Process Development of TAFIa Inhibitor: Strategic Application of Asymmetric Hydrogenation for the API and Crystallization-Induced Asymmetric Transformation for its Prodrug

This study describes the development of manufacturing processes for TAFIa inhibitor 1 and its prodrug 2. To establish an industrial-scale production process for 1, comprehensive screening of chiral catalysts was conducted. This investigation revealed that the Ru/BINAP catalyst system in fluorous alcohol solvents (2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)) significantly enhanced both reactivity and selectivity. Consequently, a robust and efficient process was successfully developed, achieving an 85% overall yield from intermediate 12 over 5 steps. This represents a substantial improvement compared to the early-stage process (40% overall yield in 5 steps). Concurrently, a manufacturing process was developed for prodrug 2. A novel optically active prodrug fragment, (R)-32, utilizing HFIP as a leaving group, was designed to circumvent problematic chromatographic purification, and its synthetic route was established. Enzyme screening identified Chirazyme L-2, C4 as an effective catalyst, producing (R)-32 in 37% yield with 99.8% ee optical purity. Additionally, crystallization-induced asymmetric transformation (CIAT) of a diastereomeric mixture 2c from the (R,R)-form to the desired (R,S)-form was achieved, resulting in 97% yield with 94.8% de. Based on these methodologies, a manufacturing process was established for prodrug 2, achieving an overall yield of 66% from intermediate 12 through 6 steps.