Synthesis of [D₅‐ethyl]‐tamoxifen; a mechanistic probe of tamoxifen induced hepatic DNA adduct formation

Abstract

Tamoxifen which incorporates a fully deuterated ethyl group, [DS-ethyl]-tamoxifen, has been synthesised in order to probe the mechanism of tamoxifen induced hepatic DNA adduct formation. The pentadeuteroethyl group was introduced into the tamoxifen structure by treatment of the ketone precursor I-[4-(2-chloroethoxy)phenyl]-2-phenylethanone, as its sodium enolate, with [Ds]-iodoethane. Abbreviations: tamoxifen = (Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-l-butene; [D5-ethyll-tamoxifen = [3,3,4,4,4-*H5]-(2)-1-[4-[2-(dimethylamino)ethoxy]pheny~]-12-diphenyl-1butene.

Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells

“…The synthetic method for compounds 17-24 is depicted in Scheme 1. Phenyl acetic acid and 2-(chloroethoxy) benzene were condensed according to the method of Horton et al 22 to give the desired diphenylethanone intermediate, which was then alkylated and aminated to provide the compounds. Some final targets were isolated as free bases, while the ones that were purified by reversed chromatography were obtained as trifluoroacetate salts.…”