Iridium-catalyzed C–H borylation reactions are a rapid and versatile entry into Suzuki coupling partners, but their inherent safety issues can limit their use in large-scale manufacture. The stoichiometric byproduct from this reaction, HBpin, can liberate hydrogen gas on contact with moisture in air, as well as acting as an effective borylating agent in the reaction, resulting in an additional pathway for the generation of hydrogen. Using a targeted, multidisciplinary approach, a C–H borylation process to generate a key intermediate in the synthesis of an API was redesigned in preparation for large-scale manufacture. Through careful evaluation of the existing process and the use of high-throughput experimentation, PAT techniques, NMR, process safety experimentation, and process engineering, the process was constructed so that inherent risks associated with this reaction were minimized and contained to a final controlled quench of the reactive byproducts of the reaction. The final process was transferred to a manufacturing facility, delivering >70 kg of the borylated product over two batches.

中文翻译：

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扩大 C-H 硼化反应的规模：解决铱催化工艺的多公斤级制造的安全问题

铱催化的 C-H 硼化反应是 Suzuki 偶联伙伴的一种快速且通用的方法，但其固有的安全问题可能会限制其在大规模生产中的使用。该反应的化学计量副产物 HBpin 可以在与空气中的水分接触时释放氢气，并在反应中充当有效的硼化剂，从而为产生氢气提供了额外的途径。使用有针对性的多学科方法，重新设计了在 API 合成中生成关键中间体的 C-H 硼化工艺，为大规模生产做准备。通过对现有工艺的仔细评估和高通量实验、PAT 技术、NMR、工艺安全实验和工艺工程的使用，该工艺的构建使得与该反应相关的固有风险最小化，并包含在反应的反应性副产物的最终受控淬火中。最终过程被转移到制造设施，分两批交付 > 70 kg 的硼化产物。