Synthesis of 14C-labelled CGS 16949A (fadrozole HCI), a potent aromatase inhibitor

Article abstract of DOI:10.1002/(SICI)1099-1344(199711)39:11<885::AID-JLCR33>3.0.CO;2-I

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