Synthesis of Filibuvir. Part III. Development of a Process for the Reductive Coupling of an Aldehyde and a β-Keto-lactone

Development of a reductive coupling of a β-keto-lactone and an aldehyde is described, in which the Hantzsch ester serves as an inexpensive and convenient reducing agent. Structural features in the β-keto-lactone rendered standard reductive coupling conditions ineffective, requiring development of a specific addition and temperature protocol. Identification of one of the reactants as Ames positive required a single-digit parts per million control strategy for this impurity in the final active pharmaceutical ingredient (API).