IP Library › Granted Patent US 7,816,355

Granted Patent B1

US 7,816,355 · App. 12/431,272 · Granted Oct 19, 2010

Processes for the preparation of rivaroxaban and intermediates thereof

Assignee: Apotex Pharmachem Inc

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Quick Facts

Patent No.: US 7,816,355
App. No.: 12/431,272
Granted: Oct 19, 2010
Kind: B1

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Abstract

This invention provides a process for the preparation of S-Rivaroxaban and/or R-Rivaroxaban comprising reacting, in the presence of a first base, a compound of Formula 9: with a compound of Formula 8:

Claims (316)

1. A process for the preparation of at least one of S-Rivaroxaban and R-Rivaroxaban comprising reacting, in the presence of a first base, a compound of Formula 9:

with a compound of Formula 8:

wherein

R 4 is selected from the group consisting of:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

X is halogen; and

L 2 is a halogen or sulfonyloxy group.

2. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8a:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen.

3. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8a2:

4. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8b:

wherein

L 2 is a halogen or sulfonyloxy group.

5. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8c:

wherein

G OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

X is halogen; and

L 2 is a halogen or sulfonyloxy group.

6. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8c3:

7. The process of claim 2 wherein the compound of Formula 8a is prepared by a process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

wherein

L 1 is a leaving group selected from the group consisting of halogen, imidazole, ester, C 1 -C 4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; and

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming a compound of Formula 5:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ; and

ii. reacting the compound of Formula 5, in the presence of a third base, with a compound of Formula 4:

wherein

L 2 is a halogen or sulfonyloxy group, thereby forming the compound of Formula 8a.

8. The process of claim 7 wherein the reacting the compound of Formula 2 with the compound of Formula 3 occurs in the presence of a second base.

9. The process of claim 7 wherein the compound of Formula 3 is a haloformate.

10. The process of claim 9 wherein the haloformate is methyl chloroformate.

11. The process of claim 7 wherein the compound of Formula 3 is carbonyldiimidazole.

12. The process of claim 7 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

13. The process of claim 2 wherein the compound of Formula 8a is prepared by a process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4:

wherein

L 2 is a halogen or sulfonyloxy group, thereby forming a compound of Formula 6:

and;

ii. reacting the compound of Formula 6 with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8a.

14. The process of claim 13 wherein reacting the compound of Formula 6 with the compound of Formula 3 occurs in the presence of a fifth base.

15. The process of claim 13 wherein the compound of Formula 3 is a haloformate.

16. The process of claim 15 wherein the haloformate is methyl chloroformate.

17. The process of claim 13 wherein the compound of Formula 3 is carbonyldiimidazole.

18. The process of claim 13 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

19. The process of claim 5 wherein the compound of Formula 8c is prepared by a process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4:

thereby forming a compound of Formula 7:

wherein L 2 is a halogen or sulfonyloxy group; and

ii. reacting, in the presence of a sixth base, the compound of Formula 7 with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8c.

20. The process of claim 19 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

21. The process of claim 19 wherein the compound of Formula 3 is methyl chloroformate.

22. A process for preparation of a compound of Formula 8a:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming a compound of Formula 5:

wherein

G OR 1 , NR 2 R 3 , or CX 3 ; and

ii. reacting the compound of Formula 5, in the presence of a third base, with a compound of Formula 4:

wherein

L 2 is a halogen or sulfonyloxy group,

thereby forming the compound of Formula 8a.

23. The process of claim 22 wherein reacting the compound of Formula 2 with the compound of Formula 3 occurs in the presence of a second base.

24. The process of claim 22 wherein the compound of Formula 3 is a haloformate.

25. The process of claim 24 wherein the haloformate is methyl chloroformate.

26. The process of claim 22 wherein the compound of Formula 3 is carbonyldiimidazole.

27. The process of claim 22 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

28. A process for the preparation of a compound of Formula 8a:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4:

wherein

L 2 is a halogen or sulfonyloxy group,

thereby forming a compound of Formula 6:

and;

ii. reacting the compound of Formula 6 with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8a.

29. The compound of claim 28 wherein reacting the compound of Formula 6 with the compound of Formula 3 occurs in the presence of a fifth base.

30. The process of claim 28 wherein the compound of Formula 3 is a haloformate.

31. The process of claim 30 wherein the haloformate is methyl chloroformate.

32. The process of claim 28 wherein the compound of Formula 3 is carbonyldiimidazole.

33. The process of claim 28 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

34. A process for preparation of a compound of Formula 8c:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

L 2 is a halogen or sulfonyloxy group,

the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4:

thereby forming a compound of Formula 7:

wherein

L 2 is a halogen or sulfonyloxy group,

and;

ii. reacting, in the presence of a sixth base, the compound of Formula 7 with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8c.

35. The process of claim 34 wherein the compound of Formula 4 is (R)-(−)-epichlorohydrin.

36. The process of claim 34 wherein the compound of Formula 3 is methyl chloroformate.

37. A process for the preparation of a compound of Formula 8a:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising converting a compound of Formula 8c:

to the compound of Formula 8a.

