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N. Ikemoto et al. / Tetrahedron 59 (2003) 1317–1325
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mp 118–1198C. H NMR (400 MHz, CDCl3): d 7.51 (m,
3H), 7.63 (m, 2H), 7.82 (d, J¼8.6 Hz, 2H), 8.11 (d, J¼
8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 126.9, 128.7,
130.1, 130.6, 133.6, 135.9, 143.4, 146.5. Anal. Calcd for
C12H9ClO2S (252.72): C, 57.03; H, 3.59; Cl, 14.03; S,
12.69. Found: C, 56.80; H, 3.25; Cl, 14.10; S, 12.71.
(d, J¼8.2 Hz, 2H), 8.40 (d, J¼4.0 Hz, 2H), 8.46 (s, 1H),
8.49 (s, 1H), 10.32 (s, 1H). 13C NMR (100 MHz,
d6-DMSO): d 41.8, 46.6, 69.5, 119.1, 120.9, 123.5, 126.2,
127.2, 127.4, 128.1, 128.7, 129.0, 130.1, 132.9, 134.1,
135.9, 136.6, 137.7, 139.0, 141.2, 148.1, 148.6, 154.3,
165.9, 170.5. Anal. Calcd for C31H25F3N4O4S2 (638.68): C,
58.30; H, 3.95; N, 8.77; F, 8.92; S, 10.04. Found: C, 58.21;
H, 3.93; N, 8.67; F, 8.91; S, 9.99.
4.2.17. 2-Methoxy-dibenzofuran-3-sulfonyl chloride (27).
3-Amino-2-methoxydibenzofuran 26 (4.26 g, 20.0 mmol)
was processed to afford sulfonyl chloride 27 (4.97 g, 84%
yield) as a purple solid; mp 197–1988C. 1H NMR
(400 MHz, CDCl3): d 4.17 (s, 3H), 7.43 (m, 1H), 7.58–
7.62 (m, 3H), 8.00 (d, J¼7.8 Hz, 1H), 8.16 (s, 1H). 13C
NMR (100 MHz, CDCl3): d 57.1, 104.1, 112.4, 113.2,
121.7, 122.6, 123.4, 129.6, 130.3, 131.8, 148.1, 153.8,
158.5. Anal. Calcd for C13H9ClO4S (296.73): C, 52.62; H,
3.06; Cl, 11.95; S, 10.81. Found: C, 52.65; H, 2.76; Cl,
12.18; S, 10.82.
4.2.21. (R)-N-{4-[2-(2-Hydroxy-2-pyridin-3-yl-ethyl-
amino)-ethyl]-phenyl}-4-[4-(4-trifluoromethyl-phenyl)-
thiazol-2-yl]-benzenesulfonamide, hydrochloride (33).
To a solution of amide 32 (6.74 g, 97% pure, 10.2 mmol)
in 50 mL of THF was added 1 M BH.3THF (50 mL) and was
stirred 6 h at 308C. The reaction mixture was quenched by
careful addition of 1 M H2SO4 solution (50 mL), and the
resulting solution was heated at reflux for 2 h. The mixture
was cooled to room temperature and was diluted with 50 mL
of isopropyl acetate, and was adjusted to pH 8.2 with 50%
NaOH (6.5 mL). The layers were separated, and the organic
layer was washed with 50 mL of water. The organic layer
was assayed for yield of 33 free base, evaporated, flushed
with isopropyl acetate, and then with absolute ethanol. To
the resulting slurry in ethanol (70 mL) was added a solution
of dry HCl in ethanol (1.62N, 6.3 mL) and was warmed to
358C to dissolve the solids. Cooling to to room temperature
formed a slurry, which was and age overnight, and heptanes
(70 mL) was added over 3 h. This slurry was aged overnight
and was then filtered, rinsed with a 1:1 mixture of ethanol–
heptanes (30 mL), and dried to afford mono-HCl salt 33
4.2.18. 9,10-Dioxo-9,10-dihydro-anthracene-2-sulfonyl
chloride (29). 2-Aminoanthraquinone 28 (4.46 g,
20.0 mmol was processed to afford sulfonyl chloride 29
1
(5.14 g, 84% yield) as a brown solid; mp 207–2088C. H
NMR (400 MHz, d6-DMSO): d 7.89 (m, 2H), 8.07 (m,
1H), 8.16 (m, 3H), 8.39 (m, 1H). 13C NMR (100 MHz,
d6-DMSO): d 124.1, 127.1, 127.4, 131.6, 133.3, 133.5,
133.5, 134.9, 134.9, 153.9, 182.5, 182.7. Anal. Calcd for
C14H7ClO4S (306.72): C, 54.82; H, 2.30; Cl, 11.56; S,
10.45. Found: C, 54.48; H, 2.01; Cl, 11.84; S, 10.35.
1
4.2.19. 4-Methylbenzenesulfonyl chloride (31). p-Tolu-
idine 30 (2.14 g, 20.0 mmol) was processed to afford
sulfonyl chloride 31 (3.92 g, 99% yield) as a white solid;
mp 71–728C. 1H NMR (400 MHz, CDCl3): d 2.50 (s, 3H),
7.41 (d, J¼8.1 Hz, 2H), 7.92 (dd, J¼6.7, 1.8 Hz, 2H). 13C
NMR (100 MHz, CDCl3): d 21.7, 126.9, 130.1, 141.6,
146.7. Anal. Calcd for C7H7ClO2S (190.65): C, 44.10; H,
3.70; Cl, 18.60; S, 16.82. Found: C, 44.00; H, 3.56; Cl,
18.63; S, 16.94.
