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 can cer. Development of a prototype adequate process for its preparation i s 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 me thyl -dimethoxyphenyl)-ethenyl]-2-hydroxy-(E)-benzoate. Without purifi cation, this intermediate was hydrogenated using 10% Pd/C at 40 degree s C to afford 1, in >99.5% purity after recrystallization from absolut e ethanol. The process research into the Horner-Wadsworth-Emmons-type olefination and a bromination reaction are also discussed; improvement s in these transformations permitted elimination of column chromatogra phy.