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K. Rikimaru et al. / Bioorg. Med. Chem. 20 (2012) 3332–3358
was concentrated under reduced pressure, the obtained residue
was subjected to silica gel column chromatography, (hexane-
EtOAc, 2:1) to give 12g (351 mg, 92%) as colorless crystals. 1H
NMR (CDCl3): d 1.29 (t, J = 7.2 Hz, 3H), 1.52 (s, 9H), 2.35 (s, 3H),
3.41 (s, 3H), 3.69–3.72 (m, 2H), 4.05–4.08 (m, 2H), 4.20 (q,
J = 7.2 Hz, 2H), 6.36 (d, J = 15.9 Hz, 1H), 6.34–6.40 (m,1H), 6.49 (d,
J = 2.7 Hz, 1H), 6.74 (dd, J = 8.7, 2.7 Hz, 1H), 7.57 (d, J = 8.7 Hz,
1H), 7.78–7.79 (m, 1H), 7.85 (d, J = 15.9 Hz, 1H), 7.93 (s, 1H).
5.1.1.73. (2E)-3-[2-[2-Chloro-4-(trifluoromethyl)phenoxy]-
4-(2-methoxyethoxy)phenyl]-N-(pentylsulfonyl)acrylamide
(13a).
Compound 13a (colorless crystals) was prepared from
37a and pentane-1-sulfonamide in 30% yield following a similar
procedure to provide 8f. Mp 134.1–135.1 °C (EtOAc/hexane). 1H
NMR (CDCl3): d 0.89 (t, J = 7.1 Hz, 3H), 1.30–1.45 (m, 4H), 1.77–
1.90 (m, 2H), 3.41 (s, 3H), 3.42–3.52 (m, 2H), 3.69–3.74 (m, 2H),
4.05–4.12 (m, 2H), 6.33 (s, 1H), 6.49 (d, J = 15.7 Hz, 1H), 6.74–
6.79 (m, 1H), 7.02 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.56
(d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.77 (s, 1H), 7.92 (d, J = 15.7 Hz,
1H). Anal. Calcd for C24H27ClF3NO6S: C, 52.41; H, 4.95; N, 2.55.
Found: C, 52.34; H, 4.82; N, 2.41.
5.1.1.68. (2E)-3-[2-[2-Chloro-4-(trifluoromethyl)phenoxy]-4-(2-
methoxyethoxy)phenyl]acrylic acid (37a).
Compound 37a
(colorless crystals) was prepared from 12a in 97% yield following
a similar procedure to provide 7a. Mp 165.6–166.0 °C (EtOAc/hex-
ane). 1H NMR (DMSO-d6): d 3.27 (s, 3H), 3.60–3.64 (m, 2H), 4.10–
4.14 (m, 2H), 6.47 (d, J = 16.2 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H),
6.94 (dd, J = 8.7, 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.59 (d,
J = 16.2 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H),
8.07 (s, 1H), 12.34 (s, 1H). Anal. Calcd for C19H16ClF3O5: C, 54.75;
H, 3.87. Found: C, 54.80; H, 3.79.
5.1.1.74. Potassium [(2E)-3-(4-(2-methoxyethoxy)-2-{[5-(tri-
fluoromethyl)pyridin-2-yl]oxy}phenyl)acryl](pentylsulfo-
nyl)azanide
(13b).
(2E)-3-(4-(2-methoxyethoxy)-2-{[5-
(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-N-(pentylsulfonyl)acryl
amide (a colorless amorphous solid) was prepared from 37b and
pentane-1-sulfonamide in 91% yield following a similar procedure
to provide 13c (described below). 1H NMR (CDCl3): d 0.88 (t,
J = 7.0 Hz, 3H), 1.25–1.46 (m, 4H), 1.74–1.89 (m, 2H), 3.43 (s, 3H),
3.43–3.45 (m, 2H), 3.71–3.79 (m, 2H), 4.10–4.16 (m, 2H), 6.38 (d,
J = 15.6 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.7, 2.4 Hz,
1H), 7.09 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.81 (d,
J = 15.6 Hz, 1H), 7.95 (dd, J = 8.7, 2.4 Hz, 1H), 8.15 (s, 1H), 8.42 (s,
1H). Anal. Calcd for C23H27F3N2O6S: C, 53.48; H, 5.27; N, 5.42.
