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Med Chem Res (2013) 22:3170–3176
aromatic urea 4a–n (0.01 mol) in 100 ml dry dichloro-
methane 15 drops of BF3ꢀOEt2 was added. The mixture was
stirred at room temperature 2 h, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography on silica gel using petroleum ether/ethyl
acetate as eluent.
J = 3.3 Hz, 1H, 10-H), 5.04 (t, 1H, N–H), 5.32 (s, 1H,
12-H), 6.35 (s, 1H, N–H), 7.12–7.23 (m, 3H, Ar–H), 7.37
(m, 1H, Ar–H). MS m/z: 483.4 (M?Na)?, 499.4 (M?K)?.
Anal. calcd. For C25H36N2O6: C, 65.20; H, 7.88; N, 6.08.
Found: C, 65.24; H, 7.87; N, 6.11.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-phenylurea (1e)
1
1-[2-(10a-Dihydroartemisininoxy)ethyl]-3-(4-nitrophenyl)urea
(1a) Yellow solid (0.22 g, 18.61 %). m.p.: 97–98 °C. H
White solid (0.13 g, 13.23 %). m.p.: 60–62 °C. H NMR
1
(CDCl3) d: 0.84 (d, J = 7.5 Hz, 3H, 9-CH3), 0.90 (d,
J = 5.7 Hz, 3H, 6-CH3), 1.22–1.26 (m, 3H), 1.43 (s, 3H,
3-CH3), 1.58–2.05 (m, 6H), 2.33–2.62 (m, 2H), 3.44–3.82
(m, 4H), 4.76 (d, J = 3.3 Hz, 1H, 10-H), 5.42 (s, 1H,
12-H), 5.49 (s, 1H, N–H), 6.98 (s, 1H, N–H), 7.05–7.35 (m,
5H, Ar–H). MS m/z: 469.3 (M?Na)?, 485.3 (M?K)?,
481.2 (M?Cl)-, 491.3 (M?HCOO-)-. Anal. calcd. For
C24H34N2O6: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.56;
H, 7.70; N, 6.29.
NMR (CDCl3) d: 0.91 (d, J = 7.2 Hz, 3H, 9-CH3), 0.99 (d,
J = 5.7 Hz, 3H, 6-CH3), 1.20–1.34 (m, 3H), 1.40 (s, 3H,
3-CH3), 1.47–2.10 (m, 6H), 2.41–2.42 (m, 1H), 3.36–3.86
(m, 4H), 4.52 (d, J = 9.3 Hz, 1H, 10-H), 5.30 (s, 1H, N–
H), 5.46 (s, 1H, 12-H), 7.56 (d, J = 9.0 Hz, 2H, Ar–H),
7.82 (s, 1H, N–H), 8.13 (d, J = 9.0 Hz, 2H, Ar–H). MS m/
z: 514.2 (M?Na)?, 530.1 (M?K)?, 490.0 (M-H)-, 526.0
(M?Cl)-, 536.0 (M?HCOO-)-. Anal. calcd. For
C24H33N3O8: C, 58.64; H, 6.77; N, 8.55. Found: C, 58.61;
H, 6.74; N, 8.59.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-(2,5-dimethylphenyl)
urea (1f) White solid (0.39 g, 20.33 %). m.p.: 64–66 °C.
1H NMR (CDCl3) d: 0.71 (d, J = 7.2 Hz, 3H, 9-CH3), 0.93
(d, J = 5.7 Hz, 3H, 6-CH3), 1.20–1.25 (m, 3H), 1.41 (s,
3H, 3-CH3), 1.51–2.04 (m, 6H), 2.23 (s, 3H, Ar–CH3), 2.30
(s, 3H, Ar–CH3), 3.33–3.88 (m, 4H), 4.72 (d, J = 3.3 Hz,
1H, 10-H), 4.87 (s, 1H, N–H), 5.31 (s, 1H, 12-H), 5.96 (s,
1H, N–H), 6.94–7.26 (m, 3H, Ar–H). MS m/z: 497.5
(M?Na)?, 513.4 (M?K)?. Anal. calcd. For C26H38N2O6:
C, 65.80; H, 8.07; N, 5.90. Found: C, 65.84; H, 8.03; N,
5.93.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-(4-methoxyphenyl)
urea (1b) White solid (0.56 g, 38.31 %). m.p.: 66–68 °C.
