An Efficient Large-Scale Synthesis of Methyl 5-[2-(2,5-Dimethoxyphenyl)ethyl]-2-hydroxybenzoate

Methyl 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate (1) is a new chemical entity designed by Novartis Pharmaceuticals Corporation for the treatment of hyperproliferative and inflammatory disorders and cancer. Development of a prototype adequate process for its preparation is described. The finalized process was six steps in length and started with the commercially available compounds 2,5-dimethoxybenzaldehhyde and 5-formylsalicylic acid. The methyl ester of 5-formylsalicylic acid was condensed with dimethyl [(2,5-dimethoxyphenyl)methyl]phosphonate, prepared from 2,5-dimethoxybenzaldehyde in three steps, to afford methyl 5-[2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxy-(E)-benzoate. Without purification, this intermediate was hydrogenated using 10% Pd/C at 40 °C to afford 1, in >99.5% purity after recrystallization from absolute ethanol. The process research into the Horner−Wadsworth−Emmons-type olefination and a bromination reaction are also discussed; improvements in these transformations permitted elimination of column chromatography.