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.
5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride (1) facilitates
5-HT neurotransmission and was an antidepressant drug candidate.
The
development of a safe, rugged process for the large-scale,
chromatography-free preparation of this compound is described. The main areas of optimization included a
Fischer
indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to
prepare the drug substance.
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