A Scaleable Route to the Pure Enantiomers of Verapamil

A versatile route to single enantiomer verapamil from readily available raw materials is described. The key intermediate, 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (verapamilic acid), was resolved efficiently with α-methyl benzylamine. Stereochemical integrity at the quarternary carbon centre was preserved through subsequent steps to give either (R)-or (S)-verapamil in good overall yield. This sequence incorporated a selective borane-mediated reduction of a tertiary amide. Process scale-up to the pilot plant has been demonstrated successfully for the resolution step.