Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, a penultimate intermediate in the synthesis of nemtabrutinib. A key reaction in this synthetic sequence is a reductive acetal ring opening using boron trifluoride diethyl etherate as a Lewis acid and triethylsilane as the reducing agent. Detailed mechanistic inquisition revealed that in the presence of sulfolane, boron trifluoride is reduced by triethylsilane to generate diborane as the active reductant. Diborane poses many process safety hazards; it is highly reactive, flammable, and acutely toxic. The reaction headspace was studied using infrared spectroscopy and gas chromatography, while the reaction stream was studied using heat flow and adiabatic calorimetry to ensure safe scale-up of the process. Process understanding demonstrated that containing diborane within the reactor was essential to control key impurities. Extensive development efforts were directed to design a process that could safely sequester the hazardous gas. Herein, we describe the process safety analysis, the optimization, and the scale-up of the reduction reaction and the isolation, producing two batches of the amino alcohol tosylate salt with high purity at a pilot scale.

中文翻译：

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整合工艺开发和安全分析以扩大乙硼烷生成还原反应的规模

我们公司开发了一种稳健且可扩展的工艺来合成氨基醇甲苯磺酸盐，这是合成 nemtabrutinib 的倒数第二个中间体。该合成顺序中的一个关键反应是使用三氟化硼二乙基醚合物作为路易斯酸和三乙基硅烷作为还原剂进行还原性缩醛开环。详细的机理研究表明，在环丁砜存在下，三氟化硼被三乙基硅烷还原生成乙硼烷作为活性还原剂。乙硼烷会带来许多工艺安全隐患；它具有高反应性、易燃性和剧毒性。使用红外光谱和气相色谱研究反应顶空，使用热流和绝热量热法研究反应流，以确保工艺的安全放大。工艺理解表明，在反应器中含有乙硼烷对于控制关键杂质至关重要。广泛的开发工作旨在设计一种可以安全隔离有害气体的工艺。在此，我们描述了还原反应和分离的过程安全分析、优化和放大，在中试规模上生产了两批高纯度的氨基醇甲苯磺酸盐。