METHODS OF PREPARING INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20180282330A1
• Filed: 06/06/2018
• Published: 10/04/2018
• Est. Priority Date: 11/13/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Tanoury, Gerald J., Nugent, William Aloysius, Dvornikovs, Vadims, Rose, Peter Jamison
• Granted Patent: US 10,640,501 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: B01J 2231/44 Allylic alkylation, amination, alkoxylation or analogues
• CPC Class Codes: B01J 2531/824 Palladium
• CPC Class Codes: B01J 31/04 containing carboxylic acids or their salts B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof:

comprises: (a) reacting Compound (X):

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

in the presence of a palladium catalyst and a carbonate or phosphate base to form compound (Z):

or a pharmaceutically acceptable salt thereof; and (b) deprotecting the Ts group of Compound (Z) to form Compound (1) or a pharmaceutically acceptable salt thereof.

Claims

1. A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

2. The method of claim 1, wherein the palladium-XPhos complex is prepared in situ by mixing a Pd(0) or a Pd(II) source with XPhos.

3. The method of claim 2, wherein the Pd(0) or the Pd(II) source comprises Pd₂(dba)₃, Pd(OAc)₂, PdCl₂, or any combination thereof, wherein dba is dibenzyllideneacetone and OAc is acetate.

4. The method of claim 3, wherein the palladium-XPhos complex is prepared in situ by mixing Pd(OAc)₂ and XPhos.

5. The method of any one of claims 1-4, wherein each of X¹ and X² are —

F.

6. The method of any one of claims 1-4, wherein X¹ is —

Cl and X² is —

F.

7. The method of any one of claims 1-6, wherein the base is a phosphate base or a carbonate base selected from Na₂CO₃, K₂CO₃, K₃PO₄, or Na₃PO₄.

8. The method of claim 7, wherein the base is selected from K₂CO₃ or K₃PO₄.

9. The method of any one of claims 1-8, wherein step (a) is performed in a solvent system comprising water and an organic solvent selected from 2-methyl THF or THF, or any combination thereof.

10. The method of any one of claims 1-9, wherein step (b) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with an inorganic hydroxide comprising LiOH, NaOH, KOH, or any combination thereof.

11. The method of claim 10, wherein step (b) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with LiOH in a solvent system that comprises THF.

12. The method of any one of claims 1-11, further comprising:

(c) reacting Compound (F)

13. The method of claim 12, further comprising:

(e) reacting Compound (C)

14. The method of either of claims 12 or 13, further comprising:

(g) reacting Compound (A)

15. The method of claim 14, wherein the epimerization step comprises treating Compound (C-1) with a C_1-6 alkoxide.

16. The method of claim 15, wherein the C_1-6 alkoxide comprises tert-butoxide, tert-amylate, or any combination thereof.

17. The method of any one of claims 14-16, wherein R¹ is ethyl.

18. The method of claim 12, further comprising hydrogenating Compound (S)

19. The method of claim 18, further comprising reacting Compound (R)

20. The method of claim 19, further comprising:

(j) reacting 1,3-cyclohexadiene with CH≡

CHC(O)OR¹ in the presence of an aluminum catalyst to form Compound (Q)

21. The method of claim 20, wherein R¹ is ethyl.

22. The method of claim 20 or 21, wherein the aluminum catalyst comprises EtAlCl₂, Et₂AlCl, a mixture of AlCl₃ and trioctylaluminum, or any combination thereof.

23. The method of any one of claims 20-22, wherein the hydrogenation of Compound (R) comprises reacting Compound (R) with H₂ in the presence of a Rh(I) catalyst or a poisoned Pd(0) catalyst.

24. The method of claim 23, wherein the Rh(I) catalyst comprises (PPh₃)₃RhCl, a mixture of (PPh₃)₃RhCl and ethyl propiolate, or any combination thereof, wherein Ph is phenyl.

25. The method of claim 23, wherein the poisoned Pd(0) catalyst comprises a lead-poisoned Pd(0) catalyst on CaCO₃ (Pd(Pb)/CaCO₃).

26. The method of any one of claims 1-25, further comprising reacting Compound (O)

27. The method of claim 26, wherein the palladium catalyst comprising a phosphine ligand is Pd(Ph₃P)₄.

28. The method of claim 26 or 27, further comprising treating Compound (N)

29. The method of any one of claims 26-28, further comprising:

(l) reacting Compound (J)

30. The method of claim 29, wherein the C_1-6 alkoxide base comprises potassium tert-amylate, potassium tert-butoxide, potassium methoxide, sodium tert-amylate, sodium tert-butoxide, sodium methoxide, or any combinations thereof.

31. The method of any one of claims 29-30, wherein the reaction of Compound (K) or a pharmaceutically acceptable salt thereof with trimethylsilyl acetylene is performed in the presence of a palladium catalyst comprising Pd(Ph₃P)₄, Pd(PPh₃)₂Cl₂, Pd(dppf)₂Cl₂, or any combination thereof, a copper (I) halide catalyst, or any combination thereof.

32. The method of claim 31, wherein the reaction of Compound (K) or a pharmaceutically acceptable salt thereof with trimethylsilyl acetylene is performed in the presence of CuI, Pd(Ph₃P)₄, Pd(PPh₃)₂Cl₂, Pd(dppf)₂Cl₂, or any combination thereof.

