Synthesis of 16α-bromoacetoxy androgens and 17 β-bromoacetylamino-4-androsten-3-one: Potential affinity labels of human placental aromatase

Abstract A novel synthesis of 16α-hydroxy-4-androstene-3,17-dione ( 3 ), 16α-hydroxy-4-androstene-3, 6,17-trione ( 4 ), 17β-amino-5-androsten-3β-ol ( 10 ) and 17β-amino-4-androsten-3-one (14) is described. 16α-Bromoacetoxy-4-androstene-3, 17-dione ( 5 ), 16α-bromoacetoxy-4-androstene-3, 6,17-trione ( 6 ) and 17β-bromoacetylamino-4-androsten-3-one ( 15 ) were synthesized as potentially selective irreversible inhibitors of androgen aromatases. 16α-Bromo-4-androstene-3,17-dione ( 1 ) and 16α-bromo-4-androstene-3, 6,17-trione ( 2 ) were converted to compounds 3 and 4 in 80–90% yield by controlled stereospecific hydrolysis using sodium hydroxide in aqueous pyridine. Reductive amination of 3β-hydroxy-5-androsten-17-one and 3-methoxy-3,5-androstadien-17-one ( 11 ) using ammonium acetate and sodium cyanohydridoborate (NaBH 3 CN) and a subsequent treatment with acid gave the amines 10 and 14 respectively, as a salt. The corresponding 17-imino compounds 9 and 13 were also isolated from the reaction mixtures when methanol was used as a solvent for the reaction. The 16α-hydroxyl compounds 3 and 4 and the 17β-amino compound 14 were con- verted to the corresponding bromoacetyl derivatives, 5 , 6 , and 15 , with bromoacetic acid and N,N'-dicyclohexylcarbodiimide.