Herein, we describe the development of two continuous manufacturing processes for the synthesis of 6-chloro-1H-pyrazolo[3,4-b]pyrazine, which is a key intermediate en route to the SHP2 inhibitor GDC-1971 (migoprotafib). The reaction sequence starts with a plug-flow metalation/formylation of readily available 2,6-dichloropyrazine using i-Pr₂NMgCl·LiCl (MgDA) as the base, whereupon the resulting unstable heteroaryl aldehyde intermediate is isolated as its easier-to-handle and bench-stable bisulfite adduct. The ensuing cyclization step to the pyrazolopyrazine product necessitates the use of excess amounts of hydrazine reagent, and involves the accumulation of highly energetic, nitrogen-rich intermediates. A continuous stirred-tank reactor (CSTR) process was engineered to address the associated safety concerns while accommodating for the heterogeneity of the reaction mixture. These two safe and robust continuous processes have been demonstrated on multikilogram scale, and serve as enabling contributions toward large-scale manufacturing of GDC-1971.

中文翻译：

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通过连续流甲酰化/肼环化级联可大规模合成 6-氯-1H-吡唑并[3,4-b]吡嗪


在此，我们描述了用于合成 6-氯-1H-吡唑并[3,4-b]吡嗪的两种连续生产工艺的开发，6-氯-1H-吡唑并[3,4-b]吡嗪是合成 SHP2 抑制剂 GDC-1971 (migoprotafib) 过程中的关键中间体。反应顺序以使用 i-Pr ₂ NMgCl·LiCl (MgDA) 作为碱对容易获得的 2,6-二氯吡嗪进行活塞流金属化/甲酰化开始，随后分离出所得的不稳定杂芳基醛中间体因为其更易于处理且实验室稳定的亚硫酸氢盐加合物。随后的吡唑并吡嗪产物环化步骤需要使用过量的肼试剂，并且涉及高能、富氮中间体的积累。连续搅拌釜反应器 (CSTR) 工艺的设计旨在解决相关的安全问题，同时适应反应混合物的异质性。这两种安全、稳健的连续工艺已在公斤级规模上得到验证，并为 GDC-1971 的大规模生产做出了贡献。