Methodological Advances in Organic Synthesis: A Case Study on Rufinamide via Flow and Batch Processes

Abstract

The pharmaceutical active compound Rufinamide (1) was first approved by the U.S. Food and Drug Administration (FDA) in 2008 and is used as an anti-seizure medication for the treatment of childhood-onset epilepsy called Lennox-Gastaut syndrome that happens to 4 years old children and progresses into adulthood. Since its establishment as a valuable treatment a large number of patents, reports and literature publications have been disclosed pertaining to improved syntheses of Rufinamide (1).
The general synthetic strategy to Rufinamide (1) is shown above, but there are various disadvantages to these schemes, such as the need for the explosive azide 3 intermediate; formation of regioisomers and the use of toxic, flammable and expensive dipolarophiles. Therefore, this thesis aims to develop a safer, more regioselectivity and lower cost Rufinamide (1) synthesis, incorporating other important manufacturing criteria such as higher yield, higher efficiency, reduced energy consumption and improved wastage control.
This project had successfully demonstrated the synthesis of Rufinamide (1) starting from the esterification of 2,6-difluorobenzolic acid (16) to methyl and ethyl 2,6-difluorobenzoate (18a and 18b). Then, after the optimisation from the original method, at ratio 1:2 of ester to NaBH4, both esters were reduced to 2,6-difluorobenzyl alcohol (19) with methanol added into the reaction mixture dropwise. With ILs theory applied, the 2,6-difluorobenyl chloride (2) and 2,6-difluorobenzyl mesylate (62) were synthesised from the alcohol in a time efficient manner in flow, or neat condition. And in comparison, with chloride leaving group, 2,6-difluorobenzyl tosylate (65) was also synthesised in a blending reaction and had its methodology optimised. Although all three leaving groups (chloride 2, mesylate 62 and tosylate 65) could successfully react into amine rufinamide precursor 21, an alternative method, which used DPPA 76 to synthesis 2,6-difluorobenzyl azide (3) from 2,6-difluorobenzyl alcohol (19) was achieved, which skipped the synthesis of leaving group together with the application of flow reactors. And finally, by using NaNO2 in THF, deamination of amine rufinamide precursor 21 was achieved and pure Rufinamide (1) was
collected.