Optimization and synthesis of ( E )‐4‐[2‐(3,4‐dihydro‐4,4‐dimethyl‐2 H ‐1‐benzopyran‐6‐y1)‐1‐propenyl]benzoic acid‐11‐[ 14 C

Abstract

Heteroarotinoids may be useful in the treatment of skin disorders and a wide variety of cancers. A synthesis of the C-14 labelled heteroarotinoid, (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl]benzoic acid-11-[ 14 C] ( * 1) is described via a multistep procedure similar to that used to obtain the unlabelled compound 2. The latter has shown good activity in several assays compared to the standard trans-retinoic acid (3). Reduction of the carbonyl group in 4,4-dimethylchroman-6-yl methyl ketone-(carbonyl- 14 C) ( * 5) with LiAlH 4 gave alcohol * 6. Phosphorylation with triphenylphospine hydrobromide in methanol led to the corresponding phosphonium salt * 7. Addition of n-butyllithium to * 7 in ether at -78 °C generated the Wittig reagent in situ and to this was added ethyl 4-formylbenzoate. Workup and chromatography afforded E-ester * 8 and Z-ester * 9 which were both hydrolyzed to labelled * 1. Labelled * 1 was identical to unlabelled 2 in terms of spectral data and melting point. The specific activity of * 1 was determined to be 57.2 μCi/mg.