Journal of Medicinal Chemistry
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was collected by filtration, washed with water, and dried (yield, 40−
70%).
TLC. The title compound, which precipitated in the medium, was
collected by filtration, washed with acetone, and dried (4.87 g, 90%):
mp 94−96 °C. The compound was used in the next step without
further purification.
(RS)-7-Fluoro-3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothia-
diazine 1,1-Dioxide Monohydrate (10a). White solid: mp 196−
1
198 °C; H NMR (80 MHz, DMSO-d6) δ 1.75 (d, 3H, CH(CH3)
3-Isopropylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-Dioxide
(19). Potassium carbonate (0.54 g) and isopropyl isothiocyanate
(0.45 g, 4.45 mmol) were added to a solution of 4-chloropyridine-3-
sulfonamide (17) (0.70 g, 3.63 mmol) in acetone (20 mL). The
reaction mixture was heated under reflux until completion of the
reaction as monitored by TLC. Then the solvent was removed by
distillation under reduced pressure and the residue of the title
compound was suspended in water (20 mL). The insoluble material
was dissolved by addition of an aqueous 10% NaOH solution. The
alkaline solution was clarified by treatment with charcoal, and after
filtration, the clear solution was adjusted to pH 4−5 by means of 2 N
HCl. The resulting precipitate of the title compound was collected by
filtration, washed with water, and dried (0.78 g, 83%): mp 137−138
C6H5), 5.00 (q, 1H, CH(CH3)C6H5), 7.50 (m, 6H, C6H5 + 5-H), 7.75
(m, 1H, 6-H), 7.85 (m, 1H, 8-H), 12.65 (s, 1H, NH); 13C NMR (125
MHz, DMSO-d6) δ 21.9, 45.0, 109.5, 120.0, 121.4, 122.7, 127.5, 127.8,
128.7, 132.3, 140.9, 157.7, 159.7. Anal. (C15H13FN2O2S2·H2O)
theoretical: C, 50.83; H, 4.27; N, 7.90; S, 18.09. Found: C, 50.69;
H, 3.98; N, 8.08; S, 18.01.
4-Chloro-3-sulfamoylbenzamide (15). The mixture of 4-chloro-
3-sulfamoylbenzoic acid (14) (23.5 g, 0.1 mol) and thionyl chloride
(200 mL) was refluxed for 3 h. The reaction mixture was concentrated
under reduced pressure, and the residue was dissolved in dioxane (100
mL). The resulting solution was added dropwise under stirring to a 7%
aqueous solution of ammonia (375 mL). After 30 min, the excess
ammonia was removed under reduced pressure by concentration of
the solution to a third of its volume. The resulting precipitate of the
title compound was collected by filtration, washed with water, and
dried (11.7 g, 50%): mp 220−222 °C (lit. 223−225 °C).27
1
°C; H NMR (80 MHz, DMSO-d6) δ 1.10 (d, 6H, CH(CH3)2), 4.05
(m, 1H, CH(CH3)2), 7.70 (bd, 1H, 5-H), 8.65 (bd, 1H, 6-H), 8.95 (bs,
1H, 8-H), 9.70 (bd, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δ
21.4, 46.1, 122.5, 128.3, 140.0, 144.2, 151.5, 159.5. Anal.
(C9H11N3O2S2) theoretical: C, 42.01; H, 4.31; N, 16.33; S, 24.92.
Found: C, 42.19; H, 4.25; N, 16.32; S, 25.01.
4-Chloro-3-sulfamoylbenzonitrile (16). Triethylamine (11.5
mL) and trifluoroacetic anhydride (10 mL) were added to a cold
suspension of 4-chloro-3-sulfaloylbenzamide (15) (6.25 g, 26.6 mmol)
in anhydrous THF (40 mL). After completion of the reaction as
monitored by TLC, the reaction mixture was concentrated under
reduced pressure. The residue was taken off with water (50 mL), and
the resulting precipitate was collected by filtration, washed with water,
and dissolved in a 2 N aqueous solution of NaOH (35 mL). After 30
min at room temperature, the solution was clarified by treatment with
charcoal, and the filtrate was adjusted to pH 1 by means of 2 N HCl.
