C. Pirat et al. / European Journal of Medicinal Chemistry 137 (2017) 310e326
321
1H, J ¼ 16.3 Hz); 7.02 (d,1H, J ¼ 16.3 Hz); 7.17 (d, 2H, J ¼ 8.7 Hz); 7.32
(d, 1H, J ¼ 8.7 Hz); 7.48 (dd, 1H, J ¼ 1.75 Hz, 8.7 Hz); 7.60 (d, 1H,
J ¼ 1,75 Hz). MS (ESIþ) m/z 833.2 [MþH]þ.
111.6, 114.3, 120.15, 123.1, 125.0, 128.0, 128.3, 129.0, 130.7, 132.8,
137.0, 139.0, 157.1, 160.5, 161.0, 170.2, 172.8. MS (ESIþ) m/z 550.2
[MþH]þ. Anal. Calcd (%) for C30H31NO7S: C, 65.56; H, 5.68; N, 2.55;
found C, 65.88; H, 5.41; N, 2.91.
4.1.12. General procedure for deprotection of silyl ethers (13e,f)
A solution of silyl ether 13c (0.47 g, 0.6 mmol) or 13d (0.50 g,
0.6 mmol) and 1 M TBAF solution in THF (5.6 mL, 5.6 mmol) is
stirred for 3h at room temperature. After removal of the solvent in
vacuo, diethyl ether is added and the solution is washed with a
saturated ammonium chloride solution. The organic layer is dried
over MgSO4 and evaporated under vacuum. The residue is purified
by flash column chromatography (cyclohexane/ethyl acetate 7:3) to
yield the corresponding phenol.
4.1.13.2. 3-[4-(2-{6-[2-(3,5-dimethoxyphenyl)vinyl]-2-oxo-benzo-
thiazol-3-yl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propionic acid
(14b). Colourless solid; 62% yield; C30H28F3NO7S; MW ¼ 603.62 g/
mol; m.p. 76e78 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d 2.82 (dd, 1H,
J ¼ 7.75 Hz, 14.2 Hz); 2.95 (dd, 1H, J ¼ 4.2 Hz, 14.4 Hz); 3.77 (s, 6H);
3.92e4.18 (m, 3H); 4.24 (t, 2H, J ¼ 4.65 Hz); 4.34 (t, 2H,
J ¼ 4,65 Hz); 6.41 (t, 1H, J ¼ 2.3 Hz); 6.74e6.78 (m, 4H); 7.10 (d, 2H,
J ¼ 8.65 Hz); 7.15 (d, 1H, J ¼ 16.6 Hz); 7.28 (d, 1H, J ¼ 16.6 Hz); 7.47
(d, 1H, J ¼ 8.45 Hz); 7.60 (dd, 1H, J ¼ 1.75 Hz, 8.45 Hz); 7.90 (d, 1H,
4.1.12.1. Ethyl
benzothiazol-3-yl}ethoxy)phenyl]-2-ethoxypropionate
Colourless solid; 47% yield; C30H31NO7S; MW ¼ 549.65 g/mol; m.p.
61e63 ꢀC. 1H NMR (300 MHz, DMSO-d6):
3-[4-(2-{6-[2-(3,5-dihydroxyphenyl)-vinyl]-2-oxo-
J ¼ 1,75 Hz). 13C NMR (75 MHz, DMSO-d6):
d 37.6, 42.5, 55.7, 65.4,
(13e).
66.5, 66.95, 80.6, 100.3, 104.8, 112.6, 114.4, 120.7, 122.4, 122.7,
125.8, 126.45, 128.3, 128.5, 130.0, 130.8, 132.9, 137.2, 139.5, 157.0,
161.1, 169.3, 172.6. MS (ESIþ) m/z 604.1 [MþH]þ. Anal. Calcd (%) for
d
1.03 (t, 3H, J ¼ 7.1 Hz);
1.10 (t, 3H, J ¼ 7.3 Hz); 2.83 (d, 2H, J ¼ 6.7 Hz); 3.30 (m, 1H); 3.46 (m,
1H); 3.98e4.07 (m, 3H); 4.24 (t, 2H, J ¼ 4.1 Hz); 4.35 (t, 2H,
J ¼ 4.1 Hz); 6.15 (t, 1H, J ¼ 2.0 Hz); 6.43 (d, 2H, J ¼ 2.0 Hz); 6.76 (d,
2H, J ¼ 8.7 Hz); 7.07 (m, 4H); 7.45 (d, 1H, J ¼ 8.4 Hz); 7.59 (dd, 1H,
J ¼ 1.45 Hz, 8.4 Hz); 7.91 (d, 1H, J ¼ 1,45 Hz); 9.27 (s, 2H); 13C NMR
C30H28F3NO7S: C, 59.69; H, 4.68; N, 2.32; found C, 59.74; H, 4.73;
N, 2.25.
