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Synfacts 2019; 15(09): 0967
DOI: 10.1055/s-0039-1690491
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-8150

Contributor(s):
Philip Kocienski
Zhong Y.-L. * Weisel M, Humphrey GR, Muzzio DJ, Zhang L, Huffman MA, Zhong W, Maloney KM, Campos KR. Merck & Co., Inc., Rahway, USA
Scalable Synthesis of Diazeniumdiolates: Application to the Preparation of MK-8150.

Org. Lett. 2019;
21: 4210-4214
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Publication History

Publication Date:
20 August 2019 (online)

 
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Key words

MK-8150 - diazeniumdiolates - nitric oxide

Significance

Nitric oxide (NO) plays a key role in the regulation of cardiovascular, immune, and nervous systems. Diazeniumdiolate (DAZD)-based NO donors release two equivalents of NO at pH 7.4 and 37 °C, thereby enabling modulation of NO concentration in cellular environments and control physiological processes. MK-8150 is a DAZD NO donor and a potent and significant blood-pressure-­lowering drug candidate.


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Comment

The synthesis of MK-8150 depicted is based on an efficient synthesis of stable diazeniumdiolate calcium salt B by reaction of secondary amine A with NO at high pressure (250 psi) in water containing calcium hydroxide. Under these conditions calcium salt B precipitated driving the reaction to completion. O-Alkylation of calcium diazeniumdiolate salt B followed by reductive deallylation afforded MK-8150 in 85% yield from C.

• Use of barium hydroxide or magnesium hydroxide in place of calcium hydroxide gave lower yields.

• 29 examples; yields typically >90% yield (four ­exceptions)


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