The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate

(±)-Reboxetine mesylate is a selective norepinephrine uptake (NRI) inhibitor which is marketed as the racemate, under the trade name EdronaxTM, for the treatment of depression, in more than 60 countries. The (S,S)-enantiomer is significantly more active than the racemate in a number of studies and has undergone clinical evaluation as the succinate salt 2 for a number of indications in the pain therapeutic area. The chemical development program for (S,S)-reboxetine succinate was very much influenced by the unusual history of the compound. Pharmacia had manufactured 15000 kg of (±)-reboxetine mesylate or late stage intermediates, such as 3 in readiness for a US approval of EdronaxTM. When this approval did not occur it was clear that only a small proportion of the stock would be required to support the other markets and the remainder was“written off” and made available to the research organisation. Not surprisingly the large stock pile ofmaterialwas initially used as a starting point for the synthesis of (S,S)-reboxetine succinate, the single enantiomer which was being developed for new indications in the pain area. The development work was being carried out at a time when the discipline of Green Chemistry was becoming more established in the pharmaceutical industry. As such, in this article we focus on the environmental (and cost) improvements that were achieved through process development and synthetic route design coupled with rigorous measurement and analysis of Green Chemistry metrics.

Pharmacia intended to commercialise this synthesis based on a very fast development program and a desire to use up the existing stocks and in late 2003 the chemistry was successfully transferred to a manufacturing site. Following the takeover of Pharmacia by Pfizer, the program was reassessed both from a clinical and chemistry point of view and this led to an evaluation of new routes and processes. From a Green Chemistry perspective the chemistry outlined in Schemes 1 and 2 had a number of disadvantages:

  1. The use of a late stage resolution meant that by definition more than half of the materials used to prepare (±)-reboxetine were wasted.
  2. The isolation of the mesylate salt (Scheme 1) and breaking that salt back to reboxetine free base was clearly historical and produced large quantities of unnecessary chemical waste.
  3. Differentiation of the two hydroxyl groups in compound 4 required a protection and deprotection strategy which was sub-optimal, as the initial TMS protection was poorly selective for the primary alcohol.
  4. Chloroacetyl chloride was used as a two carbon fragment to build up the morpholine ring, however this produced intermediate 5 at the wrong oxidation level so necessitating a reduction reaction with a strong metal hydride reagent (VitrideTM).
  5. Dichloromethane was used as a solvent in the processes to break both the mesylate and mandelate salts.
  6. In total more than 1098 kg of solvent, 77 kg of reagents and 770 kg of water was used to convert the (±)-diol 4 into (S,S)-reboxetine succinate.



Georges Assaf, Graham Checksfield, Doug Critcher, Peter J. Dunn, Laurence J. Harris*. Green Chem., 2012, 14, 123–129