Synthesis And Process Improvement Of Bexarotene As An Anti-tumor Drug

Bexarotene (trade name Targretin), was the third generation of retinoic acid drugs which was developed by the United States Ligand Pharmaceuticals Inc and was indicated by the FDA in 2000 January 15. It has been used off-label for cutaneous T-cell lymphoma.Skin T-cell lymphoma symptoms, treatment and retinoic acid on the treatment of drug classification, research and progress of the retinoic acid drugs are included in this paper. Especially, the research background and clinical effect of bexarotene are discussed in details.In view of the domestic market has not yet finished Bexarotene, for the industrialization of the product in domestic, based on available literatures, we studied the synthesis and process improvement of the drug. According to the known synthetic methods of Bexarotene, we use cheap 2,5-dimethyl-2,5-hexanediol as the starting material, followed by the five steps of chlorine-substituted, Friedel-Crafts Alkylation, Friedel-Crafts Acylation, Wittig reaction and ester hydrolysis to complete the synthesis of the product. The melting points of target compound measured is consistent with that reported in the literature, and the structure were confirmed by 1H-NMR.In order to obtain the optimum conditions, the synthesis process of each intermediate and final product have been improved and we investigated the reaction temperature, time, raw material ratio, the amount of catalyst, the reaction solvent, and so on. In the meantime, in the stage of Friedel-Crafts Acylation, we used acyl chloride slowly trickle-down into the 1,2-dichloroethane solution of arene and aluminum chloride, changed the patent in one-pot method to reduce the by-product isomers generation and finally, improved product yield of the step; In the Wittig reaction stage, the reported literature used toluene as solvent and sodium amide as base, and we used THF as solvent and sodium hydride as base, compared to that, the reaction time was shorten and reaction yield was increased. Various factors that affect the product yield have been researched; it reached to the purpose of reducing costs, increasing yield and making moderate reaction conditions, and consequently reached a better synthesis process condition.