Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
Tubulin Polymerization Inhibitors
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(s, 3H, –OCH3), 3.81 (s, 3H, –OCH3), 3.70–3.75 (dd, 2H, –CH2–),
3.46 (s, 3H, –OCH3), 2.64–2.69 (t, 2H, –CH2–); ESI-MS m/z: 367.41
(Mþ1)þ; HRMS calcd for C18H17Cl2NO3 365.0585, found
365.0592.
3059, 3015, 2986, 2959, 2939, 2895, 2834, 2717, 1591, 1556,
1529; ESI-MS m/z 344.59 (Mþ1)þ; HRMS calcd for C19H21NO5
343.142, found 343.1430.
4-(6,7,8-Trimethoxy-3,4-dihydroisoquinolin-1-yl)aniline
(5o) hydrochloride
1-(2,6-Dichlorophenyl)-6,7,8-trimethoxy-3,4-
dihydroisoquinoline (5j)
Catalytic amount Raney Ni was added slowly into a solution of 4l
(0.006 mol) in methanol (10 mL) and 85% NH2NH2 H2O (2.5 mL),
and the reaction mixture was stirred at room temperature for
30 min. After evaporation of solvent, the residue was dissolved in
5% aqueous HCI solution and washed with ethyl acetate
(3 ꢁ 5 mL). Then the pH value of the solution was adjusted to
13–14, extracted with dichloromethane and dried over Na2SO4.
After filtration, the filtrate was treated with HCl gas. The resulting
solid was filtered and recrystallized from ethanol and acetone to
provide 6o hydrochloride (85%) as orange crystal: mp 2158C, dec.;
1H NMR (CDCl3, 300 MHz, d): 7.37–7.38 (d, 1H, J ¼ 1.8 Hz, ar-H),
7.35 (d, 1H, J ¼ 1.8 Hz, ar-H), 6.67–6.68 (d, 1H, J ¼ 1.8 Hz, ar-H),
6.65–6.66 (d, 1H, J ¼ 1.8 Hz, ar-H), 6.60 (s, 1H, ar-H), 3.93 (s, 3H,
–OCH3), 3.82 (s, 3H, –OCH3), 3.64–3.68 (m, 2H, –CH2–), 3.43 (s, 3H,
–OCH3), 2.60–2.65 (t, 2H, –CH2–); ESI-MS m/z: 312.40 (Mþ1)þ; HRMS
calcd for C18H20N2O3 312.1474, found 312.1482.
Light yellow crystal, 59.5%, mp 147–1498C; 1H NMR (CDCl3,
300 MHz, d): 7.35–7.36 (d, 1H, J ¼ 0.9 Hz, ar-H), 7.30 (d, 1H,
J ¼ 0.9 Hz, ar-H), 7.17–7.20 (m, 1H, ar-H), 6.59 (s, 1H, ar-H),
3.93 (s, 3H, –OCH3), 3.84–3.89 (m, 2H, –CH2–), 3.77 (s, 3H,
–OCH3), 3.35 (s, 3H, –OCH3), 2.76–2.81 (t, 2H, –CH2–); ESI-MS:
m/z: 366.81 (Mþ1)þ; HRMS calcd for C18H17Cl2NO3 365.0585,
found 365.0593.
1-(3,5-Dinitrophenyl)-6,7,8-trimethoxy-3,4-
dihydroisoquinoline (5k) hydrochloride
Brown crystal, 64.3%, mp 211–2138C; 1H NMR (CDCl3, 300 MHz,
d): 9.19 (s, 1H, ar-H), 8.90 (s, 2H, ar-H), 6.77 (s, 1H, ar-H), 4.15 (s, 2H,
–CH2–), 4.06 (s, 3H, –OCH3), 3.81 (s, 3H, –OCH3), 3.51 (s, 3H,
–OCH3), 3.15 (s, 2H, –CH2–); ESI-MS m/z: 388.85 (Mþ1)þ; HRMS
calcd for C18H17N3O7 387.1066, found 387.1073.
General procedure for the preparation of 6n, 6d and 6g
0.24 g (0.0064 mol) NaBH4 was added slowly into a solution of
5n, 5d, or 5g (0.0021 mol) in methanol (5 mL) in an ice bath, and
the mixture was refluxed for 2 h. After evaporation of the
solvent, the residue was dissolved in water (5 mL), extracted with
ether (3 ꢁ 10 mL), and dried over Na2SO4. Distillation of the
solvent under reduced pressure and recrystallization of the
residue yielded compounds 6n, 6d, or 6g (85–95%).
6,7,8-Trimethoxy-1-(4-nitrophenyl)-3,4-
dihydroisoquinoline (5l) hydrochloride
Brown crystal, 60.2%, mp 180–1828C; 1H NMR (CDCl3, 300 MHz,
d): 8.30–8.37 (m, 2H, ar-H), 7.79–7.83 (m, 2H, ar-H), 6.72 (s, 1H,
ar-H), 4.03 (s, 3H, –OCH3), 3.96–3.99 (m, 2H, –CH2–), 3.80 (s, 3H,
–OCH3), 3.47 (s, 3H, –OCH3), 2.99–3.04 (t, 2H, –CH2–); ESI-MS
m/z: 343.57 (Mþ1)þ; HRMS calcd for C18H18N2O5 342.1216, found
342.1224.
