Removal of Copper Residues

The commercial route to Fulvestrant (the active ingredient in Faslodex, a treatment for advanced breast cancer) involves two steps where copper reagents are used.  The first of these steps, which  is the introduction of the side chain via a 1,6-addition of an organocuprate to a dienone, uses 5 mol % of CuCl.  The next step is the aromatisation of enone ring which requires the use of stoichiometric CuBr₂ and LiBr in acetonitrile as solvent.  Acetic anhydride is added to prevent bromination of the aromatic ring in the product.  Removal of the copper residues is achieved by adding the reaction mass to a mixture of toluene and an aqueous solution of thiourea.  The pH is adjusted to ~3 by addition of K₂HPO₄ and the insoluble copper – thiourea complex is filtered off.  The final stages of the synthesis involve hydrolysis of the acetate groups, oxidation of the sulphide to sulphoxide and separation of the C-7 isomers.  The final product is a mixture of sulphoxide isomers.

E.J. Brazier, P.J. Hogan, C.W. Leung, A. O’Kearney-McMullan, A.K. Norton, L. Powell,* G.E. Robinson, and E.G. Williams AstraZeneca), Org. Proc. Res. Dev., 2010, 14, 544-552.