Pivaloyl-directed regioselective syntheses of 2,3,6-trioxygenated benzamides: phenolic metabolites of remoxipride

The regioselective syntheses of (S)-5-bromo-2,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-hydroxybenzamide (2) and (S)-5-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-hydroxy-6-methoxy- salicylamide (3) from 2,6-dimethoxybenzoic acid and 4-methoxycatechol are described. The latter compound was protected and ortho-lithiated to introduce the carboxyl function in a regioselective manner. Regiocontrol in bromination and demethylation was achieved by introduction of a bulky pivaloyl group. This strategy also enabled the use of a common intermediate as an alternative synthesis of the catechol 3