Artemisinin Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1059
0.95 (3 H, d, J ) 6.00 Hz), and 0.94 (3H, d, J ) 6.60 Hz); 13C
NMR (75 MHz, CDCl3) δ 141.05, 138.93, 128.64, 126.80,
126.15, 104.21, 101.65, 88.06, 81.17, 69.90, 65.37, 52.62, 44.47,
37.43, 36.46, 34.65, 30.97, 26.16, 24.70, 24.51, 20.10, and 13.07;
IR (thin film)/cm-1 2945, 1633, 1510, 1455, 1374, 1359, 1240,
1142, 1099, 1011, 876 (O-O), and 825 (O-O). HRMS (EI)
6.83 (2 H, d, J ) 9.06, aromatic), 5.47 (1 H, s), 4.92 (1 H, d, J
) 4.10 Hz), 4.90 (1 H, d, J ) 12.01 Hz), 4.55 (1 H, d, J ) 12.01
Hz), 3.61 (2 H, br s), 3.22-3.17 (4 H, m), 2.69-2.61 (5 H, m),
2.39 (1 H, dt, J ) 13.50, 3.85 Hz), 2.07-1.20 (10 H, m), 1.46
(3 H, s), and 0.94 (3H, d, J ) 6.60 Hz); 13C NMR (75 MHz,
CDCl3) δ 138.50, 129.03, 128.44, 117.35, 104.19, 101.37, 88.09,
81.17, 69.64, 52.81, 49.03, 44.45, 37.45, 36.47, 34.68, 30.94,
26.19, 24.71, 24.53, 20.32, and 13.10; IR (Nujol)/cm-1 2927,
1616, 1496, 1459, 1378, 1225, 1102, 1032, 874 (O-O), and 815
(O-O); MS m/z (EI) [M]+ 422 (1), 300 (26), 193 (19), 131 (14),
and 105 (100).
C
33H43FN2O5 [M]+ requires 566.316 51; found 566.314 93.
10â-[[4-[(4-Tr iflu or om et h ylp h en ylp ip er a zyl)m et h yl]-
ben zyl]oxy]d ih yd r oa r tem isin in (10). This compound was
prepared from 1-(4-trifluoromethylphenyl)piperazine using the
general procedure in section 1.2 to give the product as a yellow
1
oil (64% yield). H NMR (300 MHz, CDCl3) δ 7.35-7.28 (5 H,
10â-[[3-[(3-Tr iflu or om et h ylp h en ylp ip er a zyl)m et h yl]-
ben zyl]oxy]d ih yd r oa r tem isin in (15). This compound was
prepared from 1-[(3-trifluoromethyl)phenyl]piperazine using
the general procedure in section 1.2 to give the product as a
brown foam (66% yield): 1H NMR (300 MHz, CDCl3) δ 7.37-
7.23 (4 H, m, aromatic), 7.10-7.06 (4 H, m, aromatic), 5.47 (1
H, s), 4.92 (1 H, d, J ) 3.98 Hz), 4.90 (1 H, d, J ) 12.16 Hz),
4.52 (1 H, d, J ) 12.16 Hz), 3.58 (2 H, s), 3.16-3.11 (4 H, m),
2.68-2.63 (5 H, m), 2.38 (1 H, dt, J ) 13.48, 4.02 Hz), 2.07-
1.20 (10 H, m), 1.45 (3 H, s), 0.95 (3 H, d, J ) 7.20 Hz), and
0.94 (3H, d, J ) 6.00 Hz); 13C NMR (75 MHz, CDCl3) δ 151.49,
138.65, 129.59, 128.40, 118.74, 115.81, 112.22, 104.19, 101.38,
88.09, 81.17, 69.68, 62.81, 52.80, 52.64, 48.64, 44.46, 37.46,
36.46, 34.69, 30.95, 26.19, 24.71, 24.53, 20.31, and 13.10; IR
(Nujol)/cm-1 2921, 1612, 1496, 1454, 1350, 1228, 1120, 1011,
875 (O-O), and 826 (O-O); MS m/z (EI) [M]+ 616 (1), 334 (11),
227 (7), 105 (100), and 56 (10).
m, aromatic), 7.10-7.03 (3 H, m, aromatic), 5.46 (1 H, s), 4.92
(1 H, d, J ) 12.30 Hz), 4.88 (1 H, d, J ) 3.80 Hz), 4.52, (1 H,
d, J ) 12.30 Hz), 3.61 (2 H, m, CH2), 3.27 (4 H, m, CH2), 2.70-
2.65 (5 H, m, CH2), 2.39 (1 H, m, CH2), 2.07-1.20 (10 H, m),
1.45 (3 H, s, CH3), 0.97-0.94 (6 H, d, 2 × CH3); 13C NMR (75
MHz, CDCl3) δ 129.59, 129.32, 127.33, 118.78, 112.29, 104.19,
101.50, 88.09, 81.17, 69.61, 62.58, 52.73, 48.55, 44.48, 37.46,
36.48, 34.67, 30.96,26.18, 24.71, 24.54, 20.31, 13.06; IR (thin
film)/cm-1 (2925), (1454), (1136), (1011); LC/MS (NH3) m/z 618
[M + H+, (100)], 603 (100), 333 (7).
