Process Development toward a Key Fragment of the PCSK9 Inhibitor Enlicitide Decanoate

Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two N-tert-butyloxycarbonyl (N-Boc) groups and a tert-butyl ester; and (4) process development of the magnesium chloride (MgCl2)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.