The resulting precipitate was collected by filtration, washed with water,
and dried (4.04 g, 70%): mp 199−201 °C (lit. 197−199 °C).27
7-Cyano-3-isopropylamino-1,4,2-benzodithiazine 1,1-Diox-
ide (6d). Potassium carbonate (0.54 g) and isopropyl isothiocyanate
(0.39 g, 3.85 mmol) were added to a solution of 4-chloro-3-
sulfamoylbenzonitrile (16) (0.70 g, 3.23 mmol) in acetone (20 mL).
The reaction mixture was heated under reflux until completion of the
reaction as monitored by TLC. Then the solvent was removed by
distillation under reduced pressure and the residue of the title
compound was suspended in water (20 mL). The insoluble material
was dissolved by addition of an aqueous 2% NaOH solution. The
alkaline solution was clarified by treatment with charcoal, and after
filtration, the clear solution was adjusted to pH 2 by means of 2 N
HCl. The resulting precipitate of the title compound was collected by
filtration, washed with water, and dried (0.64 g, 70%): mp 243−244
3-Isopropylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1,7-Triox-
ide (20). The title compound was obtained as described for 19,
starting from 4-chloropyridine-3-sulfonamide N-oxide (18) (0.75 g,
3.60 mmol) and isopropyl isothiocyanate (0.45 g, 4.45 mmol) (0.72 g,
1
73%): mp 255−256 °C; H NMR (80 MHz, DMSO-d6) δ 1.10 (d,
6H, CH(CH3)2), 4.05 (m, 1H, CH(CH3)2), 7.70 (d, 1H, 5-H), 8.30
(bd, 1H, 6-H), 8.45 (s, 1H, 8-H), 9.80 (bs, 1H, NH); 13C NMR (125
MHz, DMSO-d6) δ 21.4, 46.4, 125.1, 126.0, 131.4, 134.0, 141.5, 160.6.
Anal. (C9H11N3O3S2) theoretical: C, 39.55; H, 4.06; N, 15.37; S,
23.46. Found: C, 39.29; H, 3.89; N, 15.14; S, 23.35.
(R)-3-(1-Phenylethyl)amino-7-trifluoromethyl-1,4,2-benzo-
dithiazine 1,1-Dioxide (23). A solution of 2-chloro-5-trifluorome-
thylbenzenesulfonamide (12e) (0.3 g, 1.16 mmol) in a 1:1 mixture of
acetone and DMF (10 mL) was supplemented with potassium
carbonate (0.23 g, 1.66 mmol) and (R)-1-phenylethyl isothiocyanate
(0.2 g, 1.23 mmol). The suspension was refluxed for 5 h and then
concentrated under reduced pressure. The residue was picked up with
water (20 mL), and the resulting suspension was alkalinized with a
10% w/v aqueous solution of NaOH until solubilization of the title
compound. After treatment with charcoal and filtration, the filtrate was
acidified with 6 N HCl. The resulting precipitate was collected by
filtration, washed with water, and dried. The compound was
crystallized in ethyl acetate−hexane (0.25 g, 56%): mp 214−216 °C;
1
°C; H NMR (80 MHz, DMSO-d6) δ 1.10 (d, 6H, CH(CH3)2), 4.05
(m, 1H, CH(CH3)2), 7.80 (bd, 1H, 5-H), 8.05 (bd, 1H, 6-H), 8.30 (bs,
1H, 8-H), 9.70 (bd, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δ
21.4, 46.2, 111.6, 117.2, 128.0, 129.6, 133.6, 134.9, 135.1, 160.5. Anal.
(C11H11N3O2S2) theoretical: C, 46.96; H, 3.94; N, 14.93; S, 22.79.
Found: C, 46.31; H, 4.11; N, 14.70; S, 22.45.
