METHODS OF PREPARING INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20180065962A1
• Filed: 11/09/2017
• Published: 03/08/2018
• Est. Priority Date: 05/13/2015
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Farmer, Luc J., Boyd, Michael John, Miller, JR., David B., Cwynar, Valerie Ann
• Granted Patent: US 10,533,004 B2
• Time in Patent Office: Days
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

A method of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

comprises: (a) reacting Compound (1):

or a pharmaceutically acceptable salt thereof with Compound (2):

in the presence of water, an organic solvent, a base, and a transition metal catalyst to generate a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Claims

1. A process for preparing a compound of Formula I:

2. The process of claim 1, wherein the base of step i) is an organic base.

3. The process of claim 2, wherein the organic base comprises a tertiary amine.

4. The process of claim 3, wherein the tertiary amine comprises diisopropylethylamine, triethylamine, triethylenediamine, or any combination thereof.

5. The process of any one of claims 1-4, wherein the organic solvent of step i) is an aprotic solvent.

6. The process of claim 5, wherein the aprotic solvent is acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, methyl tert-butyl ether, or any combination thereof.

7. The process of any one of claims 1-6, wherein R¹ is —

F.

8. The process of any one of claims 1-6, wherein R¹ is —

Cl.

9. The process of any one of claims 1-8, wherein X¹ is —

Cl.

10. The process of any one of claims 1-9, wherein the reaction of step i) is performed at a temperature between about 50°

C. and about 110°

C.

11. The process of claim 10, wherein the reaction of step i) is performed at a temperature between about 60°

C. and about 95°

C.

12. The process of claim 11, wherein the reaction of step i) is performed at a temperature between about 65°

C. and about 80°

C.

13. The process of any one of claims 1-12, further comprising the step of:

ii) deprotecting a compound of Formula 3 to generate a compound of Formula I;

14. The process of claim 13, wherein step ii) comprises deprotecting the compound of Formula 3 in the presence of a base.

15. The process of claim 14, wherein the base comprises an inorganic base.

16. The process of claim 15, wherein the inorganic base is an alkali metal hydroxide.

17. The process of claim 16, wherein the alkali metal hydroxide is LiOH, NaOH, KOH, or any combination thereof.

18. The process of any one of claims 1-17, further comprising the step of:

via) reacting a compound of Formula 8 with a compound of Formula 9,

19. The process of claim 18, further comprising the steps of:

vii) reacting the mixture comprising the compound of Formula 2 and the compound of Formula 10 with HCl in the presence of an organic solvent to generate a mixture of hydrochloride salts of the compound of Formula 2 and the compound of Formula 10; and

viii) recrystalizing the mixture of the hydrochloride salts of the compound of Formula 2 and the compound of Formula 10 to generate the hydrochloride salt of the compound of Formula 2.

20. The process of any one of claims 1-17, further comprising the steps of:

vib) reacting a compound of Formula 8 with a compound of Formula 9 in the presence of a solvent and a base to generate the compound Formula 2

21. The process of claim 20, wherein the base of step vib) is an inorganic base selected from tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

22. The process of either of claims 20 or 21, wherein the solvent of step vib) comprises water.

23. The process of claim 22, wherein the solvent of step vib) further comprises an alcohol selected from methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or any combination thereof.

24. The process of any one of claims 20-23, wherein the reaction of step vib) is performed at a temperature of from about 50°

C. to about 100°

C.

25. The process of claim 24, wherein the reaction of step vib) is performed at a temperature of from about 60°

C. to about 80°

C.

26. The process of any one of claims 1-25, wherein the compound of Formula 1 is 1a

27. The process of any one of claims 1-26, wherein the compound of Formula 2 is 2a

28. The process of any one of claims 1-27, wherein the compound of Formula I is Ia