Continuous-Flow Total Synthesis of Rufinamide

In each of the three steps, safety hazards were very significantly minimized because organoazide intermediate was neither accumulated nor isolated. The otherwise costly and unstable propiolamide was prepared in line and could be employed without concerns of polymerization or storage and also without the need for further functional group manipulation. The overall average residence time was 11 min, and rufinamide was obtained in 92% overall yield and high selectivity. 

Novel process window principles were applied to the 1,3 dipolar cycloaddition to yield the rufinamide precursor. The conditions for the activation of the reaction and the regioselectivity toward the 1,4-cycloadduct were optimized. 

Life-cycle assessment of multistep mfinamide synthesis from isolated reactions in a batch to a continuous microreactor network is reported [148]. A continuous solvent- and catalyst-free flow process utilizing relatively inexpensive and green dipolarophile, ( )-methyl 3-methoxyacrylate, was shown. Here, benzyl chloride, instead of very reactive benzyl bromide, was employed for azide formation, which was produced utilizing benzyl alcohol and hydrogen chloride. 

Flow chemistry [149] as a versatile tool for the synthesis of triazoles has been reviewed. Catalyst-free continuous-flow reactions between azides and further dipolarophiles complement the copper-catalyzed transformations and have been proven to be convenient for the synthesis of diversely substituted triazoles. The safety aspects associated with the handling of azides have been recognized as one of the most important driving forces behind the advent of continuous-flow processes for triazole synthesis. Better heat-transfer characteristics and increased mixing efficiency can be accounted for an improved safety profile as well as for the elimination of common by-products such as diacetylenes and bis-triazoles. 

Although, click chemistry has several limitations, the importance of click chemistry in medicinal chemistry is undeniable. Click chemistry has proven to be a powerful tool in the pharmaceutical field, in particular, in the early discovery phase. However, given the fact that 1,2,3-triazole may be not a suitable moiety in the design of drugs, other cores exhibiting more biocompatibUity and that are similar to 1,2,3-triazole can be designed based on the concept of click chemistry discovery. 

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