Imiquimod production process
View Patent ↗The present invention provides a process for preparing highly pure 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod). The process preferably includes heating 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline of formula (II) with ammonia in a polar aprotic solvent at relatively moderate pressure to produce imiquimod, and optionally purifying the imiquimod. The process of the present invention can produce highly pure imiquimod in high yield.
1. A process for preparing 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline of formula (I) (imiquimod):
the process comprising:
heating a mixture comprising 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline of formula (II):
and ammonia in a polar, aprotic solvent, which is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetramethylene sulfone (sulfolane), hexamethylphosphorotriamide (HMPA), or a mixture thereof, at relatively moderate pressure, to produce the compound of formula (I);
cooling the reaction mixture;
isolating the compound of formula (I); and
optionally purifying the compound of formula (I).
2. The process of claim 1 , wherein the solvent is dimethyl sulfoxide (DMSO).
3. The process of claim 1 , wherein the pressure is at most about 5 bars.
4. The process of claim 1 , wherein the mixture comprises at least about 2 equivalents of ammonia relative to one equivalent of formula (II), and is heated at a temperature in the range of from about 140° C. to about 150° C.
5. The process of claim 1 , comprising cooling the reaction mixture after reaction completion to precipitate imiquimod, isolating the imiquimod precipitate by filtration, and washing the precipitate.
6. The process of claim 5 , wherein the precipitate is washed with water, methanol, ethanol, 1-propanol, 2-propanol, or a mixture thereof.
7. The process of claim 6 , wherein the precipitate is washed with water, methanol or a mixture thereof.
8. The process of claim 1 , wherein the crude imiquimod is obtained in greater than 85% yield.
9. The process of claim 1 , wherein imiquimod is isolated from the reaction mixture and purified by precipitation, crystallization, slurrying, washing in a suitable solvent, filtration through a packed-bed column, dissolution in an appropriate solvent and re-precipitation by addition of a second solvent in which the compound is insoluble, or any combination of such purification methods.
10. The method of claim 9 , wherein the compound of formula (I) is purified by a method comprising:
suspending the crude imiquimod in a slurrying solvent;
mixing the suspension, optionally at elevated temperature, to dissolve at least a portion of the imiquimod;
optionally filtering the solution;
cooling to produce crystals of imiquimod;
collecting the crystals by filtration; and
optionally washing and drying the crystals.
11. The method of claim 10 , wherein the slurrying solvent comprises 1-propanol, 2-propanol, toluene, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), 2-methylterahydrofuran, or a mixture thereof.
12. The method of claim 11 , wherein the solvent used for washing the crystals comprises water, methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.
13. The method of claim 12 , wherein the solvent used for washing the crystals is methanol.
14. The method of claim 10 , wherein the imiquimod: slurrying solvent ratio is at least 2 g:2 ml (imiquimod: slurrying solvent).
15. The method of claim 14 , wherein the imiquimod: slurrying solvent ratio is about 2 g:3-30 ml (imiquimod: slurrying solvent).
16. The process of claim 1 , wherein the 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity of at least about 98.5%.
17. The method of claim 16 , wherein the 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity of at least about 99.5%.
18. The method of claim 17 , wherein the 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity of at least about 99.8%.