Process and intermediates for preparing a JAK inhibitor

1. A process of preparing baricitinib, or a salt thereof, comprising:

reacting a compound of formula 3:

or a salt thereof, with a reagent which is selected from: (i) a salt of formula 2a, and (ii) a compound of formula 2b:

wherein X − is a counter anion.

2. The process of claim 1 , wherein the reagent is the compound of formula 2b.

3. The process of claim 1 , wherein the salt of formula 2a, or the compound of formula 2b is prepared by a process comprising:

reacting a compound of formula 1a:

or a salt thereof, with a Vilsmeier reagent formed from dimethylformamide.

4. The process of claim 3 , wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

5. The process of claim 4 , wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

6. The process of claim 3 , wherein the product of the reacting with the Vilsmeier reagent is a salt of formula 2d:

7. The process of claim 6 , further comprising reacting the salt of formula 2d with a base to form a salt of formula 2c:

8. The process of claim 3 , wherein the product of the reacting with the Vilsmeier reagent is a salt of formula 2c:

9. The process of claim 8 , further comprising reacting the salt of formula 2c with a salt of formula M + X − to form the salt of formula 2a, wherein:

M + is a counter cation; and

X − is a counter anion other than Cl − .

10. The process of claim 3 , wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:

deprotecting a compound of formula 1aP:

wherein P 1 is an amino protecting group.

11. The process of claim 10 , wherein the compound of formula 1aP is prepared by a process comprising:

reacting a compound of formula 2P:

with MeMgBr in the presence of a Grignard catalyst,

wherein P 1 is an amino protecting group.

12. The process of claim 11 , wherein the compound of formula 2P is prepared by a process comprising:

protecting a compound of formula 12a:

to form the compound of formula 2P.

13. The process of claim 12 , wherein the compound of formula 12a is prepared by a process comprising:

reacting a compound of formula 11a:

or a salt thereof, with a strong acid.

14. The process of claim 13 , wherein the compound of formula 11a, or a salt thereof, is prepared by a process comprising:

reacting a compound of formula 10a:

or a salt thereof, with (methoxymethyl)triphenylphosphonium chloride and a base.

15. The process of claim 14 , wherein the compound of formula 10a, or a salt thereof, is prepared by a process comprising:

reacting a compound of formula 9a:

with ammonia.

16. The process of claim 15 , wherein the compound of formula 9a is prepared by a process comprising:

reacting a compound of formula 8a:

with a Vilsmeier reagent formed from dimethylformamide.

17. The process of claim 12 , wherein the compound of formula 12a is prepared by a process comprising:

reacting a compound of formula 15a:

with a chlorinating agent.

18. The process of claim 17 , wherein the compound of formula 15a is prepared by a process comprising:

(i) reacting a compound of formula 14a:

with formamidine acetate and an alkali metal alkoxide to generate a compound of formula 14aa:

and

(ii) reacting the compound of formula 14aa with a strong acid.

19. The process of claim 18 , wherein the compound of formula 14a is prepared by a process comprising:

reacting a compound of formula 13a:

with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

20. The process of claim 3 , wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:

reducing a compound of formula 23P:

wherein P 2 is an amino protecting group.

21. The process of claim 20 , wherein the compound of formula 23P is prepared by a process comprising:

reacting a compound of formula 22P:

with MeMgCl in the presence of a Grignard catalyst,

wherein P 2 is an amino protecting group.

22. The process of claim 21 , wherein the compound of formula 22P is prepared by a process comprising:

protecting a compound of formula 22a:

to form the compound of formula 22P.

23. The process of claim 22 , wherein the compound of formula 1a, or the salt thereof, is prepared by a process comprising:

reacting a compound of formula 18a:

with an acid to form the compound of formula 1a, or the salt thereof.

24. The process of claim 23 , wherein the compound of formula 18a is prepared by a process comprising:

reacting a compound of formula 17a:

with formamidine acetate and triethyl orthoformate to form the compound of formula 18a.

25. The process of claim 24 , wherein the compound of formula 17a is prepared by a process comprising:

reacting a compound of formula 20a:

with a compound of formula 21a:

to form the compound of formula 17a.

26. The process of claim 1 , wherein the salt of formula 2a or the compound of formula 2b is prepared by a process comprising:

reacting a compound of formula 5a:

or a salt thereof, with a Vilsmeier reagent formed from dimethylformamide.

27. The process of claim 1 , wherein the compound of formula 3, or a salt thereof, is formed by a process comprising:

reacting a compound of formula 6:

with hydrazine.

28. A process of preparing baricitinib, or a salt thereof, comprising reacting a salt of formula 2c:

with a compound of formula 3:

to form the baricitinib, or the salt thereof.

29. The process of claim 28 , wherein the salt of formula 2c is prepared by a process, comprising reacting a salt of formula 2d:

with a base to form the salt of formula 2c.

30. The process of claim 29 , wherein the salt of formula 2d is prepared by a process comprising:

(a) reacting a compound of formula 2P:

with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 1aP:

(b) deprotecting the compound of formula 1aP to form a compound of formula 1a:

or a salt thereof; and

(c) reacting the compound of formula 1a, or the salt thereof, with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d;

wherein P 1 is an amino protecting group.

31. The process of claim 28 , wherein the compound of formula 3, or the salt thereof, is prepared by a process comprising:

reacting a compound of formula 6:

with hydrazine.