Continuous metal scavenging and coupling to one-pot copper-catalyzed azide-alkyne cycloaddition click reaction in flow

• Continuous uninterrupted metal scavenging unit is developed and optimized.
• Effect of several parameters on the scavenging performance is investigated.
• Level of purity required for pharmaceuticals is met in one stage.
• Coupled CuAAC click reaction and copper scavenging is achieved.
• Open door to exploit continuous multi-step synthesis in flow further.

Increasing usage of catalytic chemistry calls for efficient removal of metal traces. This paper describes the development and optimization of a scavenger-based extraction in flow to remove metal catalysts. It enables liquid–liquid extraction with slug flow and phase separation with a porous fluoropolymer membrane. The use of this unit for copper scavenging of various copper sources from organic solvent was studied. The effects of scavenger type (EDTA, DTPA, EDDS), concentration and pH were also investigated. Such analysis allowed to achieve extraction performance as high as 99% at pH of the scavenger solution adjusted to 9.4 and molar ratio of scavenger to copper of 10. Process integration is achieved by coupling this unit downstream to a flow reaction using homogeneous metal-based catalysis, i.e. presenting a continuous uninterrupted metal scavenging unit. The copper-catalyzed azide-alkyne cycloaddition click reaction is studied in one-pot eliminating the need to isolate and handle potentially explosive azide. The triazole product is attained in flow with high yield of up to 92% with 30 min residence time. The level of purity requirement for pharmaceuticals is met in one stage of extraction.

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