Process for synthesizing oxidized lactam compounds
The invention provides a method for the synthesis of dehydrogenated lactam drugs of Formula I:
1. A method for preparing a compound of Formula V, comprising the step of reacting a compound of Formula VA:
with a compound of Formula II:
in the presence of an acid, wherein
Each R A , R B , R C , and R D is independently selected from hydrogen, halogen, —CN, NH 2 , NR 100 R 101 , SR 100 , OR 100 , aliphatic, substituted aliphatic, aryl and substituted aryl; wherein R 100 and R 101 , are independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
X is —S— or —O—;
X 2 is selected from CH and N;
R 1 , is selected from H, —C(R J )(R K )—OR 20 , —C(R J )(R K )—OC(O)OR 20 , —C(R J )(R K )—OC(O)R 20 , —C(R J )(R K )—OC(O)NR 20 R 21 , —(C(R J )(R K ))—OPO 3 MY, —(C(R J )(R K ))—OP(O)(OR 20 )(OR 21 ), —[C(R J )(R K )O] z —R 20 , —[C(R J )(R K )O] z —C(O)OR 20 , —[C(R J )(R K )O] z —C(O)R 20 , —[C(R J )(R K )O] z —C(O)NR 20 R 21 , —[C(R J )(R K )O] z —OPO 3 MY, —[C(R J )(R K )O] z —P(O) 2 (OR 20 )M and —[C(R J )(R K )O] z —P(O)(OR 20 )(OR 21 );
wherein each R J and R K is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation; and
z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R 2 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
n is selected from 0, 1, 2 or 3;
q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R 6 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl or substituted heterocyclyl;
R 7 and R 8 are independently selected from absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and
wherein said compound of Formula VA contain a primary, secondary or tertiary amine having a pKa of about 6 to about 45.
2. The method according to claim 1 , wherein R 6 is selected from:
wherein R 100 R 101 , and R 103 are independently selected from hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl.
3. The method according to claim 2 , wherein R 6 is selected from
4. A method according to claim 1 , wherein R 1 is selected from Tables 1-4.
TABLE 1
TABLE 2
TABLE 3
TABLE 4
5. The method according to claim 1 , wherein said compound of Formula II is selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or para-benzoquinone.
6. The method according to claim 1 , wherein said acid is selected from trifluroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, propionic acid, sulfuric acid, phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid, oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydrobromic acid, and mixtures thereof.
7. The method according to claim 6 , wherein said acid is trifluroacetic acid.
8. The method according to claim 1 , wherein the reaction is conducted in a solvent selected from tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane, benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketone and combinations thereof.
9. The method according to claim 1 , wherein said pKa range of primary, secondary or tertiary amine is between about 6 to about 30.
10. The method according to claim 1 , wherein said compound of Formula VA is selected from Table A:
TABLE A
No
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
11. A method for preparing a compound having the structure
comprising the step of reacting a compound having the structure
with a compound of Formula II:
wherein
Each R A , R B , R C , and R D is independently selected from hydrogen, halogen, —CN, NH 2, NR 100 R 101 , SR 100 , OR 100 , aliphatic, substituted aliphatic, aryl and substituted aryl; wherein R 100 and R 101 , are independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
in the presence of an acid.
12. The method according to claim 11 , wherein said compound of Formula II is selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or para-benzoquinone.
13. The method according to claim 11 , wherein said acid is selected from trifluroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, propionic acid, sulfuric acid, phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid, oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydrobromic acid, and mixtures thereof.
14. The method according to claim 13 , wherein said acid is trifluroacetic acid.
15. The method according to claim 11 , wherein the reaction is conducted in a solvent selected from tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane, benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketone and combinations thereof.