SYNTHESIS OF C-14-LABELED CGS 16949A (FADROZOLE HCL), A POTENT AROMATASE INHIBITOR

CGS 16949A (Fadrozole HCl) is an aromatase inhibitor currently used in Japan for the treatment of estrogen-dependent cancer. A C-14-labeled form of this compound was synthesized for metabolism and pharmacokinet ic studies. The synthesis pathway includes six steps, which are shown in synthetic Scheme 2. Initially, 4-bromotoluene was reacted with [C-1 4]CuCN to yield 4-tolunitrile-[C-14]-cyano. The nitrile was brominated on the a carbon to give an intermediate that was used to N-alkylate a known imidazole analogue. The product was treated with thionyl chlori de to convert a 3-hydroxy propyl moiety to its chloro analogue. Treatm ent with potassium butoxide gave [C-14] fadrozole as the free base via ring closure. Hydrogen chloride gas was used to give the desired salt [C-14]CGS 16949A. Using this procedure, [C-14]CGS 16949A was prepared with 97% radiochemical purity. The overall radiochemical yield for th e synthesis was 1% from [C-14]KCN.