methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone With Isopropenyl acetate; toluene-4-sulfonic acid at 90℃; for 5h; Stage #2: With sodium acetate; acetic acid at 100℃; for 1h;	0.4 g

11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (192704-56-6) → 3-oxo-17α-pregn-4-ene-7α,9:21,17-dicarbolactone + 7-methyl hydrogen 17α-hydroxy-3-oxopregna-4,11-diene-7α,21-dicarboxylate, γ-lactone (192704-70-4) + 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Stage #1: 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone With methanesulfonyl chloride; triethylamine In dichloromethane at 0℃; for 1.41667h; Stage #2: With formic acid; potassium formate; acetic anhydride at 40 - 95℃; for 2h;	A 2.27 g B 3.72 g C 68.8%
Stage #1: 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone With sulfuryl dichloride In tetrahydrofuran at -70℃; for 0.5h; Stage #2: With 1H-imidazole In tetrahydrofuran at -70 - 20℃; for 2h;
Stage #1: 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone With methanesulfonyl chloride; triethylamine In dichloromethane at -5 - 0℃; for 1.33333h; Stage #2: With sodium acetate; acetic anhydride; acetic acid In dichloromethane at 55 - 135℃; for 1.5 - 2h;

methanol (67-56-1) + 7a-(1,4-dicarbonylpentenyl)-9(11)-encanrenone → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
With ozone at -50℃;	49.31%

diazomethane (186581-53-3, 908094-01-9) + 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone (95716-74-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
In diethyl ether; dichloromethane for 0.166667h;	2.7 g

dimethyl sulfate (77-78-1) + 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone (95716-74-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
In water; acetone at 45℃; for 3h;	50.94 g
With tetra(n-butyl)ammonium hydrogensulfate; sodium carbonate In dichloromethane; water at 20 - 25℃; for 11.5h;
Stage #1: dimethyl sulfate; 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone In water; acetone at 45℃; for 3h; Stage #2: With potassium hydrogencarbonate; triethylamine In water; acetone at 45℃; for 1h;

17β-hydroxy-7α-(5'-methyl-2'-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone (610785-40-5) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium acetate; dibromantin / acetone; H2O / -10 °C 2.1: aq. HCl / CH2Cl2 / 2.5 h / 20 °C 3.1: O3/O2 / CH2Cl2; propan-2-ol / 0.17 h / -55 °C 3.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.83 h / 20 °C 4.1: 0.865 mg / H2O2; KHCO3 / H2O; methanol / 16 h / 20 °C 5.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium acetate; dibromantin / acetone; H2O / -10 °C 2.1: O3/O2; H2O / CH2Cl2; propan-2-ol / 0.04 h / -55 °C 2.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.75 h / 20 °C 2.3: 86.1 percent / H2O2; KHCO3 / H2O; methanol / 15 h / 20 °C 3.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 5 steps 1.1: O3/O2 / CH2Cl2; methanol / -78 °C 1.2: O2; trimethylphosphite / 1 h / 20 °C 2.1: 1.40 g / aq. HCl / 0.33 h / 20 °C 3.1: O3/O2 / CH2Cl2 / -78 - 20 °C 4.1: H2O2; KHCO3 / H2O / 1.5 h / 20 °C 5.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

C25H32O6 → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.865 mg / H2O2; KHCO3 / H2O; methanol / 16 h / 20 °C 2: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

17β-hydroxy-7α-(2'-hydroperoxy-2'-methoxyacetyl)-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone (610785-44-9) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2O2; KHCO3 / H2O / 1.5 h / 20 °C 2: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

17β-hydroxy-7α-(cis-4'-oxo-pent-2'-enoyl)-3-oxo-pregna-4,9(11)-diene-21-carboxylic acid γ-lactone (610785-50-7) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aq. HCl / CH2Cl2 / 2.5 h / 20 °C 2.1: O3/O2 / CH2Cl2; propan-2-ol / 0.17 h / -55 °C 2.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.83 h / 20 °C 3.1: 0.865 mg / H2O2; KHCO3 / H2O; methanol / 16 h / 20 °C 4.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 2 steps 1.1: O3/O2; H2O / CH2Cl2; propan-2-ol / 0.04 h / -55 °C 1.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.75 h / 20 °C 1.3: 86.1 percent / H2O2; KHCO3 / H2O; methanol / 15 h / 20 °C 2.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

17β-hydroxy-7α-(trans-4'-oxo-pent-2'-enoyl)-3-oxo-pregna-4,9(11)-dien-21-carboxylic acid γ-lactone (610785-41-6) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: O3/O2 / CH2Cl2; propan-2-ol / 0.17 h / -55 °C 1.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.83 h / 20 °C 2.1: 0.865 mg / H2O2; KHCO3 / H2O; methanol / 16 h / 20 °C 3.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

