Ultrafast synthesis of 2-(benzhydrylthio)benzo[d]oxazole, an antimalarial drug, via an unstable lithium thiolate intermediate in a capillary microreactor

Abstract

We present an ultrafast approach for the synthesis of 2-(benzhydrylthio)benzo[d]oxazole, an antimalarial drug, in 75% yield from benzo[d]oxazole-2-thiol and benzhydryl bromide via an unstable lithium thiolate intermediate in the presence of n-BuLi. The precisely controlled two-step reaction at room temperature in a simple capillary microreactor enables a drastic decrease of the synthesis time to milliseconds (580 ms) from 10 min in a flask. Furthermore, a simple continuous-flow operation of the low cost reactor readily realizes a high throughput, leading to a several gram scale production (approximately 4 g per 13.3 min) at a very high flow rate of 7.6 ml min⁻¹.