Ammonia → Imiquimod

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (100.0 g, 0.385 mole) and formamide (250 ml, 6.27 mole, 16.3 equiv.) was heated to 145° C. under nitrogen atmosphere. Then, ammonia (gas) (92 g, 5.29 mole, 14 equiv.) was bubbled (4-5 g per hour) into the reaction mixture at this temperature during a period of 20 hours. Then, the reaction mixture was cooled to ambient temperature and stirred at this temperature for 3 hours. A colorless solid was collected by filtration, washed with methanol (3×100 ml), water (3×100 ml) and again with methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give a crude Imiquimod (74.1 g, 80.2% yield, purity by HPLC: 99.3%). The crude compound (74.1 g) was slurried in a boiling mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 6 ml) for 4 hours. The hot mixture was filtered and the thus obtained cake was washed with methanol (3×40 ml), water (3×50 ml) and again with methanol (3×40 ml) and dried at 50° C. under reduced pressure to yield 72.2 g of Imiquimod in 77.9% yield, having a purity of 99.85% (by HPLC)

Provenance & Evidence