Found: C, 53.27; H, 5.30; N, 5.34.
To a solution of (2E)-3-(4-(2-methoxyethoxy)-2-{[5-(trifluoro-
methyl)pyridin-2-yl]oxy}phenyl)-N-(pentylsulfonyl)acrylamide
(259 mg, 0.501 mmol) in MeOH (4 mL) was added a solution of
KHCO3 (50 mg, 0.499 mmol) in H2O (0.5 mL), and the mixture
was stirred at room temperature for 90 min. The reaction mixture
was concentrated under reduced pressure, and the obtained
crude product were recrystallized from EtOH/hexane to give
13b (254 mg, 91%) as colorless crystals. Mp 153.0–155.2 °C. 1H
NMR (DMSO-d6): d 0.77–0.84 (m, 3H), 1.16–1.29 (m, 4H), 1.40–
1.56 (m, 2H), 2.86–2.94 (m, 2H), 3.29 (s, 3H), 3.60–3.66 (m,
2H), 4.07–4.12 (m, 2H), 6.31 (d, J = 15.9 Hz, 1H), 6.77 (d,
J = 2.3 Hz, 1H), 6.89 (dd, J = 8.7, 2.3 Hz, 1H), 7.17 (d, J = 15.9 Hz,
1H), 7.27 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 8.24 (dd,
J = 8.7, 2.7 Hz, 1H), 8.55 (s, 1H). Anal. Calcd for C23H26F3KN2
O6Sꢀ0.5H2O: C, 49.01; H, 4.83; N, 4.97. Found: C, 49.27; H, 4.79;
N, 4.96.
5.1.1.69. (2E)-3-(4-(2-Methoxyethoxy)-2-{[5-(trifluoromethyl)-
pyridin-2-yl]oxy}phenyl)acrylic acid (37b).
Compound 37b
(colorless crystals) was prepared from 12b in 96% yield following
a similar procedure to provide 7a. Mp 179.5–179.8 °C (EtOH/hex-
ane). 1H NMR (DMSO-d6): d 3.29 (s, 3H), 3.60–3.66 (m, 2H), 4.10–
4.16 (m, 2H), 6.41 (d, J = 15.9 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H),
6.94 (dd, J = 8.7, 2.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.49 (d,
J = 15.9 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 8.27 (dd, J = 8.7, 2.7 Hz,
1H), 8.57 (s, 1H), 12.26 (s, 1H). Anal. Calcd for C18H16F3NO5: C,
56.40; H, 4.21; N, 3.65. Found: C, 56.49; H, 4.17; N, 3.65.
5.1.1.70. (2E)-3-[2-[(3-Chloropyridin-2-yl)oxy]-4-(2-methoxy-
ethoxy)phenyl]acrylic acid (37c).
Compound 37c (colorless
crystals) was prepared from 12c in 97% yield following a similar
procedure to provide 7a. Mp 150.5–150.9 °C (EtOH/hexane). 1H
NMR (DMSO-d6): d 3.28 (s, 3H), 3.61–3.66 (m, 2H), 4.09–4.16 (m,
2H), 6.41 (d, J = 16.2 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.92 (dd,
J = 8.9, 2.4 Hz, 1H), 7.20 (dd, J = 7.8, 4.8 Hz, 1H), 7.48 (d,
J = 16.2 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 8.06 (dd, J = 4.8, 1.6 Hz,
1H), 8.10 (dd, J = 7.8, 1.6 Hz, 1H), 12.29 (s, 1H). Anal. Calcd for
C17H16ClNO5: C, 58.38; H, 4.61; N, 4.00. Found: C, 58.32; H, 4.46;
N, 3.91.
