Synthesis Of Bexarotene

Bexarotene(1),a retinoic acid analogue,is a selective retinoid X receptor agonist developed by Ligand Inc.and first launched as Targretin^?in Amercia in January 2000.It can be used for the treatment of patients with all clinical stages of Cutaneous T-Cell gymphoma(CTCL)in the following categories:patients with early CTCL who have not tolareated other therapies,patients with refractory advanced stage CTCL therapies,and patients with refractory or persistent early stage CTCL.Here reviewed the reported synthetic routes of Bexarotene,and a novel route was designed and fulfilled in this thesis.After chlorination of 2,5-dimethyl-2,5-hexanediol,it was treated with toluene via Friedel-Crafts reaction to give 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene(4).4 was conducted for another Friedet-Crafts reaction with 4-bromobenzoic acid,and then with Wittig reaction to get(4-bromophenyl)(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)methanone(7).Compound 7 was then treated with n-BuLi,and successively bubbled with CO₂,and the target compound was obtained after acidic work-up.The target and all the key intermediates were confirmed by ¹HNMR,¹³C NMR or MS spectra.This novel synthesis is more efficient and convenient in an overall vield of 36.2%, and some column separations were cut.