4.1.13.3. 3-[4-(2-{6-[2-(3,5-dihydroxyphenyl)vinyl]-2-oxo-benzo-
thiazol-3-yl}ethoxy)phenyl]-2-ethoxypropionic
Colourless solid; 71% yield; C28H27NO7S; MW ¼ 521.59 g/mol; m.p.
122e123 ꢀC. 1H NMR (300 MHz, DMSO-d6):
acid
(14c).
(75 MHz, DMSO-d6):
d 14.5, 15.5, 38.0, 42.5, 60.6, 65.4, 79.7, 102.7,
105.0, 112.5, 114.5, 120.7, 122.3, 125.7, 127.4, 128.8, 129.7, 130.8,
133.0, 137.0, 139.2, 157.1, 159.0, 169.3, 172.1. MS (ESIþ) m/z 550.1
[MþH]þ. Anal. Calcd (%) for C30H31NO7S: C, 65.56; H, 5.68; N, 2.55;
found C, 65.67; H, 5.60; N, 2.52.
d
1.01 (t, 3H, J ¼ 7.1 Hz);
2.72e2.88 (m, 2H); 3.27 (m, 1H); 3.48 (m, 1H); 3.89 (dd, 1H,
J ¼ 5.15 Hz, 7.75 Hz); 4.23 (t, 2H, J ¼ 4.65 Hz); 4.34 (t, 2H,
J ¼ 4.65 Hz); 6.15 (t, 1H, J ¼ 2.3 Hz); 6.42 (d, 2H, J ¼ 2.3 Hz); 6.76 (d,
2H, J ¼ 8.7 Hz); 7.03e7.11 (m, 4H); 7.45 (d, 1H, J ¼ 8.7 Hz); 7.58 (dd,
1H, J ¼ 1.75 Hz, 8.7 Hz); 7.90 (d, 1H, J ¼ 1,75 Hz); 9.33 (s, 2H); 13C
4.1.12.2. Ethyl
3-[4-(2-{6-[2-(3,5-dihydroxyphenyl)-vinyl]-2-oxo-
benzothiazol-3-yl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propio-
NMR (75 MHz, DMSO-d6):
d 15.5, 38.0, 42.5, 65.3, 65.4, 79.8, 102.8,
nate (13f). Colourless solid; 52% yield;
C
30H28F3NO7S;
105.1, 112.5, 114.5, 120.7, 122.3, 125.7, 127.4, 128.8, 130.5, 130.7,
133.05, 137.0, 139.2, 157.0, 159.0, 169.3, 173.9. MS (ESIþ) m/z 522.0
[MþH]þ. Anal. Calcd (%) for C28H27NO7S: C, 64.48; H, 5.22; N, 2.69;
found C, 64.80; H, 4.98; N, 2.81.
MW ¼ 603.62 g/mol; m.p. 55e57 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
1.12 (t, 3H, J ¼ 7.1 Hz); 2.91 (m, 2H); 4.03 (m, 4H); 4.24 (t, 2H,
J ¼ 4.65 Hz); 4.32 (m, 3H); 6.15 (t, 1H, J ¼ 2.0 Hz); 6.42 (d, 2H,
J ¼ 2.0 Hz); 6.77 (d, 2H, J ¼ 8.7 Hz); 7.06 (m, 4H); 7.45 (d, 1H,
J ¼ 8.45 Hz); 7.59 (dd, 1H, J ¼ 1.45 Hz, 8.4 Hz); 7.90 (d, 1H,
4.1.13.4. 3-[4-(2-{6-[2-(3,5-dihydroxyphenyl)vinyl]-2-oxo-benzo-
thiazol-3-yl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propionic acid
(14d). Colourless solid; 92% yield; C28H24F3NO7S; MW ¼ 575.57 g/
J ¼ 1,45 Hz); 9.26 (s, 2H); 13C NMR (75 MHz, DMSO-d6):
d 14.4, 26.8,
37.6, 42.5, 61.0, 65.4, 66.65 (q, JC-F ¼ 34.2 Hz), 80.4, 102.7, 105.0,
112.5, 114.5, 120.7, 122.3, 122.7, 125.7, 126.3, 127.4, 128.8, 129.1,
130.85, 133.0, 137.0, 139.2, 157.2, 159.0, 169.3, 170.8. MS (ESIþ) m/z
604.2 [MþH]þ. Anal. Calcd (%) for C30H28F3NO7S: C, 59.69; H, 4.68;
N, 2.32; found C, 59.81; H, 4.61; N, 2.42.
