Tetsu Tsubogo, Rio Sakamoto, Haruro Ishitani, Shū Kobayashi
We report a fully hydrogen-mediated continuous-flow synthesis of the calcium receptor agonist evocalcet, leveraging molar-based space velocity (SV) as a programmable chemoselectivity parameter in heterogeneous catalytic flow reactions. Precise tuning of SV enables the interception of reactive intermediates that are otherwise prone to over-oxidation or undesired hydrogenation in batch systems. The pivotal dehydrative/dehydrogenative N-arylation was achieved using a DMPSi-Pd(ii)/AC-CP(1) catalyst, which exhibited exceptional chemoselectivity and afforded the desired coupling product in up to 90% yield. SV-dependent control was also crucial in the convergent preparation of two precursors: the partial reduction of a phenol derivative under high-SV conditions selectively produced the corresponding cyclohexanone with high productivity, while selective Cbz deprotection was accomplished without benzylic cleavage. Collectively, these results demonstrate that molar-based SV governs chemoselective outcomes more decisively than conventional residence time (τ), establishing a fundamental descriptor of flow intensity that operates independently of simple concentration or reaction-slowing effects. The integration of these three hydrogen-mediated transformations enabled the formation of the evocalcet ester in 79% yield, followed by hydrolysis to furnish evocalcet in high purity. This study establishes SV-controlled redox modulation as a powerful, general strategy for the sustainable and selective synthesis of complex, functionalized chemical scaffolds.