U.S. patent application number 12/431272 was filed with the patent office on 2010-10-28 for processes for the preparation of rivaroxaban and intermediates thereof.
This patent application is currently assigned to APOTEX PHARMACHEM INC.. Invention is credited to Prabhudas BODHURI, Gamini Weeratunga.
Application Number | 20100273798 12/431272 |
Document ID | / |
Family ID | 42941191 |
Filed Date | 2010-10-28 |
United States Patent
Application |
20100273798 |
Kind Code |
A1 |
BODHURI; Prabhudas ; et
al. |
October 28, 2010 |
PROCESSES FOR THE PREPARATION OF RIVAROXABAN AND INTERMEDIATES
THEREOF
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: ##STR00001##
with a compound of Formula 8: ##STR00002##
Inventors: |
BODHURI; Prabhudas;
(Brantford, CA) ; Weeratunga; Gamini; (Brantford,
CA) |
Correspondence
Address: |
Apotex, Inc.
150 Signet Drive
Toronto
ON
M9L 1T9
CA
|
Assignee: |
APOTEX PHARMACHEM INC.
Brantford
CA
|
Family ID: |
42941191 |
Appl. No.: |
12/431272 |
Filed: |
April 28, 2009 |
Current U.S.
Class: |
514/236.8 ;
544/137; 544/147; 544/166 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 7/00 20180101; A61P 9/00 20180101; C07D 265/32 20130101; A61P
7/02 20180101; A61K 31/5377 20130101; C07D 413/10 20130101; C07D
413/14 20130101 |
Class at
Publication: |
514/236.8 ;
544/137; 544/147; 544/166 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/14 20060101 C07D413/14; C07D 413/10 20060101
C07D413/10; C07D 295/155 20060101 C07D295/155 |
Claims
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: ##STR00102## with a compound of
Formula 8: ##STR00103## wherein R.sup.4 is selected from the group
consisting of: ##STR00104## wherein G is OR.sup.1, NR.sup.2R.sup.3,
or CX.sub.3; R.sup.1 is alkyl, substituted alkyl, aryl, substituted
aryl, arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.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.sup.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: ##STR00105## wherein G is OR.sup.1,
NR.sup.2R.sup.3 or CX.sub.3; R.sup.1 is alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;
R.sup.2 and R.sup.3 are either (a) two independent groups or (b)
together form a single ring group with the N to which they are
bonded; R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.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: ##STR00106##
4. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8b: ##STR00107## wherein L.sup.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: ##STR00108## wherein G is OR.sup.1,
NR.sup.2R.sup.3, or CX.sub.3; R.sup.1 is alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;
R.sup.2 and R.sup.3 are either (a) two independent groups or (b)
together form a single ring group with the N to which they are
bonded; R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.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.sup.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: ##STR00109##
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: ##STR00110## with a compound of Formula 3: ##STR00111## wherein
L.sup.1 is a leaving group selected from the group consisting of
halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming a compound of Formula 5: ##STR00112##
wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3; and ii.
reacting the compound of Formula 5, in the presence of a third
base, with a compound of Formula 4: ##STR00113## wherein L.sup.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: ##STR00114## with a compound
of Formula 4: ##STR00115## wherein L.sup.2 is a halogen or
sulfonyloxy group, thereby forming a compound of Formula 6:
##STR00116## and; ii. reacting the compound of Formula 6 with a
compound of Formula 3: ##STR00117## wherein L.sup.1 is a leaving
group selected from the group consisting of halogen, imidazole,
ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.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
carbonyidiimidazole.
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: ##STR00118## with a compound of Formula 4: ##STR00119## thereby
forming a compound of Formula 7: ##STR00120## wherein L.sup.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: ##STR00121## wherein L.sup.1 is a leaving group selected from
the group consisting of halogen, imidazole, ester, C.sub.1-C.sub.4
alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and G is
OR.sup.1, NR.sup.2R.sup.3, or CX.sub.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:
##STR00122## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.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:
##STR00123## with a compound of Formula 3: ##STR00124## wherein
L.sup.1 is a leaving group selected from the group consisting of
halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming a compound of Formula 5: ##STR00125##
wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3; and ii.
reacting the compound of Formula 5, in the presence of a third
base, with a compound of Formula 4: ##STR00126## wherein L.sup.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:
##STR00127## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.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: ##STR00128## with a compound of Formula 4:
##STR00129## wherein L.sup.2 is a halogen or sulfonyloxy group,
thereby forming a compound of Formula 6: ##STR00130## and; ii.
reacting the compound of Formula 6 with a compound of Formula 3:
##STR00131## wherein L.sup.1 is a leaving group selected from the
group consisting of halogen, imidazole, ester, C.sub.1-C.sub.4
alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and G is
OR.sup.1, NR.sup.2R.sup.3, or CX.sub.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
carbonyidiimidazole.
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:
##STR00132## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.3, when together form a single ring group with the N to which
they are bonded, are a heteroaryl ring; and L.sup.2 is a halogen or
sulfonyloxy group, the process comprising: i. reacting a compound
of Formula 2: ##STR00133## with a compound of Formula 4:
##STR00134## thereby forming a compound of Formula 7: ##STR00135##
wherein L.sup.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: ##STR00136## wherein L.sup.1 is a
leaving group selected from the group consisting of halogen,
imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.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:
##STR00137## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.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: ##STR00138## 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.
40-51. (canceled)
52. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8aa: ##STR00139## wherein G is OR.sup.1,
NR.sup.2R.sup.3, or CX.sub.3; R.sup.1 is alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;
R.sup.2 and R.sup.3 are either (a) two independent groups or (b)
together form a single ring group with the N to which they are
bonded; R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.3, when together form a
single ring group with the N to which they are bonded, are a
heteroaryl ring; and X is halogen.
53. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8aa2: ##STR00140##
54. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8ba: ##STR00141## wherein L.sup.2 is a halogen
or sulfonyloxy group.
55. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8ca: ##STR00142## wherein G is OR.sup.1,
NR.sup.2R.sup.3, or CX.sub.3; R.sup.1 is alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, or substituted aryl alkyl;
R.sup.2 and R.sup.3 are either (a) two independent groups or (b)
together form a single ring group with the N to which they are
bonded; R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.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.sup.2 is a halogen or
sulfonyloxy group.
56. The process of claim 1 wherein the compound of Formula 8 is a
compound of Formula 8ca3: ##STR00143##
57. The process of claim 52 wherein the compound of Formula 8aa is
prepared by a process comprising: i. reacting a compound of Formula
2: ##STR00144## with a compound of Formula 3: ##STR00145## wherein
L.sup.1 is a leaving group selected from the group consisting of
halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming a compound of Formula 5: ##STR00146##
wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3; and ii.
reacting the compound of Formula 5, in the presence of a third
base, with a compound of Formula 4a: ##STR00147## wherein L.sup.2
is a halogen or sulfonyloxy group, thereby forming the compound of
Formula 8aa.
58. The process of claim 57 wherein reacting the compound of
Formula 2 with the compound of Formula 3 occurs in the presence of
a second base.
59. The process of claim 57 wherein the compound of Formula 3 is a
haloformate.
60. The process of claim 59 wherein the haloformate is methyl
chloroformate.
61. The process of claim 57 wherein the compound of Formula 3 is
carbonyldiimidazole.
62. The process of claim 57 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
63. The process of claim 52 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: ##STR00148## with a compound
of Formula 4a: ##STR00149## wherein L.sup.2 is a halogen or
sulfonyloxy group, thereby forming a compound of Formula 6a:
##STR00150## and; ii. reacting the compound of Formula 6a with a
compound of Formula 3: ##STR00151## wherein L.sup.1 is a leaving
group selected from the group consisting of halogen, imidazole,
ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming the compound of Formula 8aa.
