Development of a Direct Photocatalytic C-H Fluorination for the Preparative Synthesis of Odanacatib

Late-stage C-H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that gamma-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow. This efficient C-H fluorination reaction compares favorably with several generations of classical gamma-fluoroleucine process syntheses.