Demethylation of 4-Methoxyphenylbutyric Acid Using Molten Pyridinium Hydrochloride on Multikilogram Scale

Abstract

4-Methoxyphenylbutyric acid (2) is smoothly demethylated in 3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid (3), a key starting material for the preclinical candidate LY518674 (1). The adaptation of this chemistry to 22-L and pilot-plant scale is described, including findings to facilitate product isolation, selection of a compatible extraction solvent, and observation of an unusual relationship between the number of solvent extractions and the Pyr·HCl stoichiometry. To the best of our knowledge, this represents the first literature report of the use of this classic demethylation chemistry on multikilogram scale.