Synthesis of 14C‐labelled EM‐800 (SCH 57050) and EM‐652·HCl (SCH 57068·HCl, acolbifene), pure selective estrogen receptor modulators

Abstract

AbstractEM‐800 (SCH 57050) and EM‐652·HCl (SCH 57068·HCl, acolbifene) are orally active pure selective estrogen receptor modulators. The corresponding 14C2‐radiolabelled compounds 1 and 2 were synthesized for metabolic studies with uniform labelling of two carbons within the benzene ring of the 2H‐1‐benzopyran moiety by optical resolution of racemic (±)‐[14C2]EM‐343 4. This pivotal intermediate amine was prepared in 6 steps with 38% yield from commercially available [U‐14C2]resorcinol (3). Resolution by selective crystallization of the diastereomeric mixture of (S)‐(+)‐camphorsulfonates salts gave the desired (+)‐[14C2]EM‐652·(+)‐CSA 13. Moreover, the racemic amine 4 was recovered from mother liquors by basic treatment, and resolved again. We obtained salt 13, at a 52% yield with 97% diastereomeric excess by repeating the resolution–racemization process. Finally, the corresponding dipivaloate (+)‐[14C2]EM‐800 1 and hydrochloride salt (+)‐[14C2]EM‐652·HCl 2 were prepared at respective specific activities of 19.7 and 24.5 µCi/mg with 96.3% radiochemical purity. Copyright © 2004 John Wiley & Sons, Ltd.