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

Scalable and sustainable synthesis of key fragments with\na low\nenvironmental impact is crucial for API synthesis. Herein, we report\nthe synthesis of benzofuran-6-carboxylic acid, a key fragment of the\ndrug lifitegrast used for treating keratoconjunctivitis sicca. Unlike\nexisting routes, this synthesis features a transition metal-free,\nthree-step protocol using general reagents. The scalability of the\nprocess was successfully demonstrated on a 100 g scale. The target\ncompound was obtained in pure form (98.2% HPLC purity) without chromatographic\npurification. The methods avoid the use of transition metals and cryogenic\ntemperatures employed in known routes. A life cycle analysis comparison\nof existing and current routes indicated that the present route leaves\na smaller carbon footprint. By using a metal-free base catalyst, the\nsynthesis route demonstrated significant environmental benefits, mainly\nCO<sub>2</sub> emission savings, enhanced human health quality, and\nlower mineral depletion, affirming the sustainability with lowering\nthe reaction steps. Designing chemical syntheses with alternative\npathways reduces chemical input, supports chemists in decision-making,\nand addresses the transition to low-carbon processes and products.