Methyl 3-oxoandrost-4-en-17beta-carboxylate (I) was converted to methyl 3-bromoandrosta-3,5-diene-17beta-carboxylate (II) by treatment with phosphorus tribromide in glacial acetic acid. Saponification of (II) in methanolic potassium hydroxide afforded 3-bromoandrosta-3,5-diene-17beta-carboxylic acid (III), which was further converted to 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17beta-carboxamide (IV) by treatment with oxalyl chloride and quenching with tert-butylamine. Treatment of (IV) with ethyl magnesium bromide, followed by halogen metal-exchange with sec-butyllithium and gassing with carbon dioxide afforded crude epristeride (V). Alternatively, 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17beta-carboxamide (IV) was prepared in one step by treatment of 17beta-androst-4-en-3-one carboxylic acid (VI) with bromomethylenedimethylammonium bromide, followed by quenching with tert-butylamine. Crude epristeride was purified and converted to the desired polymorph by heating a suspension in ethyl acetate.

The synthesis of [14C]-labeled epristeride has been reported: The oxidation and decarboxylation of 3-oxo-4-androstene-17beta-carboxylic acid methyl ester (I) gives the 3-oxo-4-oxasteroid (II), which is methylated with [14C]-labeled methyl magnesium iodide, yielding labeled 3-hydroxy-3-methyl-4-oxa-5-androstene-17beta-carboxylic acid methyl ester (III). The cyclization of (III) by means of NaOH affords labeled 3-oxo-4-androstene-17beta-carboxylic acid methyl ester (IV), which is hydrolyzed with KOH to the corresponding acid (V). The reaction of (V) with trifluoromethanesulfonic anhydride gives the androstadiene triflate (VI), which by reaction first with SOCl2 and then with tert-butylamine is converted to the amide (VII). The carboxylation of (VII) with CO and triphenylphosphine palladium diacetate complex in methanol affords [14C]-labeled 17beta-(N-tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid methyl ester (VIII), which is finally treated with K2CO3 in refluxing methanol/water.