514-36-3

Basic information

• Product Name: Fludrocortisone acetate
• Synonyms: 17-dihydroxy-20-dion(11-beta)-pregn-4-ene-21-(acetyloxy)-9-fluoro-11;20-dione,9-fluoro-11-beta,17,21-trihydroxy-pregn-4-ene-21-acetate;9-alpha-fluorohydrocortisone-21-acetate;9-alpha-fluorohydrocortisoneacetate;9-fluoro-11-beta,17,21-trihydroxypregn-4-ene-3,20-dione21-acetate;9-fluoro-17-hydroxy-corticosteron21-acetate;alfloroneacetate;cortineff
• CAS NO: 514-36-3
• Molecular Formula: C₂₃H₃₁FO₆
• Molecular Weight: 422.49
• EINECS: 208-180-4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;FLORINEF;Inhibitors
• Mol File: 514-36-3.mol
• Article Data: 2

Chemical Properties

• Melting Point: 233-234°C
• Boiling Point: 575.1 °C at 760 mmHg
• Flash Point: 301.6 °C
• Appearance: Crystalline solid
• Density: 1.0953 (rough estimate)
• Vapor Pressure: 1.27E-15mmHg at 25°C
• Refractive Index: 1.5980 (estimate)
• Storage Temp.: -20°C Freezer
• Solubility: Practically insoluble in water, sparingly soluble in anhydrous ethanol.
• PKA: 12.06±0.70(Predicted)
• Water Solubility: 54mg/L(25 oC)
• CAS DataBase Reference: Fludrocortisone acetate(CAS DataBase Reference)
• NIST Chemistry Reference: Fludrocortisone acetate(514-36-3)
• EPA Substance Registry System: Fludrocortisone acetate(514-36-3)

Safety Data

• Hazard Codes: Xn
• Statements: 63
• Safety Statements: 22-26-36
• WGK Germany: 3
• RTECS: TU5050000
• Hazardous Substances Data: 514-36-3(Hazardous Substances Data)

Usage

Description

Fludrocortisone acetate is the acetate form of the synthetic corticosteroid fludrocortisone, which is a mineralocorticoid receptor agonist. Fludrocortisone acetate (0.1-5 μg/animal) promotes sodium retention in rats in a dose-dependent manner with 37% of sodium excreted compared with control when used at a dose of 5 μg/animal. Formulations containing fludrocortisone acetate have been used in the treatment of Addison’s disease.

Chemical Properties

Crystalline Solid

Definition

ChEBI: An acetate ester resulting from the formal condensation of the primary hydroxy group of fludrocortisone with acetic acid. A synthetic corticosteroid, it has glucocorticoid actions about 10 times as potent as hydrocortisone, while its mineralocorticoid acti ns are over 100 times as potent. It is used in partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing adrenal hyperplasia.

General Description

Fludrocortisone acetate,21-acetyloxy-9-fluoro-11β,17-dihydroxypregn-4-ene-3,20-dione, 9α-fluorohydrocortisone (Florinef Acetate), isused only for the treatment of Addison disease and for inhibitionof endogenous adrenocortical secretions. It has up to about 800 times the MC activity of hydrocortisone and about 11 times the GC activity. Its potent activity stimulated the synthesis and study of the many fluorinated steroids. Although its great salt-retaining activity limits its use to Addison disease, it has sufficient GC activity that in some cases of the disease, additional GCs need not be prescribed.

Biochem/physiol Actions

Fludrocortisone acetate is a synthetic corticosteroid with more mineralocorticoid than glucocorticoid activity.

Clinical Use

Replacement therapy in adrenal insufficiency

Veterinary Drugs and Treatments

Fludrocortisone is used in small animal medicine for the treatment of adrenocortical insufficiency (Addison’s disease). It can also be used as adjunctive therapy in hyperkalemia. Additionally, in humans, fludrocortisone has been used in saltlosing, congenital adrenogenital syndrome and in patients with severe postural hypotension.

Drug interactions

Potentially hazardous interactions with other drugs Aldesleukin: avoid concomitant use. Antibacterials: metabolism accelerated by rifamycins; metabolism possibly inhibited by erythromycin; possibly reduce isoniazid concentration. Anticoagulants: efficacy of coumarins and phenindione may be altered. Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone. Antifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism possibly inhibited by itraconazole and ketoconazole. Antivirals: concentration possibly increased by ritonavir. Cobicistat: concentration of fludrocortisone increased. Vaccines: high dose corticosteroids can impair immune response to vaccines - avoid concomitant use with live vaccines

Metabolism

Fludrocortisone is hydrolysed to produce the nonesterified alcohol. In human volunteers, excretion through urine was about 80%, and it was concluded that about 20% were excreted by a different route. It is likely that, as for the metabolism of other steroids, excretion into the bile is balanced by re-absorption in the intestine and some part is excreted with the faeces

