Synthesis of N -Linked Amino-Hexyl Fluorotryptophan for Enlicitide, Part 2: Process Improvements toward Commercial Manufacture

Herein, we report the development of a robust manufacturing process for N-linked amino-hexyl fluorotryptophan 3, a key building block for enlicitide decanoate (MK-0616), which is an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). Targeted process development enabled safe operation of the Delépine reaction, increased yields for the hexamine hydrolysis and enzymatic tryptophan synthesis, and established a robust and selective N-alkylation of 5-fluorotryptophan. Collectively, these improvements afforded the target product with high yield, >98.5% purity, and favorable physical properties suitable for commercial manufacture.