Y. Yu, Q. Yu, S. Liu et al.
European Journal of Medicinal Chemistry xxx (xxxx) xxx
The purity (ꢂ95%) of the target compounds used for biological
testing was evaluated by high-performance liquid chromatography
(HPLC) analysis, performed on an Amethyst C18e P (4.6 ꢃ 150 mm,
4.4.4. 3-((3,5-Dimethoxyphenyl)amino)benzo[d]isothiazole 1,1-
dioxide (7)
White solid. Yield 81.8%. mp 219.0e219.6 ꢁC. 1H NMR (400 MHz,
5
m
M, Merck) column eluting with methanol/water (80:20 v:v) at a
DMSO‑d6)
7.96e7.85 (m, 2H), 7.12 (d, J ¼ 2.2 Hz, 2H), 6.44 (t, J ¼ 2.2 Hz, 1H),
3.79 (s, 6H). 13C NMR (75 MHz, DMSO‑d6)
161.03, 157.14, 141.02,
d
10.72 (s, 1H), 8.48 (d, J ¼ 7.6 Hz, 1H), 8.12e8.06 (m, 1H),
flow rate of 0.5 mL/min; the peaks were detected at 254 nm under
UV. The data collection of a single crystal of 12 was performed on a
Bruker Smart Aapex2 CCD and Rigaku Saturn CCD diffractometer
d
139.67, 134.20, 133.80, 128.81, 124.03, 122.00, 100.91, 97.76, 55.84,
40.77, 40.51, 40.24, 39.96, 39.68, 39.40, 39.12. HRMS (ESI): calcd. for
equipped with graphite monochromated Mo-K
a
radiation
(
l
¼ 0.7107 Å) at room temperature. The structure was solved with
C
15H14N2O4S [M þ H]þ ¼ 319.0747, found 319.0751. tR ¼ 3.378 min,
direct methods and refined using OLEX2 and SHELXL-97 programs.
The non-hydrogen atoms were located in the successive difference
Fourier synthesis. The final refinement was performed by full-
matrix least-squares methods with anisotropic thermal parame-
ters for no-hydrogen atoms on F2. The hydrogen atoms were added
theoretically and riding on the concerning atoms. The parameters
used intensity collection and refinements are summarized in
Table S1; the selected bond lengths and angles of 12 are summa-
rized in Table S2 and Table S3, respectively.
HPLC purity: 98.56%.
4.4.5. 3-((3,5-Difluorophenyl)amino)benzo[d]isothiazole 1,1-
dioxide (8)
White solid. Yield 52.6%. mp > 300 ꢁC. 1H NMR (300 MHz,
DMSO‑d6)
d 11.05 (s, 1H), 8.51e8.37 (m, 1H), 8.15e8.06 (m, 1H),
7.99e7.86 (m, 2H), 7.71e7.56 (m, 2H), 7.26e7.11 (m, 1H). HRMS
(ESI): calcd. for C13H8F2N2O2S [M þ H]þ ¼ 295.0347, found
295.0349. tR ¼ 3.720 min, HPLC purity: 99.63%.
General Procedure for the Preparation of Compounds M1002(4)
ꢀ11. Saccharin (1a, 15 g, 0.082 mol) was added to a round bottom
flask, and then phosphorus pentachloride (50 g, 0.163 mol) was
added. The reaction was heated to 160 ꢁC under a nitrogen atmo-
sphere and stirred for 4 h. The reaction mixture was cooled to room
temperature and then slowly added into ice water (500 mL). A
yellow solid precipitated, and the suspension was filtered. The filter
cake was dried to give the crude product 2a as a yellow solid, which
was directly used in the next reaction without further purification.
Compound 2a was added to a round bottom flask, and the corre-
sponding aniline or phenol (the equivalent ratio of 2a to aniline or
phenol: 1 to 1) was added. Dry pyridine (5 mL) was then added to
the mixture. The reaction mixture was heated to reflux and stirred
for 2e5 h. After the reaction was complete, the solution was cooled
to room temperature and poured into water (25 mL). A precipitate
precipitated, and the suspension was filtered. The resultant filter
cake was purified by chromatography column (hexane: ethyl
acetate ¼ 10: 1) to afford the target compounds 4e11.
4.4.6. 3-((3,5-Dichlorophenyl)amino)benzo[d]isothiazole 1,1-
dioxide (9)
White solid. Yield 43.1%. mp > 300 ꢁC. 1H NMR (300 MHz,
DMSO‑d6)
1H), 8.02e7.86 (m, 4H), 7.54 (t, J ¼ 1.8 Hz,1H). HRMS (ESI): calcd. for
13H8Cl2N2O2S [M 326.9756, found 326.9757.
H]þ
tR ¼ 5.143 min, HPLC purity: 97.80%.
d
11.03 (s, 1H), 8.49e8.40 (m, 1H), 8.12 (dd, J ¼ 6.3, 1.9 Hz,
C
þ
¼
4.4.7. 3-((3,5-Dibromophenyl)amino)benzo[d]isothiazole 1,1-
dioxide (10)
White solid. Yield 60.3%. mp > 300 ꢁC. 1H NMR (300 MHz,
DMSO‑d6)
d
10.97 (s, 1H), 8.42 (d, J ¼ 7.2 Hz, 1H), 8.13 (d, J ¼ 13.7 Hz,
3H), 7.95 (q, J ¼ 6.6 Hz, 2H), 7.75 (s, 1H). 13C NMR (75 MHz,
DMSO‑d6)
d 157.54, 140.78, 140.66, 134.54, 134.09, 130.51, 128.32,
124.16, 123.70, 122.91, 122.19, 40.81, 40.53, 40.25, 39.98, 39.70,
39.42, 39.14. HRMS (ESI): calcd. for
C
13H8Br2N2O2S [M
þ
H]þ ¼ 414.8746, found 416.8725. tR ¼ 5.804 min, HPLC purity:
99.52%.
