Definition
ChEBI: A fluorinated steroid that is flunisolide in which the hydrogen at position 9 is replaced by fluorine. A corticosteroid with glucocorticoid activity, it is used (both as the anhydrous form and as the dihydrate) in creams, gels and ointments for the treatme
t of various skin disorders.
Indications
Fluocinolone acetonide (Derma-Smoothe/FS, Flurosyn, Capex, Synalar) is a synthetic
fluorinated corticosteroid.
Manufacturing Process
A mixture of 1.2 grams of 6α-fluoro-16α-hydroxy-hydrocortisone, 4 cc of
acetic anhydride and 8 cc of pyridine was heated at 60°C for 2 hours and then
kept at room temperature for 2 hours. Ice and water were added and the
solid was collected, washed with water, dried and recrystallized from
methylene chloride-methanol, thus giving 1.05 grams of the 16,21-diacetate
of 6α-fluoro-16α-hydroxy-hydrocortisone (solvated) of MP 182° to 187°C;concentration of the mother liquors afforded an additional 130 mg of the same
compound, MP 184° to 187°C. By recrystallization from the same solvents
there was obtained the compound with a lower constant melting point of 175°
to 177°C.
2.94 grams of the 16,21-diacetate of 6α-fluoro-16α-hydroxy-hydrocortisone
was mixed with 60 cc of dimethylformamide, 3.6 cc of pyridine and 2.4 cc of
methane-sulfonyl chloride was heated on the steam bath for 2 hours. The
diacetate of 6α-fluoro-16α-hydroxy-hydrocortisone had been prepared as set
forth above, and further dried by azeotropic distillation with benzene; the
dimethylformamide had been previously distilled. After the 2 hours on the
steam bath the mixture was cooled and poured into saturated aqueous
sodium bicarbonate solution; the product was extracted with methylene
chloride, the extract was washed with water, dried over anhydrous sodium
sulfate and the solvent was evaporated.
The residue was chromatographed on 90 grams of silica gel eluting the
product with methylene chloride-acetone (9:1) and then recrystallizing from
methylene chloride-methanol. There was thus obtained 1.6 grams of the
16,21-diacetate of 6α-fluoro-δ4,9(11)-pregnadiene-16α,-17α,21-triol-3,20-dione
with MP 110° to 114°C; the analytical sample melted at 115° to 117°C,
[α]D+23.5° (chloroform), λ max. 234 to 236 nm, log ε 4.18.
A mixture of 1.38 grams of the above compound and 15 cc of dioxane was
treated with 1.9 cc of a 0.5 N aqueous solution of perchloric acid and 600 mg
of N-bromoacetamide, adding the latter in the dark, in three portions, in the
course of half an hour and under continuous stirring, It was then stirred for a
further 1% hours in the dark, then the excess of reagent was decomposed by
the addition of aqueous sodium bisulfite solution and ice water was added; the
product was extracted with methylene chloride, washed with water, dried over
anhydrous sodium sulfate and the solvent was evaporated under reduced
pressure, thus giving a yellow oil consisting of the 16,21-diacetate of 6α-
fluoro-9α-bromo-16α-hydroxy-hydrocortisone which was used for the next
step without further purification.
The above crude bromohydrin was mixed with 2.5 grams of potassium acetate
and 60 cc of acetone and refluxed for 6 hours, at the end of which the
acetone was distilled, water was added to the residue and the product was
extracted with methylene chloride. The extract was washed with water, dried
over anhydrous sodium sulfate and the solvent was evaporated.
Recrystallization of the residue from methanol furnished 800 mg of the 16,21-
diacetate of 6α-fluoro-9β,11β-oxido-δ4-pregnene-16α,17α,21-triol-3,20-dione
with MP 120° to 124°C; by chromatography of the mother liquors on silica gel
there was obtained 180 milligrams more of the same compound with MP 117°
to 119°C. The analytical sample was obtained by recrystallization from
methanol; it showed MP 125° to 127°C.
To a solution of 1.6 grams of anhydrous hydrogen fluoride in 2.85 grams of
tetrahydrofurane and 10 cc of methylene chloride cooled to -60°C was added
a solution of 650 mg of the 16,21-diacetate of 6α-fluoro-9β,11β-oxido-δ4-
pregnene-16α,17α,21-triol-3,20-dione in 20 cc of methylene chloride and the
mixture was kept at -10°C for 72 hours. It was then poured into saturated
aqueous sodium bicarbonate solution and the organic layer was separated,
washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was reacetylated by heating with 3 cc of acetic anhydride and 6 cc of
pyridine for 1 hour on the steam bath. The reagents were evaporated under
reduced pressure and the residue was chromatographed on 30 grams of silica
gel. Upon elution with methylene chloride-acetone (9:1) and recrystallization
of the residue from methylene chloride-methanol there was obtained 290 mg
of the 16,21-diacetate of 6α,9α-difluoro-16α-hydroxy-hydrocortisone which
melted with loss of solvent at 140° to 150°C. Recrystallization from acetonehexane
afforded the analytical sample which was dried at 130°C; it then
showed a MP of 182° to 185°C.
General Description
Fluocinolone acetonide,6α,9-difluoro-11β,21-dihydroxy-16α,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione, also known as6α-fluorotriamcinolone acetonide, is the 21-acetate derivativeof fluocinolone acetonide and is about 5 times morepotent than fluocinolone acetonide in at least one topicalactivity assay.
Synthesis
Fluocinolone acetonide can be synthesized from natural steroid derivatives such as diosgenin, tigogenin, and hecogenin via intermediates 11α-hydrocortisone or 16,17α-epoxy-11-hydroxyprogesterone, yielding total yields of 5.2% or 2.8% respectively[1]. Starting from 21-acetyloxy-17α-hydroxy-4,9(11)-diene-3,20-dione, fluocinolone acetonide is prepared in 9 steps with an overall yield of 38.5%[1][2]. The final synthesis step involves adding an epoxy compound to 70% hydrofluoric acid cooled to -15°C, while other routes describe conversion using formic acid or dichloromethane/methanol/potassium carbonate[1][2].
References
[1]Tang, J., Zeng, C., Xie, L., Wang, J., Tian, M., & Guo, C. (2018). Improved Synthesis of Fluocinolone Acetonide and Process Research of 6α,9α-Fluorination. Chemistry Letters, 47(1), 110–112.
https://doi.org/10.1246/cl.170923 [2]Grinenko, G. S., Bayunova, V. I., Karpenko, R. G., & Kolyvanova, T. S. (1978). Preparation of fluocinolone acetonide. Pharmaceutical Chemistry Journal, 12(7), 922–924.
https://doi.org/10.1007/bf00777641