38. The process of claim 37 wherein converting the compound of Formula 8c comprises treating of the compound of Formula 8c with sodium iodide.

39. The process of claim 38 wherein the treating of the compound of Formula 8c occurs in the presence of a seventh base.

40. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8aa:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen.

41. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8aa2:

42. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8ba:

wherein

L 2 is a halogen or sulfonyloxy group.

43. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8ca:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

X is halogen; and

L 2 is a halogen or sulfonyloxy group.

44. The process of claim 1 wherein the compound of Formula 8 is a compound of Formula 8ca3:

45. The process of claim 40 wherein the compound of Formula 8aa is prepared by a process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming a compound of Formula 5:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ; and

ii. reacting the compound of Formula 5, in the presence of a third base, with a compound of Formula 4a:

wherein

L 2 is a halogen or sulfonyloxy group, thereby forming the compound of Formula 8aa.

46. The process of claim 45 wherein reacting the compound of Formula 2 with the compound of Formula 3 occurs in the presence of a second base.

47. The process of claim 45 wherein the compound of Formula 3 is a haloformate.

48. The process of claim 47 wherein the haloformate is methyl chloroformate.

49. The process of claim 45 wherein the compound of Formula 3 is carbonyldiimidazole.

50. The process of claim 45 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

51. The process of claim 40 wherein the compound of Formula 8aa is prepared by a process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4a:

wherein

L 2 is a halogen or sulfonyloxy group, thereby forming a compound of Formula 6a:

and;

ii. reacting the compound of Formula 6a with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8aa.

52. The process of claim 51 wherein reacting the compound of Formula 6a with the compound of Formula 3 occurs in the presence of a fifth base.

53. The process of claim 51 wherein the compound of Formula 3 is a haloformate.

54. The process of claim 53 wherein the haloformate is methyl chloroformate.

55. The process of claim 51 wherein the compound of Formula 3 is carbonyldiimidazole.

56. The process of claim 51 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

57. The process of claim 43 wherein the compound of Formula 8ca is prepared by a process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4a:

thereby forming a compound of Formula 7a:

wherein L 2 is a halogen or sulfonyloxy group;

and;

ii. reacting, in the presence of a sixth base, the compound of Formula 7a with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8ca.

58. The process of claim 57 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

59. The process of claim 57 wherein the compound of Formula 3 is methyl chloroformate.

60. A process for preparation of a compound of Formula 8aa:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming a compound of Formula 5:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ; and

ii. reacting the compound of Formula 5, in the presence of a third base, with a compound of Formula 4a:

wherein L 2 is a halogen or sulfonyloxy group,

thereby forming the compound of Formula 8aa.

61. The process of claim 60 wherein reacting the compound of Formula 2 with the compound of Formula 3 occurs in the presence of a second base.

62. The process of claim 60 wherein the compound of Formula 3 is a haloformate.

63. The process of claim 62 wherein the haloformate is methyl chloroformate.

64. The process of claim 60 wherein the compound of Formula 3 is carbonyldiimidazole.

65. The process of claim 60 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

66. A process for the preparation of a compound of Formula 8aa:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising:

i. reacting, in the presence of a fourth base, a compound of Formula 2:

with a compound of Formula 4a:

wherein

L 2 is a halogen or sulfonyloxy group,

thereby forming a compound of Formula 6a:

and;

ii. reacting the compound of Formula 6a with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ,

thereby forming the compound of Formula 8aa.

67. The compound of claim 66 wherein the reacting the compound of Formula 6a with the compound of Formula 3 occurs in the presence of a fifth base.

68. The process of claim 66 wherein the compound of Formula 3 is a haloformate.

69. The process of claim 68 wherein the haloformate is methyl chloroformate.

70. The process of claim 66 wherein the compound of Formula 3 is carbonyldiimidazole.

71. The process of claim 66 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

72. A process for preparation of a compound of Formula 8ca:

wherein

G OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl; arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

L 2 is a halogen or sulfonyloxy group,

the process comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 4a:

thereby forming a compound of Formula 7a:

wherein

L 2 is a halogen or sulfonyloxy group,

and;

ii. reacting, in the presence of a sixth base, the compound of Formula 7a with a compound of Formula 3:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

thereby forming the compound of Formula 8ca.

73. The process of claim 72 wherein the compound of Formula 4a is (S)-(+)-epichlorohydrin.

74. The process of claim 72 wherein the compound of Formula 3 is methyl chloroformate.

75. A process for the preparation of a compound of Formula 8aa:

wherein

G is OR 1 , NR 2 R 3 , or CX 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl,

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

X is halogen,

the process comprising converting a compound of Formula 8ca:

to the compound of Formula 8aa.

76. The process of claim 75 wherein the converting the compound of Formula 8ca comprises treating the compound of Formula 8ca with sodium iodide.

77. The process of claim 76 wherein the treating the compound of Formula 8ca occurs in the presence of a seventh base.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 6, 2025

From: APOTEX PHARMACHEM INC.

To: APOTEX INC.

Reel/Frame 069751/0977 →

SECURITY INTEREST Recorded Apr 15, 2023