64. The process of claim 63 wherein reacting the compound of
Formula 6a with the compound of Formula 3 occurs in the presence of
a fifth base.
65. The process of claim 63 wherein the compound of Formula 3 is a
haloformate.
66. The process of claim 65 wherein the haloformate is methyl
chloroformate.
67. The process of claim 63 wherein the compound of Formula 3 is
carbonyidiimidazole.
68. The process of claim 63 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
69. The process of claim 55 wherein the compound of Formula 8ca is
prepared by a process comprising: i. reacting a compound of Formula
2: ##STR00152## with a compound of Formula 4a: ##STR00153## thereby
forming a compound of Formula 7a: ##STR00154## wherein L.sup.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: ##STR00155## wherein L.sup.1 is a leaving group selected from
the group consisting of halogen, imidazole, ester, C.sub.1-C.sub.4
alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and G is
OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3; thereby forming the
compound of Formula 8ca.
70. The process of claim 69 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
71. The process of claim 69 wherein the compound of Formula 3 is
methyl chloroformate.
72. A process for preparation of a compound of Formula 8aa:
##STR00156## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.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:
##STR00157## with a compound of Formula 3: ##STR00158## wherein
L.sup.1 is a leaving group selected from the group consisting of
halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming a compound of Formula 5: ##STR00159##
wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3; and ii.
reacting the compound of Formula 5, in the presence of a third
base, with a compound of Formula 4a: ##STR00160## wherein L.sup.2
is a halogen or sulfonyloxy group, thereby forming the compound of
Formula 8aa.
73. The process of claim 72 wherein reacting the compound of
Formula 2 with the compound of Formula 3 occurs in the presence of
a second base.
74. The process of claim 72 wherein the compound of Formula 3 is a
haloformate.
75. The process of claim 74 wherein the haloformate is methyl
chloroformate.
76. The process of claim 72 wherein the compound of Formula 3 is
carbonyidiimidazole.
77. The process of claim 72 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
78. A process for the preparation of a compound of Formula 8aa:
##STR00161## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.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: ##STR00162## with a compound of Formula
4a: ##STR00163## wherein L.sup.2 is a halogen or sulfonyloxy group,
thereby forming a compound of Formula 6a: ##STR00164## and; ii.
reacting the compound of Formula 6a with a compound of Formula 3:
##STR00165## wherein L.sup.1 is a leaving group selected from the
group consisting of halogen, imidazole, ester, C.sub.1-C.sub.4
alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and G is
OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3, thereby forming the
compound of Formula 8aa.
79. The compound of claim 78 wherein the reacting the compound of
Formula 6a with the compound of Formula 3 occurs in the presence of
a fifth base.
80. The process of claim 78 wherein the compound of Formula 3 is a
haloformate.
81. The process of claim 80 wherein the haloformate is methyl
chloroformate.
82. The process of claim 78 wherein the compound of Formula 3 is
carbonyldiimidazole.
83. The process of claim 78 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
84. A process for preparation of a compound of Formula 8ca:
##STR00166## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
the group consisting of: H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl, R.sup.2 and
R.sup.3, when together form a single ring group with the N to which
they are bonded, are a heteroaryl ring; and L.sup.2 is a halogen or
sulfonyloxy group, the process comprising: i. reacting a compound
of Formula 2: ##STR00167## with a compound of Formula 4a:
##STR00168## thereby forming a compound of Formula 7a: ##STR00169##
wherein L.sup.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: ##STR00170## wherein L.sup.1 is a
leaving group selected from the group consisting of halogen,
imidazole, ester, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and
N-hydroxybenzotriazole; and G is OR.sup.1, NR.sup.2R.sup.3, or
CX.sub.3; thereby forming the compound of Formula 8ca.
85. The process of claim 84 wherein the compound of Formula 4a is
(S)-(+)-epichlorohydrin.
86. The process of claim 84 wherein the compound of Formula 3 is
methyl chloroformate.
87. A process for the preparation of a compound of Formula 8aa:
##STR00171## wherein G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl; R.sup.2 and R.sup.3 are
either (a) two independent groups or (b) together form a single
ring group with the N to which they are bonded; R.sup.2 and
R.sup.3, when independent groups, are independently selected from
H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl, R.sup.2 and R.sup.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: ##STR00172## to the compound
of Formula 8aa.
88. The process of claim 87 wherein the converting the compound of
Formula 8ca comprises treating the compound of Formula 8ca with
sodium iodide.
89. The process of claim 88 wherein the treating the compound of
Formula 8ca occurs in the presence of a seventh base.
90-100. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to the field of chemical
synthesis of organic compounds and in particular to methods for the
synthesis of Rivaroxaban and intermediates thereof.
BACKGROUND
[0002] Rivaroxaban (1)
(5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl-
]methyl}thiophene-2-carboxamide) is a low molecular weight, orally
administrable anticoagulant drug. The pharmaceutical directly
inhibits the active form of serine protease Factor Xa (FXa).
Rivaroxaban can be used for the prevention and treatment of various
thromboembolic diseases, in particular of deep vein thrombosis
(DVT), pulmonary embolism (PE), myocardial infract, angina
pectoris, reocclusions and restenoses after angioplasty or
aortocoronary bypass, cerebral stroke, transitory ischemic attacks,
and peripheral arterial occlusive diseases.
[0003] Rivaroxaban is disclosed in WO 01/47919 and has the
following structure:
##STR00003##
[0004] US2007/0149522 relates to a method for producing
5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin--
5-yl}-methyl)-2-thiophene carboxamide starting from
5-chlorothiophene-2-carbonyl chloride and
(2S)-3-amino-propane-1,2-diol and
4-(4-aminophenyl)-3-morpholinone.
[0005] US2007/0066611 relates to a process for preparing
4-(4-aminophenyl)-3-morpholinone by reacting
4-(4-nitrophenyl)-3-morpholinone with hydrogen in the presence of a
hydrogenation catalyst, characterized in that the reaction is
effected in an aliphatic alcohol.
[0006] U.S. Pat. No. 7,351,823 relates to a process for preparing
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin--
5-yl}methyl)-2-thiophenecarboxamide starting from
2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione,
4-(4-aminophenyl)-3-morpholinone and 5-chlorothiophene-2-carbonyl
chloride.
[0007] WO 2009/023233 relates to novel compounds that are
substituted oxazolidinones derivatives and pharmaceutically
acceptable salts thereof. More specifically, this invention relates
to novel oxazolidinone compounds that are derivatives of
Rivaroxaban. The invention also provides pyrogen-free compositions
comprising one or more compounds of the invention and a carrier,
along with the use of the disclosed compounds and compositions in
methods of treating diseases and condition that are beneficially
treated by administering a selective inhibitor of factor Xa, such
as Rivaroxaban.
SUMMARY
[0008] This invention is based, in part, on preparing Rivaroxaban
by reacting a compound of Formula 8a, 8b or 8c with
5-chlorothiophene-2-carboxamide of Formula 9 in Scheme 1.
[0009] The present invention is directed to methods of preparation
of Rivaroxaban, various intermediates useful in the preparation of
Rivaroxaban and methods of preparation of such intermediates.
[0010] In illustrative embodiments of the present invention,
Rivaroxaban and the intermediates thereof may be prepared by an
exemplary process as set out in Scheme 1. Exemplary reagents and
conditions for these reactions are disclosed herein.
