(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.
