Development of a new synthetic route of the key intermediate of riociguat

Abstract

Herein, we describe a new synthetic route to prepare 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (9), a key intermediate of riociguat (1). In this new route, 9 was obtained from commercially available methyl 2-chloronicotinate (28) as the staring material in four steps with an overall yield of 55%. The hydrazinolysis and intramolecular substitution were completed in one step to obtain 1H-pyrazolo[3,4-b]pyridin-3-ol (30). Regioselective N1-benzylation of 30 afforded 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (31), whose structure was confirmed by ¹H NMR, ¹³C NMR, MS and single-crystal X-ray crystallography. Pd-catalyzed cyanation of 1-(2-fluorobenzyl)-3-bromo-1H-pyrazolo[3,4-b]pyridine (32) was applied to prepare key intermediate 9. Compound 32 in our approach has not been previously reported in the literature. The related impurities and process parameters were studied. The new synthetic route provides an alternative method for the preparation of riociguat.

Graphical Abstract

Keywords:

• hydrazinolysis
• intramolecular substitution
• Pd-catalyzed cyanation
• regioselective benzylation
• riociguat