##STR00004##
[0011] In illustrative embodiments of the present invention, the
(R)-enantiomer of Rivaroxaban is prepared by the processes of the
present invention by replacing the compound of Formula 4 of Scheme
1 with the (S)-enantiomer (ie. (S)-(+)-epichlorohydrin) and
preparing compounds having the stereochemistry as shown in Scheme
1a.
##STR00005##
[0012] In illustrative embodiments of the present invention, there
is provided 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:
##STR00006##
with a compound of Formula 8:
##STR00007##
wherein R.sup.4 is selected from the group consisting of:
##STR00008##
wherein
[0013] G is OR.sup.1, NR.sup.2R.sup.3 or CX.sub.3;
[0014] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0015] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0016] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0017] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring;
[0018] X is halogen; and
[0019] L.sup.2 is a halogen or sulfonyloxy group.
[0020] In illustrative embodiments of the present invention, there
is provided a process described herein wherein a compound of
Formula 8 is a compound of Formula 8a and/or 8aa:
##STR00009##
[0021] In illustrative embodiments of the present invention, there
is provided a process described herein wherein a compound of
Formula 8 is a compound of Formula 8b and/or 8ba:
##STR00010##
[0022] In illustrative embodiments of the present invention, there
is provided a process described herein wherein a compound of
Formula 8 is a compound of Formula 8c and/or 8ca:
##STR00011##
[0023] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8a:
##STR00012##
wherein
[0024] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0025] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0026] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0027] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0028] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0029] X is halogen, the process comprising:
[0030] i. reacting, optionally in the presence of a second base, a
compound of Formula 2:
##STR00013##
with a compound of Formula 3:
##STR00014##
wherein
[0031] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0032] G is as defined above for Formula 8a, thereby forming a
compound of Formula 5:
##STR00015##
wherein G is as defined above for Formula 8a; and
[0033] ii. reacting the compound of Formula 5, in the presence of a
third base, with a compound of Formula 4:
##STR00016##
wherein L.sup.2 is a halogen or sulfonyloxy group, thereby forming
the compound of Formula 8a.
[0034] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8a:
##STR00017##
wherein
[0035] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0036] R is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0037] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0038] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0039] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded are a heteroaryl ring; and
[0040] X is halogen, the process comprising:
[0041] i. reacting, in the presence of a fourth base, a compound of
Formula 2:
##STR00018##
with a compound of Formula 4:
##STR00019##
wherein L.sup.2 is a halogen or sulfonyloxy group, thereby forming
a compound of Formula 6:
##STR00020##
and;
[0042] ii. reacting, optionally in the presence of a fifth base,
the compound of Formula 6 with a compound of Formula 3:
##STR00021##
wherein
[0043] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0044] G is as defined above for Formula 8a, thereby forming the
compound of Formula 8a.
[0045] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8c:
##STR00022##
wherein
[0046] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0047] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0048] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0049] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0050] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0051] L.sup.2 is a halogen or sulfonyloxy group, the process
comprising:
[0052] i. reacting a compound of Formula 2:
##STR00023##
with a compound of Formula 4:
##STR00024##
wherein L.sup.2 is a halogen or sulfonyloxy group; thereby forming
a compound of Formula 7:
##STR00025##
wherein
[0053] L.sup.2 is as defined for Formula 4; and
[0054] ii. reacting, in the presence of a sixth base, the compound
of Formula 7 with a compound of Formula 3:
##STR00026##
wherein
[0055] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0056] G is as defined above for Formula 8c, thereby forming the
compound of Formula 8c.
[0057] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8a:
##STR00027##
wherein
[0058] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0059] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0060] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0061] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0062] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring;
[0063] X is halogen, the process comprising conversion of a
compound of Formula 8c to the compound of Formula 8a.
[0064] In illustrative embodiments of the present invention, there
is provided a compound of Formula 5a:
##STR00028##
wherein
[0065] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl.
[0066] In illustrative embodiments of the present invention, there
is provided a compound of Formula 5a:
##STR00029##
wherein
[0067] R.sup.1 is alkyl or substituted alkyl.
[0068] In illustrative embodiments of the present invention, there
is provided a compound of Formula 5b:
##STR00030##
[0069] In illustrative embodiments of the present invention, there
is provided a compound of Formula 6:
##STR00031##
[0070] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8a:
##STR00032##
wherein
[0071] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0072] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0073] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0074] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0075] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0076] X is halogen.
[0077] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8a1:
##STR00033##
wherein
[0078] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted arylalkyl.
[0079] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8a1:
##STR00034##
wherein
[0080] R.sup.1 is alkyl or substituted alkyl.
[0081] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8a2:
##STR00035##
[0082] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8c:
##STR00036##
wherein
[0083] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0084] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted arylalkyl;
[0085] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0086] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0087] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0088] L.sup.2 is a halogen or sulfonyloxy group.
[0089] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8c1:
##STR00037##
wherein
[0090] R.sup.1 is alkyl or substituted alkyl and L.sup.2 is a
halogen or sulfonyloxy group.
[0091] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8c2:
##STR00038##
wherein
[0092] L.sup.2 is a halogen or sulfonyloxy group.
[0093] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8c3:
##STR00039##
[0094] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8aa:
##STR00040##
wherein
[0095] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0096] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0097] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0098] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0099] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0100] X is halogen, the process comprising:
[0101] i. reacting, optionally in the presence of a second base, a
compound of Formula 2:
##STR00041##
with a compound of Formula 3:
##STR00042##
wherein
[0102] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0103] G is as defined above for Formula 8aa, thereby forming a
compound of Formula 5:
##STR00043##
wherein G is as defined above for Formula 8aa; and
[0104] ii. reacting the compound of Formula 5, in the presence of a
third base, with a compound of Formula 4a:
##STR00044##
wherein L.sup.2 is a halogen or sulfonyloxy group, thereby forming
the compound of Formula 8aa.
[0105] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8aa:
##STR00045##
wherein
[0106] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0107] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0108] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0109] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0110] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded are a heteroaryl ring; and
[0111] X is halogen, the process comprising:
[0112] i. reacting, in the presence of a fourth base, a compound of
Formula 2:
##STR00046##
with a compound of Formula 4a:
##STR00047##
wherein L.sup.2 is a halogen or sulfonyloxy group, thereby forming
a compound of Formula 6a:
##STR00048##
and;
[0113] ii. reacting, optionally in the presence of a fifth base,
the compound of Formula 6a with a compound of Formula 3:
##STR00049##
wherein
[0114] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0115] G is as defined above for Formula 8aa, thereby forming the
compound of Formula 8aa.
[0116] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8ca:
##STR00050##
wherein
[0117] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0118] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0119] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0120] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0121] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0122] L.sup.2 is a halogen or sulfonyloxy group, the process
comprising:
[0123] i. reacting a compound of Formula 2:
##STR00051##
with a compound of Formula 4a:
##STR00052##
wherein L.sup.2 is a halogen or sulfonyloxy group; thereby forming
a compound of Formula 7a:
##STR00053##
wherein
[0124] L.sup.2 is as defined for Formula 4a; and
[0125] ii. reacting, in the presence of a sixth base, the compound
of Formula 7a with a compound of Formula 3:
##STR00054##
wherein
[0126] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0127] G is as defined above for Formula 8ca, thereby forming the
compound of Formula 8ca.
[0128] In illustrative embodiments of the present invention, there
is provided a process for the preparation of a compound of Formula
8aa:
##STR00055##
wherein
[0129] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0130] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0131] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0132] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl;
[0133] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; X is
halogen, the process comprising conversion of a compound of Formula
8ca to the compound of Formula 8aa.
