Due to the potential for safety improvements, enablement of extreme reaction conditions, equipment flexibility, productivity, etc., the field of continuous processing has been emphasized greatly in recent years in the Lilly process chemistry and engineering groups.  Our progress towards the direct production of an aromatic amide via continuous Schotten-Baumann reaction and continuous reactive crystallization will be disclosed.  The highly efficient acylation of an amine substrate has been accomplished by use of an acid chloride in aqueous alcohol solvent, which afforded a hydrochloride salt solution.  This solution was then neutralized in a continuous mixing elbow system with sodium hydroxide to afford the highly insoluble freebase, which rapidly crystallized in a recirculation loop.  Numerous flow reaction studies along with scale up to > 1 kg of isolated product will be discussed.  Non-cGMP reactor and equipment configuration, mixing studies, kinetic modeling, comparative purity profiles for the reaction mixture and isolated product, and crystallization data will be presented.  We will compare the batch data versus that from the continuous process, as well as discuss the areas for this particular project that we see as drivers for further continuous development.

Continuous amide bond formation and reactive crystallization

246th National Meeting (2013)

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