Intensified Continuous Flow Synthesis and Workup of 1,5-Disubstituted Tetrazoles Enhanced by Real-Time Process Analytics

Continuous flow processing presents a solution for the safe and effective formation of 1,5-tetrazoles due to the small reactive inventory and absence of a reactor headspace. This has been exemplified using a model amide, 2-chloro-N-methylacetamide, activated using POCl3 to its corresponding imidoyl chloride, which reacts with trimethylsilyl azide. Initial scoping revealed that an excess of azide is vital to facilitate a clean reaction but also that a high concentration would dramatically accelerate the reaction without the need for greatly elevated temperature. In a short residence time of 10 min, complete conversion was achieved, resulting in 77-86% yield of the desired product in high purity (>99.7%) after recrystallization, omitting any chromatographic purification. The developed process reached an excellent space-time yield (1.16 kg L-1 h(-1)) due to its high concentration and short residence time. Successful technology transfer included development of a continuous workup, with pH-controlled quench in a CSTR, followed by extraction. During flow optimization, two orthogonal PAT methods were separately employed, NMR and FTIR, enabling real-time starting material and product quantification. Finally, the developed reaction protocol was demonstrated on a number of other substrates, achieving high yields in most cases, up to quantitative.