[0134] In illustrative embodiments of the present invention, there
is provided a compound of Formula 6a:
##STR00056##
In illustrative embodiments of the present invention, there is
provided a compound of Formula 8aa:
##STR00057##
wherein
[0135] G is OR.sup.1 NR.sup.2R.sup.3, or CX.sub.3;
[0136] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0137] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0138] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0139] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0140] X is halogen;
[0141] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8aa1:
##STR00058##
wherein
[0142] R.sup.1is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted arylalkyl.
[0143] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8aa1:
##STR00059##
wherein
[0144] R.sup.1 is alkyl or substituted alkyl.
[0145] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8aa2:
##STR00060##
[0146] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8ca:
##STR00061##
wherein
[0147] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0148] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0149] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0150] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0151] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0152] L.sup.2 is a halogen or sulfonyloxy group.
[0153] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8ca1:
##STR00062##
wherein
[0154] R.sup.1 is alkyl or substituted alkyl and L.sup.2 is a
halogen or sulfonyloxy group.
[0155] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8ca2:
##STR00063##
wherein
[0156] L.sup.2 is a halogen or sulfonyloxy group.
[0157] In illustrative embodiments of the present invention, there
is provided a compound of Formula 8ca3:
##STR00064##
[0158] Other aspects and features of the present invention will
become apparent to those ordinarily skilled in the art upon review
of the following description of specific embodiments of the
invention in conjunction with the accompanying figures.
DETAILED DESCRIPTION
[0159] As used herein, the term "substituted" refers to the
replacement of a hydrogen atom on a compound with a substituent
group. A substituent may be a non-hydrogen atom or multiple atoms
of which at least one is a non-hydrogen atom and one or more may or
may not be hydrogen atoms. For example, without limitation,
substituted compounds may comprise one or more substituents
selected from the group consisting of: R'', OR'', NR''R''', SR'',
halogen, SiR''R'''R'''', OC(O)R'', C(O)R'', CO.sub.2R'',
CONR''R''', NR'''C(O).sub.2R'', S(O)R'', S(O).sub.2R'', CN, and
NO.sub.2.
[0160] As used herein, each R'', R''', and R'''' may be selected,
independently, from the group consisting of: hydrogen, halogen,
oxygen, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted alkyl, alkoxy or
thioalkoxy groups, and arylalkyl groups.
[0161] As used herein, the term "alkyl" by itself or as part of
another substituent, means, unless otherwise stated, a saturated
straight or branched chain, or cyclic hydrocarbon radical, or
combination thereof having the number of carbon atoms designated
(e.g. C.sub.1-C.sub.10 or 1- to 10-membered means one to ten
carbons). When there is no indication of the number of carbon atoms
in the alkyl, it is meant, unless otherwise indicated by context,
that there are from 1 to 10 carbons. Examples of saturated
hydrocarbon radicals include, but are not limited to, groups such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,
sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl,
homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,
n-octyl, and the like.
[0162] As used herein, the term "aryl" by itself or as part of
another substituent, means, unless otherwise stated, a
polyunsaturated, aromatic, hydrocarbon substituent which can be a
single ring or multiple rings (often from 1 to 3 rings) which are
fused together or linked covalently. "Aryl" includes, but is not
limited to, "heteroaryl" groups. "Heteroaryl" refers to an aryl
group that contain from one to four heteroatoms selected from N, O,
and S, wherein the nitrogen and sulfur atoms are optionally
oxidized, and the nitrogen atom(s) are optionally quaternized. A
heteroaryl group can be attached to the remainder of the molecule
through a heteroatom. Non-limiting examples of aryl and heteroaryl
groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,
4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The
term "aryl" when used in combination with other terms (e.g.,
aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl
rings as defined above. Thus, the term "arylalkyl" is meant to
include those radicals in which an aryl group is attached to an
alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.)
including those alkyl groups in which a carbon atom containing
group (e.g., a methylene group) has been replaced by, for example,
an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, etc).
[0163] The present invention is directed to methods of preparation
of Rivaroxaban, various intermediates useful in the preparation of
Rivaroxaban and methods of preparation of such intermediates.
[0164] A person of skill in the art recognizes that by appropriate
choice of reagents, the processes of the present invention may be
equally applied to the preparation of the (R)-enantiomer of
Rivaroxaban. By replacing (R)-(-)-epichlorohydrin (compound of
Formula 4) of the present invention with (S)-(+)-epichlorohydrin,
the (R)-enantiomer of Rivaroxaban is obtained. The processes of the
present invention encompass preparation of both enantiomers of
Rivaroxaban.
[0165] According to illustrative embodiments of the present
invention, there is provided 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:
##STR00065##
with a compound of Formula 8:
##STR00066##
wherein
[0166] R.sup.4 is one of the following:
##STR00067##
wherein
[0167] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0168] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0169] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0170] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0171] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring;
[0172] X is halogen; and
[0173] L.sup.2 is a halogen or sulfonyloxy group.
[0174] The first base may be a strong base suitable for
deprotonation of an amide. The first base may be an organometallic
compound. The organometallic compound may be selected from the
group consisting of organomagnesium, organozinc, organosodium,
organolithium compounds and mixtures thereof. The first base may be
selected from the group consisting of alkylmagnesium halide,
arylmagnesium halide, alkylzinc halide, alkyllithium, aryllithium,
lithium hexaalkyldisilazide, sodium hexaalkyldisilazide, potassium
hexaalkyldisilazide, potassium t-butoxide, sodium hydride, lithium
hydride, L-selectride, superhydride, lithium amide, sodium amide,
lithium dialkylamide, and mixtures thereof. The first base may be
lithium hexamethyldisilazide, n-butyllithium, or potassium
t-butoxide. The first base may be combined with an inorganic salt
additive such as LiX or CuX wherein X is halogen.
[0175] The reaction of the compound of Formula 8 with the compound
of Formula 9 may be conducted in a first solvent. The first solvent
may be a suitable aprotic organic solvent. The first solvent may be
selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether,
diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl acetate,
isopropyl acetate), ketones (e.g. acetone, methyl ethyl ketone,
methyl isobutyl ketone), aromatic, and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitriles (e.g.
acetonitrile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), and
mixtures thereof.
[0176] According to illustrative embodiments of the present
invention, there is provided a process for preparation of a
compound of Formula 8a:
##STR00068##
wherein
[0177] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0178] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0179] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0180] R.sup.2 and R.sup.3, when independent groups, are
independently selected from H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl,
[0181] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0182] X is halogen, the process comprising:
[0183] i. reacting, optionally in the presence of a second base, a
compound of Formula 2:
##STR00069##
with a compound of Formula 3:
##STR00070##
wherein
[0184] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0185] G is as defined above for Formula 8a, thereby forming a
compound of Formula 5:
##STR00071##
wherein
[0186] G is as defined above for Formula 8a; and
[0187] ii. reacting the compound of Formula 5, in the presence of a
third base, with a compound of Formula 4:
##STR00072##
wherein
[0188] L.sup.2 is a halogen or sulfonyloxy group, thereby forming
the compound of Formula 8a.
[0189] In some embodiments, the compound of Formula 3 is a compound
in which L.sup.1 is halogen and G is OR.sup.1. In some embodiments
the compound of Formula 3 is a compound in which L.sup.1 is chloro
and R.sup.1 is alkyl. In some embodiments the compound of Formula 3
is a compound in which L.sup.1 is chloro and R.sup.1 is methyl. In
some embodiments the compound of Formula 3 is a compound in which
L.sup.1 and G are imidazole.
[0190] In some embodiments the compound of Formula 4 is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4 is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4 is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4 is a compound in which
L.sup.2 is chloro.