1
enantiomeric purity (by chiral HPLC), 99.8%; H NMR (500 MHz,
DMSO-d6) 1.50 (d, 3H, CH(CH3)C6H5), 5.23 (q, 1H, CH(CH3)-
C6H5), 7.28 (dd, 1H, 4′-H), 7.36 (d, 4H, 2′-H + 3′-H + 5′-H + 6′-H),
8.00 (d, 1H, 5-H), 8.06 (dd, 1H, 6-H), 8.15 (s, 1H, 8-H), 10.29 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) δ 21.6, 53.0, 120.8, 122.0,
124.2, 126.1, 127.4, 128.5, 128.6, 129.0, 129.3, 130.0, 133.4, 134.2,
142.0, 161.2. Anal. (C16H13F3N2O2S2) theoretical: C, 49.73; H, 3.39;
N, 7.25; S, 16.60. Found: C, 49.54; H, 3.62; N, 7.16; S, 16.49.
(S)-3-(1-Phenylethyl)amino-7-trifluoromethyl-1,4,2-benzodi-
thiazine 1,1-Dioxide (24). The title compound was obtained as
described for 23, starting from 2-chloro-5-trifluoromethylbenzenesul-
fonamide (12e) (0.3 g, 1.16 mmol) and (S)-1-phenylethyl
isothiocyanate (0.2 g, 1.23 mmol). The compound was crystallized
in ethyl acetate−hexane (0.27 g, 60%): mp 214−216 °C; enantiomeric
purity (by chiral HPLC), 99.9%; 1H NMR (500 MHz, DMSO-d6) 1.50
(d, 3H, CH(CH3)C6H5), 5.23 (q, 1H, CH(CH3)C6H5), 7.28 (dd, 1H,
4′-H), 7.36 (d, 4H, 2′-H + 3′-H + 5′-H + 6′-H), 8.00 (d, 1H, 5-H),
8.06 (dd, 1H, 6-H), 8.15 (s, 1H, 8-H), 10.29 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δ 21.7, 53.0, 120.8, 122.0, 124.2, 126.1, 127.4,
128.5, 128.6, 129.0, 129.2, 130.0, 133.4, 134.2, 142.1, 161.1. Anal.
(C16H13F3N2O2S2) theoretical: C, 49.73; H, 3.39; N, 7.25; S, 16.60.
Found: C, 49.32; H, 3.57; N, 7.13; S, 16.22.
3-Isopropylamino-1,4,2-benzodithiazine-7-carboxylic Acid
1,1-Dioxide Monohydrate (6e). A solution of 7-cyano-3-isopropy-
lamino-1,4,2-benzodithiazine 1,1-dioxide (6d) (0.4 g, 1.42 mmol) in a
15% aqueous solution of NaOH (30 mL) was stirred at room
temperature for 15 h. Then the alkaline solution was clarified by
treatment with charcoal and the filtrate was adjusted to pH 1 by means
of 2 N HCl. The resulting precipitate of the title compound was
collected by filtration, washed with water, and dried (0.43 g, 95%): mp
>300 °C; 1H NMR (80 MHz, DMSO-d6) δ 1.15 (d, 6H, CH(CH3)2),
4.00 (m, 1H, CH(CH3)2), 7.75 (d, 1H, 5-H), 8.05 (bd, 1H, 6-H), 8.30
(s, 1H, 8-H), 9.60 (bd, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δ
21.4, 46.0, 124.5, 128.9, 131.3, 132.1, 132.9, 133.8, 160.8, 165.6. Anal.
(C11H12N2O4S2·H2O) theoretical: C, 41.50; H, 4.43; N, 8.80; S, 20.14.
Found: C, 41.13; H, 4.28; N, 8.68; S, 20.46.
4-Chloropyridine-3-sulfonamide N-Oxide (18). A solution of
4-chloropyridine-3-sulfonamide (17) (5 g, 26 mmol) and 3-
chloroperbenzoic acid (17.89 g, 104 mmol) in acetone (40 mL) was
heated under reflux until completion of the reaction as monitored by
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dx.doi.org/10.1021/jm301743b | J. Med. Chem. 2013, 56, 3247−3256