Synthesis and Antiviral Activity
155
2-((Dimethylamino)methyl)-5-hydroxy-1-methyl-6-(pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl ester dihydro-
chloride (7a). 1H NMR (DMSO-d ), d , ppm: 10.25 (broad s, 1H), 10.17 (s, 1H), 9.14 (s, 1H), 8.81 (d, J 5.6 Hz, 1H), 8.77 (d, J
8.0 Hz, 1H), 8.04 (dd, J 8.0 Hz, J 5.6 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 4.87 (s, 2H), 4.38 (q, J 7.2 Hz, 2H), 4.00 (s, 3H), 2.85
6
1
2
(s, 6H), 1.44 (t, J 7.2 Hz, 3H). GC-MS (ESI) [M + H]+ 354. C H N O .
20 23
3
3
5-Hydroxy-1-methyl-6-(pyridin-3-yl)-2-(pyrrolidin-1-ylmethyl)-1H-indole-3-carboxylic acid ethyl ester dihydrochlo-
1
ride (7b). H NMR (DMSO-d ), d , ppm: 10.77 (broad s, 1H), 10.14 (s, 1H), 9.14 (s, 1H), 8.81 (d, J 6.0 Hz, 1H), 8.78 (d, J
6
8.0 Hz, 1H), 8.04 (dd, J 1 8.0 Hz, J 2 6.0 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 4.95 (s, 2H), 4.37 (q, J 7.0 Hz, 2H), 4.02 (s, 3H),
3.49 (broad m, 2H), 3.30 (broad m, 2H), 2.07 (broad m, 2H), 1.95 (broad m, 2H), 1.43 (t, J 7.0 Hz, 3H). GC-MS (ESI) [M + H]+
380. C H N O .
22 25
3
3
1
5-Hydroxy-1-methyl-2-(morpholinomethyl)-6-(pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl ester (7c). H NMR
(DMSO-d ), d , ppm: 9.38 (s, 1H), 8.81 (s, 1H), 8.49 (m, 1H), 8.02 (m, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.43 (m, 1H), 4.29 (dk, J
7.2 Hz, J 1.6 Hz, 2H), 4.08 (s, 2H), 3.83 (d, J 1.6 Hz, 3H), 3.54 (broad m, 4H), 2.46 (broad m, 4H), 1.39 (dt, J 7.2 Hz, J
6
1
2
2
1
1.6 Hz, 3H). GC-MS (ESI) [M + H]+ 396. C H N O .
22 25
3
4
2-((Dimethylamino)methyl)-5-hydroxy-1-methyl-6-(pyridin-4-yl)-1H-indole-3-carboxylic acid ethyl ester dihydro-
chloride (7d). 1H NMR (DMSO-d ), d , ppm: 10.42 (s, 1H), 10.22 (broad s, 1H), 8.90 (d, J 6.2 Hz, 2H), 8.39 (d, J 6.2 Hz, 2H),
6
7.99 (s, 1H), 7.79 (s, 1H), 4.88 (s, 2H), 4.38 (q, J 7.2 Hz, 2H), 4.01 (s, 3H), 2.86 (s, 6H), 1.44 (t, J 7.2 Hz, 3H). GC-MS (ESI) [M
+ H]+ 354. C H N O .
20 23
3
3
5-Hydroxy-1-methyl-6-(pyridin-4-yl)-2-(pyrrolidin-1-ylmethyl)-1H-indole-3-carboxylic acid ethyl ester dihydrochlo-
ride (7e). 1H NMR (DMSO-d ), d , ppm: 10.69 (broad s, 1H), 10.40 (s, 1H), 8.90 (d, J 6.0 Hz, 2H), 8.40 (d, J 6.0 Hz, 2H), 7.99
6
(s, 1H), 7.78 (s, 1H), 4.96 (s, 2H), 4.38 (q, J 7.2 Hz, 2H), 4.04 (s, 3H), 3.49 (broad m, 2H), 3.32 (broad m, 2H), 2.07 (broad m,
2H), 1.95 (broad m, 2H), 1.43 (t, J 7.2 Hz, 3H). GC-MS (ESI) [M + H]+ 380. C H N O .
22 25
3
3
2-((Dimethylamino)methyl)-5-hydroxy-1-isopropyl-6-(pyridin-3-yl)-1H-indole-3-carboxylic acid ethyl ester dihyd-
rochloride (7f). 1H NMR (DMSO-d ), d , ppm: 10.16 (s, 1H), 9.76 (broad s, 1H), 9.11 (d, J 1.2 Hz, 1H), 8.83 (d, J 5.6 Hz, 1H),
8.75 (d, J 8.0 Hz, 1H), 8.05 (dd, J 8.0 Hz, J 5.6 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 5.12 (m, 1H), 4.90 (d, J 2.4 Hz, 2H), 4.38
6
1
2
(q, J 7.0 Hz, 2H), 2.85 (s, 6H), 1.66 (d, J 6.8 Hz, 6H), 1.44 (t, J 7.0 Hz, 3H). GC-MS (ESI) [M + H]+ 382. C H N O .
