Originator
Fluderma,Farmitalia,Italy,1970
Manufacturing Process
4.8 grams of 9α-fluoro-4-pregnene-11β,16α,17α,21-tetrol-3,20-dione-21-
acetate-16α,17α-acetonide, melting at 248° to 250°C and prepared by
acetylation of the corresponding 21-alcohol (J. Amer. Chem. Soc., 1959, 81,
page 1689), were refluxed for 20 hours with 80 cc of dioxane, 5.2 cc of
ethylene glycol, 4.8 cc of ethyl orthoformate and 60 mg of p-toluenesulfonic
acid. After cooling, 0.6 cc of pyridine were added and the mixture was
concentrated in vacuo, diluted with ethyl acetate, poured into a separatory
funnel, and washed with water, with a solution of 5% aqueous sodium
bicarbonate and then with water to neutrality. After distilling off the solvent, a
residue of 5.5 grams remained, which was dissolved in benzene and
chromatographed over 100 grams of Florisil (chromatographic adsorbent). 3
grams of 9α-fluoro-5-pregnene-11β,16α,17α,21-tetrol-3,20-dione-21-acetate-
3-ethyleneketal-16α,17α-acetonide, melting at 145° to 147°C, were collected
from the fractions eluted with benzene-ether 9:1.
1 gram of this 9α-fluoro-5-pregnene-11β,16α,17α,21-tetrol-3,20-dione-21-
acetate-3-ethyleneketal-16α,17α-acetonide in 2 cc of dimethylformamide and
2 cc of trichloroethylene was heated for 3 hours on an oil bath at 70°C with
the reagent obtained from 0.5 cc of dimethylformamide in 4 cc of
trichloroethylene with 0.5 cc phosphorus oxychloride. After cooling to 0°C, 1
gram of sodium acetate dissolved in 3 cc of water were slowly added with
stirring. The mixture was extracted with ethyl acetate and the extracts were
washed with water, with a 5% aqueous solution of sodium bicarbonate and
then with water to neutrality. On distillation of the solvent 1.1 grams of a
residue was obtained from which, after dissolution in ether and precipitation
with petroleum ether, 0.500 gram of 3-(2'-chloroethoxy)-6-formyl-9α-fluoro-
3,5-pregnadien-11β,16α,17α,21-tetrol-20-one-21-acetate-16α,17α-acetonide,
melting at 180° to 182°C were obtained.
