Integrating Process Safety Consideration to Enhance Route Development and Optimization

In the development of a route to an advanced intermediate, methyl 1-amino-7-(benzyloxy)thieno[3,2-f]quinoline-2-carboxylate (1), significant safety hazards were identified in both the tandem cyanation/nitro reduction and tert-butyl nitrite (TBN)-mediated Sandmeyer reactions. The cyanation exhibited substantial thermal accumulation and severe decomposition due to the use of dimethyl sulfoxide (DMSO) as a solvent, resulting in a Criticality 5 risk level according to Stoessel. Similarly, the TBN-mediated Sandmeyer reaction showed strong decomposition, further compounding the safety concerns. In response to these hazards, a new route was developed. Process safety evaluations played a crucial role in guiding the development of this safer route, which was successfully implemented, leading to substantial improvements in safety, yield, and overall efficiency. This success underscores the critical importance of integrating process safety evaluation during the early stages of process and route development.