Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow

Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of ( R )-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I ) afforded the desired product ( R )-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II ) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II .