Within the scope of developing a new route to an active
pharmaceutical
ingredient intermediate, we had need of a fluorinated indazole. Although
an established route was in place, it was undesirable due to safety
and selectivity concerns. A concise and improved route was developed
to form the desired indazole, which takes advantage of an electronically
directed metalation/formylation sequence followed by condensation
with methyl hydrazine to form a hydrazone and culminates in a copper-catalyzed
intramolecular Ullmann cyclization. The Ullmann reaction was plagued
with difficulties ranging from poor reactivity to thermal hazard concerns,
but use of high-throughput screening, statistical modeling, and an
unusual isolation method for fine chemicals, safe and optimal conditions
were found that produce high-purity isolated material in excellent
yields at a laboratory scale.
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