Pyrrolo[2,1-
f
][1,2,4]triazine (
1
)
is an important regulatory starting material in the production of
the antiviral drug remdesivir. Compound
1
was produced
through a newly developed synthetic methodology utilizing simple building
blocks such as pyrrole, chloramine, and formamidine acetate by examining
the mechanistic pathway for the process optimization exercise. Triazine
1
was obtained in 55% overall yield in a two-vessel-operated
process. This work describes the safety of the process, impurity profiles
and control, and efforts toward the scale-up of triazine for the preparation
of kilogram quantity.
A bioinspired synthesis of Pinoxaden
metabolites 2–5 is described herein. A site-selective
C–H oxidation strategy
validated by density functional theory (DFT) calculations was devised
for preparing metabolites 2–4. Oxidation of the
benzylic C–H bond in tertiary alcohol 7 using
K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access
to metabolites 3 and 4 in a single step.
Unlike most metal/persulfate-catalyzed transformations reported for
the C–C and C–O bond formation reactions wherein the
metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation
of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C–H
oxidation to form metabolites 3 and 4 as
a mixture that were purified to isolate pure standards of these metabolites.
Metabolite 5 was synthesized from readily available advanced
intermediate 9
via a House–Meinwald-type
rearrangement in one step using a base
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