1H NMR (CDCl3) d: 0.80 (d, J = 7.5 Hz, 3H, 9-CH3), 0.92
(d, J = 5.4 Hz, 3H, 6-CH3), 1.16–1.29 (m, 3H), 1.42 (s,
3H, 3-CH3), 1.53–2.05 (m, 6H), 2.31–2.60 (m, 2H),
3.37–3.85 (m, 4H), 3.78 (s, 3H, –OCH3), 4.75 (d,
J = 3.3 Hz, 1H, 10-H), 5.23 (s, 1H, N–H), 5.38 (s, 1H,
12-H), 6.84 (d, J = 9.0 Hz, 2H, Ar–H), 7.20 (d, J =
9.0 Hz, 2H, Ar–H). MS m/z: 477.2 (M?H)?, 499.2
(M?Na)?, 515.2 (M?K)?, 475.1 (M-H)-, 511.0
(M?Cl)-, 521.1 (M?HCOO-)-. Anal. calcd. For C25H36
N2O7: C, 63.01; H, 7.61; N, 5.88. Found: C, 62.98; H, 7.65;
N, 5.85.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-(3-chloro-2-methyl
phenyl)urea (1g) Yellow solid (0.34 g, 20.01 %). m.p.:
1
90–93 °C. H NMR (CDCl3) d: 0.75 (d, J = 7.5 Hz, 3H,
9-CH3), 0.92 (d, J = 5.7 Hz, 3H, 6-CH3), 1.21–1.34 (m,
3H), 1.39 (s, 3H, 3-CH3), 1.43–2.05 (m, 6H), 2.3 (s, 3H,
Ar–CH3), 2.39–2.60 (m, 2H), 3.34–3.86 (m, 4H), 4.73 (d,
J = 3.6 Hz, 1H, 10-H), 5.07 (m, 1H, N–H), 5.34 (s, 1H,
12-H), 6.53 (m, 1H, N–H), 7.09–7.14 (m, 1H, Ar–H),
7.22–7.25 (m, 1H, Ar–H), 7.32–7.34 (m, 1H, Ar–H). MS
m/z: 517.3 (M?Na)?, 533.2 (M?K)?, 493.2 (M-H)-,
529.2 (M?Cl)-, 539.3 (M?HCOO-)-. Anal. calcd. For
C25H35ClN2O6: C, 60.66; H, 7.13; N, 5.66. Found: C,
60.65; H, 7.10; N, 5.70.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-[4-(trifluoromethyl)
phenyl)]urea (1c) Yellow solid (0.11 g, 7.81 %). m.p.:
1
74–76 °C. H NMR (CDCl3) d: 0.88–0.90 (m, 6H, 9-CH3,
6-CH3), 1.26–1.28 (m, 3H), 1.44 (s, 3H, 3-CH3), 1.56–2.07
(m, 6H), 2.39–2.63 (m, 1H), 3.42–3.77 (m, 4H), 4.76 (d,
J = 3.6 Hz, 1H, 10-H), 5.49 (s, 1H, 12-H), 5.83 (s, 1H, N–
H), 7.50 (m, 4H, Ar–H). MS m/z: 515.4 (M?H)?, 537.5
(M?Na)?, 553.4 (M?K)?, 513.3 (M-H)-, 549.2
(M?Cl)-, 559.3 (M?HCOO-)-. Anal. calcd. For C25H33
F3N2O6: C, 58.36; H, 6.46; N, 5.44. Found: C, 58.33; H,
6.50; N, 5.40.
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-(4-fluorophenyl)
urea (1h) White solid (0.25 g, 13.67 %). m.p.: 70–72 °C.
1H NMR (CDCl3) d: 0.85 (d, J = 7.2 Hz, 3H, 9-CH3), 0.91
(d, J = 5.4 Hz, 3H, 6-CH3), 1.22–1.26 (m, 3H), 1.42 (s,
3H, 3-CH3), 1.53–2.05 (m, 6H), 2.32–2.63 (m, 2H),
3.41–3.82 (m, 4H), 3.41–3.82 (m, 4H), 4.75 (d,
J = 3.3 Hz, 1H, 10-H), 5.42 (s, 1H, 12-H), 6.94–7.00 (m,
2H, Ar–H), 7.14 (s, 1H, N–H), 7.29-7.31 (m, 2H, Ar–H).
1-[2-(10b-Dihydroartemisininoxy)ethyl]-3-(2-methylphenyl)
urea (1d) White solid (0.13 g, 10.41 %). m.p.: 57–59 °C.
1H NMR (CDCl3) d: 0.73 (d, J = 7.5 Hz, 3H, 9-CH3), 0.92
(d, J = 5.7 Hz, 3H, 6-CH3), 1.18–1.26 (m, 3H), 1.41 (s,
3H, 3-CH3), 1.56–2.05 (m, 6H), 2.28 (s, 3H, Ar–CH3),
2.31–2.29 (m, 2H), 3.34–3.90 (m, 4H), 4.72 (d,
123