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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 ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option 4, which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing. One such technique highlighted uses systematic, semiquantitative calculations to define the degree of "purge" of PMIs within a synthetic route to an active pharmaceutical ingredient (API) based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken. This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semiquantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent, and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from the published literature and experimental data is also discussed. Furthermore, this paper describes the application of Mirabilis software for the processes involved in the synthesis of verubecestat, naloxegol oxalate, and camicinal.

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In the article they were spelled incorrectly as Didier Shilds and Wim Vermuelen.