Sutezolid is an in-development
thiomorpholine derivative
of the
FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic
routes for preparing sutezolid start with thiomorpholine as a key
structural building block; unfortunately, this material was identified
as a major cost driver for the API, which will limit the potential
uptake of this treatment in lower income regions. In this work, an
alternative, lower-cost synthetic strategy to a known p-phenylenediamine intermediate to sutezolid has been demonstrated.
The key step in this process is the construction of the thiomorpholine
ring by a nucleophilic sulfide ring closure on an activated bis(2-hydroxyethyl)-functionalized
aniline, which was in turn made by reaction of 3,4-difluoronitrobenzene
and diethanolamine. This sulfide treatment has the added benefit of
affecting a Zinin reduction of the nitro functional group, which alleviates
the need for the transition metal reduction used in previous routes.
After optimization, this key reaction was able to provide the desired
aniline intermediate in yields between 65 and 80% and, after a standard
charcoal treatment, purity of >94%. Initial demonstrations of the
full 3-step strategy were successfully conducted on scales up to 100
g with overall yields of 53–68%. This preliminary work will
serve as the foundation for a broader low-cost redesign of the sutezolid
synthetic process.