Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen

• DOI: 10.1021/acs.oprd.1c00256
• Publication Date: 2021-08-11T17:55:10Z
• Authors: Cuixian Yang; Tao Wang; Daniel J. Muzzio; Stephen Van Cleaf; Eric M. Phillips; Adam J. Fine; Thomas P. Vickery; Alexei Kalinin; Stephen M. Dalby; Theodore R. Furman; Ryan Flessner; Analisse Rosario; Ralph Zhao; Megan Roth
• Keywords: Flammable liquid; Process Safety; Scale-up; Mixed waste

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