Actelion has applied for a patented synthesis of daridorexant. Starting from the raw amino acid 13.1, it was protected by N-Boc with a yield of 80% (Figure 3.4). Next, amide 13.4 was obtained by HATU-mediated amide coupling with o-phenylenediamine 13.3, which was used directly as a crude product in subsequent reactions. Condensation in hot acetic acid gave benzimidazole 13.5 with a yield of 81%. Removal of the N-Boc protecting group with anhydrous dioxane-hydrochloric acid gave pyrrolidine 13.6; however, the salt equivalent and yield of this step were not reported. Carboxylic acid 13.7 was prepared from the corresponding aryl iodide and 1,2,3-triazole by copper-mediated C-N bond coupling, which finally formed an amide bond with pyrrolidine 13.6 to generate daridorexant (13).
