Synthesis of Benzofuran-6-carboxylic Acid, an Intermediate of Lifitegrast with Low-Carbon Footprints

Scalable and sustainable synthesis of key fragments with a low environmental impact is crucial for API synthesis. Herein, we report the synthesis of benzofuran-6-carboxylic acid, a key fragment of the drug lifitegrast used for treating keratoconjunctivitis sicca. Unlike existing routes, this synthesis features a transition metal-free, three-step protocol using general reagents. The scalability of the process was successfully demonstrated on a 100 g scale. The target compound was obtained in pure form (98.2% HPLC purity) without chromatographic purification. The methods avoid the use of transition metals and cryogenic temperatures employed in known routes. A life cycle analysis comparison of existing and current routes indicated that the present route leaves a smaller carbon footprint. By using a metal-free base catalyst, the synthesis route demonstrated significant environmental benefits, mainly CO2 emission savings, enhanced human health quality, and lower mineral depletion, affirming the sustainability with lowering the reaction steps. Designing chemical syntheses with alternative pathways reduces chemical input, supports chemists in decision-making, and addresses the transition to low-carbon processes and products.