H. Zhang et al. / European Journal of Medicinal Chemistry 89 (2015) 524e539
535
6.1.6.8. Isopropyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-3-ethoxy-5-
145.11, 148.23, 154.79, 166.44, 169.32. HRMS (ESI) m/z 396.1389
([MþH]þ).
fluorophenyl) acetate (47). Yellow oil; Yield: 76%; 1H NMR (CDCl3)
d
1.13 (t, 3H, J ¼ 6.97 Hz), 1.23 (t, 3H, J ¼ 6.97 Hz), 1.32 (d, 6H,
J ¼ 6.86 Hz), 1.45 (t, 3H, J ¼ 7.24 Hz), 3.35e3.42 (m, 4H), 3.54 (s, 2H),
6.1.6.15. 1,1,1-Trifluoropropan-2-yl 2-(4-(2-(diethylamino)-2-
oxoethoxy)-2-fluoro-5-methoxyphenyl) acetate (54). Yellow oil;
4.04e4.10 (m, 2H), 4.72 (s, 2H), 4.99e5.05 (m, 1H), 6.69e6.77 (m,
2H). 13C NMR (CDCl3)
d
12.77, 13.84, 14.22, 21.73, 21.91, 34.25, 40.46,
Yield: 87%; 1H NMR (CDCl3)
d
1.15 (t, 3H, J ¼ 7.10 Hz), 1.23 (t, 3H,
56.45, 59.66, 68.41, 68.51, 102.75, 113.42, 114.04, 145.62, 147.42,
J ¼ 7.10 Hz),1.29 (d, 3H, J ¼ 6.96 Hz), 3.39e3.44 (m, 4H), 3.83 (s, 3H),
4.03e4.09 (m, 2H), 4.72 (s, 2H), 5.29e5.36 (m, 1H), 6.70e6.80 (m,
154.59, 166.45, 170.43. HRMS (ESI) m/z 370.2031 ([MþH]þ).
2H). 13C NMR (CDCl3)
d 12.75, 13.44, 14.27, 33.61, 40.33, 41.55, 60.99,
65.22, 67.46, 68.67, 102.83, 113.10, 115.60, 145.07, 147.89, 155.68,
6.1.6.9. 2,2,2-Trifluoroethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-3-
ethoxy-5-fluorophenyl) acetate (48). Yellow oil; Yield: 81%; 1H
166.68, 169.24. HRMS (ESI) m/z 410.1592 ([MþH]þ).
NMR (CDCl3)
d
1.13 (t, 3H, J ¼ 6.97 Hz), 1.23 (t, 3H, J ¼ 6.97 Hz), 1.44
6.1.6.16. Ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-
(t, 3H, J ¼ 7.24 Hz), 3.35e3.42 (m, 4H), 3.54 (s, 2H), 4.04e4.10 (m,
fluorophenyl) acetate (55). Yellow oil; Yield: 87%; 1H NMR (CDCl3)
2H), 4.47e4.53 (m, 2H), 4.70 (s, 2H), 6.68e6.78 (m, 2H). 13C NMR
d
1.15 (t, 3H, J ¼ 7.12 Hz), 1.22 (t, 3H, J ¼ 7.12 Hz), 1.27 (t, 3H,
(CDCl3) d 12.77, 13.84, 14.22, 21.88, 34.26, 39.95, 40.46, 56.45, 59.66,
J ¼ 7.12 Hz), 1.42 (t, 3H, J ¼ 7.02 Hz), 3.38e3.44 (m, 4H), 3.57 (s, 2H),
4.03e4.09 (m, 2H), 4.14e4.20 (m, 2H), 4.70 (s, 2H), 6.70e6.80 (m,
68.46, 102.67, 113.44, 114.04, 145.61, 147.40, 154.92, 166.45, 170.43.
HRMS (ESI) m/z 410.1592 ([MþH]þ).
2H). 13C NMR (CDCl3)
