Imiquimod production process

1. A process for preparing 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) of formula (I), the process comprising:

reacting 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline of formula (II) in an organic solvent with a non-gaseous amine precursor, which is guanidine or a salt thereof, or urea, to produce the compound of formula (I);

isolating the compound of formula (I); and

optionally purifying the compound of formula (I).

2. The process of claim 1 , wherein the organic solvent comprises dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetramethylene sulfone (sulfolane), diisoamyl ether, diglyme, triglyme, decahydronaphthalene, paraffins, or a mixture thereof.

3. The process of claim 2 , wherein the organic solvent is dimethyl sulfoxide (DMSO).

4. The process of claim 1 , wherein the non-gaseous amine precursor is guanidine carbonate.

5. The process of claim 1 , wherein said reacting comprises heating the compound of formula (II) and guanidine carbonate in the organic solvent at a temperature of from about 140° C. to about 150° C. optionally without application of pressure.

6. The process of claim 5 , wherein about 2 equivalents of guanidine carbonate are used per 1 equivalent of the compound of formula (II).

7. The process of claim 1 , wherein the non-gaseous amine precursor is urea.

8. The process of claim 7 , wherein the urea and the compound of formula (II) are heated at a temperature of from about 135° C. to about 140° C., optionally without application of pressure.

9. The process of claim 8 , wherein at least about 5 equivalents of urea are used per 1 equivalent of the compound of formula (II).

10. The process of claim 1 , comprising isolating the imiquimod from the reaction mixture and purifying the imiquimod by one or more methods selected from precipitation, crystallization, slurrying, washing with a suitable solvent, filtration , re-precipitation from a solvent system comprising at least one solvent and at least one additional solvent in which the imiquimod is insoluble, and combinations thereof.

11. The process of claim 10 , wherein the imiquimod is purified by a crystallization method comprising:

dissolving the imiquimod in a solvent, optionally at elevated temperature;

optionally adding a base and mixing;

optionally filtering the solution at elevated temperature;

optionally cooling to about 20° C. to produce imiquimod crystals; and

collecting imiquimod crystals,

optionally washing the crystals with at least one solvent, and

optionally drying the crystals.

12. The process of claim 11 , wherein the crystallization solvent is water, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), or a mixture thereof.

13. The process of claim 12 , wherein the crystallization solvent is dimethyl sulfoxide (DMSO).

14. The process of claim 11 , wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof.

15. The process of claim 14 , wherein the base is sodium hydroxide.

16. The process of claim 11 , wherein the solvent used for washing the crystals is water, methanol, ethanol, 1-propanol, 2-propanol, or a mixture thereof.

17. The process of claim 16 , wherein the solvent is water, methanol or a mixture thereof.

18. The process of claim 11 , wherein 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity of at least about 98.5%.

19. The process of claim 18 , wherein 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity of at least about 99.5%.

20. The process of claim 19 , wherein 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (imiquimod) (I) is obtained in a purity equal to or greater than about 99.8%.