InChI:InChI=1/C23H31FO6/c1-13(25)30-12-19(28)22(29)9-7-16-17-5-4-14-10-15(26)6-8-20(14,2)23(17,24)18(27)11-21(16,22)3/h10,16-18,27,29H,4-9,11-12H2,1-3H3/t16-,17-,18-,20-,21-,22-,23-/m0/s1

Synthetic route

9β,11β-epoxy-17α-hydroxypregna-4‐ene-3,20-dione-21-acetate (4383-30-6) → fludrocortisone acetate (514-36-3)

Conditions	Yield
With pyridine hydrogenfluoride In dichloromethane at 0 - 10℃; for 2h; Reagent/catalyst; Solvent;	57.4%

21-acetoxy-9,11β-epoxy-17-hydroxy-9β-pregn-4-ene-3,20-dione (4383-30-6, 96843-90-2) → fludrocortisone acetate (514-36-3)

Conditions	Yield
With hydrogen fluoride

chloroform (67-66-3) + hydrogen fluoride (7664-39-3) + 21-acetoxy-9,11β-epoxy-17-hydroxy-9β-pregn-4-ene-3,20-dione (4383-30-6, 96843-90-2) → fludrocortisone acetate (514-36-3) + 21-acetoxy-11β,17-dihydroxy-pregna-4,8(14)-diene-3,20-dione (96843-89-9)

Epicortisol (566-35-8) → fludrocortisone acetate (514-36-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: dann mit Methansulfonylchlorid 2: sodium acetate; acetic acid 3: HClO4; aqueous dioxane 4: dioxane; potassium acetate; ethanol 5: HF View Scheme

anecortave (7753-60-8) → fludrocortisone acetate (514-36-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: HClO4; aqueous dioxane 2: dioxane; potassium acetate; ethanol 3: HF View Scheme

21-acetoxy-9-bromo-11β,17-dihydroxy-pregn-4-ene-3,20-dione (50733-54-5) → fludrocortisone acetate (514-36-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: dioxane; potassium acetate; ethanol 2: HF View Scheme

21-acetoxy-17-hydroxy-11α-methanesulfonyloxy-pregn-4-ene-3,20-dione (113862-93-4) → fludrocortisone acetate (514-36-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium acetate; acetic acid 2: HClO4; aqueous dioxane 3: dioxane; potassium acetate; ethanol 4: HF View Scheme

methanol (67-56-1) + fludrocortisone acetate (514-36-3) → 9-fluoro-11β-hydroxy-21,21-dimethoxy-pregn-4-ene-3,20-dione (125544-23-2)

Conditions	Yield
With hydrogenchloride; chloroform

formaldehyd (50-00-0) + fludrocortisone acetate (514-36-3) → (20Ξ)-9-fluoro-11β-hydroxy-17,20;20,21-bis-methylenedioxy-pregn-4-en-3-one (2821-53-6)

Conditions	Yield
With hydrogenchloride; chloroform

fludrocortisone acetate (514-36-3) → 9-fluoro-1ξ,11β,17,21-tetrahydroxy-pregn-4-ene-3,20-dione (805-91-4)

Conditions	Yield
mit Hilfe von Streptomyces-Kulturen;

fludrocortisone acetate (514-36-3) → Fludrocortisone (127-31-1)

Conditions	Yield
With potassium carbonate

fludrocortisone acetate (514-36-3) → 21-acetoxy-9-fluoro-17-hydroxy-pregn-4-ene-3,11,20-trione (382-63-8)

Conditions	Yield
With chromium(VI) oxide

fludrocortisone acetate (514-36-3) → isoflupredone (338-95-4)

Conditions	Yield
With didymella lycopersicin
Multi-step reaction with 3 steps 1: palladium / Hydrogenation 2: bromine; acetic acid / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin 3: aqueous methanol.K2CO3 View Scheme

fludrocortisone acetate (514-36-3) → 21-acetoxy-9-fluoro-11β,17-dihydroxy-5α-pregnane-3,20-dione (1812-91-5)

Conditions	Yield
With palladium Hydrogenation;

fludrocortisone acetate (514-36-3) → isoflupredone acetate (338-98-7)

Conditions	Yield
With selenium(IV) oxide
With periodic acid
Multi-step reaction with 2 steps 1: didymella lycopersicin 2: pyridine View Scheme
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine; acetic acid / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin View Scheme

fludrocortisone acetate (514-36-3) + acetyl chloride (75-36-5) → 11β,17,21-Triacetoxy-3-chlor-9α-fluor-pregna-3,5-dien-20-on (864-24-4)