d 12.76, 14.15, 14.29, 20.88, 33.97, 40.29, 41.52,
60.98, 65.21, 68.74, 102.84, 113.31, 115.85, 144.98(d, 1C, J ¼ 2.98 Hz),
147.92 (d, 1C, J ¼ 10.08 Hz), 153.07 (d, 1C, J ¼ 241.20 Hz), 166.56,
170.93. HRMS (ESI) m/z 356.1875 ([MþH]þ).
6.1.6.10. 1,1,1-Trifluoropropan-2-yl 2-(4-(2-(diethylamino)-2-
oxoethoxy)-3-ethoxy-5-fluorophenyl) acetate (49). Yellow oil;
Yield: 79%; 1H NMR (CDCl3)
d
1.15 (t, 3H, J ¼ 7.08 Hz), 1.22 (t, 3H,
J ¼ 7.06 Hz), 1.31 (d, 3H, J ¼ 6.87 Hz), 1.43 (t, 3H, J ¼ 7.12 Hz),
3.38e3.43 (m, 4H), 3.69 (s, 2H), 4.03e4.08 (m, 2H), 4.71 (s, 2H),
6.1.6.17. Propyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-
fluorophenyl) acetate (56). Yellow oil; Yield: 88%; 1H NMR (CDCl3)
4.99e5.05 (m, 1H), 6.70e6.78 (m, 2H). 13C NMR (CDCl3)
d 12.75,
d
0.92 (t, 3H, J ¼ 7.44 Hz), 1.15 (t, 3H, J ¼ 7.27 Hz), 1.23 (t, 3H,
14.26, 14.83, 21.88, 21.91, 33.27, 39.95, 40.86, 61.19, 65.24, 68.60,
103.07, 111.95, 115.65, 123.21, 147.12, 155.69, 166.44, 169.32. HRMS
(ESI) m/z 424.1702 ([MþH]þ).
J ¼ 6.96 Hz), 1.42 (t, 3H, J ¼ 6.96 Hz), 1.62e1.68 (m, 2H), 3.38e3.43
(m, 4H), 3.58 (s, 2H), 4.03e4.09 (m, 4H), 4.70 (s, 2H), 6.70e6.79 (m,
2H). 13C NMR (CDCl3)
d 10.29, 12.76, 14.28, 14.88, 21.91, 33.98, 40.28,
41.52, 65.21, 66.57, 68.75, 102.83, 113.36, 115.91, 145.01, 147.81,
153.68 (d, 1C, J ¼ 243.68 Hz), 166.56, 171.00. HRMS (ESI) m/z
370.2031 ([MþH]þ).
6.1.6.11. Ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-2-fluoro-5-
methoxyphenyl) acetate (50). Yellow oil; Yield: 82%; 1H NMR
(CDCl3)
J ¼ 6.99 Hz), 3.38e3.43 (m, 4H), 3.54 (s, 2H), 3.83 (s, 3H), 4.15e4.21
(m, 2H), 4.71 (s, 2H), 6.71e6.80 (m, 2H). 13C NMR (CDCl3)
12.77,
d
1.14 (t, 3H, J ¼ 7.09 Hz), 1.22 (t, 3H, J ¼ 7.09 Hz), 1.27 (t, 3H,
6.1.6.18. Isopropyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-
d
fluorophenyl) acetate (57). Yellow oil; Yield: 85%; 1H NMR (CDCl3)
14.13, 14.23, 33.96, 40.33, 41.47, 56.54, 60.95, 68.66, 102.80 (d, 1C,
J ¼ 27.47 Hz), 113.34 (d, 1C, J ¼ 17.46 Hz), 114.23 (d, 1C, J ¼ 5.19 Hz),
145.77, 147.61 (d, 1C, J ¼ 9.87 Hz), 154.85 (d, 1C, J ¼ 240.38 Hz),
166.46, 170.85. HRMS (ESI) m/z 342.1716 ([MþH]þ).
d
1.15 (t, 3H, J ¼ 7.27 Hz), 1.22 (t, 3H, J ¼ 7.44 Hz), 1.32 (d, 6H,
J ¼ 6.96 Hz), 1.42 (t, 3H, J ¼ 6.96 Hz), 3.38e3.43 (m, 4H), 3.58 (s, 2H),
4.05e4.10 (m, 2H), 4.72 (s, 2H), 4.95e5.01 (m, 1H), 6.71e6.78 (m,
2H). 13C NMR (CDCl3)
d 12.28,12.76, 14.36,14.88, 21.93, 33.96, 40.28,
41.52, 65.21, 66.57, 68.75, 102.83, 113.53, 115.85, 144.98, 147.91,
156.07 (d, 1C, J ¼ 238.72 Hz), 165.67, 172.11. HRMS (ESI) m/z
370.2031 ([MþH]þ).
6.1.6.12. Propyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-2-fluoro-5-
methoxyphenyl) acetate (51). Yellow oil; Yield: 81%; 1H NMR
(CDCl3)
d
0.93 (t, 3H, J ¼ 7.63 Hz), 1.15 (t, 3H, J ¼ 7.19 Hz), 1.22 (t, 3H,
J ¼ 6.97 Hz), 1.61e1.70 (m, 2H), 3.39e3.44 (m, 4H), 3.59 (s, 2H), 3.85
6.1.6.19. 2,2,2-Trifluoroethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-
ethoxy-2-fluorophenyl) acetate (58). Yellow oil; Yield: 82%; 1H
(s, 3H), 4.08 (t, 2H, J ¼ 6.68 Hz), 4.71 (s, 2H), 6.71e6.79 (m, 2H). 13
C
NMR (CDCl3)
d 10.25, 12.76, 14.22, 21.92, 33.96, 40.33, 41.47, 56.54,
NMR (CDCl3)
d
1.13 (t, 3H, J ¼ 7.02 Hz), 1.23 (t, 3H, J ¼ 6.98 Hz), 1.42
66.56, 68.67, 102.78 (d, 1C, J ¼ 28.13 Hz), 113.39 (d, 1C, J ¼ 17.50 Hz),
114.23 (d, 1C, J ¼ 5.13 Hz), 145.75, 147.60 (d, 1C, J ¼ 9.98 Hz), 154.85
(d, 1C, J ¼ 240.20 Hz), 166.46, 170.93. HRMS (ESI) m/z 356.1875
([MþH]þ).