[0191] The second base may be inorganic or organic. The second base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The
second base may be selected from the group consisting of sodium
hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, sodium bicarbonate, potassium carbonate, lithium
carbonate, potassium phosphate, sodium phosphate, triethylamine,
diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline,
pyridine, and mixtures thereof.
[0192] The reaction of the compound of Formula 2 with the compound
of Formula 3 may be conducted in a second solvent. The second
solvent may be selected from the group consisting of alkyl ethers
(e.g. tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl
ether, diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl
acetate, isopropyl acetate), ketones (e.g. acetone, methyl ethyl
ketone, methyl isobutyl ketone), aromatic and aliphatic
hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes),
nitriles (e.g. acetonitile, propionitrile, butyronitrile, and
benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), water and mixtures
thereof.
[0193] The third base may be a suitable non-nucleophillic base. The
third base may be selected from the group consisting of lithium
hexamethyldisilazide, lithium dialkyl amide, sodium hydride,
potassium t-butoxide and n-butyllithium.
[0194] The reaction of the compound of Formula 5 with the compound
of Formula 4 may be conducted in a third solvent. The third solvent
may be a suitable aprotic organic solvent. The third solvent may be
selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether,
diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl acetate,
isopropyl acetate), ketones (e.g. acetone, methyl ethyl ketone,
methyl isobutyl ketone), aromatic and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitriles (e.g.
acetonitrile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), and
mixtures thereof.
[0195] According to illustrative embodiments of the present
invention, there is provided a process for the preparation of a
compound of Formula 8a:
##STR00073##
wherein
[0196] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0197] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0198] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0199] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0200] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0201] X is halogen, the process comprising:
[0202] i. reacting, in the presence of a fourth base, a compound of
Formula 2:
##STR00074##
with a compound of Formula 4:
##STR00075##
wherein
[0203] L.sup.2 is a halogen or sulfonyloxy group, thereby forming a
compound of Formula 6:
##STR00076##
and;
[0204] ii. reacting, optionally in the presence of a fifth base,
the compound of Formula 6 with a compound of Formula 3:
##STR00077##
wherein
[0205] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0206] G is as defined above for Formula 8a, thereby forming the
compound of Formula 8a.
[0207] In some embodiments the compound of Formula 4 is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4 is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4 is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4 is a compound in which
L.sup.2 is chloro.
[0208] In some embodiments the compound of Formula 3 is a compound
in which L.sup.1 is halogen and G is OR.sup.1. In some embodiments
the compound of Formula 3 is a compound in which L.sup.1 is chloro
and R.sup.1 is alkyl. In some embodiments the compound of Formula 3
is a compound in which L.sup.1 is chloro and R.sup.1 is methyl. In
some embodiments the compound of Formula 3 is a compound in which
L.sup.1 and G are imidazole.
[0209] The fourth base may be inorganic or organic. The fourth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The
fourth base may be selected from the group consisting of sodium
hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, sodium bicarbonate, potassium carbonate, lithium
carbonate, potassium phosphate, sodium phosphate, triethylamine,
diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline,
pyridine, and mixtures thereof.
[0210] Reaction of the compound of Formula 2 with the compound of
Formula 4 may be conducted in a fourth solvent. The fourth solvent
may be selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, diethyl ether, methyl t-butyl ether, diisopropyl
ether, butyl ether), alkyl esters (e.g. ethyl acetate, isopropyl
acetate), ketones (e.g. acetone, methyl ethyl ketone, methyl
isobutyl ketone), aromatic and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitriles (e.g.
acetonitile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), water and mixtures
thereof.
[0211] The fifth base may be inorganic or organic. The fifth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The fifth
base may be selected from the group consisting of sodium hydroxide,
potassium hydroxide, lithium hydroxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, lithium carbonate, potassium
phosphate, sodium phosphate, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, N,N-diethylaniline, pyridine, and mixtures
thereof.
[0212] In some embodiments, the compound of Formula 2 may be
treated with the compound of Formula 4 without base to yield an
intermediate of Formula 7, which may or may not be isolated, before
treatment with a fourth base to yield the compound of Formula
6.
[0213] Reaction of the compound of Formula 6 with the compound of
Formula 3 may be conducted in a fifth solvent. The fifth solvent
may be selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether,
diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl acetate,
isopropyl acetate), ketones (e.g. acetone, methyl ethyl ketone,
methyl isobutyl ketone), aromatic and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitriles (e.g.
acetonitrile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), water and mixtures
thereof.
[0214] According to illustrative embodiments of the present
invention, there is provided a process for preparation of a
compound of Formula 8c:
##STR00078##
wherein
[0215] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0216] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0217] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0218] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0219] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0220] L.sup.2 is a halogen or sulfonyloxy group, the process
comprising:
[0221] i. reacting a compound of Formula 2:
##STR00079##
with a compound of Formula 4:
##STR00080##
wherein
[0222] L.sup.2 is a halogen or sulfonyloxy group; thereby forming a
compound of Formula 7:
##STR00081##
wherein
[0223] L.sup.2 is as defined for Formula 4, and;
[0224] ii. reacting, in the presence of a sixth base, the compound
of Formula 7 with a compound of Formula 3:
##STR00082##
wherein
[0225] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0226] G is as defined above for Formula 8c, thereby forming the
compound of Formula 8c.
[0227] In some embodiments the compound of Formula 4 is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4 is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4 is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4 is a compound in which
L.sup.2 is chloro.
[0228] In some embodiments the compound of Formula 3 is a compound
in which R.sup.1 is alkyl. In some embodiments the compound of
Formula 3 is a compound in which R.sup.1 is methyl. In some
embodiments the compound of Formula 3 is a compound in which X is
chloro and R.sup.1 is methyl.
[0229] The sixth base may be inorganic or organic. The sixth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines and aryl amines. The sixth
base may be selected from the group consisting of sodium hydroxide,
potassium hydroxide, lithium hydroxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, lithium carbonate, potassium
phosphate, sodium phosphate, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, N,N-diethylaniline, pyridine, and mixtures
thereof.
[0230] Reaction of the compound of Formula 2 with the compound of
Formula 4 may be conducted in a sixth solvent that is the same as
the fourth solvent above.
[0231] Reaction of the compound of Formula 7 with the compound of
Formula 3 may be conducted in a seventh solvent that is the same as
the fifth solvent above.
[0232] According to illustrative embodiments of the present
invention, there is provided a process for the preparation of a
compound of Formula 8a:
##STR00083##
wherein
[0233] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0234] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0235] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0236] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0237] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0238] X is halogen, the process comprising conversion of a
compound of Formula 8c to the compound of Formula 8a.
[0239] Conversion of the compound of Formula 8c to the compound of
Formula 8a may be conducted by treatment of the compound of Formula
8c with a suitable alkali halide optionally in the presence of a
seventh base. The suitable alkali halide may be sodium iodide. The
seventh base may be the same as the sixth base above.
[0240] A compound of Formula 8b:
##STR00084##
wherein
[0241] L.sup.2 is as defined above for Formula 4, may be prepared
from the compound of Formula 7 or the compound of Formula 8c. For
example, when the compound of Formula 7 is treated with the
compound of Formula 3 in the presence of a suitable base, the
cyclized compound of Formula 8b may be obtained. Similarly, the
compound of Formula 8c may be converted to the compound of Formula
8b under suitable conditions. For example, when the compound of
Formula 8c is treated with a suitable base, the compound of Formula
8b may be obtained. Other methods for converting the compound of
Formula 7 or Formula 8c to the compound of Formula 8b are known to
those skilled in the art.
