94
Y. Yang et al. / European Journal of Medicinal Chemistry 104 (2015) 86e96
[MþH]þ.
4.16. 2-(2-(2-(4-((4-methoxybenzyl)oxy)phenoxy)ethoxy)ethoxy)
ethyl 4-methylbenzenesulfonate (4f)
4.12. 2-(2-(4-((4-(dimethylamino)benzyl)oxy)phenoxy)ethoxy)
ethyl 4-methylbenzenesulfonate (4b)
The reaction described above to prepare 4a was employed to
give 4f as a colorless oil from 3c and (4-methoxyphenyl)methanol
(177.5 mg, 69%). 1H NMR (400 MHz, CDCl3)
d
7.79 (d, J ¼ 7.9 Hz, 2H,
The reaction described above to prepare 4a was employed to
Ph), 7.37e7.30 (m, 4H, Ph), 6.93e6.82 (m, 6H, Ph), 4.93 (s, 2H,
OCH2), 4.19e4.13 (m, 2H, CH2), 4.08e4.02 (m, 2H, CH2), 3.83e3.76
(m, 5H, CH2, OCH3), 3.71e3.58 (m, 6H, CH2), 2.43 (s, 3H, CH3); 13C
give 4b as
a white solid from 3b (394.7 mg, 69%). m.p.
101.1e101.6 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.79 (d, J ¼ 8.3 Hz, 2H,
Ph), 7.31e7.27 (m, 4H, Ph), 6.89 (d, J ¼ 9.2 Hz, 2H, Ph), 6.80 (d,
J ¼ 9.2 Hz, 2H, Ph), 6.73 (d, J ¼ 8.7 Hz, 2H, Ph), 4.89 (s, 2H, OCH2),
4.21e4.17 (m, 2H, CH2), 4.00e3.96 (m, 2H, CH2), 3.77e3.73 (m, 4H,
CH2), 2.95 (s, 6H, N(CH3)2), 2.41 (s, 3H, CH3); 13C NMR (101 MHz,
NMR (101 MHz, CDCl3) d 159.44, 153.25, 153.12, 144.76, 133.17,
129.81, 129.36, 129.18, 127.96, 115.91, 115.66, 113.99, 70.81, 70.75,
70.52, 69.93, 69.25, 68.74, 68.13, 55.29, 21.59. MS (EI): m/z calcd for
C
27H32O8S 516; found 516 [M]þ.
CDCl3)
d 153.50, 152.80, 150.50, 144.77, 133.03, 129.80, 129.18,
127.96, 124.75, 115.88, 115.56, 112.51, 70.85, 69.98, 69.26, 68.83,
68.06, 40.57, 21.59. MS (ESI): m/z calcd for C26H32NO6S 486.2; found
486.2 [MþH]þ.
4.17. 4-((4-(2-fluoroethoxy)phenoxy)methyl)-N,N-dimethylaniline
(5a)
To a solution of 4a (132.5 mg, 0.30 mmol) in 10 mL of dry THF
was added anhydrous TBAF (600
mL, 1 M in THF). The reaction
4.13. 2-(2-(2-(4-((4-(dimethylamino)benzyl)oxy)phenoxy)ethoxy)
ethoxy)ethyl 4-methylbenzenesulfonate (4c)
mixture was refluxed for 2 h. Upon completion, the reaction was
concentrated and purified by silica gel chromatography (petroleum
ether/AcOEt ¼ 3/1, v/v) to give 5a as a white solid (61.4 mg, 71%).
HPLC 13.3 min, 99.2%. m.p. 145.1e145.3 ꢀC. 1H NMR (400 MHz,
The reaction described above to prepare 4a was employed to
give 4c as a white solid from 3c (986.3 mg, 70%). m.p. 72.2e72.8 ꢀC.
