Description
Naloxegol oxalate (XXI) is a peripherally acting μ-opioid
receptor antagonist that was approved in the USA and EU for the
treatment of opioid-induced constipation in adults with chronic
non-cancer pain. The drug, a pegylated version of naloxone, has
significantly reduced central nervous system (CNS) penetration
and works by inhibiting the binding of opioids in the gastrointestinal
tract. Naloxegol oxalate was developed by Nektar and
licensed to AstraZeneca. Although we were unable to find a single
report in the primary or patent literature that describes the exact
experimental procedures to prepare naloxegol oxalate, there have
been reports on the preparation of closely related analogs with
specific reports on improving the selectivity of the reduction
step156 and the salt formation of the final drug substance.
Uses
Naloxegol Oxalate is an oxalate form of Naloxegol (N284470) which is a peripherally-selective opioid antagonist.
Synthesis
Naloxone (180) was treated with methoxyethyl
chloride in the presence of Hunigˉs base to give the protected
ketone 181. Reduction of the ketone with potassium trisec-
butylborohydride exclusively provided the a-alcohol 182 in
85% yield. Alternatively, sodium trialkylborohydrides could also
be used to provide similar a-selective reduction in high yield.
Deprotonation of the alcohol with sodium hydride followed by
alkylation with CH3(OCH2CH2)7Br (183) provided the pegylated
intermediate 184 in 88% yield. Acidic removal of the methoxyethyl
ether protecting group followed by treatment with oxalic acid and
crystallization provided naloxegol oxalate (XXI) in good yield.