(t, 3H, J ¼ 7.00 Hz), 3.39e3.44 (m, 4H), 3.61 (s, 2H), 4.03e4.09 (m,
2H), 4.48e4.54 (m, 2H), 4.70 (s, 2H), 6.70e6.79 (m, 2H). 13C NMR
(CDCl3)
d 12.78, 14.28, 14.82, 21.91, 33.96, 40.28, 41.52, 65.21, 66.57,
68.75, 102.83, 113.36, 115.91, 145.65, 147.81, 155.68, 166.58, 171.09.
HRMS (ESI) m/z 410.1592 ([MþH]þ).
6.1.6.13. Isopropyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-2-fluoro-5-
methoxyphenyl) acetate (52). Yellow oil; Yield: 89%; 1H NMR
6.1.6.20. 1,1,1-Trifluoropropan-2-yl 2-(4-(2-(diethylamino)-2-
oxoethoxy)-5-ethoxy-2-fluorophenyl) acetate (59). Yellow oil;
(CDCl3)
J ¼ 6.24 Hz), 3.35e3.42 (m, 4H), 3.54 (s, 2H), 3.83 (s, 3H), 4.70 (s,
2H), 4.99e5.05 (m, 1H), 6.69e6.77 (m, 2H). 13C NMR (CDCl3)
12.77,
d
1.13 (t, 3H, J ¼ 6.97 Hz), 1.29 (t, 3H, J ¼ 7.24 Hz), 1.23 (d, 6H,
Yield: 84%; 1H NMR (CDCl3)
d
1.15 (t, 3H, J ¼ 7.27 Hz), 1.23 (t, 3H,
d
J ¼ 6.96 Hz), 1.43 (d, 3H, J ¼ 6.96 Hz), 3.38e3.43 (m, 4H), 3.58 (s,
13.84, 14.22, 21.91, 34.25, 40.33, 41.46, 56.45, 68.41, 68.51, 102.75,
113.35, 114.04, 145.60, 147.48, 154.59, 166.45, 170.43. HRMS (ESI) m/
z 356.1875 ([MþH]þ).
2H), 4.03e4.09 (m, 2H), 4.70 (s, 2H), 4.93e4.96 (m, 1H), 6.70e6.79
(m, 2H). 13C NMR (CDCl3)
d 12.76, 14.26, 14.88, 21.91, 33.96, 33.98,
40.28, 41.52, 65.21, 66.57, 68.75, 103.10, 113.53, 115.85, 144.98,
147.91, 155.67, 166.56, 171.00. HRMS (ESI) m/z 424.1702 ([MþH]þ).
6.1.6.14. 2,2,2-Trifluoroethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-2-
fluoro-5-methoxyphenyl) acetate (53). Yellow oil; Yield: 84%; 1H
6.1.6.21. Ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-2-fluoro-3-
methoxyphenyl) acetate (60). Yellow oil; Yield: 85%; 1H NMR
NMR (CDCl3)
3.38e3.43 (m, 4H), 3.69 (s, 2H), 3.73 (s, 3H), 4.47e4.53 (m, 2H), 4.71
(s, 2H), 6.70e6.78 (m, 2H). 13C NMR (CDCl3)
12.75, 14.26, 23.26,
33.28, 60.09, 60.83, 61.19, 65.24, 68.60, 102.80, 112.03, 115.62,
d
1.15 (t, 3H, J ¼ 7.08 Hz), 1.23 (t, 3H, J ¼ 7.08 Hz),
(CDCl3)
J ¼ 7.06 Hz), 3.39e3.50 (m, 4H), 3.53 (s, 2H), 3.82 (s, 3H), 4.14e4.20
(m, 2H), 4.69 (s, 2H), 6.64e6.69 (m, 2H). 13C NMR (CDCl3)
12.77,
d
1.14 (t, 3H, J ¼ 7.06 Hz), 1.24 (t, 3H, J ¼ 7.06 Hz), 1.28 (t, 3H,
d
d