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Z.-H. Zhang et al. / European Journal of Medicinal Chemistry 86 (2014) 542e549
by 2 N HCl (2 mL), then stirred at room temperature for 1 h and
extracted with CHCl3 (3 ꢀ 5 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure to give the crude product, which was purified using silica
gel column chromatography (CHCl3/MeOH ¼ 20:1) to give com-
pounds 4aem with yields ranging from 16.4 to 65.1%.
(s, 2H, OCH2O), 7.15 (s, 1H, ArH), 7.31 (s, 1H, ArH), 7.98 (d, J ¼ 8.7 Hz,
1H, ArH), 8.04 (d, J ¼ 8.7 Hz, 1H, ArH), 9.99 (s, 1H, ArH); 13C NMR
(100 MHz, DMSO-d6) d: 22.0, 22.0, 27.3, 27.6, 27.8, 27.8, 56.8, 102.1,
104.7, 108.4,109.2,111.3, 119.5, 120.2,120.2, 131.4, 134.1, 134.9, 135.3,
143.5, 145.0, 146.5, 147.0, 149.0; ESI-MS (m/z): 390.2 [MꢁCl]þ.
4.3.7. Quaternary 13-hexylcoptisine (4g)
Yield: 21.2%; Yellow powder; 1H NMR (400 MHz, DMSO-d6)
d:
4.3.1. Quaternary 13-methylcoptisine (4a)
Yield: 65.1%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.85 (t, J ¼ 6.4 Hz, 3H, CH2CH2CH2 (CH2)2CH3), 1.25 (m, 4H,
CH2CH2CH2(CH2)2CH3), 1.37 (m, 2H, CH2CH2CH2(CH2)2CH3), 1.75
(m, 2H, CH2CH2CH2(CH2)2CH3), 3.09 (m, 2H, NCH2CH2), 3.35 (m, 2H,
CH2CH2CH2(CH2)2CH3), 4.78 (m, 2H, NCH2CH2), 6.19 (s, 2H, OCH2O),
6.56 (s, 2H, OCH2O), 7.17 (s, 1H, ArH), 7.28 (s, 1H, ArH), 8.04 (s, 2H,
2.90 (s, 3H, ArCH3), 3.10 (t, J ¼ 5.1 Hz, 2H, NCH2CH2), 4.77 (t,
J ¼ 5.1 Hz, 2H, NCH2CH2), 6.17 (s, 2H, OCH2O), 6.55 (s, 2H, OCH2O),
7.13 (s, 1H, ArH), 7.45 (s, 1H, ArH), 7.97 (d, J ¼ 9.0 Hz, 1H, ArH), 8.05
(d, J ¼ 9.0 Hz,1H, ArH), 9.95 (s,1H, ArH); 13C NMR (100 MHz, DMSO-
ArH (H-11,12)), 10.00 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6)
d:
d6) d: 18.1, 27.2, 56.4, 102.0, 104.7, 108.1, 110.7, 110.8, 119.5, 120.1,
120.4, 130.7, 132.2, 133.7, 135.4, 143.1, 144.7, 146.3, 147.0, 148.9; ESI-
13.8, 22.0, 27.3, 28.3, 29.3, 30.2, 30.6, 56.8, 102.1, 104.7, 108.3, 109.1,
111.2,119.6,120.1,120.3,131.4,134.0,134.9,135.3,143.5,144.9,146.5,
147.0, 149.0; ESI-MS (m/z): 404.2 [MꢁCl]þ.
MS (m/z): 334.2 [MꢁCl]þ.
4.3.2. Quaternary 13-ethylcoptisine (4b)
Yield: 40.7%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
4.3.8. Quaternary 13-heptylcoptisine (4h)
1.44 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 3.07 (t, J ¼ 5.1 Hz, 2H, NCH2CH2),
3.33 (q, J ¼ 6.9 Hz, 2H, CH2CH3), 4.75 (m, 2H, NCH2CH2), 6.18 (s, 2H,
OCH2O), 6.55 (s, 2H, OCH2O), 7.15 (s, 1H, ArH), 7.29 (s, 1H, ArH), 8.04
(s, 2H, ArH (H-11,12)), 9.97 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-
Yield: 24.4%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.85 (t, J ¼ 6.6 Hz, 3H, CH2CH2CH2(CH2)3CH3), 1.23e1.26 (m, 6H,
CH2CH2CH2(CH2)3CH3), 1.26e1.36 (m, 2H, CH2CH2CH2(CH2)3CH3),
1.75 (m, 2H, CH2CH2CH2(CH2)3CH3), 3.08 (t, J ¼ 4.8 Hz, 2H,
NCH2CH2), 3.34 (m, 2H, CH2CH2CH2(CH2)3CH3), 4.76 (m, 2H,
NCH2CH2), 6.19 (s, 2H, OCH2O), 6.56 (s, 2H, OCH2O), 7.17 (s,1H, ArH),
7.29 (s, 1H, ArH), 8.04 (s, 2H, ArH (H-11,12)), 9.98 (s, 1H, ArH); 13C
d6) d: 15.4, 22.8, 27.2, 56.8, 102.1, 104.7, 108.4, 109.0, 111.3, 119.6,
120.1,120.2,131.2,134.1,135.1,136.0,143.6,145.0,146.5,147.0,149.0;
ESI-MS (m/z): 348.2 [MꢁCl]þ.