CDCl3)
d
7.28 (d, J ¼ 8.8 Hz, 2H, Ph), 6.91 (d, J ¼ 9.3 Hz, 2H, Ph), 6.85
1H NMR (400 MHz, CDCl3)
d
7.79 (d, J ¼ 8.3 Hz, 2H, Ph), 7.32 (d,
(d, J ¼ 9.3 Hz, 2H, Ph), 6.73 (d, J ¼ 8.7 Hz, 2H, Ph), 4.90 (s, 2H, OCH2),
J ¼ 8.0 Hz, 2H, Ph), 7.29 (d, J ¼ 8.3 Hz, 2H, Ph), 6.89 (d, J ¼ 9.2 Hz, 2H,
Ph), 6.83 (d, J ¼ 9.2 Hz, 2H, Ph), 6.79e6.69 (m, 2H, Ph), 4.89 (s, 2H,
OCH2), 4.18e4.14 (m, 2H, CH2), 4.08e4.03 (m, 2H, CH2), 3.81e3.76
(m, 2H, CH2), 3.71e3.67 (m, 2H, CH2), 3.66e3.63 (m, 2H, CH2),
4.79e4.65 (m, 2H, CH2), 4.21e4.11 (m, 2H, CH2), 2.95 (s, 6H,
N(CH3)2); 13C NMR (101 MHz, CDCl3)
d 153.80, 152.64, 150.58,
129.24, 124.77, 115.98, 115.79, 112.56, 82.10 (d, J ¼ 170.4 Hz), 70.90,
67.97 (d, J ¼ 20.5 Hz), 40.61. HRMS (ESI): m/z calcd for C17H21FNO2
290.1551; found 290.1551 [MþH]þ.
3.62e3.58 (m, 2H, CH2), 2.96 (s, 6H, N(CH3)2), 2.43 (s, 3H, CH3); 13
C
NMR (101 MHz, CDCl3)
d 153.45, 152.93, 150.48, 144.77, 133.09,
129.81, 129.20, 127.97, 124.88, 115.87, 115.60, 112.58, 70.86, 70.80,
4.18. 4-((4-(2-(2-fluoroethoxy)ethoxy)phenoxy)methyl)-N,N-
dimethylaniline (5b)
70.74, 69.93, 69.25, 68.73, 68.10, 40.63, 21.61. MS (ESI): m/z calcd for
C
28H36NO7S 530.2; found 530.1 [MþH]þ.
The reaction described above to prepare 5a was employed to
give 5b as a white solid from 4b (56.4 mg, 58%). HPLC 11.5 min,
4.14. 2-(4-((4-methoxybenzyl)oxy)phenoxy)ethyl 4-
98.6%. m.p. 111.5e111.8 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.28 (d,
methylbenzenesulfonate (4d)
J ¼ 8.6 Hz, 2H, Ph), 6.89 (d, J ¼ 9.2 Hz, 2H, Ph), 6.84 (d, J ¼ 9.2 Hz, 2H,
Ph), 6.73 (d, J ¼ 8.6 Hz, 2H, Ph), 4.89 (s, 2H, OCH2), 4.67e4.50 (m, 2H,
CH2), 4.12e4.07 (m, 2H, CH2), 3.89e3.75 (m, 4H, CH2), 2.95 (s, 6H,
The reaction described above to prepare 4a was employed to
give 4d as a white solid from 3a and (4-methoxyphenyl)methanol
(317.4 mg, 74%). m.p. 107.0e107.3 ꢀC. 1H NMR (400 MHz, CDCl3)
N(CH3)2); 13C NMR (101 MHz, CDCl3)
d 153.53, 152.90, 150.53,
129.21, 124.84, 115.90, 115.67, 112.57, 83.18 (d, J ¼ 169.1 Hz), 70.89,
d
7.81 (d, J ¼ 8.1 Hz, 2H, Ph), 7.37e7.31 (m, 4H, Ph), 6.91 (d,
70.58 (d, J ¼ 19.8 Hz), 70.10, 68.22, 40.62. HRMS (ESI): m/z calcd for
J ¼ 8.4 Hz, 2H, Ph), 6.85 (d, J ¼ 8.7 Hz, 2H, Ph), 6.72 (d, J ¼ 8.9 Hz, 2H,
Ph), 4.92 (s, 2H, OCH2), 4.37e4.31 (m, 2H, CH2), 4.12e4.07 (m, 2H,
CH2), 3.81 (s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR (101 MHz,
C
19H25FNO3 334.1813; found 334.1812 [MþH]þ.
