An Efficient Synthetic Method for the Key Fragment of Lifitegrast: Benzofuran-6-carboxylic Acid

This article presents a simple and efficient method for synthesizing the key fragment of lifitegrast, benzofuran-6-carboxylic acid. The synthetic pathway involves two key conversions such as intramolecular cross-coupling and oxidative dehydrogenation reactions to obtain the target compound. The first key reaction, the cross-coupling reaction, proceeds smoothly with the use of 1.2 equivalents of zinc dust in a dimethylacetamide medium at 60^°C. The second key reaction, the oxidative dehydrogenation of dihydrobenzofuran occurs comfortably with the catalytic amount of DDQ along with 6 equivalents of MnO₂ in a chlorbenzene medium to generate the benzofuran moiety in good yield. We also discussed in-detail about the impurity formation and its control by adjusting the pH, reagent quantity, solvent quality etc. The proposed synthetic route has been scaled up to a multi-gram scale.The proposed approach offers several advantages, including scalability and cost-effectiveness by utilizing inexpensive and readily available raw materials.