NMR (100 MHz, DMSO-d6) d: 13.9, 22.0, 27.3, 28.0, 28.5, 29.2, 30.2,
4.3.3. Quaternary 13-propylcoptisine (4c)
31.1, 56.8, 102.1, 104.7, 108.3, 109.2, 111.3, 119.6, 120.1, 120.3, 131.4,
134.0, 134.9, 135.3, 143.4, 144.9, 146.5, 146.9, 149.0; ESI-MS (m/z):
418.2 [MꢁCl]þ.
Yield: 40.0%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.96 (t, J ¼ 6.9 Hz, 3H, CH2CH2CH3), 1.76e1.79 (m, 2H, CH2CH2CH3),
3.07 (m, 2H, NCH2CH2), 3.27e3.33 (m, 2H, CH2CH2CH3), 4.76 (m, 2H,
NCH2CH2), 6.18 (s, 2H, OCH2O), 6.54 (s, 2H, OCH2O), 7.14 (s,1H, ArH),
7.23 (s, 1H, ArH), 8.03 (s, 2H, ArH (H-11,12)), 9.99 (s, 1H, ArH); 13C
4.3.9. Quaternary 13-octylcoptisine (4i)
Yield: 18.0%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
NMR (100 MHz, DMSO-d6) d: 13.6, 23.8, 27.3, 31.4, 56.8, 102.1, 104.7,
0.83 (t, J ¼ 6.6 Hz, 3H, CH2CH2CH2(CH2)4CH3), 1.20e1.33 (m, 8H,
CH2CH2CH2(CH2)4CH3), 1.33 (m, 2H, CH2CH2CH2(CH2)4CH3), 1.73
(m, 2H, CH2CH2CH2(CH2)4CH3), 3.06 (m, 2H, NCH2CH2), 3.33 (m, 2H,
CH2CH2CH2(CH2)4CH3), 4.75 (m, 2H, NCH2CH2), 6.17 (s, 2H, OCH2O),
6.54 (s, 2H, OCH2O), 7.15 (s, 1H, ArH), 7.27 (s, 1H, ArH), 8.02 (s, 2H,
108.3, 109.1, 111.2, 119.7, 120.1, 120.3, 131.4, 134.0, 134.8, 135.3, 143.5,
144.9, 146.5, 147.0, 149.0; ESI-MS (m/z): 362.2 [MꢁCl]þ.
4.3.4. Quaternary 13-butylcoptisine (4d)
Yield: 31.1%; Yellow powder; 1H NMR (400 MHz, DMSO-d6)
d:
ArH (H-11,12)), 9.97 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6)
d:
0.90 (t, J ¼ 7.2 Hz, 3H, CH2CH2CH2CH3), 1.38e1.43 (m, 2H,
CH2CH2CH2CH3), 1.76 (m, 2H, CH2CH2CH2CH3), 3.09 (t, J ¼ 5.2 Hz,
2H, NCH2CH2), 3.33 (m, 2H, CH2CH2CH2CH3), 4.77 (m, 2H,
NCH2CH2), 6.19 (s, 2H, OCH2O), 6.56 (s, 2H, OCH2O), 7.16 (s,1H, ArH),
7.29 (s, 1H, ArH), 8.04 (s, 2H, ArH (H-11,12)), 9.98 (s, 1H, ArH); 13C
13.9, 22.0, 27.3, 28.3, 28.6, 28.6, 29.2, 30.2, 31.2, 56.8, 102.1, 104.7,
108.3,109.2,111.3,119.6,120.1,120.3,131.4, 134.0,134.9,135.3, 143.4,
144.9, 146.5, 147.0, 149.0; ESI-MS (m/z): 432.2 [MꢁCl]þ.