17β-hydroxy-7α-(cis-3'-acetoxyacryloyl)-3-oxo-pregna-4,9(11)-diene-21-carboxylic acid γ-lactone (610785-42-7) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.40 g / aq. HCl / 0.33 h / 20 °C 2: O3/O2 / CH2Cl2 / -78 - 20 °C 3: H2O2; KHCO3 / H2O / 1.5 h / 20 °C 4: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 4 steps 1: 1.40 g / aq. HCl / 0.33 h / 20 °C 2: O3/O2 / CH2Cl2 / 0.02 h / -55 °C 3: H2O2; potassium bicarbonate / H2O / 18 h / 20 °C 4: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

17β-hydroxy-7α-(trans-3'-acetoxyacryloyl)-3-oxo-pregna-4,9(11)-diene-21-carboxylic acid γ-lactone (610785-43-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: O3/O2 / CH2Cl2 / -78 - 20 °C 2: H2O2; KHCO3 / H2O / 1.5 h / 20 °C 3: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 3 steps 1: O3/O2 / CH2Cl2 / 0.02 h / -55 °C 2: H2O2; potassium bicarbonate / H2O / 18 h / 20 °C 3: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

C26H32O8 → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2O2; potassium bicarbonate / H2O / 18 h / 20 °C 2: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

Δ9(11)-canrenone (95716-71-5) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 77.7 percent / boron trifluoride diethyl etherate; EtOH; isopropanol / acetonitrile / 24 h / -18.4 °C 2.1: potassium acetate; dibromantin / acetone; H2O / -10 °C 3.1: aq. HCl / CH2Cl2 / 2.5 h / 20 °C 4.1: O3/O2 / CH2Cl2; propan-2-ol / 0.17 h / -55 °C 4.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.83 h / 20 °C 5.1: 0.865 mg / H2O2; KHCO3 / H2O; methanol / 16 h / 20 °C 6.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 4 steps 1.1: 77.7 percent / boron trifluoride diethyl etherate; EtOH; isopropanol / acetonitrile / 24 h / -18.4 °C 2.1: potassium acetate; dibromantin / acetone; H2O / -10 °C 3.1: O3/O2; H2O / CH2Cl2; propan-2-ol / 0.04 h / -55 °C 3.2: dimethylsilfide / CH2Cl2; propan-2-ol / 0.75 h / 20 °C 3.3: 86.1 percent / H2O2; KHCO3 / H2O; methanol / 15 h / 20 °C 4.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme
Multi-step reaction with 6 steps 1.1: 77.7 percent / boron trifluoride diethyl etherate; EtOH; isopropanol / acetonitrile / 24 h / -18.4 °C 2.1: O3/O2 / CH2Cl2; methanol / -78 °C 2.2: O2; trimethylphosphite / 1 h / 20 °C 3.1: 1.40 g / aq. HCl / 0.33 h / 20 °C 4.1: O3/O2 / CH2Cl2 / -78 - 20 °C 5.1: H2O2; KHCO3 / H2O / 1.5 h / 20 °C 6.1: 50.94 g / acetone; H2O / 3 h / 45 °C View Scheme

C23H30O4 (188988-15-0) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 6.6 g / aq. CrO3, H2SO4 / acetone / 0.5 h / 5 °C 2: 2.7 g / CH2Cl2; diethyl ether / 0.17 h View Scheme

17β-hydroxy-7α-cyano-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone (95716-72-6) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

methanol (67-56-1) + C24H27NO4 + sodium methylate (124-41-4) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Heating / reflux;

methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone (192704-58-8) → 3-oxo-17α-pregn-4-ene-7α,9:21,17-dicarbolactone + 7-methyl hydrogen 17α-hydroxy-3-oxopregna-4,11-diene-7α,21-dicarboxylate, γ-lactone (192704-70-4) + 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
With sodium acetate; acetic acid at 40 - 100℃; for 1.21667h;
With potassium acetate; trifluoroacetic acid; trifluoroacetic anhydride at 30 - 40℃; for 5h;

methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone (192704-58-8) → 3-oxo-17α-pregn-4-ene-7α,9:21,17-dicarbolactone + 7-methyl hydrogen 5β-cyano-17-hydroxy-3-oxo-17α-pregn-9(11)-ene-7α,21-dicarboxylate, γ-lactone + 7-methyl hydrogen 17α-hydroxy-3-oxopregna-4,11-diene-7α,21-dicarboxylate, γ-lactone (192704-70-4) + 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
With formic acid; potassium formate; acetic anhydride at 40 - 100℃; for 18h;

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

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

17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone (95716-74-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Stage #1: 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone With dimethyl sulfate In water; acetone at 45℃; for 3h; Stage #2: With potassium hydrogencarbonate; triethylamine In water; acetone at 45℃; for 1h;

