Process for preparing 2-methyl-1-(2-methylpropyl)-1

1. A method for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, the method comprising:

providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier comprising a lower alcohol;

combining the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an ammonia-or ammonium-containing reagent and an arylsulfonyl halide to form a mixture; and

allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.

2. The method of claim 1 further comprising combining the mixture with an aqueous base.

3. The method of claim 2 wherein sufficient aqueous base is added to adjust the mixture to a pH of greater than 8.

4. The method of claim 3 wherein the aqueous base comprises aqueous sodium hydroxide.

5. The method of claim 1 wherein the ammonia- or ammonium-containing reagent comprises ammonium hydroxide in water.

6. The method of claim 5 wherein the ammonia- or ammonium-containing reagent comprises less than ten equivalents of ammonium hydroxide.

7. The method of claim 1 wherein the arylsulfonyl halide is benzenesulfonyl chloride or p-toluenesulfonyl chloride.

8. The method of claim 1 wherein the period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c][1,5]naphthyridin-4-amine is 45 minutes to 75 minutes.

9. The method of claim 1 wherein providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier comprising a lower alcohol; combining the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an ammonia- or ammonium-containing reagent and an arylsulfonyl halide to form a mixture; and allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine are carried out at a temperature of 20° C. to 30° C.

10. The method of claim 1 wherein the ammonia- or ammonium-containing reagent is added prior to the arylsulfonyl halide.

11. The method of claim 1 further comprising cooling the mixture to a temperature of 5° C. to 15° C.

12. The method of claim 1 further comprising separating at least a portion of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine from at least a portion of the mixture.

13. The method of claim 12 further comprising washing and at least partially drying the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.

14. The method of claim 1 wherein providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine comprises:

providing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier comprising a non-chlorinated solvent at a temperature of 25° C. to 70° C.;

combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent to form a mixture and maintaining the mixture at a temperature of 25° C. to 70° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and

isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.

15. The method of claim 14 wherein the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof.

16. The method of claim 15 wherein the non-chlorinated solvent is toluene.

17. The method of claim 14 wherein the oxidizing agent comprises peracetic acid.

18. The method of claim 14 wherein the period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine comprises a period of time sufficient to react at least 80% of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine.

19. The method of claim 18 wherein the period of time sufficient to react at least 80% of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine is 5 hours to 7 hours.

20. The method of claim 14 wherein isolating the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine comprises:

combining the mixture comprising the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine with an aqueous solution of a reducing agent followed by an aqueous base;

cooling the mixture to form solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and

separating at least a portion of the solid 2-methyl-1-(2-methylpropyl-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine from at least a portion of the mixture.

21. The method of claim 20 wherein the reducing agent is selected from the group consisting of sodium metabisulfite, sodium sulfite, ferrous sulfate, and combinations thereof.

22. The method of claim 21 wherein the reducing agent is sodium metabisulfite.

23. The method of claim 22 wherein combining the mixture comprising the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine with an aqueous solution of sodium metabisulfite followed by an aqueous base comprises combining the mixture with an aqueous solution of 0.1 equivalent to 0.3 equivalent of sodium metabisulfite followed by a sufficient amount of aqueous base to adjust the mixture to a pH of greater than 10.

24. The method of claim 22 or claim 23 wherein combining the mixture comprising the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine with an aqueous solution of sodium metabisulfite followed by an aqueous base comprises combining six to ten milliliters of water per gram of 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine with a mixture comprising eight to twelve milliliters of toluene per gram of 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.

25. The method of claim 24 wherein the volume ratio of water to toluene is 0.8:1.

26. The method of claim 20 wherein cooling the mixture comprises cooling the mixture to a temperature of 0° C. to 20° C.

27. The method of claim 14 wherein combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine with an oxidizing agent comprises combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine with at least one equivalent of peracetic acid.

28. The method of claim 14 wherein providing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine comprises:

providing N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier comprising a non-chlorinated solvent at a temperature of 18° C. to 30° C.;

combining the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with an organic acid to form a mixture;

combining the mixture comprising the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.; and

maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine.

29. The method of claim 28 wherein the organic acid is selected from the group consisting of p-toluenesulfonic acid, trifluoroacetic acid, ethanesulfonic acid, and mixtures thereof.

30. The method of claim 29 wherein the organic acid is p-toluenesulfonic acid.

31. The method of claim 28 wherein the trialkyl orthoacetate is triethyl orthoacetate.

32. The method of claim 28 wherein the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof.

33. The method of claim 32 wherein the non-chlorinated solvent is toluene.

34. The method of claim 28 further comprising cooling the mixture comprising 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 25° C. to 70° C.

35. The method of claim 28 wherein the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine is not isolated prior to combining it with the oxidizing agent.

36. The method of claim 28 wherein combining the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine with an organic acid comprises combining the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine with 0.02 equivalent to 0.08 equivalent of the organic acid.

37. The method of claim 28 wherein combining the mixture comprising the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate comprises combining the mixture comprising the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with at least one equivalent of the trialkyl orthoacetate.