4.3.10. Quaternary 13-nonylcoptisine (4j)
NMR (100 MHz, DMSO-d6) d: 13.3, 21.9, 27.3, 29.2, 32.3, 56.8, 102.1,
Yield: 20.3%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
104.7, 108.3, 109.2, 111.3, 119.6, 120.1, 120.3, 131.4, 134.0,134.9,135.3,
143.5, 144.9, 146.5, 147.0, 149.0; ESI-MS (m/z): 376.2 [MꢁCl]þ.
0.84 (t, J ¼ 6.3 Hz, 3H, CH2CH2CH2(CH2)5CH3), 1.20e1.33 (m, 10H,
CH2CH2CH2(CH2)5CH3), 1.33 (m, 2H, CH2CH2CH2(CH2)5CH3), 1.73
(m, 2H, CH2CH2CH2(CH2)5CH3), 3.07 (m, 2H, NCH2CH2), 3.33 (m, 2H,
CH2CH2CH2(CH2)5CH3), 4.76 (m, 2H, NCH2CH2), 6.17 (s, 2H, OCH2O),
6.55 (s, 2H, OCH2O), 7.15 (s, 1H, ArH), 7.27 (s, 1H, ArH), 8.03 (s, 2H,
4.3.5. Quaternary 13-pentylcoptisine (4e)
Yield: 37.4%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.84 (t, J ¼ 7.2 Hz, 3H, CH2CH2(CH2)2CH3), 1.16e1.33 (m, 4H,
CH2CH2(CH2)2CH3), 1.75 (m, 2H, CH2CH2(CH2)2CH3), 3.07 (t,
J ¼ 5.4 Hz, 2H, NCH2CH2), 3.30 (m, 2H, CH2CH2(CH2)2CH3), 4.76 (m,
2H, NCH2CH2), 6.18 (s, 2H, OCH2O), 6.55 (s, 2H, OCH2O), 7.15 (s, 1H,
ArH), 7.26 (s, 1H, ArH), 8.03 (s, 2H, ArH (H-11,12)), 9.99 (s, 1H, ArH);
ArH (H-11,12)), 9.99 (s, 1H, ArH); 13C NMR (100 MHz, DMSO-d6)
d:
13.9, 22.0, 27.3, 28.4, 28.5, 28.6, 28.9, 29.2, 30.2, 31.2, 56.8, 102.1,
104.7, 108.3,109.2,111.2, 119.6, 120.1, 120.3, 131.4, 134.0, 134.9, 135.3,
143.4, 144.9, 146.5, 146.9, 149.0; ESI-MS (m/z): 446.3 [MꢁCl]þ.
13C NMR (100 MHz, DMSO-d6)
d: 13.8, 21.5, 27.3, 29.4, 30.0, 30.9,
56.8, 102.1, 104.7, 108.3, 109.1, 111.3, 119.6, 120.1, 120.3, 131.4, 134.0,
134.9, 135.3, 143.5, 144.9, 146.5, 147.0, 149.0; ESI-MS (m/z): 390.2
[MꢁCl]þ.
4.3.11. Quaternary 13-decylcoptisine (4k)
Yield: 19.1%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.83 (t, J ¼ 6.6 Hz, 3H, CH2CH2(CH2)7CH3), 1.20e1.32 (m, 14H,
CH2CH2(CH2)7CH3), 1.72 (m, 2H, CH2CH2(CH2)7CH3), 3.06 (m, 2H,
NCH2CH2), 3.32 (m, 2H, CH2CH2(CH2)3CH3), 4.74 (m, 2H, NCH2CH2),
6.16 (s, 2H, OCH2O), 6.54 (s, 2H, OCH2O), 7.14 (s,1H, ArH), 7.26 (s,1H,
ArH), 8.02 (s, 2H, ArH (H-11,12)), 9.95 (s, 1H, ArH); 13C NMR
4.3.6. Quaternary 13-isopentylcoptisine (4f)
Yield: 38.2%; Yellow powder; 1H NMR (300 MHz, DMSO-d6)
d:
0.91 (d,
J
¼
5.4 Hz, 6H, CH2CH2CH(CH3)2), 1.68 (m, 3H,
CH2CH2CH(CH3)2), 3.07 (m, 2H, NCH2CH2), 3.35 (m, 2H,
CH2CH2CH(CH3)2), 4.76 (m, 2H, NCH2CH2), 6.17 (s, 2H, OCH2O), 6.55
(100 MHz, DMSO-d6)
d: 13.9, 22.0, 27.3, 28.4, 28.5, 28.6, 28.9, 28.9,
29.2, 30.2, 31.2, 56.8, 102.1, 104.7, 108.3, 109.2, 111.3, 119.6, 120.1,