Originator
Parabolan,Negma,France,1980
Manufacturing Process
Stage A: Preparation of 17β-Benzoyloxy-Estra-4,9,11-Trien-3-one - 0.400 g of
17β-benzoyloxy-4,5-seco-estra-9,11-diene-3,5-dione is dissolved in 4 cc of
toluene under an inert atmosphere. The solution is cooled to 3°C, then 0.48
cc is added of the solution of sodium tert-amylate in anhydrous toluene,
diluted by the addition of a further 4.8 cc of anhydrous toluene.
This reaction mixture is kept between 0°C and +5°C for six hours, with
agitation and under an inert atmosphere, then 5 cc of a 0.2 N solution of
acetic acid in toluene are added. The mixture is extracted with toluene, and
the extracts are washed with water and evaporated to dryness. The residue is
taken up in ethyl acetate, and then the solution is evaporated to dryness in
vacuo, yielding a resin which is dissolved in methylene chloride, and the
solution passed through a column of 40 g of magnesium silicate. Elution is
carried out first with methylene chloride, then with methylene chloride
containing 0.5% of acetone, and 0.361 g is thus recovered of a crude product,
which is dissolved in 1.5 cc of isopropyl ether; then hot methanol is added
and the mixture left at 0°C for one night.
0.324 g of the desired 17β-benzoyloxy-estra-4,9,11-trien-3-one are thus
finally obtained, being a yield of 85%, melting point is 154°C.
Stage B: Preparation of 17β-Hydroxy-Estra-4,9,11-Trien-3-one - 3 g of 17β-
benzoyloxy-estra-4,9,11-trien-3-one, obtained as described in Stage A are
dissolved in 15 cc of methanol. 0.03 g of hydroquinone is added, and the
mixture is taken to reflux while bubbling in nitrogen. Then 1.2 cc of 11%
methanolic caustic potash is added and reflux is maintained for three hours,
after which the reaction product is acidified with 0.36 cc of acetic acid.
The methyl benzoate thus formed is eliminated by steam distillation, and
2.140 g of crude product are obtained, which are dissolved in 20 cc of
methylene chloride. This solution is passed through 10 parts of magnesium
silicate, elution being performed with 250 cc of methylene chloride containing
5% of acetone. After evaporation of the solvent 2.050 g of product is
recovered, which is recrystallized from isopropyl ether.
In this way 1.930 g of the desired 17β-hydroxy-estra-4,9,11-trien-3-one is
obtained being a yield of 89%, melting point is 186°C. It is converted to the
acetate by acetic anhydride.