22 27
3
3
2-((Dimethylamino)methyl)-5-hydroxy-6-(pyridin-3-yl)-1-cyclopropyl-1H-indole-3-carboxylic acid ethyl ester dihyd-
rochloride (7g). 1H NMR (DMSO-d ), d , ppm: 10.15 (s, 1H), 10.10 (broad s, 1H), 9.12 (d, J 1.6 Hz, 1H), 8.82 (d, J 5.6 Hz,
1H), 8.73 (d, J 8.0 Hz, 1H), 8.04 (dd, J 8.0 Hz, J 5.6 Hz, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 4.89 (d, J 4.0 Hz, 2H), 4.37 (q, J
6
1
2
7.2 Hz, 2H), 3.70 (m, 1H), 2.88 (d, J 4.0 Hz, 6H), 1.42 (t, J 7.2 Hz, 3H), 1.34 (m, 2H), 1.12 (m, 2H). GC-MS (ESI) [M + H]+
380. C H N O .
22 25
3
3
2-((Dimethylamino)methyl)-5-hydroxy-6-(pyridin-3-yl)-1-cyclohexyl-1H-indole-3-carboxylic acid ethyl ester dihyd-
rochloride (7h). 1H NMR (DMSO-d ), d , ppm: 10.11 (s, 1H), 9.62 (broad s, 1H), 9.09 (m, 1H), 8.82 (m, 1H), 8.70 (broad m,
6
1H), 8.03 (broad m, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 4.92 (d, J 2.6 Hz, 2H), 4.64 (broad m, 1H), 4.39 (q, J 7.2 Hz, 2H), 2.86 (d, J
2.6 Hz, 6H), 2.41 (m, 2H), 1.85 (m, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.44 (t, J 7.2 Hz, 3H). GC-MS (ESI) [M + H]+ 422.
C H N O .
25 31
3
3
2-((Dimethylamino)methyl)-5-hydroxy-6-(pyridin-3-yl)-1-phenyl-1H-indole-3-carboxylic acid ethyl ester dihydro-
1
chloride (7i). H NMR (DMSO-d ), d , ppm: 10.27 (s, 1H), 9.51 (broad s, 1H), 8.96 (s, 1H), 8.74 (d, J 5.2 Hz, 1H), 8.53 (d, J
7.6 Hz, 1H), 7.92 (dd, J 7.6 Hz, J 5.2 Hz, 1H), 7.86 (s, 1H), 7.66 (m, 5H), 7.12 (s, 1H), 4.57 (s, 2H), 4.44 (q, J 6.8 Hz, 2H),
6
1
2
2.65 (s, 6H), 1.47 (t, J 6.8 Hz, 3H). GC-MS (ESI) [M + H]+ 416. C H N O .
25 25
3
3
2-Dimethylaminomethyl-5-hydroxy-1-methyl-6-fluoro-1H-indole-3-carboxylic acid ethyl ester hydrochloride (11).
Acetic anhydride (0.358 ml, 3.74 mmol) was added to a solution of 470 mg (1.87 mmol) of 5-hydroxy-1,2-dimethyl-6-
fluoro-1H-indole-3-carboxylic acid ethyl ester (compound 8) in 5 ml of pyridine. The reaction was mixed for 12 h and poured
into 10 ml of 5% NaHCO solution; the resulting precipitate was collected by filtration, washed with water, and dried in vacuo.
3
This produced 5-acetoxy-1,2-dimethyl-6-fluoro-1H-indole-3-carboxylic acid (compound 9), GC-MS (ESI) [M + H]+ 294
(C H FNO ). Compound 9 (380 mg, 1.3 mmol) was boiled with NBS (277 mg, 1.56 mmol) in 20 ml of CCl for 4 h. After
15 16
4
4
cooling, the precipitate was collected by filtration and washed with benzene. The filtrate was evaporated in vacuo and
recrystallized from heptane. The produced 5-acetoxy-2-bromomethyl-1-methyl-6-fluoro-1H-indole-3-carboxylic acid (com-
pound 10), 1H NMR (CDCl ), d , ppm: 7.86 (d, J 8.0 Hz, 1H), 7.13 (d, J 10.0 Hz, 1H), 5.11 (s, 2H), 4.40 (q, J 7.0 Hz, 2H), 3.76
3
(s, 3H), 2.35 (s, 3H), 1.43 (t, J 7.0 Hz, 3H). Dimethylamine (3.6 ml, 1 M) solution in benzene was added to a solution of com-
pound 10 (335 mg, 0.9 mmol) in 15 ml of benzene. The reaction was mixed for 24 h and then evaporated in vacuo; the residue
was dissolved in 25 ml of dichloromethane, washed with 10% potash solution, dried over Na SO , and evaporated in vacuo.
2
4
This produced compound 11, which was converted to the hydrochloride by addition of an equivalent quantity of 3 M HCl solu-
tion in dioxane to 5 ml of a solution of compound 11 in acetone; the resulting precipitate was collected by filtration, washed with
ether, and dried in vacuo. This was recrystallized from absolute ethanol. The procedure produced 214 mg (72%) of compound 11