A new and practical procedure is described for the preparation of benproperine phosphate enantiomers. Starting from the source of o-benzylphenol and (S)-(＋)-epichlorohydrin, the key intermediate (R)-1-(2-benzylphenoxy) propan-2-ol (2) was prepared by etherification, selective ring opening reaction in a simple and efficient step. (R)-1-(2-Benzylphenoxy)propan-2-yl 4-methylbenzenesulfonate (3) was obtained with p-toluenesulfonate, then followed by the S_N2-type reaction with piperdine furnishing (S)-(－)-benproperine, while (R)-(＋)-benproperine was obtained by submitting the same tosylate to two con-secutive S_N2-type reaction with LiBr and piperidine. The (S)-(－)- and (R)-(＋)-benproperine phosphates were recrystallized by ethanol, respectively. And the enantiomers of benproperine phosphate were character- rized by ¹H NMR and HRMS techniques. The improved method presented here features mild reaction conditions, simple operation, easy separation of product, high yield and was suitable for manufacturing in commercial scale.

Key words: chiral drug; benproperine, synthesis, enantiomer