Process and intermediates for preparing a JAK inhibitor

Patent metadata

Field	Value
Publication number	US-12071439-B2
Application number	US-202217861597-A
Country	US
Kind code	B2
Filing date	Jul 11, 2022
Priority date	Jul 12, 2021
Publication date	Aug 27, 2024
Grant date	Aug 27, 2024

Abstract

The present disclosure is related to processes for preparing baricitinib, salts thereof, and related synthetic intermediate compounds and salts thereof.

First claim

What is claimed is:

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:

Assignees

• Incyte Corp

Inventors

• Zhou Jiacheng
• Chen Shili
• Jia Zhongjiang
• Liu Pingli
• Meloni David
• Pan Yongchun
• Su Naijing
• Xia Michael

Classifications

• C07D205/04 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title