4.19. 4-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenoxy)methyl)-
N,N-dimethylaniline (5c)
CDCl3)
d 159.46, 153.57, 152.32, 144.89, 133.01, 129.84, 129.18,
128.00, 115.88, 115.76, 114.00, 70.45, 68.27, 66.26, 55.29, 21.62. MS
(EI): m/z calcd for C23H24O6S 428; found 428 [M]þ.
The reaction described above to prepare 5a was employed to
give 5c as a white solid from 4c (74.7 mg, 40%). HPLC 9.8 min, 99.1%.
m.p. 71.7e72.1 ꢀC. 1H NMR (400 MHz, CDCl3)
d 7.29 (s, 2H, Ph), 6.89
4.15. 2-(2-(4-((4-methoxybenzyl)oxy)phenoxy)ethoxy)ethyl 4-
methylbenzenesulfonate (4e)
(d, J ¼ 9.2 Hz, 2H, Ph), 6.84 (d, J ¼ 9.2 Hz, 2H, Ph), 6.74 (s, 2H, Ph),
4.90 (s, 2H, OCH2), 4.64e4.51 (m, 2H, CH2), 4.11e4.07 (m, 2H, CH2),
3.87e3.82 (m, 2H, CH2), 3.81e3.78 (m, 1H, CH2), 3.76e3.71 (m, 5H,
The reaction described above to prepare 4a was employed to
give 4e as a colorless oil from 3b and (4-methoxyphenyl)methanol
CH2), 2.97 (s, 6H, N(CH3)2); 13C NMR (101 MHz, CDCl3)
d 153.41,
152.93, 150.51, 129.22, 124.77, 115.81, 115.58, 112.52, 83.17 (d,
J ¼ 169.0 Hz), 70.87, 70.86, 70.83, 70.46 (d, J ¼ 19.7 Hz), 69.95, 68.09,
40.62. HRMS (ESI): m/z calcd for C21H29FNO4 378.2075; found
378.2076 [MþH]þ.
(298.6 mg, 58%). 1H NMR (400 MHz, CDCl3)
d
7.67 (d, J ¼ 8.3 Hz, 2H,
Ph), 7.29 (d, J ¼ 8.2 Hz, 2H, Ph), 7.26 (d, J ¼ 8.6 Hz, 2H, Ph), 6.87 (d,
J ¼ 8.7 Hz, 2H, Ph), 6.86 (d, J ¼ 9.2 Hz, 2H, Ph), 6.77 (d, J ¼ 9.1 Hz, 2H,
Ph), 4.50 (s, 2H, OCH2), 4.09e4.05 (m, 2H, CH2), 3.85e3.81 (m, 2H,
CH2), 3.80 (s, 3H, OCH3), 3.73e3.70 (m, 2H, CH2), 3.63e3.60 (m, 2H,
4.20. 1-(2-fluoroethoxy)-4-((4-methoxybenzyl)oxy)benzene (5d)
CH2), 2.44 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3)
d 159.22, 157.47,
145.29, 143.17, 132.24, 130.27, 129.73, 129.38, 128.55, 123.31, 115.20,
113.77, 72.92, 70.90, 69.61, 69.13, 67.84, 55.25, 21.68. MS (ESI): m/z
calcd for C25H28NaO7S 495.1; found 495.2 [MþNa]þ.
The reaction described above to prepare 5a was employed to give
5d as a white solid from 4d (71.7 mg, 87%). HPLC 9.6 min, 96.6%. m.p.
96.8e97.3 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.34 (d, J ¼ 8.2 Hz, 2H, Ph),