Synfacts 2017; 13(09): 0897
DOI: 10.1055/s-0036-1590758
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Vericiguat

Contributor(s): Philip Kocienski
Follmann M. * et al. Bayer AG, Wuppertal, Germany
Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.

J. Med. Chem. 2017;
60: 5146-5161
Further Information

Publication History

Publication Date:
18 August 2017 (online)

 
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Significance

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.


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Comment

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.


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