Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen,Organic Process Research & Development

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Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-08-11 , DOI: 10.1021/acs.oprd.1c00256
Cuixian Yang ₁ , Tao Wang ₁ , Daniel J. Muzzio ₁ , Stephen Van Cleaf ₁ , Eric M. Phillips ₁ , Adam J. Fine ₁ , Thomas P. Vickery ₁ , Alexei Kalinin ₂ , Stephen M. Dalby ₁ , Theodore R. Furman ₁ , Ryan Flessner ₁ , Analisse Rosario ₁ , Ralph Zhao ₁ , Megan Roth ₁

Affiliation

Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issues such as waste container overpressurization or fire. In this study, multiple module calorimeter (MMC) testing along with micro-GC tests of small scale (1–2 mL) representative lab samples were performed to detect and predict the potential safety hazards associated with the scale-up of an ATH process. Due to the safety concern discovered in the early safety screening tests, methanesulfonic acid (MSA) quench was implemented at the end of the ATH reaction to suppress hydrogen generation, avoiding possible overpressurizing the waste drum and the need to use special hydrogen-rated equipment at pilot- and production-scale. A safety assessment was performed to ensure that the subsequent vacuum distillation poses no risk of hydrogen combustion caused by using a standard pump/system. The process improvements and rigorous safety assessments enable the ATH reaction to be scaled-up using standard pilot plant equipment without the need for special handling and monitoring requirements for hydrogen gas. This study provides useful guidance and recommendations for safer scaling-up of similar organic synthetic reactions which may also generate flammable gas.

中文翻译：

支持扩大涉及氢的化学的安全评估

不对称转移氢化 (ATH) 是制药行业中常用的一种转化，用于还原酮以建立关键立体中心。然而，在反应、后处理和废物处理过程中产生氢气的可能性可能会被忽视，从而导致严重的安全问题，例如废物容器过压或火灾。在本研究中，对小规模（1–2 mL）代表性实验室样品进行了多模块量热仪 (MMC) 测试和微型气相色谱测试，以检测和预测与 ATH 工艺放大相关的潜在安全隐患。由于早期安全筛选测试中发现的安全问题，在 ATH 反应结束时实施甲磺酸 (MSA) 淬火以抑制氢气产生，避免废物桶可能的过压以及在中试和生产规模中使用特殊氢气额定设备的需要。进行了安全评估，以确保后续的真空蒸馏不会因使用标准泵/系统而造成氢气燃烧风险。工艺改进和严格的安全评估使 ATH 反应能够使用标准的中试设备扩大规模，而无需对氢气进行特殊处理和监测要求。这项研究为更安全地扩大类似的有机合成反应提供了有用的指导和建议，这些反应也可能产生易燃气体。进行了安全评估，以确保后续的真空蒸馏不会因使用标准泵/系统而造成氢气燃烧风险。工艺改进和严格的安全评估使 ATH 反应能够使用标准的中试设备扩大规模，而无需对氢气进行特殊处理和监测要求。这项研究为更安全地扩大类似的有机合成反应提供了有用的指导和建议，这些反应也可能产生易燃气体。进行了安全评估，以确保后续的真空蒸馏不会因使用标准泵/系统而造成氢气燃烧风险。工艺改进和严格的安全评估使 ATH 反应能够使用标准的中试设备扩大规模，而无需对氢气进行特殊处理和监测要求。这项研究为更安全地扩大类似的有机合成反应提供了有用的指导和建议，这些反应也可能产生易燃气体。

更新日期：2021-08-20

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