10â-[[4-[(Ben zylp ip er a zyl)m eth yl]ben zyl]oxy]d ih yd r o-
a r tem isin in (11). This compound was prepared from 1-benz-
ylpiperazine using the general procedure in section 1.2 to give
the product as a yellow oil (72% yield): 1H NMR (300 MHz,
CDCl3) δ 7.32-7.20 (9 H, m, aromatic), 5.45 (1 H, s), 4.91 (1
H, d, J ) 3.90 Hz), 4.90 (1 H, d, J ) 12.50 Hz), 4.52 (1 H, d,
J ) 12.50 Hz), 3.54 (4 H, br s), 2.68 (1 H, m), 2.54-2.49 (8 H,
m), 2.38 (1 H, dt, J ) 14.10, 3.90 Hz), 2.07-1.20 (10 H, m),
1.45 (3 H, s), 0.94 (3 H, d, J ) 5.70 Hz) and 0.94 (3H, d, J )
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 129.34, 128.28, 127.19,
104.16, 101.51, 88.08, 81.18, 69.67, 62.98, 62.68, 52.92, 52.66,
44.49, 37.43, 36.49, 34.67, 30.97, 26.19, 24.71, 24.52, 20.31,
and 13.06; IR (thin film)/cm-1 2938, 1609, 1495, 1457, 1374,
1344, 1227, 1099, 1010, 876 (O-O), and 826 (O-O).
10â-[[3-[(P h en ylp ip er a zyl)m eth yl]ben zyl]oxy]d ih yd r o-
a r tem isin in (12). This compound was prepared from 1-phen-
ylpiperazine using the general procedure in section 1.2 to give
the product as a brown foam (59% yield): 1H NMR (300 MHz,
CDCl3) δ 7.30-7.22 (4 H, m, aromatic), 6.94-6.85 (5 H, m,
aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J ) 3.70 Hz), 4.90 (1 H,
d, J ) 12.20 Hz), 4.55 (1 H, d, J ) 12.20 Hz), 3.59 (2 H, br s),
3.27-3.21 (4 H, m), 2.69-2.61 (5 H, m), 2.38 (1 H, dt, J )
13.30, 3.80 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s), 0.95 (3 H,
d, J ) 7.40 Hz), and 0.94 (3H, d, J ) 6.00 Hz); 13C NMR (75
MHz, CDCl3) δ 139.10, 129.17, 128.38, 116.16, 104.19, 101.40,
88.10, 81.18, 69.68, 52.65, 44.47, 37.45, 36.48, 34.69, 30.96,
26.19, 24.71, 24.53, 20.32, and 13.10; IR (Nujol)/cm-1 2925,
1601, 1504, 1455, 1375, 1228, 1101, 1013, 875 (O-O), and 825
(O-O). HRMS (EI) C33H44N2O5 [M]+ requires 548.325 01;
found 548.326 04.
10â-[[3-[(4-Nitr op h en ylp ip er a zyl)m eth yl]ben zyl]oxy]-
d ih yd r oa r tem isin in (13). This compound was prepared from
1-(4-nitrophenyl)piperazine using the general procedure in
section 1.2 to give the product as an orange foam (85% yield):
1H NMR (300 MHz, CDCl3) δ 8.13 (2 H, d, J ) 9.50 Hz,
aromatic), 7.36-7.25 (4 H, m, aromatic), 6.82 (2 H, d, J ) 9.50
Hz, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J ) 5.00 Hz), 4.90 (1
H, d, J ) 12.30 Hz), 4.56 (1 H, d, J ) 12.30 Hz), 3.61 (2 H, s),
3.49-3.43 (4 H, m), 2.71 (1 H, m), 2.69-2.63 (4 H, m), 2.39 (1
H, dt, J ) 13.87, 3.98 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s),
and 0.94 (6H, d, J ) 7.40 Hz); 13C NMR (75 MHz, CDCl3) δ
151.00, 128.50, 128.00, 125.99, 112.79, 104.00, 101.00, 88.09,
81.50, 69.56, 60.38, 52.61, 52.20, 46.96, 44.20, 37.47, 36.45,
34.50, 30.93, 26.00, 24.70, 24.55, 20.32, and 13.00; IR (Nujol)/
cm-1 2923, 1598, 1506, 1456, 1378, 1328, 1248, 1099, 1010,
875 (O-O), and 826 (O-O); MS m/z (EI) [M]+ 593 (1), 264 (43),
219 (18), 105 (100), and 56 (30).
