A new
continuous-flow process is presented for synthesis of the
pharmaceutical intermediate norketamine (
5
). Our approach
has been to take the well-established and industrially applied batch
synthetic route to this promising antidepressant precursor and convert
it to a telescoped multi-stage continuous-flow platform. This involves
the α-bromination of a ketone, an imination/rearrangement sequence
with liquid ammonia, and a thermally induced α-iminol rearrangement.
Our approach is high yielding and provides several processing advantages
including the reduction of many of the hazards conventionally associated
with this route, particularly in the handling of liquid bromine, hydrogen
bromide gas, and liquid ammonia. Each of these presents serious operational
challenges in a batch process at scale.
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