Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture

Abstract

The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.

Industrial Applications of Enzymes: Recent Advances, Techniques, and Outlooks

“…In a study by Hayes et al, authors reported an improved commercial-scale synthesis route for (S,S)-reboxetine succinate, a noradrenergic anti-depressant for the treatment of fibromyalgia in the latter stages of development at Pfizer [35,36]. The production of reboxetine requires an acetylation of diol intermediate.…”

“…However, conventional synthesis routes rely on classical chemical acetylation that suffers from di-acetylation and poor enantioselectivity, therefore generating considerable amounts of unwanted byproducts [2]. The proposed generation synthesis route successfully employed Candida antartica lipase B, an active, commercially available enzyme, for the highly enantioselective acetylation of diol intermediate [36]. The lipase-catalyzed process resulted in the selective mono-acetylation of diol intermediate with 98% regioselectivity and greater than 99% yield.…”

“…The lipase-catalyzed process resulted in the selective mono-acetylation of diol intermediate with 98% regioselectivity and greater than 99% yield. Furthermore, it was possible for the enzyme to be removed from the reaction mixture via simple filtration, and it thus maintained high regioselectivity at the lab scale upon reuse, all at low costs [36]. As such, the new generation synthesis route resulted in a 58% improvement in the commercial product yield of (S,S)-reboxetine succinate and a nearly 1300 MT year −1 reduction in process waste at peak process throughput [36].…”

Kinetic Resolution of Nitrogen Heterocycles with a Reusable Polymer‐Supported Reagent

“…[4] As an alternative, stoichiometric chiral acylating agents can be used for enantioselective amidation of racemic amines. Researchers, including Fu, [5] Mioskowski, [6] Atkinson, [7] and others, [8] have reported progress on such methods but their widespread use has been precluded by restricted substrate scope, inconvenient reaction procedures, and lengthy syntheses of the reagents.…”

Kinetische Racematspaltung von Stickstoffheterocyclen durch ein wiederverwendbares polymergebundenes Reagens

“…[1] Überraschenderweise sind enzymatische und andere katalytische Racematspaltungen dieser wichtigen Bausteine weniger fortgeschritten; [2,3] Stand der Technik bleibt die Auftrennung durch Bildung der diastereomeren Salze oder Racematspaltung durch Chromatographie mit chiraler stationärer Phase. [4] Alternativ kçnnen chirale Acylierungsmittel stçchiometrisch für die enantioselektive Amidierung von racemischen Aminen eingesetzt werden. Die Gruppen um Fu, [5] Mioskowski, [6] Atkinson [7] sowie weitere [8] haben über Fortschritte bei diesen Methoden berichtet, jedoch wurde deren weit verbreiteter Einsatz durch eine eingeschränkte Substratbreite, umständliche Reaktionsprotokolle und langwierige Synthesen der Reagentien limitiert.Wir haben kürzlich eine Methode für die katalytische kinetische Racematspaltung von cyclischen sekundären Aminen entwickelt, welche die In-situ-Erzeugung der chiralen O-Acylhydroxamsäure 1 beinhaltet.…”