Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy
Organic Process Research & Development,
Journal Year:
2024,
Volume and Issue:
28(2), P. 404 - 412
Published: Feb. 5, 2024
An
improved
synthesis
has
been
developed
for
belzutifan,
a
novel
HIF-2α
inhibitor
the
treatment
of
Von
Hippel–Lindau
(VHL)
disease-associated
renal
cell
carcinoma
(RCC).
The
efficiency
previous
supply
and
commercial
routes
was
encumbered
by
lengthy
5-step
sequence,
needed
to
install
chiral
benzylic
alcohol
traditional
methods.
Identification
directed
evolution
FoPip4H,
an
iron/α-ketoglutarate
dependent
hydroxylase,
enabled
direct
enantioselective
C–H
hydroxylation
simple
indanone
starting
material.
While
this
enabling
transformation
set
stage
greatly
synthesis,
several
other
key
innovations
were
made
including
development
base-metal-catalyzed
sulfonylation,
KRED-catalyzed
dynamic
kinetic
resolution,
facile
SNAr
reaction
in
water.
Together,
these
improvements
resulted
significantly
shorter
(9
steps)
versus
route
(16
75%
reduction
process
mass
intensity
(PMI),
while
also
removing
reliance
on
third-row
transition
metals
toxic
solvents.
Language: Английский
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 2─Development of a Scalable Nickel-Catalyzed Sulfonylation
Organic Process Research & Development,
Journal Year:
2024,
Volume and Issue:
28(2), P. 413 - 421
Published: Jan. 30, 2024
A
nickel-catalyzed
sulfonylation
reaction
was
discovered
and
developed
into
a
robust
process
for
the
manufacturing
of
belzutifan,
an
FDA-approved
treatment
Von
Hippel-Lindau
disease-associated
renal
cell
carcinoma.
The
proceeds
via
reductive
sulfinylation
utilizing
two
insoluble
salts
(potassium
metabisulfite
potassium
formate),
followed
by
methylation
with
nontoxic
methylating
reagent
(trimethylphosphate).
doubly
heterogeneous
nature
proved
difficult
to
scale
due
mixing
particle
size
issues.
Controlled
addition
solution
formate
in
ethylene
glycol
found
mitigate
all
scaling
issues,
mechanistic
studies
revealed
this
be
control
catalyst
speciation.
demonstrated
on
multikilogram
kinetics
between
scales.
Reaction
discovery,
development,
multikilogram-scale
demonstration,
insights
are
detailed
within.
Language: Английский
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5─Chemoenzymatic Diastereoselective Fluorination/DKR
Organic Process Research & Development,
Journal Year:
2024,
Volume and Issue:
28(2), P. 441 - 450
Published: Feb. 7, 2024
A
ketone
fluorination/reduction
dynamic
kinetic
resolution
(DKR)
was
developed
for
a
third-generation
synthesis
of
belzutifan.
This
new
process
replaced
precious
metal
catalyst
with
ketoreductase
(KRED)
in
the
DKR.
Achieving
this
one-pot
reaction
required
several
rounds
enzyme
evolution
that
improved
stability
presence
acetonitrile
and
methanol.
To
maintain
development
progress
satisfy
program
timelines,
around
reaction,
workup,
isolation
operations
performed
parallel
ongoing
modification,
as
variants
were
made
available.
Additionally,
opportunities
improvements
to
product
quality
robustness
identified
by
resolving
issues
observed
piloting
experiments.
Language: Английский
Serendipity results as a driving force in the synthesis of EDG-substituted isatins
Synthesis,
Journal Year:
2024,
Volume and Issue:
56(22), P. 3431 - 3442
Published: Aug. 7, 2024
Abstract
An
efficient
synthetic
procedure
for
the
synthesis
of
isatins
was
found
after
careful
analysis
serendipitous
results
unexpected
products
obtained
by
aromatic
nucleophilic
substitution
when
it
attempted
to
introduce
6-fluoroisatins
classic
Pfitzinger
reaction.
Attentive
these
led
elaborating
a
methodology
synthesizing
electron-enriched
isatins,
including
those
with
hydroxy-,
alkoxy-,
alkylthio-,
and
dialkylamino-substituted
rings.
Limitations
method
were
established.
The
reaction
conditions
optimized
according
understanding
water’s
role.
Finally,
modified
yield
expected
2-substituted
7-fluoroquinoline-4-carboxylic
acids.
Language: Английский