Study The Synthesis Of All-trans Retinoids

The retinoids, a class of chemical compounds that are chemically to vitamin A, were widely used in the treatment of skin disease. Retinoic acid (tretinoin) and its isomers can inhibit the growth of some tumor cell. All-trans retinoic acid analogues such as tretinoin and acitretin are more stable than the other retinoids and can be used in the treatment of acne, psoriasis and several other skin diseases. In recent years, its clinical application on cancer prevention and treatment has become a hotspot in the field of medicine.In first chapter, the progress on the synthesis of some retinoids such as tretinoin, isotretinoin, acitretin, tocoretinate and fenretinide was reviewed.In second chapter, the synthesis of tretinoin via Wittig reaction of C15with C5synthons was studied. We used3-methyl-5-(2,6,6-trimethyl cyclohex-l-enyl)penta-2,4-dienyltriphenylphosphonium chloride and5-hydroxy-4-methylfuran-2-one as C15and C5synthon respectively. The Wittig product was isomerized to all-trans retinoic acid molecular iodine as catalyst. When CH3ONa was selected as base, methanol as solvent,5-hydroxy-4-methylfuran-2-one can be ring-opened into trans-at35-40℃in2h, which was olefinated with C15phosphonium salt at0℃. to give the mixture of11-cis,13-trans and11-cis,13-trans retinoic acid. The mixture was finally isomerized to all-trans retinoic acid with high purity using molecular iodine as catalyst in total yield of55%. The process we developed with high yield and purity, avoiding using of heavy metal make it attractive in the future large scale production.In third chapter, a simple and efficient process for the preparation of desired all trans-isomer of acitretin in high purity is developed, via Aldol condensation, Grignard reaction, phosphonium salt and Wittig reaction gave the mixture of11-cis,13-trans and11-cis,13-trans acitretin using4-methoxy-2,3,6-trimethylbenzaldehyde as the starting material. The mixture was finally isomerized to all-trans acitretin with high purity using molecular iodine as catalyst. The present invention avoid the process of ester hydrlysis and provides a simple process of the synthesis of all-trans isomer with high purity and in total yield of25.5%.At last, we choose the retinoic acid, prepared during previous chapter, as our starting point. Esterified of this material with DL-a-tocopherol gave the tocoretinate, and acylated with4-aminophenol gave the fenretinimide, two widely used derivatives of retinoid.