A safe and scalable synthesis of A, a key aryl boronate ester intermediate toward an immunology asset udifitimod, via a Ni-catalyzed Miyaura borylation is reported. High-throughput experimentation, design of experiment, and reagent stability/compatibility studies were used to optimize the reaction conditions and furnish the borylation of aryl sulfamate B in 80–85% yield and >98% purity/potency. Significant hydrogen off-gassing was observed during the reaction, metal remediation, and crystallization steps of the first-generation process, and efforts were made to quantify, understand, and mitigate this off-gassing to ensure a safe and reliable scale-up. Two multikilogram batches of the process were successfully run to afford A in an average 85% yield, >99% potency, and ≤28 ppm residual Ni. Using the mechanistic learnings from this work, a second-generation process was developed which significantly reduced hydrogen off-gassing at all steps of the process, as well as increasing final yield and reducing process mass intensity. This second-generation process was demonstrated on a 1 kg scale to afford the product in 90% yield, >99% purity/potency, and 50 ppm residual Ni.

中文翻译：

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开发一种本质安全且可扩展的芳基氨基磺酸酯镍催化硼酸化工艺


据报道，通过 Ni 催化的 Miyaura 硼酸硼酸化反应，A（一种关键的芳基硼酸酯中间体）合成为免疫学资产 udifitimod。采用高通量实验、实验设计和试剂稳定性/相容性研究来优化反应条件，并以 80–85% 的产率和 >98% 的纯度/效力提供芳基氨基磺酸酯 B 的硼化反应。在第一代工艺的反应、金属修复和结晶步骤中观察到明显的氢气脱气，并努力量化、了解和减轻这种脱气，以确保安全可靠的放大生产。该工艺成功运行了两个数公斤批次，以平均 85% 的产率、>99% 的效力和 ≤28 ppm 的残留镍获得 A。利用从这项工作中学到的机理知识，开发了第二代工艺，该工艺显著减少了工艺所有步骤的氢气排放，同时提高了最终产量并降低了工艺质量强度。第二代工艺在 1 kg 的规模上进行了演示，该产品的产量为 90%，纯度/效力为 >99%，残留镍为 50 ppm。