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(s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.81 (s, 1H), 6.75–6.67 (m, 4H), 5.05
(s, 2H), 4.42 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.27 (t, J = 7.7 Hz, 2H),
3.03 (s, 3H), 2.18-2.09 (m, 5H), 1.92 (s, 6H); 13C NMR (75 MHz,
DMSO-d6) d 170.6, 156.9, 152.2, 150.3, 140.2, 137.6, 136.6, 133.9,
128.6, 128.5, 127.2, 125.7, 117.7, 113.3, 112.3, 112.2, 69.4, 65.5,
65.4, 50.6, 22.0, 20.7, 16.1; MS (ESI), m/z: 511.0 (MꢁH)ꢁ. Anal.
Calcd for C28H32O7S: C, 65.60; H, 6.26. Found: C, 65.97; H, 6.62.
4.1.9.3. Methyl 2-(4-acetyl-2-fluorophenoxy)acetate (14).
The titled compound was prepared from 13 as described for com-
pound 5. Compound 14 (0.87 g, 84.7%) as a colorless solid.
4.1.9.4. Methyl 2-(4-acetoxy-2-fluorophenoxy)acetate (15).
The titled compound was prepared from 14 as described for com-
pound 7. Compound 15 (0.62 g, 68.1%) as a colorless solid.
4.1.7. 2-(4-((20,60-Dimethyl-40-(3-(methylsulfonyl)propoxy)-
[1,10-biphenyl]-3-yl)methoxy)-2-ethylphenoxy)acetic acid (10e)
Compound 10e (0.12 g, 12.5%) as a colorless solid. mp: 110–
112 °C; 1H NMR (300 MHz, DMSO-d6): d 7.42–7.37 (m, 2H), 7.15
(s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 2H), 6.71 (s,
2H), 5.08 (s, 2H), 4.59 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.27–3.25
(d, 2H), 3.03 (s, 3H), 2.59–2.54 (t, 2H), 2.17–2.11 (m, 2H), 1.92 (s,
6H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d=170.5, 156.9, 152.4, 149.8, 140.2, 137.6, 136.6, 134.0, 133.2,
128.6, 128.5, 128.4, 125.8, 116.2, 113.3, 112.3, 112.1, 69.4, 65.4,
50.6, 22.8, 22.1, 20.7, 14.1 MS (ESI), m/z: 525.3 (MꢁH)ꢁ. Anal. Calcd
for C29H34O7S: C, 66.14; H, 6.51. Found: C, 66.34; H, 6.78.
4.1.9.5. Methyl 2-(2-fluoro-4-hydroxyphenoxy)acetate (16).
The titled compound was prepared from 15 as described for com-
pound 8. Compound 16 (0.4 g, 80.7%) as a colorless solid. 1H NMR
(300 MHz, CDCl3): d 9.44 (s, 1H), 6.92 (t, J = 9.2 Hz, 2H), 6.61 (dd,
J = 13.05, 2.8 Hz, 1H), 6.51–6.47 (m, 1H), 4.73 (s, 2H), 3.69 (s, 3H).
4.1.9.6. Methyl 2-(4-((20,60-dimethyl-40-(3-(methylsulfonyl)pro-
poxy)-[1,10-biphenyl]-3-yl)methoxy)-2-fluorophenoxy)acetate
(17). The titled compound was prepared from 16 as described for
compound 9. Compound 17 (0.21 g, 81.4%) as a colorless solid.
4.1.9.7. 2-(4-((20,60-Dimethyl-40-(3-(methylsulfonyl)propoxy)-[1,
10-biphenyl]-3-yl)methoxy)-2-fluorophenoxy)acetic acid (18b).
The titled compound was prepared from 17 as described for com-
pound 10a. Compound 18b (0.17 g, 87.3%) as a colorless solid. mp:
106–107 °C; 1H NMR (300 MHz, DMSO-d6): d 7.47–7.38 (m, 2H),
7.15 (s, 1H), 7.07–6.94 (m, 3H), 6.77–6.71 (m, 3H), 5.11 (s, 2H),
4.65 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.28 (t, J = 7.6 Hz, 2H), 3.03 (s,
3H), 2.19–2.10 (m, 2H), 1.92 (s, 6H); 13C NMR (75 MHz, DMSO-
d6) d 167.0, 156.9, 153.4, 152.8, 152.6, 150.2, 140.3, 139.8, 137.0,
136.6, 133.9, 128.8, 128.6, 128.6, 125.9, 115.9, 113.3, 110.3,
104.3, 104.0, 69.7, 65.8, 65.4, 50.6, 22.0, 20.7; MS (ESI), m/z:
515.3 (MꢁH)ꢁ. Anal. Calcd for C27H29FO7S: C, 62.78; H, 5.66.
Found: C, 62.24; H, 5.43.
