Process for (S)‑Ketamine and (S)‑Norketamine via Resolution Combined with Racemization

A concise, recyclable, and efficient process is presented for the preparation of (S)-ketamine (esketamine, (S)-1a) via classic resolution combined with the recycling of the undesired isomer. With commercially available ketone 2 as the starting material, this procedure features three steps including (1) an unique hydroxylation-ring expansion rearrangement, (2) mild amination via methanesulfonate, and (3) chiral separation using L-(+)-tartaric acid. The three simple steps are all performed in mild conditions and (S)-1a tartrate is obtained in 99.5% ee without recrystallization. Subsequently, racemization of the unwanted (R)-1a remained in resolution mother liquor was performed in the presence of a Lewis acid in quantitative yield with >99.0% chemical purity. This original and economical process afforded esketamine in 67.4% (28.9% without racemization) overall yield with two times recycling of the mother liquor without column purification. In addition, this procedure can also be applied to the preparation of (S)-norketamine, which is a safer potential antidepressant.