Abstract
The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alternative photochemical oxaziridine rearrangement under mild conditions, which when converted to continuous-flow in a simple and efficient flow reactor allowed the first photochemical scale-up of a homopiperazine.
Highlights
Seven-membered heterocycles are important structures in pharmaceutical and industrial chemistry.[1]
As part of our cancer research program into lysyl oxidase (LOX) inhibitors, we required a scalable route to chiral 3,6-diazabicyclo[3.2.2]nonanes 1 (Figure 1).[2]
The oxaziridine intermediate could be formed selectively via a combination of diaxial and chiral amine-controlled imine oxidation and upon photochemical activation by ultraviolet light would rearrange under stereoelectronic control to one lactam with high selectivity.[33]
Summary
Seven-membered heterocycles are important structures in pharmaceutical and industrial chemistry.[1]. The oxaziridine intermediate could be formed selectively via a combination of diaxial and chiral amine-controlled imine oxidation and upon photochemical activation by ultraviolet light would rearrange under stereoelectronic control to one lactam with high selectivity.[33] For α-substituted ketones, a product distribution complementary to that from the Schmidt reaction was possible.[27]. An efficient and inexpensive microreactor was designed to achieve scalable photochemistry using continuous-flow
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