The synthesis of meso-Hexoestrol[3,4-D₂] and some related specifically deuterated compounds

Abstract

Condensation of p-methoxyphenylacetonitrile with p-methoxypropiophenone in the presence of sodium hydride in dimethyl sulphoxide at 65º gave (Z)-(23%) and (E)-2,3-bis(p-methoxyphenyl)pent-2-enenitrile(16%). The reduction of this α,β-unsaturated nitrile with lithium aluminium deuteride in tetrahydrofuran, and workup with D₂O or with H₂O, gave high yields of erythro-2,3-bis(p-methoxy-phenyl)valeronitrile[2,3-D₂], or -[3-D], respectively. Conversion of the dideuteronitrile into the corresponding methyl ketone with methylmagnesium iodide, followed by a hydride reduction-tosylation-hydride reduction sequence, then demethylation, afforded meso-hexoestrol[3,4-D₂]. Dehydration of (3RS,4SR)-3,4-bis(p-methoxyphenyl)hexan-2ξ-ol[3,4-D₂] with phosphoryl trichloride in pyridine gave 3,4-bis(p-methoxyphenyl)hex-2-ene[4-D]. Reduction of erythro-2,3-bis(p-methoxy- phenyl)valeronitrile[3-D] to the corresponding amine followed by quaternization and Hofmann elimination afforded 2,3-bis(p-methoxypheny1)pent-1-ene[3-D].