We
describe a scalable method for preparing an aminopyrazole building
block using copper-catalyzed amidation with acetamide as an ammonia
surrogate. This procedure provides an alternative to the standard
nitration/reduction sequence and avoids energetic intermediates, specialized
hydrogenation equipment, and potentially genotoxic impurities that
arise from nitro reduction. The chemistry has been successfully scaled
to produce >50 kg of the target compound and demonstrate the viability
of this alternative route.
We
describe a series of improvements to the synthesis of a 3,8-diazabicyclo[3.2.1]octane
derivative that result in a reduced step count and higher overall
efficiency compared to previously published syntheses. Our method
includes optimization and mechanistic understanding of a key diastereoselective
cyclization to achieve a >95:5 diastereomeric ratio, as well as
demonstration
of a unique enzyme-catalyzed amidation reaction using hexamethyldisilazane
as both an ammonia source and scavenger. Finally, we identify a novel
cocrystal solid form of the target compound that provides improved
purity and material properties. Demonstration of the new chemistry
to prepare >100 kg of the target compound serves to illustrate
the
robustness of the new process.
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