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%.

中文翻译：

---

通过未受保护的吡唑起始原料的 N7 选择性还原胺化以及与 1,1'-羰基-二(1,2,4-三唑) (CDT) 形成分子内脲来大规模合成 C5aR1 拮抗剂 ACT-1014-6470


ACT-1014-6470 是一种有效的、口服的、可逆的、选择性的 C5aR1 拮抗剂。在此，我们报告了用于制备公斤级 ACT-1014-6470 的可扩展且稳健的工艺的开发。该合成序列从两种廉价的起始材料开始——3-氨基-1H-吡唑-4-甲酸乙酯和2-(三氟甲基)苯甲醛——与一种新型的贫电子杂环还原胺化方案结合在一起，该方案完全N < b0> -选择性。通过一系列 N ² -吡唑烷基化、酯水解、酰胺形成和还原构建核心 API 结构后，使用 1,1'- 的新方案进行最终的分子内尿素形成羰基二(1,2,4-三唑)，CDT。环化在室温温和条件下进行，无需额外的碱，并在水性后处理和从 EtOH 中结晶后提供高纯度的 API（HPLC 检测为 99.4% a/a，99% w/w）。总共超过 2.5 公斤的 ACT-1014-6470 使用所述的 11 步合成在内部制备，其中最长的线性序列（6 步）的总产率为 42%。