Synthetic Story of a Blockbuster Drug: Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

Abstract

α-Aryloxybenzyl analogues of morpholine are a significant class of compounds because of their influence on the central nervous system (CNS), with particular concentration on their antidepressant potency. (±)-Reboxetine, an example of such α-aryloxybenzyl analogues, is an orally active and selective noradrenaline reuptake inhibitor that is presently recognized as a prescription drug in over 60 countries for depressive sickness and has been spaciously studied for its pharmacological characteristics. (+)-(S,S)-Reboxetine is presently undergoing advanced clinical evaluation as a potential treatment for neuropathic and fibromyalgia pain. Scheming well-organized approaches to access reboxetine and its derivatives represents a significant endeavor not only for developing antidepressant drugs but also advancing medical studies by radiolabeling of reboxetine derivatives with 11C, 18F, or 123I as potential positron emission tomography radioligands for imaging the brain norepinephrine transporter system. Therefore, to fulfill the challenge of creating the reboxetine architecture by improved synthetic routes, the review combines all of the literature synthetic processes for reboxetine and its derivatives on one platform. Cons and pros of each synthetic method are discussed in this review, which will be very fruitful for the synthetic and medical communities to increase the diversity of synthetic procedures and to develop new concepts and perceptions.

Scalable Synthesis of Cinnamylamines Via the Heck Reaction: Application in the Synthesis of Abamine, Naftifine and Reboxetine

“…In that rigorously developed reboxetine synthesis by Pfizer, cinammyl alcohol 38 is converted to 35 in 41 % yield over seven steps, nevertheless our four‐step synthesis at 31 % yield has the potential of further optimization and reduced processing costs since it is three steps shorter. Arguably our approach is superior to previously reported academic syntheses, [2] not only because it is shorter, safer, chromatography‐free, more efficient, economically viable and scalable but also because it lends itself well for accessing each reboxetine enantiomer through classical resolution of the chiral amine intermediate 35 .…”

“…Reboxetine comprises of a 3‐phenyl propylamine core which bears two contiguous stereogenic centers therefore presents a much more formidable target molecule than abamine and naftifine. There have been several academic syntheses of reboxetine, [2] however they lack significant process development credentials to be considered as viable/suitable routes for the manufacture of reboxetine. Pfizer has reported two large scale diastereoselective syntheses for reboxetine [38,39] and a third, enantioselective variant for the ( S,S ) enantiomer [40] .…”

“…Both the trans-cinnamylamine (trans-3-aryl-allylamine) motif and its saturated counterpart, 3-aryl-propylamine, are regarded as privileged scaffolds in medicinal chemistry as they elicit significant pharmacological activities at a wide range of biological targets with dozens of such compounds being advanced clinical candidates or approved drugs for various indications (Scheme 1, top six and bottom three molecules respectively). [1][2][3][4][5][6][7][8][9][10][11] Despite their importance in medicinal chemistry, the simplest analogue, trans-cinnamylamine, is available at a disproportionally high cost given its structure simplicity, whereas other cinammylamines or 3-aryl-propylamines are only rarely found, if at all, among commercially available compounds. Perhaps the relatively lengthy syntheses of trans-cinammylamines and 3-aryl-propylamines and/or limitations in the aza-substitution of suitable aza-substrates, has contributed to this gap between usefulness and accessibility for this scaffold.…”

Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260

“…While this approach allowed medicinal chemistry researchers to access small quantities of 1 for early evaluation, it was clear that the route needed modification prior to further scale up: (i) the use of tributyl­(vinyl)­stannane and osmium tetroxide had to be avoided during the synthesis of larger quantities of API because of the well-documented hazards of these reagents and their remnants; − (ii) the synthesis of TosMIC reagent 10 was low yielding and warranted improvement; and (iii) most of the intermediates in the medicinal chemistry approach were purified by column chromatography, which was clearly not the preferred purification method on a large scale. However, we also recognized that the existing chemistry to convert aldehyde 6 to API 1 could be scaled up with minor improvements in the isolation conditions.…”

Synthesis of (S,S)‐Reboxetine

“…A survey of the synthetic sequences of reboxetines reveals that the pathways for reboxetine diastereomers are not parallel to each other, as in the hexose synthesis, but require different starting materials or different strategies . For example, following the asymmetric dihydroxylation (AD) process, syn ‐reboxetine was synthesized via O–Aryl disconnection strategy, while anti ‐diastereomer required an O–Benzyl disconnection strategy.…”