Modulation of catalyst reactivity for the chemoselective hydrogenation of a functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate

In the synthesis of the beta B-2-adrenoceptor agonist (R,R)-formterol, a ke y step in the synthesis was the development of a highly chemoselective redu ction of (1R)-2-bromo-1-[3-nitro-4-(phenylmethoxy) phenyl]ethan-1-ol to giv e (1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan- l-ol. The aniline product was isolated as the corresponding formamide, The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a s econdary benzylic hydroxyl group, and a primary bromide, and with no racemi zation at the stereogenic carbinol carbon atom. The development of a synthe tic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, t he oxidation state of the poison, and the substituents on the sulfur atom h ad a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulf ide was the poison of choice, possessing all of the required characteristic s for providing a highly chemoselective and high yielding reaction. The pra cticality and robustness of the process was demonstrated by preparing the f inal formamide product with high chemoselectivity, chemical yield, and prod uct purity on a multi-kilogram scale.