[0242] According to illustrative embodiments of the present
invention, there is provided a process for preparation of a
compound of Formula 8aa:
##STR00085##
wherein
[0243] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0244] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0245] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0246] R.sup.2 and R.sup.3 when independent groups, are
independently selected from H, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl and substituted arylalkyl,
[0247] R.sup.2 and R.sup.3 when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0248] X is halogen, the process comprising:
[0249] i. reacting, optionally in the presence of a second base, a
compound of Formula 2:
##STR00086##
with a compound of Formula 3:
##STR00087##
wherein
[0250] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0251] G is as defined above for Formula 8aa, thereby forming a
compound of Formula 5:
##STR00088##
wherein
[0252] G is as defined above for Formula 8aa; and
[0253] ii. reacting the compound of Formula 5, in the presence of a
third base, with a compound of Formula 4a:
##STR00089##
wherein
[0254] L.sup.2 is a halogen or sulfonyloxy group, thereby forming
the compound of Formula 8aa.
[0255] In some embodiments, the compound of Formula 3 is a compound
in which L.sup.1 is halogen and G is OR.sup.1. In some embodiments
the compound of Formula 3 is a compound in which L.sup.1 is chloro
and R.sup.1 is alkyl. In some embodiments the compound of Formula 3
is a compound in which L.sup.1 is chloro and R.sup.1 is methyl. In
some embodiments the compound of Formula 3 is a compound in which
L.sup.1 and G are imidazole.
[0256] In some embodiments the compound of Formula 4a is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4a is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4a is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4a is a compound in which
L.sup.2 is chloro.
[0257] The second base may be inorganic or organic. The second base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The
second base may be selected from the group consisting of sodium
hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, sodium bicarbonate, potassium carbonate, lithium
carbonate, potassium phosphate, sodium phosphate, triethylamine,
diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline,
pyridine, and mixtures thereof.
[0258] The reaction of the compound of Formula 2 with the compound
of Formula 3 may be conducted in a second solvent. The second
solvent may be selected from the group consisting of alkyl ethers
(e.g. tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl
ether, diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl
acetate, isopropyl acetate), ketones (e.g. acetone, methyl ethyl
ketone, methyl isobutyl ketone), aromatic and aliphatic
hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes),
nitriles (e.g. acetonitile, propionitrile, butyronitrile, and
benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), water and mixtures
thereof.
[0259] The third base may be a suitable non-nucleophillic base. The
third base may be selected from the group consisting of lithium
hexamethyldisilazide, lithium dialkyl amide, sodium hydride,
potassium t-butoxide and n-butyllithium.
[0260] The reaction of the compound of Formula 5 with the compound
of Formula 4a may be conducted in a third solvent. The third
solvent may be a suitable aprotic organic solvent. The third
solvent may be selected from the group consisting of alkyl ethers
(e.g. tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl
ether, diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl
acetate, isopropyl acetate), ketones (e.g. acetone, methyl ethyl
ketone, methyl isobutyl ketone), aromatic and aliphatic
hydrocarbons (e.g. toluene, xylenes, hexanes, and heptanes),
nitriles (e.g. acetonitrile, propionitrile, butyronitrile, and
benzonitrile), N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), and
mixtures thereof.
[0261] According to illustrative embodiments of the present
invention, there is provided a process for the preparation of a
compound of Formula 8aa:
##STR00090##
wherein
[0262] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0263] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0264] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0265] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0266] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0267] X is halogen, the process comprising:
[0268] i. reacting, in the presence of a fourth base, a compound of
Formula 2:
##STR00091##
with a compound of Formula 4a:
##STR00092##
wherein
[0269] L.sup.2 is a halogen or sulfonyloxy group, thereby forming a
compound of Formula 6a:
##STR00093##
and;
[0270] ii. reacting, optionally in the presence of a fifth base,
the compound of Formula 6a with a compound of Formula 3:
##STR00094##
wherein
[0271] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0272] G is as defined above for Formula 8a, thereby forming the
compound of Formula 8aa.
[0273] In some embodiments the compound of Formula 4a is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4a is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4a is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4a is a compound in which
L.sup.2 is chloro.
[0274] In some embodiments the compound of Formula 3 is a compound
in which L.sup.1 is halogen and G is OR.sup.1. In some embodiments
the compound of Formula 3 is a compound in which L.sup.1 is chloro
and R.sup.1 is alkyl. In some embodiments the compound of Formula 3
is a compound in which L.sup.1 is chloro and R is methyl. In some
embodiments the compound of Formula 3 is a compound in which
L.sup.1 and G are imidazole.
[0275] The fourth base may be inorganic or organic. The fourth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The
fourth base may be selected from the group consisting of sodium
hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, sodium bicarbonate, potassium carbonate, lithium
carbonate, potassium phosphate, sodium phosphate, triethylamine,
diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline,
pyridine, and mixtures thereof.
[0276] Reaction of the compound of Formula 2 with the compound of
Formula 4a may be conducted in a fourth solvent. The fourth solvent
may be selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, diethyl ether, methyl t-butyl ether, diisopropyl
ether, butyl ether), alkyl esters (e.g. ethyl acetate, isopropyl
acetate), ketones (e.g. acetone, methyl ethyl ketone, methyl
isobutyl ketone), aromatic and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitriles (e.g.
acetonitrile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), water and mixtures
thereof.
[0277] The fifth base may be inorganic or organic. The fifth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines, and aryl amines. The fifth
base may be selected from the group consisting of sodium hydroxide,
potassium hydroxide, lithium hydroxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, lithium carbonate, potassium
phosphate, sodium phosphate, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, N,N-diethylaniline, pyridine, and mixtures
thereof.
[0278] In some embodiments, the compound of Formula 2 may be
treated with the compound of Formula 4a without base to yield an
intermediate of Formula 7a, which may or may not be isolated,
before treatment with a fourth base to yield the compound of
Formula 6a.
[0279] Reaction of the compound of Formula 6a with the compound of
Formula 3 may be conducted in a fifth solvent. The fifth solvent
may be selected from the group consisting of alkyl ethers (e.g.
tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether,
diisopropyl ether, butyl ether), alkyl esters (e.g. ethyl acetate,
isopropyl acetate), ketones (e.g. acetone, methyl ethyl ketone,
methyl isobutyl ketone), aromatic and aliphatic hydrocarbons (e.g.
toluene, xylenes, hexanes, and heptanes), nitrites (e.g.
acetonitrile, propionitrile, butyronitrile, and benzonitrile),
N,N-dialkylamides (e.g. N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone), sulfoxides
and sulfones (e.g. dimethyl sulfoxide and sulfolane), halogenated
hydrocarbons (e.g. dichloromethane and dichloroethane), alcohols
(e.g. methanol, ethanol, isopropanol, butanol), and mixtures
thereof.
[0280] According to illustrative embodiments of the present
invention, there is provided a process for preparation of a
compound of Formula 8ca:
##STR00095##
wherein
[0281] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0282] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0283] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0284] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0285] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0286] L.sup.2 is a halogen or sulfonyloxy group, the process
comprising:
[0287] i. reacting a compound of Formula 2:
##STR00096##
with a compound of Formula 4a:
##STR00097##
wherein
[0288] L.sup.2 is a halogen or sulfonyloxy group; thereby forming a
compound of Formula 7a:
##STR00098##
wherein
[0289] L.sup.2 is as defined for Formula 4, and;
[0290] ii. reacting, in the presence of a sixth base, the compound
of Formula 7a with a compound of Formula 3:
##STR00099##
wherein
[0291] L.sup.1 is a leaving group selected from the group
consisting of halogen, imidazole, ester, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol,
N-hydroxyphthalimide, and N-hydroxybenzotriazole; and
[0292] G is as defined above for Formula 8ca, thereby forming the
compound of Formula 8ca.
