SYNTHESIS OF 4-(4-METHOXY-2,3,6-TRIMETHYLPHENYL)-3-BUTEN-2-ONE, A KEY SYNTHON FOR ETRETINATE AND ITS METABOLITES

A synthetic route to 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (2), a valuable synthon to etretinate (1), a potent antipsoriatic drug is described. The keto acids (3a) and (3b) obtained from 2,5-dimethylanisole by acylation with methylsuccinic and succinic anhydrides, respectively are elaborated separately to the identical methoxytrimethyldihydronaphthalene (7a) which on ozonolysis furnishes the ring opened arylketoaldehyde (8). Strategtic manipulation of the keto and aldehyde functions of 8 leads to the arylbutanone (14). Side chain bromination of 14 gives the bromoketone (15) which provides on dehydrobromination the key synthon (2).