It’s interesting to note that 15 people at Merck were involved in the safety analysis work. I suspect that this level of teamwork requires a well established safety culture in the organizatin.

- Ralph

https://pubs.acs.org/doi/10.1021/acs.oprd.3c00018

Integrating Process Development and Safety Analysis for Scale-Up of a Diborane-Generating Reduction Reaction
• Brittany M. Armstrong*,
• Taylor Behre*,
• Ben W. H. Turnbull,
• Daniel Bishara,
• Clara Hartmanshenn,
• Erin McCarthy,
• Michael Whittington,
• Yining Ji,
• Anna Jenks,
• Richard Desmond,
• Daniel J. Muzzio,
• James Corry,
• Ralph Zhao,
• Nadine Kuhl, and
• Cheol K. Chung

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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