[0293] In some embodiments the compound of Formula 4a is a compound
in which L.sup.2 is a sulfonyloxy group. In some embodiments the
compound of Formula 4a is a compound in which L.sup.2 is a
toluenesulfonyloxy, methanesulfonyloxy or
trifluoromethanesulfonyloxy group. In some embodiments the compound
of Formula 4a is a compound in which L.sup.2 is a halogen. In some
embodiments the compound of Formula 4a is a compound in which
L.sup.2 is chloro.
[0294] In some embodiments the compound of Formula 3 is a compound
in which R.sup.1 is alkyl. In some embodiments the compound of
Formula 3 is a compound in which R.sup.1 is methyl. In some
embodiments the compound of Formula 3 is a compound in which X is
chloro and R.sup.1 is methyl.
[0295] The sixth base may be inorganic or organic. The sixth base
may be selected from the group consisting of metal hydroxides,
carbonates, phosphates, tertiary amines and aryl amines. The sixth
base may be selected from the group consisting of sodium hydroxide,
potassium hydroxide, lithium hydroxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, lithium carbonate, potassium
phosphate, sodium phosphate, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, N,N-diethylaniline, pyridine, and mixtures
thereof.
[0296] Reaction of the compound of Formula 2 with the compound of
Formula 4a may be conducted in a sixth solvent that is the same as
the fourth solvent above.
[0297] Reaction of the compound of Formula 7a with the compound of
Formula 3 may be conducted in a seventh solvent that is the same as
the fifth solvent above.
[0298] According to illustrative embodiments of the present
invention, there is provided a process for the preparation of a
compound of Formula 8aa:
##STR00100##
wherein
[0299] G is OR.sup.1, NR.sup.2R.sup.3, or CX.sub.3;
[0300] R.sup.1 is alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, or substituted aryl alkyl;
[0301] R.sup.2 and R.sup.3 are either (a) two independent groups or
(b) together form a single ring group with the N to which they are
bonded;
[0302] R.sup.2 and R.sup.3, when independent groups, are
independently selected from the group consisting of: H, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl and
substituted arylalkyl,
[0303] R.sup.2 and R.sup.3, when together form a single ring group
with the N to which they are bonded, are a heteroaryl ring; and
[0304] X is halogen, the process comprising conversion of a
compound of Formula 8ca to the compound of Formula 8aa.
[0305] Conversion of the compound of Formula 8ca to the compound of
Formula 8aa may be conducted by treatment of the compound of
Formula 8ca with a suitable alkali halide optionally in the
presence of a seventh base. The suitable alkali halide may be
sodium iodide. The seventh base may be the same as the sixth base
above.
[0306] A compound of Formula 8ba:
##STR00101##
wherein
[0307] L.sup.2 is as defined above for Formula 4a, may be prepared
from the compound of Formula 7a or the compound of Formula 8ca. For
example, when the compound of Formula 7a is treated with the
compound of Formula 3 in the presence of a suitable base, the
cyclized compound of Formula 8ba may be obtained. Similarly, the
compound of Formula 8ca may be converted to the compound of Formula
8ba under suitable conditions. For example, when the compound of
Formula 8ca is treated with a suitable base, the compound of
Formula 8ba may be obtained. Other methods for converting the
compound of Formula 7a or Formula 8ca to the compound of Formula
8ba are known to those skilled in the art.
EXAMPLES
[0308] The following examples are illustrative of some of the
embodiments of the invention described herein. These examples
should not be considered to limit the spirit or scope of the
invention in any way.
Example 1
[0309] Preparation of methyl
N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b):
N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3
min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2,
25 g, 130.07 mmol) in CH.sub.2Cl.sub.2 (750 mL). The reaction
mixture was stirred at room temperature for 15 min and methyl
chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10
min. The resulting thick suspension was stirred for another 1 h and
filtered through a Buchner funnel. The solid was washed with
CH.sub.2Cl.sub.2 (2.times.75 mL) and dried under vacuum to obtain
methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g,
95%) as a crystalline solid.
[0310] .sup.1HNMR (300 MHz, DMSO-d6) .delta. 3.66-3.69 (m, 2H),
3.67 (s, 3H), 3.93-3.97 (m, 2H), 4.17 (s, 2H), 7.28 (d, J=8.8 Hz,
2H), 7.46 (d, J=8.8 Hz, 2H), 9.72 (brs, 1H).
Example 2
[0311] Preparation of methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2): NaH (1.772 g, 48 mmol, 65% in mineral oil) was washed with
heptane (30 mL) under a nitrogen atmosphere and DMF (30 mL) was
added. A suspension of methyl
N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 10 g, 40 mmol) in
DMF (60 mL) was added in one portion. (R)-(-)-epichlorohydrin (4.7
mL, 60 mmol) was added and the reaction mixture was heated at
60.degree. C. for 3 h. The reaction mixture was cooled to room
temperature and diluted with a mixture of water (700 mL) and sat.
aq. NH.sub.4Cl. The aqueous layer was extracted with EtOAc (100 mL)
followed by CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic
layers were dried (Na.sub.2SO.sub.4) and evaporated. The residue
was purified by flash chromatography over silica gel (6.times.20
cm) using 70% EtOAc-heptane to obtain methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2, 5.075 g, 42%) as a crystalline solid.
[0312] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 2.55 (dd, J=5.5,
2.5 Hz, 1H), 2.82 (t, J=4.5 Hz, 1H), 3.24-3.28 (m, 1H), 3.54, (dd,
J14.8, 6.1 Hz, 1H), 3.72 (s, 3H), 3.77 (m, 2H), 3.98 (dd, J=14.8,
3.8 Hz, 1H), 4.03 (m, 2H), 4.33 (s, 2H), 7.34 (s, 4H).
Example 3
[0313] Preparation of
4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (6):
R-(-)epichlorohydrin (1.3 mL, 16.5 mmol) was added to a suspension
of 4-(4-aminophenyl)-3-morpholinone (2, 2.883 g, 15 mmol) in IPA
(75 mL). The reaction mixture was refluxed for 20 h and a solution
of NaHCO.sub.3 (1.513 g, 18 mmol) in water (30 mL) was added and
reflux continued for another 1.5 h. Solvent was evaporated using a
rotary evaporator and the residue was diluted with water (100 mL)
and extracted with EtOAc (3.times.50 mL). Combined organic extracts
were dried (Na.sub.2SO.sub.4), evaporated and the residue was
purified by flash chromatography over silica gel (4.times.12 cm)
using 80% EtOAc-heptane to obtain
4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (6,1.675
g, 46%) as a crystalline white solid.
[0314] .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 2.69 (dd, J=5.0,
2.2 Hz, 1H), 2.82 (t, J4.3 Hz, 1H), 3.20-3.27 (m, 2H), 3.51-3.58
(m, 1H), 3.67-3.71 (m, 2H), 3.96-4.02 (m, 3H), 4.32 (s, 2H), 6.66
(d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H).
Example 4
[0315] Preparation of methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2): Methyl chloroformate (0.17 mL, 2.214 mmol) and
N,N-Diisopropylethylamine (0.39 mL, 2.214 mmol) were added in that
order to a stirred and cooled (0.degree. C.) solution of
4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (6, 500
mg, 2.013 mmol) in MeCN (10 mL). The cooling bath was removed after
5 min and stirring continued for another 30 min. The reaction
mixture was diluted with water (70 mL) and extracted with EtOAc
(3.times.30 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4), evaporated and the residue was purified by
flash chromatography over silica gel (2.times.16 cm) using 90%
EtOAc-heptane to obtain methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2, 536 mg, 87%) as a crystalline white solid.
