p-Toluenesulfonic acid → 18,18-Difluoro-17beta-hydroxy-17-methyl-androst-4-en-3-one

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Reaction Steps

500 mg of 18,18-difluoro-androst-4-ene-3,17-dione are dissolved in 20 ml of dioxane and, after adding 1 ml of orthoformic acid ethyl ester and 30 mg of p-toluenesulphonic acid, the mixture is stirred for 8 hours at room temperature. The reaction mixture is then poured into water (containing traces of pyridine) and extracted twice with ethyl acetate and the extracts are washed until neutral, dried and evaporated in an aspirator vacuum. The crude amorphous enol ether (3-ethoxy-18,18-difluoro-androsta-3,5-dien-17-one) is dissolved direct in 30 ml of absolute ether and the solution is added dropwise to an ethereal solution of methyl magnesium iodide prepared from 300 mg of magnesium turnings and an equivalent amount of methyl iodide, whilst stirring and cooling. The reaction mixture is refluxed for 2 hours and then worked up in the customary manner. The crude carbinol is subjected to hydrolysis direct, without purification. For this purpose, the compound is dissolved in 10 ml of 66% strength acetic acid and the solution is stirred for 2 hours at 30° C. It is then diluted with water and extracted with ethyl acetate and the extracts are washed until neutral (twice with saturated sodium bicarbonate solution and with water), dried and evaporated in an aspirator vacuum. Chromatography of the crude product over 100 times the amount by weight of silica gel (system: hexane/ethyl acetate, 3:1) gives 18,18-difluoro-17β-hydroxy-17-methyl-androst-4-en-3-one.

Provenance & Evidence