Gram-Scale Synthesis of Perdeuterated Paracetamol

The synthesis of deuterated compounds is a major stumbling block in the field of neutron total scattering on disordered materials. This is due to the requirement for large quantities of pure sample with high deuterium content across all positions. Typical deuterations in literature focus on site-specific deuterations typically on milligram scales. Here, we successfully synthesised paracetamol-d₉, as well as its related isotopologues, on a multigram scale. We proceeded through an acid-catalysed deuteration of 4-aminophenol under microwave irradiation. We were able to efficiently purify the unstable intermediate, 4-aminophenol-d₄ by sublimation, which meant we could avoid the formation of strongly coloured impurities that could not be removed from the final product otherwise. The pure intermediate then underwent acetylation with a 75% yield. More than 10 g of the final perdeuterated product was synthesised with an average deuterium incorporation of > 93% and no less than 78% at any individual position.