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)

Chloroformylation reactions are versatile reactions that allow the introduction of a chlorine atom and an aldehyde group in enolizable ketones, employing the well-known Vilsmeier reagent. However, the use of this unstable reagent is usually associated with hazards, especially when it is used on an industrial scale. The present article describes the preparation and use of the Vilsmeier reagent under continuous flow conditions for the preparation of an important intermediate in the synthesis of cyanine dyes. In addition, the traditionally used dimethylformamide has been substituted with more desirable formamides, together with the removal of the halogenated solvent usually employed in the reaction. Consequently, the optimized conditions allow the continuous production of the target compound in a 79–81% isolated yield in a more environmentally friendly, fast, and secure manner.

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