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A simple and operationally practical method to sequester and remove fluoride generated through the S_NAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubber of the hydrofluoric acid byproduct, which is simply precipitated and filtered from the reaction mixture during standard aqueous workup. The method has been tested from 10 to 100 g scale of operation, showing >99.5% decrease in fluoride content in each case. Full mass recovery of calcium fluoride is demonstrated at both scales, proving this to be a general, efficient, and robust method of fluoride abstraction to help prevent corrosion of glass-lined reactors.

Development of an S_NAr Reaction: A Practical and Scalable Strategy To Sequester and Remove HF

A. John Blacker*^† , Gabriel Moran-Malagon^†, Lyn Powell^‡, William Reynolds^†, Rebecca Stones^†, and Michael R. Chapman^†

^† Institute of Process Research and Development, School of Chemistry and School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, United Kingdom

^‡ Chemical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00090

*E-mail: j.blacker@leeds.ac.uk.

///////////////aryl amines, calcium fluoride, fluoride sequestration, scale-up, S_NAr reaction,