1708 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 4
Francotte et al.
7,63 (s, 1H, 8-H), 8.10 (t, 1H, N-H). Anal. (C9H10BrFN2O2S)
C, H, N, S.
reduced pressure. The dry residue was then recrystallized from
a mixture of acetone/water (1:10) (0.47 g, 50%): mp 127-131
°C; IR (KBr) 3418, 3362, 3273, 1602, 1509, 1452, 1313, 1147,
4-(2-Fluoroethyl)-7-iodo-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-Dioxide (12d). The title compound was obtained as described
for 12a starting from 7-iodo-4-(2-fluoroethyl)-4H-1,2,4-benzo-
thiadiazine 1,1-dioxide (11d) (0.25 g, 0.71 mmol) (0.18 g, 71%):
mp 156-158 °C; IR (KBr) 3244, 1591, 1494, 1332, 1315, 1300,
1151, 980 cm-1; 1H NMR (DMSO-d6, 500 MHz) δ 3.74 (dt, 2H,
NCH2CH2F), 4.59 (dt, 2H, NCH2CH2F), 4.76 (s, 2H, 3-H2), 6.83
(d, 1H, 5-H), 7.65 (d, 1H, 6-H), 7,73 (s, 1H, 8-H), 8.15 (t, 1H,
N-H). Anal. (C9H10FIN2O2S) C, H, N, S.
1057 cm-1 1H NMR (DMSO-d6, 500 MHz) δ 3.73 (t, 2H,
;
2-NHCH2CHF2), 6.18 (m, 2H, 4-NHCH2CHF2), 7.01 (d, 1H,
3-H), 7.42 (d, 1H, 4-H), 7.54 (bs, 2H, SO2NH2), 7.61 (s, 1H,
6-H). Anal. (C8H9ClF2N2O2S) C, H, N, S.
7-Chloro-4-(2,2-difluoroethyl)-4H-1,2,4-benzothiadiazine 1,1-
Dioxide (16). 5-Chloro-4-(2,2-difluoroethylamino)benzenesulfon-
amide (15) (300 mg, 1.10 mmol) was suspended in triethyl ortho-
formate (1.5 mL). The mixture was heated at 180 °C in an open
vessel for 45 min. After the mixture was cooled, the insoluble
material that appeared was collected by filtration, washed with
diethyl ether, and dried (0.26 g, 84%): mp 183-186 °C; IR (KBr)
1617, 1590, 1482, 1459, 1428, 1412, 1307, 1171, 1158, 1138, 1071,
4-(2-Fluoroethyl)-7-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-Dioxide (12e). The title compound was obtained as described for
12a starting from 7-methyl-4-(2-fluoroethyl)-4H-1,2,4-benzothia-
diazine 1,1-dioxide (11e) (0.3 g, 1.2 mmol) (0.24 g, 79%): mp
88-90 °C; IR (KBr) 3246, 1621, 1513, 1358, 1337, 1313, 1164,
784 cm-1 1H NMR (DMSO-d6, 500 MHz) δ 4.73 (t, 2H,
;
NCH2CHF2), 6.49 (td, 1H, NCH2CHF2), 7.78 (d, 1H, 5-H),
7.88 (d, 1H, 6-H), 7.97 (s, 1H, 8-H), 8.14 (s, 1H, 3-H). Anal.
(C9H7ClF2N2O2S) C, H, N, S.
1
1150, 983 cm-1; H NMR (DMSO-d6, 500 MHz) δ 2.21 (s, 3H,
7-CH3), 3.70 (dt, 2H, NCH2CH2F), 4.58 (dt, 2H, NCH2CH2F),
4.71 (d, 2H, 3-H2), 6.87 (d, 1H, 5-H), 7.21 (d, 1H, 6-H), 7.35 (s, 1H,
8-H), 7.96 (t, 1H, N-H). Anal. (C10H13FN2O2S) C, H, N, S.