4.4.1. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)benzo[d]
isothiazole 1,1-dioxide (M1002, 4)
4.4.8. 3-(3,5-Bis(trifluoromethyl)phenoxy)benzo[d]isothiazole 1,1-
dioxide (11)
White solid. Yield 83.2%. mp 279.2e279.4 ꢁC. 1H NMR (300 MHz,
White solid. Yield 40.2%. mp 92.2e92.4 ꢁC. 1H NMR (300 MHz,
DMSO‑d6)
d
11.26 (s, 1H), 8.58 (s, 2H), 8.42 (d, J ¼ 7.5 Hz, 1H),
DMSO‑d6)
8.17e8.13 (m, 1H), 8.08 (td, J ¼ 7.6, 1.5 Hz, 1H), 8.04e7.98 (m, 1H),
7.92e7.89 (m, 2H). 13C NMR (75 MHz, DMSO‑d6)
149.23, 137.17,
d
8.33e8.29 (m, 1H), 8.24 (dq, J ¼ 1.6, 0.8 Hz, 1H),
8.21e8.10 (m, 1H), 7.95 (ddd, J ¼ 15.1, 9.8, 6.0 Hz, 3H). HRMS (ESI):
calcd. for C15H8F6N2O2S [M þ Na]þ ¼ 417.0102, found 417.0098.
tR ¼ 4.993 min, HPLC purity: 98.71%.
d
136.52, 134.95, 134.87, 133.30, 132.85, 132.40, 131.95, 131.78, 124.66,
122.65, 120.95, 115.43, 111.06, 40.79, 40.51, 40.23, 39.95, 39.68,
39.40, 39.12. HRMS (ESI): calcd. for
C
15H7F6N1O3S [M
þ
4.4.2. 3-(Phenylamino)benzo[d]isothiazole 1,1-dioxide (5)
Na]þ ¼ 417.9943, found 417.9947. tR ¼ 6.092 min, HPLC purity:
White solid. Yield 81.8%. mp > 300 ꢁC. 1H NMR (300 MHz,
100%.
DMSO‑d6)
2.0 Hz, 1H), 7.96e7.80 (m, 4H), 7.54e7.43 (m, 2H), 7.27 (t, J ¼ 7.4 Hz,
1H). 13C NMR (75 MHz, DMSO‑d6)
157.23, 141.23, 137.98, 134.22,
d
10.86 (s, 1H), 8.49 (d, J ¼ 7.1 Hz, 1H), 8.08 (dd, J ¼ 6.6,
4.4.9. 3-((3,5-Bis(trifluoromethyl)phenyl)(methyl)amino)benzo[d]
isothiazole 1,1-dioxide (12)
d
133.82, 129.53, 128.78, 126.17, 124.07, 122.58, 121.97, 40.83, 40.52,
40.24, 39.99, 39.69, 39.41, 39.13. HRMS (ESI): calcd. for C13H10N2O2S
[M þ H]þ ¼ 259.0536, found 259.0537. tR ¼ 3.220 min, HPLC purity:
99.49%.
To a solution of M1002 (200 mg, 0.5072 mmol, 1.0 eq) in DMF
(5 mL) was added potassium carbonate (105.1 mg, 0.7608 mmol,
1.5eq) and then slowly added iodomethane (107.9 mg,
0.7608 mmol, 1.5 eq). After the addition, the reaction was stirred
overnight at room temperature. The next day, the reaction was
detected by TLC and the reaction was completed. The resulting
suspension was quenched by adding water (100 mL). The mixture
was extracted with ethyl acetate (20 mL ꢃ 3) and washed with
brine (20 ml). The organic layer was combined and purified with
chromatography column (hexane: ethyl acetate ¼ 3: 1) to afford 12.
White solid. Yield 50.2%. mp 223.9e224.3 ꢁC. 1H NMR (300 MHz,
4.4.3. 3-((3,5-Dimethylphenyl)amino)benzo[d]isothiazole 1,1-
dioxide (6)
White solid. Yield 75.2%. mp > 300 ꢁC. 1H NMR (300 MHz,
DMSO‑d6)
d
10.77 (s,1H), 8.55e8.51 (m,1H), 8.06 (dd, J ¼ 6.3, 2.3 Hz,
1H), 7.90 (ddd, J ¼ 6.5, 4.5,1.4 Hz, 2H), 7.51 (d, J ¼ 1.6 Hz, 2H), 6.92 (s,
1H), 2.33 (s, 6H). HRMS (ESI): calcd. for C15H14N2O2S [M þ
H]þ ¼ 287.0849, found 287.0849. tR ¼ 3.856 min, HPLC purity:
95.49%.
DMSO‑d6)
d
8.62e8.55 (m, 2H), 8.41e8.34 (m, 1H), 8.04 (dt, J ¼ 7.5,
0.9 Hz, 1H), 7.74 (td, J ¼ 7.5, 0.8 Hz, 1H), 7.48 (t, J ¼ 7.8 Hz, 1H), 6.11
11