Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization's list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a single Michael addition reaction. However, the reaction is notoriously slow, with reflux times on the scale of days frequently affording the product in little more than 40% yield. Herein we report a highly intensified synthesis of warfarin exploiting the assets of flow chemistry and organocatalysis. The selection of a suitable catalyst to increase the rate of the reaction was crucial to obtain high conversion and selectivity, resulting in the development of a continuous flow protocol that affords warfarin in 85% isolated yield within 15 min of residence time. The product can be obtained with >97% purity by simple precipitation in acid. The achieved throughput of 9.4 g h–1 with a space-time yield (STY) of 1570.67 g h–1 L–1 is orders of magnitude higher than those of previously published flow protocols. Not only is this protocol more environmentally favorable, but also the estimated cost of 0.07 cents per dose hints that the novel process may be more economically favorable than the patented industrial synthesis.