4.1.8. 2-(4-((20,60-Dimethyl-40-(3-(methylsulfonyl)propoxy)-
[1,10-biphenyl]-3-yl)methoxy)phenoxy)-2-methylpropanoic
acid (10f)
Compound 10f (0.13 g, 18.7%) as a colorless solid. mp: 110–
112 °C; 1H NMR (300 MHz, DMSO-d6): d 7.45–7.38 (m, 2H), 7.14
(s, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 9.1 Hz, 2H), 6.80 (d,
J = 9.1 Hz, 2H), 6.70 (s, 2H), 5.09 (s, 2H), 4.09 (t, J = 6.2 Hz, 2H),
3.27 (t, J = 8.0 Hz, 2H), 3.03 (s, 3H), 2.18–2.09 (m, 2H), 1.91 (s,
6H), 1.42 (s, 6H); 13C NMR (75 MHz, DMSO-d6) d 175.1, 156.9,
153.4, 148.9, 140.2, 137.4, 136.6, 133.9, 128.7, 128.5, 125.9,
120.9, 115.4, 113.3, 78.9, 69.4, 65.4, 50.6, 24.9, 22.0, 20.7; MS
(ESI), m/z: 525.3 (MꢁH)ꢁ. Anal. Calcd for C29H34O7S: C, 66.14; H,
6.51. Found: C, 66.63; H, 6.71.
4.1.10. 2-(2-Chloro-4-((20,60-dimethyl-40-(3-(methylsulfonyl)pro-
poxy)-[1,10-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (18a)
Compound 18a (0.14 g, 15.4%) as a colorless solid. mp: 118–
120 °C; 1H NMR (300 MHz, DMSO-d6): d 7.47–7.37 (m, 2H), 7.16
(s, 1H), 7.11 (d, J = 7.3 Hz, 1H), 6.97–6.90 (m, 2H), 6.71 (s, 2H),
5.12 (s, 2H), 4.68 (s, 2H), 4.09 (t, J = 6.2 Hz, 2H), 3.27 (t, J = 7.6 Hz,
2H), 3.03 (s, 3H), 2.19–2.10 (m, 2H), 1.95 (s, 6H); 13C NMR
(75 MHz, DMSO-d6) d 169.9, 156.9, 152.5, 147.6, 140.3, 137.0,
136.6, 133.9, 128.8, 128.6, 125.9, 121.6, 116.8, 114.6, 114.5,
113.3, 69.8, 65.6, 65.4, 50.6, 29.0, 22.0, 20.7; MS (ESI), m/z: 531.2
(MꢁH)ꢁ. Anal. Calcd for C27H29ClO7S: C, 60.84; H, 5.48. Found: C,
61.41; H, 5.72.
4.1.9. The following procedures described the synthesis of
compound 18b
These procedures can also be applied to the synthesis of com-
pounds 18a, 18c–18h.
4.1.9.1. 2-Fluorophenyl acetate (12). To a solution of 2-fluoro-
phenol (11) (1.0 g, 8.92 mmol) in CH2Cl2 was added pyridine
(1.41 g, 17.84 mmol) at 0 °C. Subsequently, a solution of AcCl
(1.05 g, 13.38 mmol) in CH2Cl2 was added dropwise at a rate to
ensure that the temperature did not exceed 0 °C. After 4 h, the
reaction was quenched with HCl (1 N). The aqueous layer was sep-
arated and extracted with CH2Cl2. The combined organic phases
were washed with HCl, H2O, NaOH, dried over Na2SO4 and filtered.
The filtrate was evaporated under vacuum to give a crude product
12 (1.3 g, 87.3%), which was used for the next reaction without fur-
ther purification.
4.1.11. 2-(2-Chloro-4-((20,60-dimethyl-40-(3-(methylsulfonyl)pro-
poxy)-[1,10-biphenyl]-3-yl)methoxy)phenoxy)-2-methylpropa-
noic acid (18c)
Compound 18c (0.16 g, 11.6%) as a colorless solid. mp: 112–
114 °C; 1H NMR (300 MHz, DMSO-d6): d 7.49–7.38 (m, 2H), 7.15
(s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.95–6.93
(m, 2H), 6.71 (s, 2H), 5.13 (s, 2H), 4.09 (t, J = 6.2 Hz, 2H), 3.28–
3.19 (m, 2H), 3.03 (s, 3H), 2.17–2.12 (m, 2H), 1.91 (s, 6H), 1.45 (s,
6H); 13C NMR (75 MHz, DMSO-d6) d 174.8, 156.9, 153.5, 145.0,
140.3, 136.9, 136.6, 133.9, 128.9, 128.6, 126.0, 121.2, 116.3,
114.6, 113.3, 80.4, 69.6, 65.4, 50.6, 24.7, 22.0, 20.7; MS (ESI), m/z:
559.2 (MꢁH)ꢁ. Anal. Calcd for C29H33ClO7S: C, 62.08; H, 5.93.
Found: C, 62.47; H, 5.78.
4.1.9.2. 1-(3-Fluoro-4-hydroxyphenyl)ethanone (13). To a solu-
tion of aluminum chloride (2.08 g, 15.57 mmol) in dichlorobenzene
was added a solution of 12 (1.2 g, 7.79 mmol) in dichlorobenzene
at room temperature. The reaction was warmed to 100 °C and fur-
ther stirred for 20 h. After the reaction mixture was allowed to cool
to room temperature, added with dichloromethane, and poured
into 10% HCl cooled at 0 °C. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic phases were washed
with water, dried over Na2SO4. The filtrate was evaporated under
vacuum, and the residue was purified by column chromatography
(EtOAc/hexane, 1:4, v/v) to give a white solid (0.75 g, 62.5%). 1H
NMR (300 MHz, CDCl3): d 7.73–7.70 (m, 2H), 7.11–7.05 (m, 1H),
2.58 (s, 3H).
4.1.12. 2-(4-((20,60-Dimethyl-40-(3-(methylsulfonyl)propoxy)-
[1,10-biphenyl]-3-yl)methoxy)-2-fluorophenoxy)-2-methylprop-
anoic acid (18d)
Compound 18d (0.15 g, 10.9%) as
a colorless solid. mp:
124–126 °C; 1H NMR (300 MHz, DMSO-d6): d 7.53–7.41 (m, 3H),