Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter: Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol and Process Implications

Development of a scalable synthesis of WAY-315193 is described. Use of LiHMDS as a base and Ti(O-i-Pr)4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylation−methylamination. The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.