Expedient Prepararation of Active Pharmaceutical Ingredient Ketamine under Sustainable Continuous Flow Conditions

According to the World Health Organization, depression has become one of
the most challenging health issue. With most current antidepressant medications,
weeks, if not months, are typically required for improving patient conditions. By
contrast, ketamine (1a), is effective within the first intake. Recent Phase III clinical
studies demonstrated the ability of ketamine to rapidly reduce the most severe
symptoms of depression. However, current synthetic routes for the preparation of 1a
require the use of toxic reagents, FDA class 1-2 solvents and are low atom economy
processes.
In this work, we describe an effective continuous flow procedure for the
expedient and sustainable preparation of 1a and analogs. This procedure involves
commercially available low-toxicity chemicals and a FDA class 3 solvent (ethanol).
The continuous flow procedure (Figure 1) features 3 steps, including a unique
hydroxylation step with molecular oxygen, an iminiation relying on triisopropyl borate
and a thermal rearrangement catalyzed by Montmorillonite K10. Each continuousflow
step can be performed individually or can be concatenated, thus providing a
compact yet robust process for the manufacture of ketamine and analogs (1a-c). The
scalability of the critical hydroxylation step was assessed in a commercial pilot
continuous-flow reactor.