Synthesis of Tafamidis via Cyanide-Catalyzed Aerobic Oxidative Cyclization

A series of practical and scalable synthetic routes to tafamidis, a medication used to delay disease progression in adults with transthyretin amyloidosis, has been developed from commercially available 4-amino-3-hydroxybenzoic acid and 3,5-dichlorobenzaldehyde via cyanide-catalyzed aerobic oxidative cyclization. In the first approach, the aldimine generated from these precursors underwent oxidative cyclization in which cyanide served dual roles as both base and catalyst, affording tafamidis in excellent yield and purity under dilute conditions. To reduce cyanide usage and provide a more environmentally benign alternative, a second approach employing NaOt-Bu or NaOH as the base was established, delivering tafamidis with comparable efficiency. To address scalability limitations associated with dilute conditions, a third approach was developed in which the oxidative cyclization was carried out at higher concentration (0.1 M), enabling efficient isolation. Collectively, these routes feature simple operation, direct filtration-based isolation, and compatibility with higher reaction concentrations, providing scalable and practical methods for the synthesis of tafamidis.