(6.15 g, 91% yield): mp 237–2388C. H NMR (400 MHz,
d6-DMSO): d 2.91 (m, 2H), 3.10 (m, 4H), 5.05 (d, J¼
9.7 Hz, 1H), 6.32 (br, 1H), 7.12 (q, 4H), 7.38 (dd, J¼4.8,
7.8 Hz, 1H), 7.77 (dt, J¼8.0 Hz, 1H), 7.83 (d, J¼8.4 Hz,
2H), 7.90 (d, J¼8.4 Hz, 2H), 8.18 (d, J¼8.5 Hz, 2H), 8.25
(d, J¼8.2 Hz, 2H), 8.50 (m, 1H), 8.51 (s, 1H), 8.58 (s, 1H),
9.2 (vbr, 2H), 10.1 (vbr, 1H). 13C NMR (100 MHz, d6-
DMSO): d 31.0, 48.2, 53.2, 66.6, 119.2, 121.1, 123.9, 126.2,
127.2, 127.3, 128.2, 129.8, 133.7, 134.2, 136.4, 136.6,
137.4, 137.7, 141.2, 148.0, 149.4, 154.3, 165.9. Anal. Calcd
for C31H28ClF3N4O3S2 (677.16): C, 56.32; H, 4.27; N, 8.47;
Cl, 5.36; F, 8.62; S, 9.70. Found: C, 56.32; H, 4.24; N, 8.35;
Cl, 5.59; F, 8.67; S, 9.82.
4.2.20. (R)-N-(2-Hydroxy-2-pyridin-3-yl-ethyl)-2-(4-{4-
[4-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfo-
nylamino}-phenyl)-acetamide (32). The aniline 2 (5.43 g,
20.0 mmol) and sulfonyl chloride 3 (8.24 g, 20.4 mol) in
63 mL of THF and 7 mL of pyridine were stirred at 358C for
3 h. The reaction mixture was diluted with 70 mL of ethyl
acetate and extracted with 70 mL of 1N HCl. The organic
layer was washed with 70 mL of 1N NaHCO3, filtered,
concentrated and flushed with 70 mL of ethyl acetate. The
concentrated residue was dissolved in 200 mL of THF to
afford a cloudy solution, which was filtered through Solka
Floc (6 g) and rinsed with 100 mL THF to remove the
sulfonic acid impurity. The filtrate was concentrated,
flushed with 70 mL of ethyl acetate, and the residue was
dissolved in 70 mL of ethyl acetate. A slurry formed in
15 min, which was stirred for two days and was then filtered.
The solids were rinsed with 35 mL of ethyl acetate and dried
to afford the amide 32 (12.2 g, 96% pure, 92% yield): mp
1668C. 1H NMR (400 MHz, d6-DMSO): d 3.24 (t, J¼6 Hz,
2H), 3.28 (s, 2H), 4.61 (m, 1H), 5.58 (d, J¼4.5 Hz, 1H),
7.03 (1, 4H), 7.23 (dd, J¼4.8, 7.8 Hz, 1H), 7.60 (dt, J¼7.8,
1.8 Hz, 1H), 7.83 (d, J¼8.4 Hz, 2H), 7.89 (d, J¼8.4 Hz,
2H), 8.03 (t, J¼5.7 Hz, 1H), 8.19 (d, J¼8.4 Hz, 2H), 8.25
4.2.22. (R)-N-{4-[2-(2-Hydroxy-2-pyridin-3-yl-ethyl-
amino)-ethyl]-phenyl}-4-[4-(4-trifluoromethyl-phenyl)-
thiazol-2-yl]-benzenesulfonamide, dihydrochloride (1).
To a suspension of the mono-HCl salt 33 (28.2 g,
42.6 mmol) in 110 mL of ethanol was added a solution of
dry HCl in ethanol (1.48N, 30 mL, 44.8 mmol). The mixture
was warmed to 318C to dissolve the solids. The solution was
filtered into a second flask with a hot ethanol rinse (21 mL).
Seed crystals of the di-HCl salt (1.2 g) were added, and the
resulting slurry was aged for 2 days. The slurry was cooled
over an ice bath and was filtered. The solids were washed
with ethanol and dried to afford the di-HCl salt 1 (28.8 g,
97% yield): mp 228–2308C. 1H NMR (400 MHz, d6-DMSO):
d 2.93 (t, 2H), 3.11 (br, 2H), 3.20 (br, 1H), 3.34 (br, 1H),
5.32 (dd, J¼2.8, 8.6 Hz, 1H), 6.9 (vbr, 1H), 7.13 (t, 4H),
7.80 (d, J¼8.3 Hz, 2H), 7.91 (d, J¼8.3 Hz, 2H), 8.04 (t,
1H), 8.16 (d, J¼8.3 Hz, 2H), 8.23 (d, J¼8.2 Hz, 2H), 8.50
(s, 1H), 8.58 (d, J¼8.0 Hz, 1H), 8.87 (br, 1H), 8.92 (br,
1H), 9.41 (br, 2H), 10.55 (s, 1H). 13C NMR (100 MHz,