Development of a Claisen Condensation in Flow toward the Synthesis of MK-7845

We report the development and scale-up of a Claisen condensation en route to MK-7845, a small molecule evaluated for the treatment of COVID-19. Compared with other synthetic approaches, the Claisen sequence described herein provides access to a key 1,3-ketoester intermediate in excellent yield, starting from readily available and inexpensive reagents. The solutions identified to overcome the reactivity challenges associated with this transformation include the design and selection of an appropriate electrophile coupling partner and the implementation of a continuous-flow cascade for the generation and immediate consumption of unstable reactive intermediates. The Claisen sequence was demonstrated on a kilogram scale, highlighting its viability, efficiency, and robustness.