38. The method of claim 28 wherein maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine comprises maintaining, the temperature at 70° C. to 100° C. for at least 30 minutes.

39. The method of claim 28 wherein providing N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine comprises:

providing N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier comprising a non-chlorinated solvent;

combining the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst to form a mixture;

subjecting the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; and

removing at least a portion of the hydrogenation catalyst from the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine.

40. The method of claim 39 wherein the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof.

41. The method of claim 40 wherein the non-chlorinated solvent is toluene.

42. The method of claim 39 wherein combining the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst comprises combining the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture.

43. The method of claim 42 further comprising removing at least a portion of the isopropanol from the mixture of N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier comprising toluene and isopropanol.

44. The method of claim 39 wherein the hydrogenation catalyst comprises platinum on carbon.

45. The method of claim 39 wherein the conditions effective to form N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine comprise a temperature of 15° C. to 30° C.

46. The method of claim 39 wherein the conditions effective to form N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine comprise a hydrogen pressure of 1×10 5 Pa to 3×10 5 Pa.

47. The method of claim 39 wherein the conditions effective to form N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine comprise a time period of at least 3 hours.

48. The method of claim 39 wherein the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine is not isolated prior to combining it with the organic acid.

49. The method of claim 39 wherein providing N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine comprises:

providing 4-chloro-3-nitro[1,5]naphthyridine in a carrier comprising a water-miscible organic liquid;

combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridine-4-amine;

combining the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and

separating at least a portion of solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water.

50. The method of claim 49 wherein the water-miscible organic liquid is selected from the group consisting of tetrahydrofuran, dichloromethane, acetonitrile, and mixtures thereof.

51. The method of claim 50 wherein the water-miscible organic liquid is tetrahydrofuran.

52. The method of claim 49 wherein the conditions effective to form a mixture comprising N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine comprise a temperature of 15° C. to 30° C.

53. The method of claim 49 wherein combining the 4-chloro-3-nitro[1,5]naphthyridine with isobutylamine comprises combining the 4-chloro-3-nitro[1,5]naphthyridine with at least two equivalents of isobutylamine.

54. The method of claim 49 wherein separating at least a portion of the solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine comprises filtering the solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine.

55. The method of claim 54 further comprising washing and drying the solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine.

56. The method of claim 49 wherein providing 4-chloro-3-nitro[1,5]naphthyridine comprises:

providing 3-nitro[1,5]naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;

combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;

combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; and

separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water.

57. The method of claim 56 wherein the conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine comprise a temperature of 15° C. to 35° C.

58. The method of claim 56 wherein the conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine comprise a time period of at least one hour.

59. The method of claim 56 wherein the conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine comprise cooling the mixture comprising the water to a temperature of less than 20° C.

60. The method of claim 56 wherein combining the 3-nitro[1,5]naphthyridin-4-ol with phosphorous oxychloride comprises combining the 3-nitro[1,5]naphthyridin-4-ol with at least one equivalent of phosphorous oxychloride.

61. The method of claim 56 wherein separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine comprises filtering the solid 4-chloro-3-nitro[1,5]naphthyridine from the mixture comprising the water.

62. The method of claim 56 wherein separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine occurs less than 30 minutes after combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water.

63. The method of claim 56 wherein the solid 4-chloro-3-nitro[1,5]naphthyridine is combined with isobutylamine within less than 4 hours of its preparation.

64. The method of claim 1 wherein providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine comprises:

providing 3-nitro-1,5-naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;

combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;

combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine;

separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water;

combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier comprising a water-miscible organic liquid;

combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;

combining the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;

separating at least a portion of solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water; and

converting the solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine to 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.

65. A method of making N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine, wherein the method comprises:

providing 3-nitro[1,5]naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;

combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;

combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine;

separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water;

combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier comprising tetrahydrofuran;

combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;

combining the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and

separating at least a portion of solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water.

66. A method of making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine, the method comprising:

providing 3-nitro[1,5]naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;

combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;

combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine;

separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water;

combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier comprising tetrahydrofuran;

combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridine-4-amine;

combining the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;

separating at least a portion of solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water

combining the separated solid N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with a carrier comprising toluene;

combining the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture;

subjecting the mixture comprising the N 4 -(2-methylpropyl)-3-nitro[1,5]naphthyridine-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine;

removing at least a portion of the hydrogenation catalyst from the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine;

removing at least a portion of the isopropanol from the mixture of N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier comprising toluene and isopropanol;

heating the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20° C. to 55° C.;

combining the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture;

combining the mixture comprising the N 4 -(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.;

maintaining the temperature at 70° C. to 100° C. for a period time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine;

cooling the mixture comprising 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45° C. to 55° C.;

combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent comprising peracetic acid to form a mixture;

maintaining the mixture comprising the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45° C. to 55° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and

isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.