Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

Acolbifene (EM‐652·HCl, SCH 57068·HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen‐sensitive breast cancer. Acolbifene‐7‐glucuronide 1 (major) and acolbifene‐4′‐glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2 H‐labelled derivatives 4 – 6 were synthesised for use as preclinical and clinical standards for LC–MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at −10°C to prevent epimerisation at the C‐2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi‐preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C 2 H 3 MgI followed by dehydration with C 2 H 3 CO 2 2 H/ 2 H 2 O. After chemical resolution and salt neutralisation, [ 2 H 3 ]acolbifene 19 was obtained with 99.4% enantiomeric purity and >98% isotopic purity. Copyright © 2007 John Wiley & Sons, Ltd.