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
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.
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)
