Processes of synthesizing dihydropyridophthalazinone derivatives

1. A method of making a compound of formula (1):

or a salt thereof, the method comprising:

reacting a compound of formula (5),

or a salt thereof, with hydrazine monohydrate; wherein R is C 1 -C 6 alkyl;

wherein the compound of formula (5), or salt thereof, is prepared by reacting a compound of formula (4):

or a salt thereof, with 4-fluorobenzaldehyde in the presence of a reducing reagent and an acid or a Lewis acid; wherein R is C 1 -C 6 alkyl.

2. The method of claim 1 wherein the reducing reagent is a metal halide.

3. The method of claim 2 wherein the metal halide is TiCl 3 or SnCl 2 .

4. The method of claim 1 wherein the reducing reagent is powdered Fe.

5. The method of claim 1 wherein the reducing reagent is hydrogen in the presence of a metal catalyst.

6. The method of claim 5 , wherein the metal catalyst is selected from the group consisting of palladium, nickel, and platinum.

7. The method of claim 1 wherein the reducing reagent is MCNBH 3 ; wherein M is selected from the group consisting of Li, Na, K, and Bu 4 N.

8. The method of claim 1 wherein the acid is an inorganic acid selected from the group consisting of HCl, HBr, HI, H 2 SO 4 , and H 3 PO 4 .

9. The method of claim 1 wherein the acid is an organic acid selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, p-toluenesulfonic acid, and methylsulfonic acid.

10. The method of claim 1 wherein the Lewis acid is selected from the group consisting of AlCl 3 , TiCl 4 , SnCl 4 , and ZnCl 2 .

11. The method of claim 1 wherein the compound of formula (4), or salt thereof, is prepared by treating a compound of formula (3):

or a salt thereof, with R—OH in the presence of an acid; wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl; and the acid is selected from the group consisting of HCl, acetic acid, p-toluenesulfonic acid, and trifluoroacetic acid.

12. The method of claim 11 , wherein the compound of formula (3), or salt thereof, is prepared by reacting a compound of formula (2):

with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde under a condensation condition.

13. The method of claim 12 , wherein the condensation condition comprises using a base in the presence of a water scavenger at a temperature of about 80 to about 90° C.

14. The method of claim 13 wherein the base is triethylamine and the water scavenger is acetic anhydride.

15. A method of making a compound of formula (1):

or a salt thereof, the method comprising:

reacting a compound of formula (8):

or a salt thereof, with a base.

16. The method of claim 15 , wherein the base is a metal carbonate or a metal hydride.

17. The method of claim 16 , wherein the metal carbonate is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 .

18. The method of claim 16 , wherein the metal hydride is NaH or KH.

19. The method of claim 15 , wherein the compound (8), or salt thereof, is prepared by reacting a compound of formula (7):

or a salt thereof, with 4-fluorobenzaldehyde.

20. The method of claim 19 , wherein the compound of formula (7), or salt thereof, is prepared by reacting a compound of formula (3):

or a salt thereof, with hydrazine monohydrate in the presence of an acid.

21. The method of claim 20 wherein the acid is selected from the group consisting of acetic acid, trifluoroacetic acid, HCl, and p-toluenesulfonic acid.

22. A method of making a compound of formula (1):

or a salt thereof, the method comprising:

reacting a compound of formula (5),

or a salt thereof, with hydrazine monohydrate; wherein R is C 1 -C 6 alkyl;

wherein the compound of formula (5), or salt thereof, is prepared by reacting a compound of formula (9):

or a salt thereof, with a reducing reagent in an inert solvent at a temperature of about 0 to about 140° C. for about 1 to about 48 hours; wherein R is C 1 -C 6 alkyl.

23. The method of claim 22 , wherein the reducing reagent is a metal borohydride.

24. The method of claim 23 , wherein the metal borohydride is NaBH 4 or NaCNBH 3 .

25. The method of claim 22 , wherein the reducing reagent is powdered Fe.

26. The method of claim 22 , wherein the reducing reagent is TiCl 3 or SnCl 2 .

27. The method of claim 22 , wherein the reducing reagent is hydrogen in the presence of a transition metal.

28. The method of claim 27 , wherein the transition metal is selected from the group consisting of palladium, nickel, and platinum.

29. A method of making a compound of formula (1):

or a salt thereof, the method comprising:

reacting a compound of formula (5),

or a salt thereof, with hydrazine monohydrate; wherein R is C 1 -C 6 alkyl;

wherein the compound of formula (5), or salt thereof, is prepared by reacting a compound of formula (10):

or a salt thereof, with a reducing reagent; wherein R is C 1 -C 6 alkyl.

30. The method of claim 29 , wherein the reducing reagent is powdered Fe.

31. The method of claim 29 , wherein the reducing reagent is a metal borohydride.

32. The method of claim 31 wherein the metal borohydride is NaBH 4 .

33. The method of claim 29 , wherein the reducing reagent is hydrogen in the presence of a transition metal.

34. The method of claim 33 , wherein the transition metal is selected from the group consisting of palladium, nickel, and platinum.

35. The method of claim 29 , wherein the compound of formula (10), or salt thereof, is prepared by reacting a compound of formula (9):

or a salt thereof, with a reducing reagent; wherein R is C 1 -C 6 alkyl.

36. The method of claim 35 , wherein the reducing reagent is hydrogen under atmospheric pressure at ambient temperature.

37. A method of making a compound of formula (1a) or (1b):

or a salt thereof, comprising reacting a compound of formula (6a) or (6b):

or a salt thereof, with hydrazine in an alcohol; wherein R is C 1 -C 6 alkyl.

38. The method of claim 37 , wherein the compound of formula (6a) or (6b) is prepared by performing chiral chromatography resolution of a compound of formula (5):

39. The method of claim 38 , wherein the chiral resolution is achieved with an Supercritical Fluid Chromatography (SFC) unit.

40. The method of claim 39 , further comprising use of a chiral stationary phase, wherein the chiral stationary phase is a CHIRALPAK column.

41. The method of claim 40 , wherein the CHIRALPAK column is an IC or AY column.

42. The method of claim 39 , further comprising use of a mobile phase, wherein the mobile phase comprises CO 2 and MeOH.

43. The method of claim 38 , wherein the chiral resolution is achieved with a Simulated Moving Bed chromatography (SMB) unit.

44. The method of claim 43 , further comprising use of a chiral stationary phase, wherein the chiral stationary phase is a CHIRALPAK column.

45. The method of claim 44 , wherein the CHIRALPAK column is an IC column.

46. The method of claim 43 , further comprising use of a mobile phase, wherein the mobile phase is acetonitrile.