Synthesis of tamoxifen

Tamoxifen is an oestrogen-receptor modulator used in the treatment of breast cancer. It is a triphenylethylene bearing a dimethylaminoethoxy group, and only the Z isomer has the desired activity.

In the classic synthesis, the Grignard reagent prepared from 1-bromo-4-[2-(dimethylamino)ethoxy]benzene adds to 1,2-diphenylbutan-1-one to give a tertiary alcohol. Acid-catalysed dehydration forms the tetrasubstituted double bond as a mixture of the E and Z isomers, which are separated by fractional crystallization. Stereoselective syntheses were developed later, for example by carbometalation of alkynes followed by cross-couplings.