The Development of a Practical Multikilogram Synthesis of the Chiral β-Amino Acid Imagabalin Hydrochloride (PD-0332334) via Asymmetric Hydrogenation

The development and implementation of a robust process for the manufacture of metric ton quantities of the alpha 2 delta ligand imagabalin hydrochloride 4 is described. Key aspects of the synthesis include a chromatography-free, two-step telescoped process to prepare a mixture of Z:E-enamides 7 followed by a robust asymmetric hydrogenation with the rhodium-trichickenfootphos catalyst 8 to install the (3S)-stereocentre. Hydrolysis of the acetarnide and ester protecting groups in the final step followed by isolation and recrystallisation of the hydrochloride salt gave high purity 4 in 40-50% overall yields.