Stereoselective Synthesis of TAFIa Inhibitors: Strategic Application of Asymmetric Hydrogenation for the API and Crystallization-Induced Asymmetric Transformation for Its Prodrug

This study details the development of manufacturing processes for TAFIa (activated thrombin-activatable fibrinolysis inhibitor) inhibitor 1 and its prodrug 2. To establish an industrial-scale production process for 1, a comprehensive screening of chiral catalysts for an asymmetric hydrogenation of intermediate 12 was conducted. This effort revealed that 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 improves both reactivity and selectivity. As a result, a practical and efficient process was successfully constructed, achieving 85% overall yield from intermediate 12 over 5 steps. This represents a notable increase compared to the early stage process (40% overall yield in 5 steps from intermediate 12). In parallel, 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 avoid a troublesome chromatographic process, and its synthetic route was established. Enzyme screening identified Chirazyme L-2, C4 as an effective choice, producing (R)-32 in 37% yield with an optical purity of 99.8%ee. A racemization method utilizing catalytic amount of Ac2O was combined with the crystallization of the desired isomer 2 utilizing diastereomer mixture of 2c ((R,R)- and (R,S)-forms). Crystallization-induced asymmetric transformation (CIAT) from (R,R)-form to the desired (R,S)-form was achieved, resulting in 97% yield with 94.8%de. Building on these methods, a manufacturing process was established for prodrug 2, attaining an overall yield of 74% from intermediate 12 through 6 steps.