Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor
The present application is directed to processes and intermediates for making 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide, which is an inhibitor of indoleamine 2,3-dioxygenase, useful in the treatment of cancer and other disorders.
1. A process comprising reacting a compound of Formula F5:
with an aldehyde of Formula F6:
wherein Pg 1 is an amino protecting group, to afford a compound of Formula F7:
2. The process of claim 1 , wherein Pg 1 is ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl.
3. The process of claim 1 , wherein Pg 1 is tert-butoxycarbonyl.
4. The process of claim 1 , wherein said reacting is performed in the presence of a reducing agent.
5. The process of claim 4 , wherein said reducing agent is a borohydride reducing agent.
6. The process of claim 5 , wherein said borohydride reducing agent is sodium triacetoxyborohydride.
7. The process of claim 1 , further comprising deprotecting said compound of Formula F7 to afford a compound of Formula F8:
8. The process of claim 7 , wherein said deprotecting comprises reacting the compound of Formula F7 with hydrochloric acid.
9. The process of claim 7 , further comprising reacting said compound of Formula F8, with Pg 2 -NH—SO 2 —X, in the presence of an organic base to afford a compound of Formula F9:
wherein:
Pg 2 is an amino protecting group; and
X is halo.
10. The process of claim 9 , wherein Pg 2 is ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl.
11. The process of claim 9 , wherein Pg 2 is tert-butoxycarbonyl.
12. The process of claim 9 , wherein X is chloro.
13. The process of claim 9 , further comprising deprotecting said compound of Formula F9 to afford a compound of Formula F10:
14. The process of claim 13 , wherein said deprotecting comprises reacting a compound of Formula F9 with hydrochloric acid.
15. The process of claim 13 , wherein said deprotecting comprises reacting a compound of Formula F9 with hydrochloric acid in a solvent component comprising ethyl acetate.
16. The process of claim 13 , further comprising reacting said compound of Formula F10 with a base to afford a compound of Formula I:
17. The process of claim 16 , wherein said base is sodium hydroxide.
18. A process, comprising reacting a compound of Formula F15:
with a compound of Formula F5:
to afford a compound of Formula F16:
wherein:
each R 1 is independently an amino protecting group; and
R 3 is C 1-6 alkyl or benzyl.
19. The process of claim 18 , wherein each R 1 is C 2-4 alkenyl-C 1-3 alkyl or phenyl-C 1-3 alkyl, wherein said phenyl-C 1-3 alkyl is optionally substituted by 1, 2, or 3 independently selected C 1-4 alkoxy groups.
20. The process of claim 18 , wherein each R 1 is allyl.
21. The process of claim 18 , wherein each R 1 is 4-methoxybenzyl.
22. The process of claim 18 , wherein R 3 is C 1-6 alkyl.
23. The process of claim 18 , wherein R 3 is tert-butyl.
24. The process of claim 18 , wherein said reacting is performed in the presence of a reducing agent.
25. The process of claim 24 , wherein said reducing agent is a borohydride reducing agent.
26. The process of claim 25 , wherein said borohydride reducing agent is sodium triacetoxyborohydride.
27. The process of claim 24 , wherein said reacting is performed in the presence of trifluoroacetic acid.
28. The process of claim 18 , further comprising deprotecting said compound of Formula F16 to afford a compound of Formula F10:
29. The process of claim 28 , wherein said deprotecting comprises reacting a compound of Formula F16 with trifluoroacetic acid.
30. The process of claim 28 , wherein said deprotecting comprises reacting a compound of Formula F16 with is hydrochloric acid.
31. The process of claim 18 , wherein said compound of Formula F15 is obtained by a process comprising treating a compound of Formula F14:
with a reducing agent to afford said compound of Formula F15; wherein R 2 is C 1-4 alkyl.
32. The process of claim 31 , wherein said reducing agent is diisobutylaluminum hydride.
33. The process of claim 31 , wherein said compound of Formula F14 is obtained by a process comprising protecting a compound of Formula F13:
with one or more independently selected amino protecting agents to afford a compound of Formula F14.
34. The process of claim 33 , wherein said one or more amino protecting agents is selected from allyl bromide and 4-methoxybenzyl chloride.
35. The process of claim 33 , wherein said protecting is performed in the presence of a base.
36. A compound of Formula F15:
wherein:
R 3 is C 1-6 alkyl or benzyl; and
each R 1 is independently an amino protecting group.
37. The compound of claim 36 , which is tert-butyl allyl{[allyl(2-oxoethyl)amino]sulfonyl}carbamate.
38. The compound of claim 36 , which is tert-butyl(4-methoxybenzyl){[(4-methoxybenzyl)(2-oxoethyl)amino]sulfonyl}carbamate.
39. A process, comprising reacting a compound of Formula F17:
wherein R 4 is C 1-6 alkyl, C 1-6 haloalkyl, benzyl, or 9H-fluoren-9-ylmethyl with a compound of Formula F5:
to afford a compound of Formula F18:
40. The process of claim 39 , wherein R 4 is tent-butyl.
41. The process of claim 39 , wherein R 4 is benzyl.
42. The process of claim 39 , wherein R 4 is ethyl.
43. The process of claim 39 , wherein R 4 is 2,2,2-trichloroethyl.
44. The process of claim 40 , wherein said reacting is carried out in the presence of a reducing agent.
45. The process of claim 44 , wherein said reducing agent is triethylsilane.
46. The process of claim 45 , wherein said reacting is carried out in the presence of an organic acid.
47. The process of claim 46 , wherein said organic acid is trifluoroacetic acid.
48. The process of claim 40 , further comprising deprotecting said compound of Formula F18 to afford a compound of Formula F10:
49. The process of claim 48 , wherein said deprotecting comprises reacting the compound of Formula F18 with zinc in the presence of acetic acid.
50. The process of claim 48 , further comprising reacting said compound of Formula F10 with a base to afford a compound of Formula I:
51. The process of claim 50 , wherein said base is sodium hydroxide.
52. The process of claim 39 , wherein R 4 is 9H-fluoren-9-ylmethyl.
53. The process of claim 52 , wherein said reacting is carried out in the presence of a reducing agent.
54. The process of claim 53 , wherein said reducing agent is triethylsilane.
55. The process of claim 54 , wherein said reacting is carried out in the presence of an organic acid.
56. The process of claim 55 , wherein said organic acid is methanesulfonic acid.
57. The process of claim 52 , further comprising converting said compound of Formula F18 to a compound of Formula I:
wherein said converting comprises combining the compound of Formula F18 with a base to form a first mixture.
58. The process of claim 57 , wherein said base is N,N-bis(2-aminoethyl)ethane-1,2-diamine.
59. The process of claim 57 , wherein said converting further comprises adding aqueous hydrochloric acid to said first mixture.
60. A compound of Formula F17:
wherein R 4 is C 1-6 haloalkyl, benzyl, or 9H-fluoren-9-ylmethyl.
61. A compound which is tert-butyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate.
62. The compound of claim 60 , which is benzyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate.
63. A compound which is ethyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate.
64. The compound of claim 60 , which is 2,2,2-trichloroethyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate.
65. The compound of claim 60 , which is (9H-fluoren-9-yl)methyl N-(2,2-dimethoxyethy)sulfamoylcarbamate.
66. A process, comprising:
i) reacting a compound of Formula F19:
with a compound of Formula F5:
in the presence of triethylsilane and methanesulfonic acid to afford a compound of Formula F20:
and
ii) converting said compound of Formula F20 to a compound of Formula I:
wherein said converting comprises combining said compound of Formula F20 with N,N-bis(2-aminoethyl)ethane-1,2-diamine.