4-Aminophenol → Fenretinide

Participants

Reaction Conditions

Reaction Steps

All-trans-retinoic acid 5.0 grams (0.0166 mol) was charged to a 250 milliliter round bottom flask, followed by 100 milliliters of methyl-t-butyl ether (MTBE) and the stirrer started. The resulting suspension was cooled to <10° C., 5.8 milliliters (0.0417 mol) of triethylamine was added and the mixture was further cooled to <5° C. While maintaining a temperature of less than 5° C., 2.5 milliliters (0.0183 mol) of isobutylchloroformate was added drop wise over approximately fifteen minutes. The resulting yellow suspension was stirred for 1 hour at which point the reaction was shown to be complete via HPLC analysis. A hazy solution of 2.73 grams (0.025 mol) of 4-aminophenol in 12 milliliters of DMF was added to the mixed carbonate over 10 minutes at less than 10° C. The reaction was again stirred for 1 hour and checked for completion by HPLC. After 1 hour the reaction was 97% complete with 9% retinoic acid regenerated. The reaction was stirred one additional hour and then quenched with 25 milliliters of aqueous 3M HCl at <10° C. The layers were separated and the aqueous phase re-extracted with 50 milliliters of MTBE. The combined organic extracts were washed once with 25 milliliters of aqueous 3M HCl, followed by 25 milliliters of H2O. The organic phase was further washed with saturated K2CO3 solution (5×25 milliliters), followed by 25 milliliters of H2O, and finally 25 milliliters of brine. The organics were concentrated to a total volume of approximately 15-20 milliliters and 40 milliliters of heptane was added with stirring. Shortly after the addition of heptane, the product began to precipitate from solution as a yellow solid. The suspension was stirred for an hour at room temperature, cooled to 0-5° C., and stirred an additional 1 hour cold. The crude product was filtered and the cake washed once with cold (0-10° C.) 50/50 (v/v) of MTBE/heptane followed by two heptane washes. The product was dried a short time on the filter to give 5.83 grams of crude fenretinide that contained a small amount of solvent (99.0% pure by area percent). The crude product was dissolved in 40 milliliters of warm ethanol and heated to 70-78° C. with stirring. Water (12 milliliters) was added at >70° C. and the heat removed. Upon cooling the product began to crystallize as a yellow solid. The suspension was stirred for 30-45 minutes at <30° C. and further cooled to 0-5° C. for an additional 30 minutes. The product was isolated via filtration and washed two times with 20 milliliters of cold 60/40 (v/v) ethanol/H2O. The product was dried at 40 to 45° C. overnight to yield 2.84 grams of fenretinide (43% overall yield from retinoic acid, 99.5% pure by area percent HPLC) as a yellow solid.

Provenance & Evidence