Synthesis of Vericiguat
Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.
J. Med. Chem. 2017;
18 August 2017 (online)
Key wordsvericiguat - soluble guanylate cyclase stimulator - (E)-pheynldia-zenylmalononitrile - pyrimidine-4,5,6-triamine ring formation - 1H-pyrazolo[3,4-b]pyridine ring formation
Vericiguat (BAY 1021189) is an orally available soluble guanylate cyclase (sGC) stimulator that has entered phase-three trials for the once-daily treatment of chronic heart failure. Key steps in the synthesis depicted are (1) construction of the 5-fluoro-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate C by condensation of the 5-amino-1H-pyrazole-3-carboxylate A with the aldehyde B and (2) construction of the pyrimidine-4,5,6-triamine derivative H through reaction of [(E)-phenyldiazenyl]malononitrile (G) with amidine F.
Experimental details are provided for the noteworthy four-step synthesis (not shown) of the crystalline 2-fluoro-(3-morpholin-4-yl)acrylaldehyde B from commercially available 2,2,3,3-tetrafluoro-1-propanol. The synthesis of pyrazole A is described in a patent (A. Straub et al. WO 2000/006569 A1). The [(E)-phenyldiazenyl]malononitrile (G) was generated in situ by reaction of phenyldiazonium chloride with malononitrile.