[0316] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 2.55 (dd, J=5.5,
2.5 Hz, 1H), 2.82 (t, J=4.5 Hz, 1H), 3.24-3.28 (m, 1H), 3.54, (dd,
J=14.8, 6.1 Hz, 1H), 3.72 (s, 3H), 3.77 (m, 2H), 3.98 (dd, J=14.8,
3.8 Hz, 1H), 4.03 (m, 2H), 4.33 (s, 2H), 7.34 (s, 4H).
Example 5
[0317] Preparation of
4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one
(7, L.sup.2 is chloro): R(-)-epichlorohydrin (2.12 mL, 27.053 mmol)
was added to a refluxing solution of
4-(4-aminophenyl)-3-morpholinone (2, 4.0 g, 20.81 mmol) in IPA (125
mL). The mixture was refluxed for 24 h and the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography over silica gel (4.times.22 cm) using 90%
EtOAc-hexane to obtain
4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one
(7, L.sup.2 is chloro, 4.89 g, 83%) as a crystalline white solid.
Alternatively the crude residue can be purified by crystallization
in EtOAc-hexane (2:1).
[0318] 1HNMR (300 MHz, CDCl.sub.3) d 2.80 (d, J=5.1 Hz, 1H),
3.15-3.22 (m, 1H), 3.33-3.38 (m, 1H), 3.57-3.71 (m, 4H), 3.96-4.05
(m, 3H), 4.13 (br s, 1H), 4,17 (s, 2H), 6.60-6.65 (m, 2H),
7.07-7.11 (m, 2H).
Example 6
[0319] Preparation of methyl
N-(3-chloro-2R-hydroxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbama-
te (8c3): Methyl chloroformate (0.05 mL, 0.631 mmol) and
N,N-diisopropylethylamine (0.09 mL, 0.5 mmol) were added in that
order to a stirred solution of
4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one
(7, L.sup.2 is chloro, 150 mg, 0.526 mmol) in MeCN (5 mL). The
mixture was stirred at room temperature for 1 h and solvent was
evaporated in vacuo at 30-35.degree. C. The residue was taken up in
CH.sub.2Cl.sub.2 (25 mL) and washed with water (10 mL). The organic
layer was dried (Na.sub.2SO.sub.4), evaporated and dried under
vacuum to obtain methyl
N-(3-chloro-2R-hydroxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbama-
te (8c3, 181 mg, ca. 100%).
[0320] 1HNMR (300 MHz, CDCl3) d 3.45 (br s, 1H), 3.52 (dd, J=11.2,
5.5 Hz, 1H), 3.60 (dd, J=11.2, 5.0 Hz, 1H), 3.67-3.80 (m, 3H), 3.70
(s, 3H), 3.88-3.96 (m, 1H), 4.02-4.06 (m, 3H), 4.34 (s, 2H),
7.28-7.37 (m, 4H).
Example 7
[0321] Preparation of Rivaroxaban: n-BuLi (2.36 mL, 3.77 mmol, 1.6
M in hexane) was added drop-wise (over ca. 2-3 min) to a stirred
and cooled (-10.degree. C.) suspension of
5-chlorothiophene-2-carboxamide (9, 831 mg, 5.141 mmol) in THF (8
mL).The cooling bath was removed after 30 min and the reaction
mixture was stirred for another 30 min. Methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2, 1.05 g, 3.427 mmol) was added as a solid in one portion. The
reaction mixture was then refluxed for 5 h and the solvent
evaporated in vacuo. A mixture of cold water (30 mL;
.about.5.degree. C.) and saturated aqueous NH.sub.4Cl (10 mL) was
added to the damp residue. The mixture was stirred for 10 min,
filtered and washed the solids with cold (.about.5.degree. C.)
water (2.times.10 mL). The solid was pulped in MeOH (40 mL) at
60.degree. C. for 1 h, concentrated to .about.10 mL and cooled to
room temperature. The solids were filtered, washed with cold
(0.degree. C.) MeOH (2.times.4 mL) and dried under vacuum to obtain
Rivaroxaban (925 mg, 62%) as a crystalline solid.
Example 8
[0322] Preparation of Rivaroxaban: LiCl (17 mg, 0.391 mmol) was
added to a solution of t-BuOK (42 mg, 0.359 mmol) in THF (1 mL).
After stirring for 30 min, 5-chlorothiophene-2-carboxamide (9, 79
mg, 0.489 mmol) was added. The suspension was stirred for another
30 min and methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2, 100 mg, 0.326 mmol) was added. The reaction mixture was
refluxed for 4 h and the solvent was evaporated using a rotary
evaporator. A mixture of cold water (8 mL; .about.5.degree. C.) and
saturated aqueous NH.sub.4Cl (2 mL) was added to the damp residue.
The mixture was stirred for 10 min, filtered and washed the solids
with cold (.about.5.degree. C.) water (2.times.2 mL). The solid was
dissolved in MeOH (8 mL) and concentrated using a rotary evaporator
to .about.1 mL. The precipitated solids were filtered, washed with
cold (0.degree. C.) MeOH (0.5 mL) and dried under vacuum to obtain
Rivaroxaban (44 mg, 31%) as a crystalline solid.
Example 9
[0323] Preparation of Rivaroxaban: LiHMDS (0.36 mL, 0.36 mmol,1M in
THF) was added dropwise to a suspension of
5-chlorothiophene-2-carboxamide (9, 95 mg, 0.587 mmol) in THF (1
mL). The resulting homogeneous solution was stirred at room
temperature for 15 min and methyl
N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate
(8a2, 100 mg, 0.326 mmol) was added as a solid. The reaction
mixture was refluxed for 3 h during which time solids separated
out. The solvent was evaporated in vacuo and a mixture of cold
(5.degree. C.) water (8 mL) plus sat. aq. NH.sub.4Cl (2 mL) was
added to the damp solids. The solids were filtered and washed with
cold (5.degree. C.) water (5 ml). The solids were dissolved in 1:1
mixture of MeOH--CH.sub.2Cl.sub.2 (10 mL) and concentrated on a
rotary evaporator to .about.1 mL. The precipitated solids were
filtered, washed with cold (5.degree. C.) MeOH (2.times.0.5 mL) and
dried under vacuum to obtain Rivaroxaban (90 mg, 64%) as a
crystalline solid.
[0324] .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 3.59-3.62 (m, 2H),
3.69-3.73 (m, 2H), 3.85 (dd, J=8.9, 6.3 Hz, 1H), 3.95-3.99 (m, 2H),
4.16-4.22 (m, 1H), 4.19 (s, 2H), 4.82-4.86 (m,. 1H), 7.19 (d, J=4.2
Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.69 (d,
J=4.2 Hz,1H), 8.97 (t, J=5.5 Hz, 1H).
[0325] Although various embodiments of the invention are disclosed
herein, many adaptations and modifications may be made within the
scope of the invention in accordance with the common general
knowledge of those skilled in this art. Such modifications include
the substitution of known equivalents for any aspect of the
invention in order to achieve the same result in substantially the
same way. Numeric ranges are inclusive of the numbers defining the
range. The word "comprising" is used herein as an open-ended term,
substantially equivalent to the phrase "including, but not limited
to", and the word "comprises" has a corresponding meaning. As used
herein, the singular forms "a", "an" and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a thing" includes more than one such thing.
Citation of references herein is not an admission that such
references are prior art to the present invention. Any priority
document(s) are incorporated herein by reference as if each
individual priority document were specifically and individually
indicated to be incorporated by reference herein and as though
fully set forth herein. The invention includes all embodiments and
variations substantially as hereinbefore described and with
reference to the examples and drawings.
* * * * *