Integrating Process Development and Safety Analysis for Scale-Up of a Diborane-Generating Reduction Reaction
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 an...
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Published in | Organic process research & development Vol. 27; no. 4; pp. 763 - 774 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Chemical Society
21.04.2023
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Subjects | |
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Abstract | 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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AbstractList | 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. |
Author | Muzzio, Daniel J. Armstrong, Brittany M. Turnbull, Ben W. H. Bishara, Daniel McCarthy, Erin Zhao, Ralph Chung, Cheol K. Kuhl, Nadine Jenks, Anna Corry, James Behre, Taylor Ji, Yining Desmond, Richard Hartmanshenn, Clara Whittington, Michael |
AuthorAffiliation | Department of Analytical Research and Development Merck & Co., Inc Department of Process Research and Development |
AuthorAffiliation_xml | – name: Merck & Co., Inc – name: Department of Analytical Research and Development – name: Department of Process Research and Development |
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CitedBy_id | crossref_primary_10_1016_j_jpba_2024_116002 crossref_primary_10_1021_acs_oprd_3c00218 crossref_primary_10_1021_acs_oprd_3c00395 crossref_primary_10_1021_acs_oprd_3c00113 crossref_primary_10_1021_acs_oprd_3c00374 |
Cites_doi | 10.1016/s1004-9541(11)60239-5 10.1039/d2gc04117k 10.1021/acs.oprd.0c00459 10.1158/2159-8290.cd-17-1409 10.1039/d1ce01721g 10.1021/acs.oprd.6b00407 10.1016/0040-6031(80)85001-5 10.1016/0040-6031(86)85180-2 10.1021/op068011l |
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Keywords | process safety calorimetry gas generation hazardous reaction process development diborane scale-up exothermic reaction infrared spectroscopy |
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Title | Integrating Process Development and Safety Analysis for Scale-Up of a Diborane-Generating Reduction Reaction |
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