Herein, the development of a streamlined manufacturing process for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The process to belvarafenib features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access the penultimate intermediate 3. The final amide coupling was accomplished by a mild and safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate as the coupling reagent, which afforded belvarafenib on a multikilogram production scale after recrystallization.

中文翻译：

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泛 RAF 抑制剂 Belvarafenib 的高效第二代制造工艺

本文报道了泛 RAF 抑制剂贝伐非尼 (GDC-5573) 的简化制造工艺的开发。贝尔伐非尼的过程具有许多有效的关键反应，包括强大且可扩展的 Pd 催化羰基化反应生成噻吩并嘧啶2和高度化学选择性的 Pt/V/C 催化硝基还原以获取倒数第二个中间体3。最终的酰胺偶联是通过温和且安全的方案完成的，采用N,N,N ' ,N'-四甲基氯甲脒六氟磷酸盐作为偶联剂，重结晶后得到数公斤生产规模的贝伐非尼。