High Yielding Continuous-Flow Synthesis of Norketamine.

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.

Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides.

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline.