Continuous-Flow Manufacture of Rivaroxaban Intermediates via Chemo-Enzymatic approach

Rivaroxaban is a direct factor Xa inhibitor whose synthesis depends on intermediates requiring efficient preparation.¹ This work aimed to optimize the synthesis of rivaroxaban intermediates through chemical and biocatalytic approaches, including the implementation of continuous-flow methodologies. The synthesis of 4-(4-aminophenyl)morpholin-3-one was investigated by catalytic hydrogenation in tube-in-tube and H-Cube reactors and by Na₂S₂O₄ reduction in a Chemtrix reactor. Kinetic resolution of glycidyl phthalimide was optimized using immobilized Lipase PS and translated to a fixed-bed reactor. Tube-in-tube hydrogenation afforded >99% conversion and 84% selectivity in 7 min, whereas H-Cube reduced the reaction time to 24 s. Na₂S₂O₄ reduction achieved >99% conversion and selectivity in 20 min, reducing the reaction time from 24 h in batch. Batch enzymatic resolution afforded E >200 (ee = 96%) in 8 h, outperforming the literature (E = 44; 20 h),² while the fixed-bed reactor achieved 44% conversion (eep = 89%; E = 46) in 30 min.