Asymmetric Hydrogenation vs. Resolution in the Synthesis of POSICOR®, a New Type of Calcium Antagonist

Abstract
The pilot-plant-scale synthesis of (S)-2-(4-fluorophenyl)-3-methylbutanoic acid by asymmetric hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid with the [Ru((R)-MeOBIPHEP)(OAc)2]-catalyst is described. The hydrogenation was performed in a continuous mode in a cascade stirred-tank reactor system at 270 bar pressure. The (S)-2-(4-fluorophenyl)-3-methylbutanoic acid is an important optically active intermediate in the synthesis of mibefradil, a new type of calcium antagonist.