Process Development for the First GMP Synthesis of SGD-9501-TFA, Part 1: Synthesis of Two Oligopeptide Fragments

The discovery of novel auristatin-derived antibody drug conjugates (ADCs) with attenuated bystander activity is an area of intense research. Recently, drug-linker SGD-9501 emerged as a promising clinical candidate possessing favorable off-target toxicity. To support the clinical supply of ADCs based on this drug-linker, we set out to develop a first-in-human (FIH) amenable GMP manufacturing route. This report describes the process development of two oligopeptide fragments covering four synthetic steps in the seven-step convergent solution phase synthesis of SGD-9501 from commercial reagents. The highlights within this report include the discovery and development of three crystallizations, the use of PAT to control impurities formed in a direct coupling of N,N-dimethyl-O-unprotected serine, and the development of mild acid promoted boc and tert-butyl ester deprotection conditions that optimized impurity control and subsequent isolation. Each step was performed on a >500 g scale for the GMP campaign and achieved a >75% yield and >98% LC area percent (LCAP) purity.