Process Development for ( S,S )-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation

Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The ( S,S )-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. ( S,S )-Reboxetine has usually been prepared by resolution of the racemate as the (−)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield ( R,R )-phenylglycidol was developed. ( R,R )-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of ( R,S )- 4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. ( S,S )-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.