4-(2-Fluoroethyl)-7-methoxy-3,4-dihydro-2H-1,2,4-benzothiadia-
zine 1,1-Dioxide (12f). The title compound was obtained as de-
scribed for 12a starting from 4-(2-fluoroethyl)-7-methoxy-4H-
1,2,4-benzothiadiazine 1,1-dioxide (11f) (0.2 g, 0.77 mmol) (0.13
g, 65%): mp 115-117 °C; IR (KBr) 3235, 3207, 1508, 1312, 1274,
1239, 1161, 992, 773 cm-1; 1H NMR (DMSO-d6, 500 MHz) δ 3.68
(dt, 2H, NCH2CH2F), 3.72 (s, 3H, 7-OCH3), 4.58 (dt, 2H,
NCH2CH2F), 4.69 (d, 2H, 3-H2), 6.90 (d, 1H, 5-H), 7.03 (m, 1H,
6-H/8-H), 7.93 (t, 1H, N-H). Anal. (C10H13FN2O3S) C, H, N, S.
4-(2-Fluoroethyl)-7-nitro-3,4-dihydro-2H-1,2,4-benzothiadi-
azine 1,1-Dioxide (12g). The title compound was obtained as
described for 12a starting from 4-(2-fluoroethyl)-7-nitro-4H-
1,2,4-benzothiadiazine 1,1-dioxide (11g) (0.25 g, 0.91 mmol)
(0.18 g, 72%): mp 165-166 °C; IR (KBr) 3188, 1605, 1521, 1314,
7-Chloro-4-(2,2-difluoroethyl)-3,4-dihydro-2H-1,2,4-benzothia-
diazine 1,1-Dioxide (17). The title compound was obtained as
described for 12a starting from 7-chloro-4-(2,2-difluoroethyl)-
4H-1,2,4-benzothiadiazine 1,1-dioxide (16) (1 g, 3.56 mmol)
(0.75 g, 75%): mp 128-130 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 3.91 (td, 2H, NCH2CHF2), 4.81 (d, 2H, 3-H2), 6.26 (td, 1H,
NCH2CHF2), 7.09 (d, 1H, 5-H), 7.46 (d, 1H, 6-H), 7,56 (s, 1H,
8-H), 8.25 (t, 1H, NH). Anal. (C9H9ClF2N2O2S) C, H, N, S.
2-(2,2,2-Trifluoroethylamino)-5-nitrobenzenesulfonamide (19).
2-Chloro-5-nitrobenzenesulfonamide (18) (1 g, 4.23 mmol) pre-
viously dissolved in dioxane (15 mL) and 2,2,2-trifluoroethyla-
mine (1.6 mL, 2.1 g, 21.15 mmol) were introduced in a closed
vessel and heated during 50 h at 160 °C. The solvent was then
removed under reduced pressure. Water was added to the residue,
and the resulting precipitate was collected by filtration, washed
with water, and dried (0.76 g, 60%): mp 169-172 °C; IR (KBr)
1
1185, 1170, 1131, 984 cm-1; H NMR (DMSO-d6, 500 MHz) δ
1
3354, 3263, 1603, 1589, 1503, 1329, 1185, 1128, 1144 cm-1; H
3.93 (dt, 2H, NCH2CH2F), 4.67 (dt, 2H, NCH2CH2F), 4.94 (d,
2H, 3-H2), 7.18 (d, 1H, 5-H), 8.19 (d, 1H, 6-H), 8.31 (s, 1H, 8-H),
8.49 (bs, 1H, NH). Anal. (C9H10FN3O4S) C, H, N, S.
NMR (DMSO-d6, 500 MHz) δ 4.41 (m, 2H, NCH2CF3), 7.14 (t,
1H, NHCH2CF3), 7.28 (d, 1H, 3-H), 7.83 (bs, 2H, SO2NH2), 8.26
(d, 1H, 4-H), 8.55 (s, 1H, 6-H). Anal. (C8H8F3N3O4S) C, H, N, S.
4-(2,2,2-Trifluoroethyl)-7-nitro-4H-1,2,4-benzothiadiazine
1,1-Dioxide (20). 2-(2,2,2-Trifluoroethylamino)-5-nitroben-
zenesulfonamide (19) (3.5 g, 11.7 mmol) was suspended in
triethyl orthoformate (20 mL). The mixture was heated at
160 °C in an open vessel for 2 h. After cooling, the insoluble
material that appeared was collected by filtration, washed
with diethyl ether, and dried (2.86 g, 79%): mp 243-246 °C;
IR (KBr) 1628, 1531, 1353, 1330, 1177, 1132, 1098 cm-1; 1H
NMR (DMSO-d6, 500 MHz) δ 5,35 (q, 2H, NCH2CF3), 8.11
(d, 1H, 5-H), 8.36 (s, 1H, 8-H), 8.59 (s, 1H, 3-H), 8.61 (d, 1H,
6-H). Anal. (C9H6F3N3O4S) C, H, N, S.
