High Yielding Continuous-Flow Synthesis of Norketamine

Abstract

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.

Scheme 1. Previous Routes to Ketamine (4) and Norketamine (5)

Figure 1

Bromination of 1 with Br₂ in a CSTR to form the α-bromoketone 2. 4 mm OD PTFE tubing was connected via PTFE GL14 screw threads to a round-bottom flask (which served as the reactor) with GL14/B19 quick-fit adaptors.

Figure 2

Reactor scheme for the continuous-flow imination/rearrangement sequence with liquid ammonia for conversion of the α-bromoketone 2 to the α-hydroxy imine 3. The substrate solution and ammonia were pumped with a Jasco (PU-980) high-performance liquid chromatography pump and a chilled Jasco pump (PU-1580-CO₂), respectively. These liquid streams were connected to the reactor via 1/16″ stainless-steel tubing and a Swagelok union.

Figure 3

Reactor scheme for the daisy-chained synthesis of α-hydroxy imine 3 from the ketone 1. The process involved bromination of 1 to form 2, in-line continuous-flow separation with a liquid–liquid membrane separator, high-pressure amination of the bromide 2 with liquid ammonia, and concomitant rearrangement to form the α-hydroxy imine 3. Under these conditions, we were able to achieve 90% conversion to the imine 3 over two steps, as determined by ¹H NMR analysis. Moreover, when the same conditions were repeated without the inclusion of an internal standard, the imine 3 was isolated by precipitation from heptane in 82% yield.

Figure 4

Schematic illustrating the principle of using pressure to superheat an ethanolic solution of α-hydroxy imine 3 to promote the α-iminol rearrangement needed to form norketamine 5 in continuous flow.