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A process for the manufacture of merimepodib (VX-497), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been developed and efficiently scaled to produce clinical supply. The process comprises five steps, incorporating simple and robust chemistry that ultimately yielded 96.5 kg with a purity of 100% (by HPLC analysis) and 99.7% w/w assay. Highlights of the process are the effective use of production-scale phosgene, manipulation of Schotten−Baumann reaction conditions to give a low pH procedure that avoids a critical impurity, and the use of online tools to better identify parameters of the API purification.

The scale-up of a prototype HCV protease inhibitor (1) from gram-scale in the laboratory to kilogram-scale in the pilot plant is described. Key features of the optimization included synthesis of bulk quantities of exomethylene proline intermediate 6, separation the diastereomers of spirocycle 2 without chromatography, isolation of the precursor to 1 to purge by-products which might raise genotoxic structural alerts, and purification of an amorphous drug substance via a crystalline acetic acid solvate.

This paper describes using real-time mid-IR, heat flow, and gas uptake data to optimize the hydrogenation of a nitroaromatic to an aniline that had been difficult to control during a previous campaign in the pilot plant. A bimetallic Pt/V catalyst was identified that eliminated the buildup of reaction intermediates and consequently resulted in an inherently more controllable process. The real-time analytics were then used to rapidly optimize the reaction conditions and develop strategies for controlling the reaction rate in the plant should an unexpected deviation occur.