butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxopregna-1,4-dien-21-oate Property

Melting point:

195.1°

alpha 

D25 +136° (c = 0.5 in chloroform)

Safety

Toxicity

LD50 in mice, rats (g/kg): >4 orally and s.c. (Günzel)

Hazard and Precautionary Statements (GHS)

butyl 6alpha-fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxopregna-1,4-dien-21-oate Chemical Properties,Usage,Production

Originator

Vaspit,Schering,W. Germany,1977

Uses

A glucocorticoid with antiinflammatory activity with little or no side effects.

Definition

ChEBI: Fluocortin butyl is a corticosteroid hormone.

Manufacturing Process

(a) A solution of 11.3 g of 6α-fluoro-11β,21-dihydroxy-16α-methyl-1,4- pregnadiene-3,20-dione in 500 ml of absolute methanol is mixed with 3.0 g of copper(II) acetate in 500 ml of absolute methanol. The solution is agitated at room temperature for 170 hours, then clarified by filtration, and concentrated under vacuum. The residue is mixed with 10% ammonium hydroxide solution and extracted with methylene chloride. The organic phase is washed several times with water, dried over sodium sulfate, and concentrated under vacuum. The residue is chromatographed on 1.3 kg of silicagel. After recrystallization from acetone-hexane, with 6-7% acetone-methylene chloride, 1.40 g of the methyl ester of 6α-fluoro-11β,20αF-di-hydroxy-3-oxo-16α-methyl-1,4- pregnadiene-21-oic acid is obtained, MP 191°C to 192°C.
(b) 2.1 g of a mixture of the methyl ester of 6α-fluoro-11β,20αF-dihydroxy-3- oxo-16α-methyl-1,4-pregnadiene-21-oic acid and the methyl ester of 6α- fluoro-11β,20βF-dihydroxy-oxo-16α-methyl-1,4-pregnadiene-21-oic acid is dissolved in 20 ml of methylene chloride. The solution is mixed with 20 g of active manganese(IV) oxide ("precipitation active for synthesis purposes" by Merck, A.G.) and refluxed for 6 hours. Then, the reaction mixture is filtered off from the manganese(IV) oxide. The filtrate is evaporated and the residue is recrystallized from acetone-hexane, thus obtaining 450 mg of the methyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid, MP 182°C to 184°C.
(c) A solution of 250 mg of the methyl ester of 6α-fluoro-11β,20αF-dihydroxy- 3-oxo-16α-methyl-1,4-pregnadiene-21-oic acid in 3 ml of methylene chloride is mixed with 2.5g of active manganese(IV) oxide and stirred for 45 minutes at room temperature. The manganese(IV) oxide is removed by filtration, the filtrate is evaporated to dryness, and the residue is recrystallized from acetone hexane, thus producing 145 mg of the methyl ester of 6α-fluoro-11β-hydroxy- 3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid, MP 188°C.
(d) 4.3 g of the methyl ester of 6α-fluoro-11β,20βF-dihydroxy-3-oxo-16α- methyl-1,4-pregnadiene-21-oic acid is dissolved, with the addition of 50 g of active manganese(IV) oxide, in 50 ml of isopropanol. The reaction mixture is agitated at room temperature for 25 hour sand filtered off from the manganese(IV) oxide. After evaporation of the solvent, the residue is recrystallized twice from hexane-acetone. Yield: 1.3 g of the methyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid, MP 189°C to 191°C.
(e) 500 mg of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4- pregnadiene-21-oic acid is dissolved in 100 ml of absolute ether, and mixed with 7 ml of butanol and 1.5 ml of dicyclohexyl carbodiimide. After 18 hours of agitation at room temperature, the reaction mixture is vacuum-filtered from the thus-precipitated dicyclohexyl urea. The filtrate is concentrated, and the crude product is chromatographed on silica gel. With 9-11% acetone-hexane, after recrystallization from acetone-hexane, 256 mg of the butyl ester of 6α- fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid is obtained, MP 185°C to 187°C.

Therapeutic Function

Antiinflammatory