Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade

Abstract

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.