In an effort to remove residual palladium from a drug
candidate
prepared by palladium-catalyzed indolization, many
treatments
were examined. The most effective treatment was to
precipitate
palladium from solution using
2,4,6-trimercapto-s-triazine
(TMT), which reduced palladium levels from 600−650 ppm
to
20−60 ppm in an isolated indole intermediate.
Subsequent
crystallizations routinely afforded active pharmaceutical
ingredient with <1 ppm of palladium. TMT treatment
should
prove useful to reduce the concentration of residual
palladium
in other reactions.
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.
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