Conditions	Yield
With trichlorophosphate

fludrocortisone acetate (514-36-3) → 1ξ,21-diacetoxy-9-fluoro-11β,17-dihydroxy-pregn-4-ene-3,20-dione (2991-63-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: mit Hilfe von Streptomyces-Kulturen 2: pyridine View Scheme

fludrocortisone acetate (514-36-3) → 21-acetoxy-9-fluoro-11β,17-dihydroxy-5α-pregn-1-ene-3,20-dione (338-97-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine / dann mit Semicarbazid und anschliessend mit Brenztraubensaeure View Scheme
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine; 2,4,6-trimethyl-pyridine View Scheme

fludrocortisone acetate (514-36-3) → 21-acetoxy-9-fluoro-11β,17-dihydroxy-pregna-4,6-diene-3,20-dione (564-57-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin View Scheme

fludrocortisone acetate (514-36-3) → 9-fluoro-11β,17-dihydroxy-pregna-1,4-diene-3,20-dione (426-20-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: palladium / Hydrogenation 2: bromine; acetic acid / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin 3: aqueous methanol.K2CO3 5: NaI; acetic acid View Scheme

fludrocortisone acetate (514-36-3) → 9α-Fluoro-11β,17α,21-trihydroxypregna-4,6-diene-3,20-dione (599-21-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium / Hydrogenation 2: bromine / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin 3: aqueous methanol.K2CO3 View Scheme

fludrocortisone acetate (514-36-3) → 21-acetoxy-2ξ-bromo-9-fluoro-11β,17-dihydroxy-pregn-4-ene-3,20-dione (631-76-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine / dann mit 2,4,6-Trimethyl-pyridin View Scheme

fludrocortisone acetate (514-36-3) → 21-acetoxy-2-bromo-9-fluoro-11β,17-dihydroxy-5α-pregn-1-ene-3,20-dione (564-51-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium / Hydrogenation 2: bromine; 2,4,6-trimethyl-pyridine View Scheme

fludrocortisone acetate (514-36-3) → 9α-fluoroprednisolone acetate (338-99-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium / Hydrogenation 2: bromine; acetic acid / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin 3: CrO3 View Scheme

fludrocortisone acetate (514-36-3) → 9-fluoro-11β,17-dihydroxy-21-methanesulfonyloxy-pregna-1,4-diene-3,20-dione (382-66-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium / Hydrogenation 2: bromine; acetic acid / Erhitzen des Reaktionsprodukts mit 2,4,6-Trimethyl-pyridin 3: aqueous methanol.K2CO3 View Scheme

fludrocortisone acetate (514-36-3) → 9α-fluoro-11β-hydroxy-4-androstene-3,17-dione (357-09-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous methanol.K2CO3 2: NaBiO3 View Scheme

fludrocortisone acetate (514-36-3) → 9α-fluorocortisone (79-60-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: CrO3 2: aqueous methanol. K2CO3 View Scheme

fludrocortisone acetate (514-36-3) → 9-fluoro-21-heptanoyloxy-11β,17-dihydroxy-pregn-4-ene-3,20-dione (599-22-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous methanol.K2CO3 View Scheme

fludrocortisone acetate (514-36-3) → succinic acid mono-(9-fluoro-11β,17-dihydroxy-3,20-dioxo-pregn-4-en-21-yl ester) (339-01-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous methanol.K2CO3 View Scheme

Upstream product

• 4383-30-6 9β,11β-epoxy-17α-hydroxypregna-4‐ene-3,20-dione-21-acetate 
• 113862-93-4 21-acetoxy-17-hydroxy-11α-methanesulfonyloxy-pregn-4-ene-3,20-dione 
• 50733-54-5 21-acetoxy-9-bromo-11β,17-dihydroxy-pregn-4-ene-3,20-dione 
• 7753-60-8 anecortave 
• 566-35-8 Epicortisol 
• 67-66-3 chloroform 
• 7664-39-3 hydrogen fluoride 
• 4383-30-6 21-acetoxy-9,11β-epoxy-17-hydroxy-9β-pregn-4-ene-3,20-dione 

Downstream Products

• 357-09-5 9α-Fluor-11β-hydroxy-3,17-dioxo-androsten-4 
• 79-60-7 9α-fluorocortisone 
• 382-66-1 9-fluoro-11β,17-dihydroxy-21-methanesulfonyloxy-pregna-1,4-diene-3,20-dione 
• 426-20-0 9-fluoro-11β,17-dihydroxy-pregna-1,4-diene-3,20-dione 
• 564-57-8 21-Acetoxy-9α-fluor-11β.17α-dihydroxy-pregna-4,6-dien-3.20-dion 
• 338-98-7 isoflupredone acetate 
• 338-95-4 isoflupredone 
• 127-31-1 Fludrocortisone 

Relevant articles and documents

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Process and intermediates for the preparation of 17 alphahydroxyprogesterones and corticoids from an enol steroid

This invention discloses an improved process for the production of corticoids from 17α-hydroxy steroids utilizing peroxymonosulfate.