4-(2,2,2-Trifluoroethyl)-7-nitro-3,4-dihydro-2H-1,2,4-benzothia-
diazine 1,1-Dioxide (21). The title compound was obtained as
described for 12a starting from 4-(2,2,2-trifluoroethyl)-7-nitro-
4H-1,2,4-benzothiadiazine 1,1-dioxide (20) (1 g, 3.23 mmol)
(0.74 g, 74%): mp 191-193 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 4.61 (m, 2H, NCH2CF3), 4.99 (d, 2H, 3-H2), 7.35 (d, 1H, 5-H),
8.27 (d, 1H, 6-H), 8.35 (s, 1H, 8-H), 8.72 (bs, 1H, NH). Anal.
(C9H8F3N3O4S) C, H, N, S.
7-Amino-4-(2,2,2-trifluoroethyl)-4H-1,2,4-benzothiadiazine
1,1-Dioxide (22). 4-(2,2,2-Trifluoroethyl)-7-nitro-4H-1,2,4-
benzothiadiazine 1,1-dioxide (20) (2.5 g, 8.08 mmol) was
dispersed in a 1:1 ethanol/water mixture (60 mL). The suspen-
sion was heated until the product dissolved. Then ammonium
chloride (1.25 g) and powdered iron (5 g) were added. After the
mixture was refluxed for 45 min, the insoluble material was
removed by filtration and rinsed with a small amount of hot
ethanol. The filtrate was concentrated under reduced pres-
sure. The beige precipitate that formed was collected by
filtration, washed with water, and dried (1.35 g, 60%): mp
246-248 °C; IR (KBr) 3453, 3366, 1607, 1500, 1420, 197, 1267,
4-(2-Fluoroethyl)-7-trifluoromethyl-3,4-dihydro-2H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (12h). The title compound was obtained
as described for 12a starting from 4-(2-fluoroethyl)-7-trifluoro-
methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (11h) (0.25 g, 0.84
1
mmol) (0.19 g, 75%): mp 142-144 °C; H NMR (DMSO-d6,
500 MHz) δ 3.84 (dt, 2H, NCH2CH2F), 4.64 (dt, 2H, NCH2-
CH2F), 4.86 (d, 2H, 3-H2), 7.16 (d, 1H, 5-H), 7.69 (d, 1H, 6-H);
7.76 (s, 1H, 8-H), 8.29 (t, 1H, N-H). Anal. (C10H10F4N2O2S)
C, H, N, S.
5-Chloro-2-(2,2-difluoroacetamido)benzenesulfonamide (14). To
2-amino-5-chlorobenzenesulfonamide (13)11(1 g, 4.84 mmol) dis-
solved in dioxane (4 mL) were added in the cold state (þ5 °C)
pyridine (0.6 mL) and difluoroacetic acid chloride (0.6 mL). The
flask was hermetically closed immediately, and contents were
vigorously stirred at ambient temperature for 10 min. The solvents
were then removed under reduced pressure. The solid residue was
taken up in water (12 mL) and the insoluble material was collected
by filtration, washed with water, and dried to yield the expected
compound (1.25 g, 91%): mp 180-181 °C; IR (KBr) 3352, 3278,
3235, 1705, 1607, 1542, 1396, 1328, 1157, 1145, 1104, 1092 cm-1;1H
NMR (DMSO-d6, 500 MHz) δ 6.51 (t, 1H, 2-NHCOCHF2), 7.76
(d, 1H, 4-H), 7.90 (bs, 3H, SO2NH2/3-H), 8.18 (d, 1H, 6-H), 10.29
(bs, 1H, 2-NHCOCHF2). Anal. (C8H7ClF2N2O3S) C, H, N, S.
5-Chloro-2-(2,2-difluoroethylamino)benzenesulfonamide (15).
5-Chloro-4-(2,2-difluoroacetamido)benzenesulfonamide (14)
(1 g, 3.51 mmol) was suspended in dry ether (15 mL) prior to the
addition of LiAlH4 (500 mg). After being stirred during 30 min,
the mixture was cooled in an ice bath and water was slowly
added. The mixture was then carefully ajusted to pH 4 by adding
concentrated HCl. The mixture was extracted with ethyl acetate
(3 ꢀ 15 mL). The combined organic layers were dried over
MgSO4 and filtered, and the filtrate was concentrated under