33. The method of any one of claims 29-32, wherein the tosylation step xiv) is performed by reacting Compound (M) or a pharmaceutically acceptable salt thereof with TsCl.

34. The method of any one of claims 29-33, wherein Compound (J) or a pharmaceutically acceptable salt thereof is reacted with an iodinating agent comprising I₂, ICl, N-iodosuccinimide, and wherein X³ is I.

35. The method of claim 34, wherein the iodinating agent is I₂.

36. The method of any one of claims 29-34, wherein Compound (J) or a pharmaceutically acceptable salt thereof is reacted with a brominating agent comprising Br₂, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or any combination thereof, and wherein X³ is Br.

37. The method of claim 36, wherein the brominating agent is Br₂.

38. The method of any one of claims 27-28, further comprising:

(q) reacting Compound (K)

39. The method of claim 38, wherein the tertiary phosphine ligand, PR₃ comprises P(^tBu)₃, PCy₃, P(i-Pr)₃, P(Bu₃), PEt₃, PMe₃, or any combination thereof.

40. The method of claim 39, wherein the tertiary phosphine ligand comprises P(^tBu)₃.

41. The method of any one of claims 1-40, further comprising treating Compound (1), after the de-protecting step (b), with HCl in a solvent system comprising water and one or more organic solvents to form a HCl salt of Compound (1), wherein the organic solvent is selected from acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimentylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran (THF), tetralin, toluene, 1,1,2-trichloroethene, xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, or any combination thereof.

42. The method of claim 41 wherein the organic solvents of the solvent system are selected from the group consisting of 2-ethoxyethanol, ethyleneglycol, methanol, 2-methoxyethanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, ethanol, 1-pentanol, 1-propanol, 2-propanol, methylbutyl ketone, acetone, methylethyl ketone, methylisobutyl ketone, butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, ethyl acetate, propyl acetate, pyridine, toluene, and xylene.

43. The method of claim 42, wherein the solvent system comprises water and acetone, or water and isopropanol.

44. A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

45. The method of claim 44, wherein the palladium catalyst of step (h) comprises a palladium-XPhos complex and a phosphate or carbonate base, wherein XPhos is 2-dicyclohexylphosphino-2′

,4′

,6′

-triisopropylbiphenyl.

46. The method of claim 45, wherein the carbonate base comprises Na₂CO₃, K₂CO₃, or a combination thereof, and the phosphate base comprises K₃PO₄, Na₃PO₄, or a combination thereof.

47. The method of claim 46, wherein carbonate base comprises K₂CO₃, and the phosphate base comprises K₃PO₄.

48. The method of claim 45, wherein the base comprises K₂CO₃.

49. The method of any one of claims 44-48, wherein deprotection step (i) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with an inorganic hydroxide comprising LiOH, NaOH, KOH, or any combination thereof.

50. The method of any one of claims 44-49, wherein each of X¹ and X² are —

F.

51. The method of any one of claims 44-50, wherein X¹ is —

Cl and X² is —

F.

52. The method of any one of claims 44-51, wherein the epimerization of step (c) comprises treating Compound (C-1) with a C_1-6 alkoxide.

53. The method of claim 52, wherein the C_1-6 alkoxide comprises tert-butoxide, tert-amylate, or any combination thereof.

54. A method of preparing Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

55. The method of claim 54, wherein the second palladium catalyst of step (e) comprises a palladium-XPhos complex and a phosphate base or a carbonate base, wherein XPhos is 2-dicyclohexylphosphino-2′

,4′

,6′

-triisopropylbiphenyl.

56. The method of claim 55, wherein the phosphate base comprises K₃PO₄ and the carbonate base comprises K₂CO₃.

57. The method of any one of claims 54-56, wherein the deprotection of step (f) comprises treating Compound (Z) or a pharmaceutically acceptable salt thereof with an inorganic hydroxide comprising LiOH, NaOH, KOH, or any combination thereof.

58. The method of any one of claims 54-57, wherein the first palladium catalyst of step (a) comprises a mixture of bis(dibenzylideneacetone) palladium and a tertiary phosphine ligand, PR₃, wherein R is C_1-6 alkyl or C_5-6 cycloalkyl.

59. The method of claim 58, wherein the tertiary phosphine ligand comprises P(^tBu)₃.

60. The method of any one of claims 54-59, wherein each of X¹ and X² are —

F.

61. The method of any one of claims 54-59, wherein X¹ is —

Cl and X² is —

F.

62. A method of preparing Compound (2) or a pharmaceutically acceptable salt thereof, wherein Compound (2) is represented by the following structural formula:

63. A method of preparing Compound (C) or pharmaceutically acceptable salt thereof, comprising:

(g) reacting Compound (A)

64. The method of claim 63, wherein epimerization step (c) includes treating Compound (C-1) with a C_1-6 alkoxide.

65. The method of claim 64, wherein the C_1-6 alkoxide comprises tert-butoxide, tert-amylate, or any combination thereof.

66. A method of preparing Compound (N), comprising:

(q) reacting Compound (K)

67. The method of claim 66, wherein the palladium catalyst of step (a) comprises a mixture of bis(dibenzylideneacetone) palladium and a tertiary phosphine ligand, PR₃, wherein R is C_1-6 alkyl or C_5-6 cycloalkyl.

68. The method of claim 67, wherein the tertiary phosphine ligand comprises P(^tBu)₃.