Synthesis of cerdulatinib

1. A process for preparing cerdulatinib, which is of formula I:

or a salt thereof, wherein the process comprises contacting Compound A or a salt thereof with Compound B or a salt thereof under conditions to form cerdulatinib or a salt thereof:

wherein Compound A is Compound A-2 or Compound A-3 or a salt thereof, or a mixture thereof,

wherein Compound A-2 or Compound A-3 or a salt thereof, or a mixture thereof, is prepared by a method comprising contacting an oxidizing agent with Compound C:

or a salt thereof;

wherein Compound C is prepared by a method comprising contacting Compound D-1

or a salt thereof with formamide and sodium ethoxide.

2. A three-step, one-pot process for preparing cerdulatinib or a salt thereof, comprising steps (1) contacting Compound F

or a salt thereof with ammonia or a salt thereof to form Compound E

or a salt thereof,

(2) contacting Compound E or a salt thereof with cyclopropylamine or a salt thereof to form Compound A

or a salt thereof, and

(3) contacting Compound A or a salt thereof with Compound B

or a salt thereof to form cerdulatinib or a salt thereof, wherein X is selected from the group consisting of Cl, Br, CH 3 S(O)— and CH 3 S(O) 2 —, X 1 and X 2 are independently a leaving group, and wherein all of steps (1)-(3) are conducted in one reactor without isolation of intermediates.

3. A three-step, one-pot process for preparing cerdulatinib or a salt thereof, comprising steps (1) contacting Compound F-1

or a salt thereof with ammonia or a salt thereof to form Compound E-1

or a salt thereof,

(2) contacting Compound E-1 or a salt thereof with cyclopropylamine or a salt thereof to form Compound A-1:

or a salt thereof, and

(3) contacting Compound A-1 or a salt thereof with Compound B:

or a salt thereof to form cerdulatinib or a salt thereof, wherein all of steps (1)-(3) are conducted in one reactor without isolation of intermediates.

4. The process of claim 3 , wherein the molar ratio of ammonia to Compound F-1 is between about 1.7:1 to about 2.3:1.

5. The process of claim 3 , wherein the molar ratio of ammonia to Compound F-1 is between about 1.9:1 to about 2.0:1.

6. The process of claim 3 , wherein the contacting of ammonia and Compound F-1 is in a solvent.

7. The process of claim 3 , wherein the contacting of ammonia and Compound F-1 is at a temperature of about −20° C. to about 0° C.

8. The process of claim 2 , wherein the molar ratio of cyclopropylamine to Compound E is between about 1:1 to about 2:1.

9. The process of claim 2 , wherein the contacting of cyclopropylamine and Compound E is in a solvent.

10. The process of claim 2 , wherein the contacting of cyclopropylamine and Compound E is at a temperature of about 20° C. to about 0° C.

11. The process of claim 3 , wherein the molar ratio of Compound A-1 to Compound B is about 1:1.

12. The process of claim 3 , wherein contacting of Compound A-1 and Compound B is under a neutral condition.

13. The process of claim 3 , wherein the contacting of Compound A-1 and Compound B under a neutral condition is at a temperature of about 70° C. to about 100° C.

14. The process of claim 2 , wherein Compound F or a salt thereof is prepared by a method comprising contacting POCl 5 with Compound G:

or a salt thereof.

15. The process of claim 14 , wherein the molar ratio of POCl 5 to Compound G is between about 2.5:1 to about 3.5:1.

16. The process of claim 14 , wherein contacting of POCl 5 and Compound G is in a solvent.

17. The process of claim 14 , wherein the contacting of POCl 5 and Compound G is under reflux conditions.

18. The process of claim 1 , wherein contacting an oxidizing agent with Compound C to form Compound A-2 or Compound A-3 or a salt thereof, or a mixture thereof, and contacting Compound A-2 or Compound A-3, or a salt thereof, or a mixture thereof, with Compound B to form cerdulatinib, or a salt thereof, are conducted as a two-step, one-pot process.

19. The process of claim 1 , wherein Compound B is prepared by a process comprising reduction of Compound H

or a salt thereof.

20. The process of claim 1 , further comprising isolating cerdulatinib.

21. The process of claim 1 , further comprising contacting cerdulatinib with an acid to form a salt of cerdulatinib.

22. The process of claim 1 , further comprising contacting cerdulatinib with hydrochloric acid in a solvent comprising dimethyl sulfoxide and ethanol to form cerdulatinib HCl salt.

23. The process of claim 22 , wherein the contacting is at about 70° C. to about 80° C.

24. The process of claim 22 , further comprising isolating and purifying cerdulatinib HCl salt.

25. A compound of Formula A:

or a salt thereof, wherein X is Cl or Br.

26. A compound

or a salt thereof.

27. The process of claim 1 , wherein the process does not comprise isolating Compound D-2:

28. The process of claim 1 , wherein Compound D-1 is prepared by a method comprising contacting Compound K

or a salt thereof with cyclopropylamine or a salt thereof to form Compound D-1.

29. The process of claim 1 , wherein the molar ratio of Compound B to Compound A is about 1:1 to about 1.1:1.

30. The process of claim 1 , wherein the conditions to form cerdulatinib comprise a temperature of about 55° C. to about 65° C.

31. The process of claim 1 , wherein Compound B and Compound A are contacted for about 8 to about 24 hours.

32. The process of claim 18 , wherein the molar ratio of the oxidizing agent to Compound C is about 1.1:1 to about 2:1.

33. The process of claim 19 , wherein Compound H is prepared by a process comprising contacting Compound J:

or a salt thereof with CH 3 CH 2 SO 2 X 3 , wherein X 3 is a leaving group.

34. The process of claim 19 , wherein Compound H is prepared by a process comprising contacting Compound L

or a salt thereof with Compound M

or a salt thereof to form Compound H or a salt thereof.

35. The process of claim 1 wherein formamide and Compound D-1 are in a molar ratio of about 5:1 to about 15:1.

36. The process of claim 1 wherein the contacting of Compound D-1 with formamide and sodium ethoxide is in a solvent.

37. The process of claim 36 wherein the solvent is THF.

38. The process of claim 1 wherein the contacting of Compound D-1 with formamide and sodium ethoxide is at a temperature of about 0° C. to about 10° C.

39. The process of claim 1 wherein the contacting of Compound D-1 with formamide and sodium ethoxide is for about 10 to about 24 hours.

40. A process for preparing cerdulatinib, which is of formula I:

or a salt thereof, wherein the process comprises contacting Compound A or a salt thereof with Compound B or a salt thereof under conditions to form cerdulatinib or a salt thereof:

wherein Compound A is Compound A-2 or Compound A-3 or a salt thereof, or a mixture thereof,

wherein Compound A-2 or Compound A-3 or a salt thereof, or a mixture thereof, is prepared by a method comprising contacting an oxidizing agent with Compound C:

or a salt thereof;

wherein Compound C is prepared by a method comprising contacting Compound D-2

or a salt thereof with formamide.

41. The process of claim 40 , wherein Compound D-2 is prepared by a method comprising hydrolyzing Compound D-1 or a salt thereof with a hydrolyzing agent to form Compound D-2 or a salt thereof.