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

Abstract

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)

The Current Status of Heterogeneous Palladium Catalysed Heck and Suzuki Cross-Coupling Reactions

“…Palladium on activated carbon is reported to be stable in air and water, acids and bases, and it often doesn’t require reactions to be performed under an inert atmosphere [ 18 , 19 ]. As a result, Pd/C catalyzed Heck and Suzuki cross-coupling reactions have been performed under a variety of reactions conditions, including in organic media [ 20 , 21 , 22 , 23 ], aqueous media [ 24 , 25 , 26 ], and under microwave conditions [ 27 , 28 , 29 , 30 , 31 ]. Generally, the Pd/C catalyst can convert a large variety of substrates with good to excellent yields, and it is recoverable and recyclable over many cycles [ 16 , 17 , 18 ].…”

REMPI spectroscopy and theoretical calculations of cis and trans 3-fluoro-N-methylaniline

“…Aniline (AN) and its halogen-substituted derivatives are popular research subjects of theoretical and experimental studies for years [1][2][3][4][5][6], due to their important applications in the pharmaceutical, agrochemical, and other chemical industries [7,8]. N-methylaniline (NMA), with the CH 3 substituent on the amino group of AN, has more flexibility, and displays different reactivity and kinetic pattern in the reactions relative to AN [9,10].…”

TMC278 (Rilpivirine): A Next‐Generation NNRTI in Phase III Clinical Development for Treatment‐Naive Patients

“…The synthesis of the cyanovinyl aniline (2) derivative was based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol%) as a catalyst [22] (Scheme 4). Therefore, TMC278, as a free base, was synthesized in six high-yield reaction steps.…”