10â-[[3-[(4-Flu or op h en ylp ip er a zyl)m eth yl]ben zyl]oxy]-
d ih yd r oa r tem isin in (16). This compound was prepared from
1-(4-fluorophenyl)piperazine using the general procedure in
section 1.2 to give the product as an off-white foam (69%
yield): 1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (4 H, m,
aromatic), 6.98-6.84 (4 H, m, aromatic), 5.47 (1 H, s), 4.91 (1
H, d, J ) 3.43 Hz), 4.90 (1 H, d, J ) 12.29 Hz), 4.54 (1 H, d,
J ) 12.29 Hz), 3.58 (2 H, s), 3.12 (4 H, t, J ) 4.81 Hz), 2.63 (1
H, m), 2.62 (4 H, t, J ) 13.80 Hz), 2.38 (1 H, dt, J ) 13.40,
3.90 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.94 (3 H, d, J )
6.00 Hz), and 0.93 (3 H, d, J ) 6.00 Hz); 13C NMR (75 MHz,
CDCl3) δ 148.04, 138.62, 128.40, 126.34, 117.89, 115.70, 115.40,
104.19, 101.36, 88.09, 81.18, 69.65, 62.82, 52.99, 52.64, 50.07,
44.46, 37.45, 36.47, 34.69, 30.95, 26.19, 24.71, 24.53, 20.32,
and 13.10; IR (Nujol)/cm-1 2924, 1510, 1460, 1377, 1229, 1160,
1102, 1012, 875 (O-O), and 826 (O-O). HRMS (EI) C33H43
-
FN2O5 [M]+ requires 566.315 61; found 566.314 37. Anal.
C33H43FN2O5 requires C 69.97%, H 7.60%, N 4.97%; found C
69.67%, H 7.72%, N 4.82%.
Dih yd r oa r tem isin in 10r-Ben zoa te (20). Benzoyl chloride
(3.17 mL, 27.29 mmol) was added to a solution of dihydroar-
temisinin (5.00 g, 17.61 mmol) in anhydrous DCM (54 mL)
and anhydrous pyridine (9 mL) at 0 °C. The mixture was
allowed to stir at room temperature for 16 h. The reaction
mixture was then partitioned between 7% citric acid (50 mL)
and ethyl acetate (2 × 50 mL). The combined organic extracts
were washed with 7% citric acid, saturated NaHCO3, and H2O.
The organic phase was then dried over MgSO4, filtered, and
concentrated under reduced pressure to afford a crude product
that was recrystallized from a small volume of an ether/hexane
mixture to give the product as a white crystalline solid (100%
yield). Further product was obtained by purification of the
mother liquors by silica gel chromatography using ethyl
1
acetate/n-hexane (10/90) as the eluent: mp 111-112 °C; H
NMR (300 MHz, CDCl3) δ 8.13 (2 H, m, aromatic), 7.57 (1 H,
m, aromatic), 7.45 (2 H, m, aromatic), 6.02 (1 H, d, J ) 9.89
Hz), 5.53 (1 H, s), 2.76 (1 H, m), 2.40 (1 H, dt, J ) 13.99, 4.26
Hz), 2.07-1.20 (10 H, m), 1.43 (3 H, s), 0.99 (3 H, d, J ) 5.91
Hz), and 0.93 (3 H, d, J ) 7.14 Hz); 13C NMR (75 MHz, CDCl3)
δ 165.41, 133.34, 130.20, 129.79, 128.36, 104.49, 92.62, 91.65,
80.23, 51.73, 45.42, 37.32, 36.32, 34.18, 32.03, 25.94, 24.62,
22.09, 20.22, 15.24, and 12.20; IR (Nujol)/cm-1 2924, 1738,
1491, 1452, 1377, 1272, 1114, 1100, 1037, 877 (O-O), and 831
(O-O). HRMS (CI) C23H32NO6 [M + NH4]+ requires 406.222 96;
found 406.222 70. Anal. C22H28O6 requires C 68.04%, H 7.22%;
found C 68.17%, H 7.32%.
10â-[[3-[(4-Ch lor op h en ylp ip er a zyl)m eth yl]ben zyl]oxy]-
d ih yd r oa r tem isin in (14). This compound was prepared from
1-(4-chlorophenyl)piperazine using the general procedure in
section 1.2 to give the product as a brown foam (64% yield):
1H NMR (300 MHz, CDCl3) δ 7.32-7.06 (6 H, m, aromatic),