Formamide → Imiquimod

HRID 2253295Notes

Reaction equation

HRID 2253295 reaction equation
Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([NH2:21])=O.[OH-].[Na+]>O>[NH2:21][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1

Participants

5

Reactant 3

HCID 713FormamideHCID 14798Sodium HydroxideHCID 3839614-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline

Product 1

HCID 57469ImiquimodYield 84.5%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
140 °C

Procedure

A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline (50.0 g, 0.192 mol) and formamide (125 ml, 3.136 mole, 16.3 equiv.) was heated at about 140° C. under nitrogen atmosphere for 26 hours. Then, the reaction mixture was cooled to 95° C. and water (10 ml) was added. The reaction mixture was heated at this temperature for 2 hours. Water (250 ml) and 47% aqueous sodium hydroxide solution were then added to produce a pH of about 9 and the mixture was stirred at ambient temperature for 2 hours. A solid was collected by filtration, washed with water (3×50 ml) and methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give crude 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (Imiquimod) (39.0 g). The crude compound (39.0 g) was slurried in a mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 33.0 ml) under reflux for 6 hours. The mixture was cooled to ambient temperature and a colorless solid was collected by filtration, washed with methanol (3×20 ml), water (3×20 ml) and methanol (3×20 ml) and dried at 50° C. under reduced pressure overnight to yield 22.0 g of Imiquimod in 47.6% yield, having a purity of 98.2% (by HPLC). The product was crystallized from N,N-dimethylformamide to afford colorless Imiquimod having a purity of 99.9% (by HPLC).

Workup

  1. temperatureThen, the reaction mixture was cooled to 95° C.
  2. temperatureThe reaction mixture was heated at this temperature for 2 hours
  3. customto produce a pH of about 9
  4. filtrationA solid was collected by filtration
  5. washwashed with water (3×50 ml) and methanol (3×50 ml)
  6. customdried at 50° C. under reduced pressure overnight

Sources & evidence

ORD record
ord-c83c7c68a45146c6bc9895f39decf3ac
Source dataset
uspto-grants-2008_01
Patent number
US07323568B2

Reaction notes

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