二硼烷
过程开发
三氟化硼
工艺工程
三乙基硅烷
流动化学
萃取蒸馏
化学
有机化学
工程类
溶剂
催化作用
硼
作者
Brittany M. Armstrong,Taylor Behre,Ben W. H. Turnbull,Daniel Bishara,Clara Hartmanshenn,Erin McCarthy,Michael Whittington,Yining Ji,Anna V. Jenks,Richard Desmond,Daniel J. Muzzio,James Corry,Ralph Zhao,Nadine Kuhl,Cheol K. Chung
标识
DOI:10.1021/acs.oprd.3c00018
摘要
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.
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