Although
diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs
were discovered over 50 years ago, the current methodology is not
safe, has a limited substrate scope, and is not amenable to large-scale
production. For example, a recent investigation utilizing the standard
methodology to prepare DAZDs resulted in two unexpected explosions,
highlighting the need for safer and more practical chemistry. Recently,
we have reported a general, scalable, safer, and high-yielding methodology
adaptable to large-scale synthesis of diazeniumdiolates in water using
a calcium hydroxide base. Herein, we report the full account for the
development of the reaction. The merit of this strategy is evidenced
by the highly efficient and safer preparation of a key DAZD intermediate,
on the kilogram scale, needed for the preparation of MK-8150 (1), a novel O2-alkylated diazeniumdiolate NO donor
under investigation as a potent and significant blood-pressure-lowering
drug candidate.