Process Development\nfor the First GMP Synthesis of\nSGD-9501-TFA, Part 1: Synthesis of Two Oligopeptide Fragments

The discovery of novel auristatin-derived antibody drug\nconjugates\n(ADCs) with attenuated bystander activity is an area of intense research.\nRecently, drug-linker SGD-9501 emerged as a promising clinical candidate\npossessing favorable off-target toxicity. To support the clinical\nsupply of ADCs based on this drug-linker, we set out to develop a\nfirst-in-human (FIH) amenable GMP manufacturing route. This report\ndescribes the process development of two oligopeptide fragments covering\nfour synthetic steps in the seven-step convergent solution phase synthesis\nof SGD-9501 from commercial reagents. The highlights within this report\ninclude the discovery and development of three crystallizations, the\nuse of PAT to control impurities formed in a direct coupling of <i>N</i>,<i>N</i>-dimethyl-<i>O</i>-unprotected\nserine, and the development of mild acid promoted boc and <i>tert</i>-butyl ester deprotection conditions that optimized\nimpurity control and subsequent isolation. Each step was performed\non a >500 g scale for the GMP campaign and achieved a >75% yield\nand\n>98% LC area percent (LCAP) purity.