mol; m.p. 110e112 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d 2.82 (dd, 1H,
J ¼ 7.9 Hz, 14.6 Hz); 2.97 (dd, 1H, J ¼ 4.1 Hz, 14.4 Hz); 3.95 (m, 1H);
4.08e4.18 (m, 2H); 4.21 (t, 2H, J ¼ 4.65 Hz); 4.34 (t, 2H, J ¼ 4.65 Hz);
6.15 (t, 1H, J ¼ 2.0 Hz); 6.42 (d, 2H, J ¼ 2.0 Hz); 6.77 (d, 2H,
J ¼ 8.45 Hz); 7.09 (m, 4H); 7.45 (d, 1H, J ¼ 8.45 Hz); 7.59 (dd, 1H,
J ¼ 1.15 Hz, 8.45 Hz); 7.90 (d, 1H, J ¼ 1,15 Hz); 9.34 (s, 2H); 13C NMR
4.1.13. General procedure for synthesis of carboxylic acids (14a-d)
A solution of ester 13a (290 mg, 0.5 mmol), 13b (315 mg,
0.5 mmol), 13e (275 mg, 0.5 mmol) or 13f (302 mg, 0.5 mmol) and
lithium hydroxide (36 mg, 1.5 mmol) in THF/H2O (3:2, 15 mL) is
stirred at room temperature for 10h. After removal of the solvent
in vacuo, 1 N HCl aqueous solution (10 mL) is added and the
resulting precipitate is filtered and purified by flash column
chromatography (DCM/MeOH 9:1) to yield the corresponding
carboxylic acid.
(75 MHz, DMSO-d6):
d 31.1, 37.6, 42.5, 65.4, 66.5, 67.0, 80.7, 102.8,
105.0, 112.5, 114.45, 120.7, 122.3, 125.7, 127.4, 128.8, 130.1, 130.75,
133.0, 137.0, 139.2, 157.05, 159.0, 169.3, 172.7. MS (ESIþ) m/z 576.2
[MþH]þ. Anal. Calcd (%) for C28H24F3NO7S: C, 58.43; H, 4.20; N,
2.43; found C, 58.54; H, 3.89; N, 2.55.
4.1.14. General procedure for synthesis of amides (15a,b)
To a stirred solution of acide 14a (275 mg, 0.5 mmol) or 14b
(302 mg, 0.5 mmol), triethylamine (150 mL, 1.1 mmol), EDC (93 mg,
4.1.13.1. 3-[4-(2-{6-[2-(3,5-dimethoxyphenyl)vinyl]-2-oxo-benzo-
0.6 mmol) and HOBt (92 mg, 0.6 mmol) in anhydrous DCM (15 mL)
is added ammonium chloride (27 mg, 0.5 mmol) or methylamine
hydrochloride (34 mg, 0.5 mmol) and the solution is stirred for 2h
at room temperature. The reaction mixture is washed with water
and the organic layer is dried over Na2SO4 and evaporated under
vacuum. The resulting residue is purified by flash column chro-
matography (ethyl acetate 100) to yield the corresponding amide.
thiazol-3-yl}ethoxy)phenyl]-2-ethoxypropionic
Colourless solid; 95% yield; C30H31NO7S; MW ¼ 549.65 g/mol; m.p.
84e85 ꢀC. 1H NMR (300 MHz, CDCl3):
1.17 (t, 3H, J ¼ 7.2 Hz); 2.93
acid
(14a).
d
(dd, 1H, J ¼ 7.4 Hz, 14.1 Hz); 3.07 (dd, 1H, J ¼ 4.0 Hz, 14.1 Hz); 3.45
(m, 1H); 3.58 (m, 1H); 3.85 (s, 6H); 4.03 (m, 1H); 4.29 (t, 2H,
J ¼ 4.7 Hz); 4.34 (t, 2H, J ¼ 4.7 Hz); 6.42 (t, 1H, J ¼ 2.0 Hz); 6.67 (d,
2H, J ¼ 2.0 Hz); 6.76 (d, 2H, J ¼ 8.8 Hz); 6.99 (d, 1H, J ¼ 16.4 Hz); 7.08
(d, 1H, J ¼ 16.4 Hz); 7.13 (d, 2H, J ¼ 8.7 Hz); 7.29 (d, 1H, J ¼ 8.7 Hz);
7.48 (dd, 1H, J ¼ 1.75 Hz, 8.7 Hz); 7.58 (d, 1H, J ¼ 1,75 Hz). 13C NMR
4.1.14.1. 3-[4-(2-{6-[2-(3,5-dimethoxyphenyl)vinyl]-2-oxo-benzo-
thiazol-3-yl}ethoxy)phenyl]-2-ethoxypropionamide
(15a).
(75 MHz, CDCl3): d 15.1, 37.4, 42.6, 55.4, 65.5, 67.0, 79.6,100.0, 104.5,
Colourless solid; 92% yield; C30H32N2O6S; MW ¼ 548.66 g/mol;