A Novel and Practical Synthesis of 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, a Key Intermediate of Vericiguat

5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (9) was a key intermediate for the preparation of vericiguat (1). A new approach for the synthesis of 9 was developed from 2-chloro-5-fluoronicotinic acid (22), a commercially available material, in an overall yield of 48.3%. The hydrazinolysis and intramolecular substitution were completed in one step to obtain 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-ol (26). N-1 benzylation of 26 afforded 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (27), whose structure was confirmed by 1H and 13C NMR spectroscopy, mass spectrometry, and single-crystal X-ray crystallography. Pd-catalyzed cyanation of 5-fluoro-1-(2-fluorobenzyl)-3-bromo-1H-pyrazolo[3,4-b]pyridine (28) was applied to prepare key intermediate 9. In the route, compounds 26, 27, and 28 have not been reported in the previous literature.