Triethylamine → Isotretinoin

Participants

Reaction Conditions

Reaction Steps

N,N-dimethylacetamide (300 milliliters (mL)) , 5-hydroxy-4-methyl-2[5H]-furanone (26.81 grams (g)), 235 millimoles (mmol), 1.2 equivalents), and triethylamine (164 mL,1.2 moles, 6 equivalents) were added to 107.26 g (197 mmol) of [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl] triphenyl phosphonium salt. The resulting mixture was cooled to 15° C. prior to addition of magnesium chloride (30.03 g, 315 mmol, 1.6 equivalents). The reaction mixture was allowed to stir at room temperature for 17 hours. The reaction solution was washed with 200 mL of heptane. Toluene (100 mL) was added and the solution was acidified with 280 mL of 20% by volume HCl . The aqueous layer was back-extracted three times, each time with 200 mL of a 9:1 heptane:toluene mixture. The combined organic layers were washed with aqueous methanol, water, and then concentrated to give an orange solid. Heptane (250 mL) was added to the crude solid and the slurry was cooled to 0° C. and then filtered. Acetone (200 mL) and heptane (800 mL) were added to the solid and the resulting mixture was stirred at 25° C. Filtration of this slurry provided isotretinoin with >98% purity as a solid. 1H NMR: (300 MHz, CDCl3):δ 1.03(s,6; H), 1.44-1.68(m,4H), 1.72(s,3H), 1.88-2.05(m,2H), 2.0(s,3H), 2.11 (d,3H), 5.67(s,1H), 6.15-6.32(m,3H), 7.03 (dd,1H), 7.76 (d,1H).

Provenance & Evidence