11β,17β-dihydroxy-7α-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (1398078-03-9) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

11β,17β-dihydroxy-7β-nitromethyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (1398078-09-5) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme

9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid γ-lactone (209253-72-5) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / 0 - 20 °C 2: triethylamine / dichloromethane / 0 °C 3: potassium formate; formic acid / acetic anhydride / 100 °C View Scheme
Multi-step reaction with 3 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 View Scheme

11α-hydroxyl canrenone (192569-17-8) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 5 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 View Scheme

9(11)-encanrenone (41850-21-9) → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

7a-(1,4-dicarbonylpentenyl)-9(11)-encanrenone → 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ozone / dichloromethane; isopropyl alcohol / -20 °C 1.2: 20 °C 2.1: potassium hydrogencarbonate / tetrahydrofuran / 10 °C View Scheme

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%

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

Conditions	Yield
Stage #1: 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester With dipotassium hydrogenphosphate; trichloroacetamide In dichloromethane at 25℃; for 0.5 - 1.5h; Stage #2: With dihydrogen peroxide In dichloromethane at 20 - 31℃; for 6.16667 - 8.25h; Product distribution / selectivity;	86.4%
Stage #1: 17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester With trichloroacetonitrile In dichloromethane for 1h; Heating / reflux; Stage #2: With dihydrogen peroxide In dichloromethane; water for 27 - 29h; Heating / reflux;

17α-pregna-4,9(11)-diene-7α,21-dicarboxylic acid-17β-hydroxy-3-oxo-γ-lactone-7-methyl ester (95716-70-4) → 9,11β-dichloro-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone

Conditions	Yield
With pyridine; sulfuryl dichloride In chlorobenzene at 0 - 20℃; for 1.5h;	41%

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

Conditions	Yield
With sodium methylate In methanol for 24h; Reflux;	A 0.78 g B 37%

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

Upstream product

• 186581-53-3 diazomethane 
• 95716-74-8 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid γ-lactone 
• 610785-45-0 5α,17β-dihydroxy-3-oxo-pregn-9(11)-ene-7α,21-dicarboxylic acid bis-γ-lactone 
• 74-88-4 methyl iodide 
• 41850-21-9 9⁽¹¹⁾-encanrenone 
• 67-56-1 methanol 
• 192569-17-8 11α-hydroxyl canrenone 
• 209253-72-5 9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic 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 
• 192704-56-6 11β,17β-dihydroxy-7α-methoxycarbonyl-pregna-4-en-3-one-21-carboxylic acid, γ-lactone 
• 192704-58-8 methyl hydrogen 17α-hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-lactone 
• 124-41-4 sodium methylate 
• 95716-72-6 17β-hydroxy-7α-cyano-pregna-4,9(11)-dien-3-one-21-carboxylic acid γ-lactone 

Downstream Products

• 107724-20-9 eplerenone 

Relevant articles and documents

Preparation method of eplerenone intermediate delta 9, 11 alkenyl ester

The invention provides a preparation method of eplerenone intermediate delta 9, 11 alkenyl ester, and the method comprises the following steps: carrying out esterification reaction on raw materials and methanesulfonyl chloride to generate methanesulfonate; and carrying out elimination reaction on the methanesulfonate to obtain an eplerenone intermediate; the method has the advantages that the process yield is about 90%, and the product purity is obviously higher than that reported in the existing literature. The delta 11, 12-alkenyl ester generated in the method has the advantages of fewer lactone impurities and high yield, and the method is an economic and environment-friendly synthetic route, greatly improves the prior art, and is suitable for industrial production.

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.

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.

PROCESS FOR THE PREPARATION OF 7 alpha -(METHOXYCARBONYL)-3-OXO-17alpha-PREGN-4,9(11)-DIEN-21,17-CARBOLACTONE, A USEFUL INTERMEDIATE FOR THE SYNTHESIS OF MOLECULES WITH PHARMACOLOGICAL ACTIVITY

An improved process for the preparation of intermediate (V) through the elimination of a molecule of water from intermediate (IV) is described. Intermediate (V) is a key molecule for the synthesis of eplerenone, a synthetic steroid with pharmacological activity used in the treatment of chronic pathological conditions, including hypertension.

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 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.

A new approach to the furan degradation problem involving ozonolysis of the trans-enedione and its use in a cost-effective synthesis of eplerenone

Whereas ozonization of furan 3a affords little or no carboxylic acid 5, ozonization of the corresponding trans-enedione 6 afforded carboxylic acid 5 in 82.4% yield (cryst., overall from furan, 100 g scale; after workup with dimethyl sulfide, followed by mildly basic hydrogen peroxide). This new approach to furan degradation is showcased in a cost-effective synthesis of eplerenone, an important new medicine for cardiovascular indications.

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,