Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 via N7-Selective Reductive Amination of an Unprotected Pyrazole Starting Material and Intramolecular Urea Formation with 1,1′-Carbonyl-di(1,2,4-triazol) (CDT)

Abstract

ACT-1014-6470 is a potent, orally available, reversible, and selective C5aR1 antagonist. Herein, we report the development of a scalable and robust process for the preparation of ACT-1014-6470 on kg scale. The synthetic sequence started from two inexpensive starting materials─ethyl 3-amino-1H-pyrazole-4-carboxylate and 2-(trifluoromethyl)benzaldehyde─which were coupled together with a novel reductive amination protocol for electron-poor heterocycles that was perfectly N⁷-selective. After building up the core API-structure via a sequence of N²-pyrazole alkylation, ester hydrolysis, amide formation, and reduction, the final intramolecular urea formation was performed with a novel protocol using 1,1′-carbonyl-di(1,2,4-triazol), CDT. The cyclization worked under mild conditions at room temperature without the need of additional base and provided the API in high purity (99.4% a/a by HPLC, 99% w/w) after aqueous workup and crystallization from EtOH. In total, over 2.5 kg of ACT-1014-6470 were prepared in-house using the described 11-step synthesis, with the longest linear sequence (6 steps) having an overall yield of 42%.