A scalable convergent synthesis of GNE-6893 (1) involving Pd-catalyzed Suzuki–Miyaura cross-coupling and C–N coupling as key steps is reported. The production of the final active pharmaceutical ingredient (API) was achieved in 33% overall yield and 98 A% HPLC purity by a one-pot process of global deprotection, pH adjustment, crystallization, and isolation. Green chemistry practices were implemented in the process development of GNE-6893 (1) by utilizing a biocatalytic resolution to produce (3R,4S)-4-methyltetrahydrofuran-3-ol and replacing toxic triphosgene with a safer alternative, disuccinimidyl carbonate (DSC), to construct the carbamate penultimate intermediate to API.

中文翻译：

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HPK1 抑制剂 GNE-6893 的聚合合成通过四取代异喹啉的钯催化功能化

报道了一种可扩展的GNE-6893会聚合成( 1 )，其中 Pd 催化的 Suzuki–Miyaura 交叉偶联和 C–N 偶联作为关键步骤。通过全局脱保护、pH 调节、结晶和分离的一锅法工艺，实现了最终活性药物成分 (API) 的生产，总收率为 33%，HPLC 纯度为 98 A%。在GNE-6893 ( 1 )的工艺开发过程中实施了绿色化学实践，利用生物催化拆分生产 (3 R ,4 S )-4-甲基四氢呋喃-3-醇，并用更安全的替代品碳酸二琥珀酰亚胺酯替代有毒的三光气 ( DSC), 以构建 API 的氨基甲酸酯倒数第二个中间体。