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.

中文翻译：

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SGD-9501-TFA 首次 GMP 合成的工艺开发，第 1 部分：两个寡肽片段的合成


发现具有减弱旁观者活性的新型 auristatin 衍生抗体药物偶联物 （ADC） 是一个深入研究的领域。最近，药物接头 SGD-9501 成为一种有前途的临床候选药物，具有良好的脱靶毒性。为了支持基于这种药物连接子的 ADC 的临床供应，我们着手开发一种适合首次人体 （FIH） 的 GMP 生产路线。本报告介绍了两种寡肽片段的工艺开发，涵盖从市售试剂合成 SGD-9501 的七步收敛溶液相中的四个合成步骤。本报告的亮点包括三种结晶的发现和开发，使用 PAT 控制 N，N-二甲基-O-未保护丝氨酸直接偶联形成的杂质，以及开发轻度酸促进的 boc 和叔丁酯脱保护条件，以优化杂质控制和后续分离。对于 GMP 活动，每个步骤均在 >500 g 规模上进行，并获得了 >75% 的产量和 >98% 的液相色谱峰面积百分比 （LCAP） 纯度。