A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.
This account depicts strategies adopted during the development of the κ-opioid receptor agonist CJ-15,161. While the original discovery synthesis was enabled for scale-up, concomitant process research aimed at identifying a novel and more efficient route was undertaken. In the former case, an efficient four-step sequence has been developed, where the process features four consecutive regioselective and stereospecific inversions at a single aziridinium stereogenic center, which leads to overall retention of stereochemistry in a single operation. The search for novel routes has also resulted in two converging methods involving efficient intermolecular N-arylation strategies. The first approach involves Pd-catalyzed intermolecular N-arylation of an appropriately functionalized diamine, obtained from the precursor α-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols. The second approach exploits efficient intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand leading to a straightforward and practical synthesis of CJ-15,161.
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