5.1.1.71.
(2E)-3-[2-[(3,5-Dichloropyridin-2-yl)oxy]-4-(2-
Compound 37d
methoxyethoxy)phenyl]acrylic acid (37d).
5.1.1.75. (2E)-3-[2-[(3-Chloropyridin-2-yl)oxy]-4-(2-methoxy-
(colorless crystals) was prepared from 12d in 92% yield following
a similar procedure to provide 7a. Mp 182.3–184.0 °C (THF/hex-
ane). 1H NMR (DMSO-d6): d 3.28 (s, 3H), 3.61–3.65 (m, 2H), 4.10–
4.14 (m, 2H), 6.42 (d, J = 16.2 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H),
6.92 (dd, J = 8.7, 2.4 Hz, 1H), 7.47 (d, J = 16.2 Hz, 1H), 7.83 (d,
J = 8.7 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H),
12.31 (s, 1H). Anal. Calcd for C17H15Cl2NO5: C, 53.14; H, 3.94; N,
3.65. Found: C, 53.24; H, 3.96; N, 3.48.
ethoxy)phenyl]-N-(pentylsulfonyl)acryl-amide (13c).
To a
stirred mixture of 37c (427 mg, 1.22 mmol), pentane-1-sulfon-
amide (193 mg, 1.28 mmol), MNBA15 (506 mg, 1.47 mmol) and
DMAP (151 mg, 1.24 mmol) in acetonitrile (10 mL) was added
TEA (385 mg, 3.80 mmol) at room temperature, and the mixture
was stirred at room temperature for 96 h. The reaction mixture
was concentrated, sat. NH4Cl was added to the residue, and the
mixture was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The obtained residue was subjected to silica gel chroma-
tography (hexane-EtOAc, 1:1) to give a white solid, which was
recrystallized from EtOAc/hexane to give 13c (523 mg, 88%) as col-
orless crystals. Mp 134.7–136.6 °C. 1H NMR (CDCl3): d 0.89 (t,
J = 7.0 Hz, 3H), 1.26–1.45 (m, 4H), 1.76–1.88 (m, 2H), 3.42 (s, 3H),
3.42–3.50 (m, 2H), 3.71–3.76 (m, 2H), 4.09–4.14 (m, 2H), 6.40 (d,
J = 15.9 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 8.7, 2.5 Hz,
1H), 7.03 (dd, J = 7.6, 4.9 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.75–
7.88 (m, 3H), 8.03 (dd, J = 4.9, 1.5 Hz, 1H). Anal. Calcd for
5.1.1.72. (2E)-3-[2-({5-[(tert-Butoxycarbonyl)amino]-3-methyl-
pyridin-2-yl}oxy)-4-(2-methoxyethoxy)phenyl]acrylic acid
(37e).
Compound 37e (colorless crystals) was prepared from
12g in 99% yield following a similar procedure to provide 7a. Mp
159.0–160.0 °C (EtOH/hexane). 1H NMR (DMSO-d6): d 1.46 (s,
9H), 2.29 (s, 3H), 3.27 (s, 3H), 3.59–3.64 (m, 2H), 4.05–4.11 (m,
2H), 6.39 (d, J = 16.1 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.82 (dd,
J = 8.7, 2.4 Hz, 1H), 7.59 (d, J = 16.1 Hz, 1H), 7.78 (d, J = 8.7 Hz,
1H), 7.87 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 9.43 (s, 1H), 12.21 (s,
1H). Anal. Calcd for C23H28N2O7: C, 62.15; H, 6.35; N, 6.30. Found:
C, 61.97; H, 6.26; N, 6.19.
C22H27ClN2O6S: C, 54.71; H, 5.63; N, 5.80. Found: C, 54.72; H,
5.63; N, 5.81.