2-Methoxy-5-(6,7,8-trimethoxy-1,2,3,4-
2-Methoxy-5-(6,7,8-trimethoxy-3,4-dihydroisoquinolin-1-
yl) phenol (5n)
A mixture of 3 hydrochloride (2.9 g, 0.012 mol), triethylamine
(5 mL), and dichloromethane (25 mL) was stirred at room
tetrahydroisoquinolin-1-yl) phenol (6n)
Light yellow crystal, 88.6%, mp 174–1768C; 1H NMR (CDCl3,
300 MHz, d): 6.76–6.79 (d, 1H, J ¼ 8.1 Hz, ar-H), 6.71–6.72
(d, 1H, J ¼ 2.1 Hz, ar-H), 6.64–6.67 (m, 1H, ar-H), 6.47 (s, 1H, ar-
H), 5.19 (s, 1H, >CH–), 3.87 (s, 3H, –OCH3), 3.86 (s, 3H, –OCH3), 3.79
(s, 3H, –OCH3), 3.40 (s, 3H, –OCH3), 2.68–3.04 (m, 4H, –CH2–CH2–);
13C NMR (CDCl3, 75 MHz, d): 152.4, 150.6, 145.5, 145.2, 140.3,
138.7, 130.9, 123.3, 119.7, 114.6, 110.2, 107.2, 60.6, 59.9, 55.9,
55.0, 38.0, 29.1; IR (KBr): 3447, 3315, 3002, 2956, 2936, 2915,
2838, 1582, 1505; ESI-MS: m/z: 346.2 (Mþ1)þ; HRMS calcd for
C19H23NO5 345.1576, found 345.1586.
temperature for 30 min. Then
a solution of 4m (2.7 g,
0.012 mol) in dichloromethane was added dropwise and the
mixture was stirred at room temperature for 4 h. After evapor-
ation of the solvent, the residue was dissolved in dry acetonitrile
(50 mL). Then POCl3 (10 mL) was added and the mixture was
refluxed for a further 4 h. After evaporation of the solvent, the
residue was dissolved in dichloromethane (50 mL), washed with
saturated solution of Na2CO3 (3 ꢁ 10 mL) and water (3 ꢁ 10 mL)
and dried over Na2SO4. The solvent was distilled under reduced
pressure and the residue was added to ethanol (25 mL) and water
(8 mL) with NaOH (1.6 g). The reaction mixture was stirred at
room temperature for 2 h. Then the pH value of the solution was
adjusted to 4–5. After evaporation of the solvent, the resulting
solid was dissolved in ethyl acetate and dried over Na2SO4.
Distillation of the solvent under reduced pressure and recrystal-
lization of the resulting solid from petroleum ether and ethyl
acetate yielded 5n (2.3 g, 57%) as light yellow crystal: mp 132–
6,7,8-Trimethoxy-1-(4-methoxy-3-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline (6d)
Light yellow crystal, 92.1%, mp 2118C, dec.; 1H NMR (CDCl3,
300 MHz, d): 7.86 (b, 1H, ar-H), 7.27 (s, 1H, ar-H), 7.15–7.17
(d, 1H, J ¼ 6 Hz, ar-H), 6.51 (s, 1H, ar-H), 5.78 (s, 1H, >CH–),
3.96 (s, 3H, –OCH3), 3.89 (s, 3H, –OCH3), 3.78 (s, 3H, –OCH3),
3.50 (s, 3H, –OCH3), 3.14–3.33 (m, 2H, –CH2–), 3.00–3.05
(m, 2H, –CH2–); ESI-MS: m/z: 375.2 (Mþ1)þ; HRMS calcd for
C19H22N2O6 374.1478, found 374.1483.
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1348C; H NMR (CDCl3, 300 MHz, d) 7.27 (s, 1H, ar-H), 7.11–7.12
(d, 1H, J ¼ 1.8 Hz, ar-H), 7.00–7.03 (dd, 1H, ar-H), 6.82–6.85 (d, 1H,
J ¼ 1.8 Hz, ar-H), 6.60 (s, 1H, ar-H), 3.94 (s, 3H, –OCH3), 3.91 (s, 3H,
–OCH3), 3.81 (s, 3H, –OCH3), 3.67–3.70 (dd, 2H, –CH2–), 3.45 (s, 3H,
–OCH3), 2.61–2.66 (t, 2H, –CH2–); 13C NMR (CDCl3, 75 MHz, d):
165.3, 155.5, 152.4, 147.4, 145.2, 140.9, 137.3, 134.8, 119.2, 115.8,
114.1, 109.8, 105.9, 61.4, 61.0, 56.0, 55.9, 47.0, 27.8; IR (KBr): 3283,
1-(4-Fluorophenyl)-6,7,8-trimethoxy-1,2,3,4-
tetrahydroisoquinoline (6g)
White crystal, 92.3%, mp 171–1738C; H NMR (CDCl3, 300 MHz,
d): 9.88 (s, 1H, N–H), 7.31–7.36 (m, 2H, ar-H), 7.03–7.09 (t, 2H, ar-H),
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