A Catalyzed and Highly Selective Ester Reduction in the Synthesis of an N-Acylpyrrolidine: Safe Design through Reaction Calorimetry and Modeling

The asymmetric synthesis of an N-acylpyrrolidine for HCV inhibition features a unique and highly selective reduction of an ester to an alcohol with NaBH4-MeOH catalyzed by NaB(OAc)(3)H. This reagent combination provides excellent chemoselectivity while avoiding formation of the thermodynamically favored but undesired epimer. Significant process safety issues including delayed onset of reaction initiation and latent, abrupt release of heat and hydrogen gas are encountered. The pyridine impurity responsible for the reaction inhibition is identified in the reaction calorimetry investigation. A series of reaction calorimetry and modeling studies have led to the safe design of a process which has been scaled up to 300 gallons for production of multikilogram quantities of the N-acylpyrrolidine target.