Ligandless Heck coupling between a halogenated aniline and acrylonitrile catalyzed by Pd/C: Development and optimization of an industrial-scale Heck process for the production of a pharmaceutical intermediate

The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst. This resulted in a process which has been successfully transferred into production on 2400 mol-scale (6000 L reactor)