L. A. Howell et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6956–6959
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at 0 °C. A solution of Boc2O (4.36 g, 10 mmol) in CH2Cl2 (40 mL) was added
dropwise over 2 h. The reaction mixture was allowed to warm to room
temperature and stirred over night. The solution was filtered to remove a white
solid and the resulting filtrate was evaporated. The colourless oil was
redissolved in EtOAc (100 mL) and washed with saturated aqueous brine
(3 Â 50 mL). The organic phase was dried over MgSO4 and concentrated to
yield a colourless oil (4.1 g, 95%). IR mmax (neat)/cmÀ1 3346 (NH2) 3297 (NH)
2932 (CH2), 1688 (C@O) 1H NMR (CDCl3, 400 MHz) dH ppm: 4.58 (1H, br s, NH),
3.06–3.04 (2H, m, CH2NHBoc), 2.64 (2H, t, J = 7.0 Hz, CH2NH2), 2.22 (2H br s,
NH2), 1.42–1.27 (17H, m, 4CH2 + 3CH3). 13C NMR (CDCl3, 100 MHz) dH ppm:
166.99 (C@O), 68.91 (C(CH3)), 41.75 (CH2), 40.41 (CH2), 33.08 (CH2), 29.96 (CH2),
28.37 (3CH3), 26.52 (CH2), 26.43 (CH2). HRMS (ES+) calcd for C11H24N2O2 (M+H)
217.1911; found 217.1913. tert-Butyl 6-(4-(2-(dimethylamino)ethylcarbamoyl)acridin-
9-ylamino)hexylcarbamate (5a) 9-chloro-N-(2-(dimethylamino)ethyl)acridine-4-
carboxamide (4a) (500 mg, 1.5 mmol) and excess dry phenol (1.5 g) were
heated and stirred at 110 °C for 15 min. On cooling to 55 °C tert-butyl 6-
aminohexylcarbamate (3) (495 mg, 2.3 mmol) was added and the reaction
stirred at 55 °C overnight. TLC confirmed the formation of the product. On
cooling to rt, 2 M NaOH (20 mL) was added to the flask. A small amount of
CH2Cl2 (10 mL) was added to a separating funnel and the reaction mixture
poured on top. After separation of the organic phase, the aqueous phase was
extracted successively with CH2Cl2 (3 Â 15 mL). The organic extracts were
combined, dried over MgSO4 and filtered. The solvent was removed under
vacuum to yield a dark yellow oil. Column chromatography (5% MeOH in
EtOAc + 1% Et3N) yielded the desired compound as a bright yellow oil (580 mg,
75%). IR mmax (neat)/cmÀ1 3329 (NH), 2930 (CH2/CH3), 2858 (CH2/CH3), 1691
(C@O). 1H NMR (CDCl3, 400 MHz) dH ppm: 8.79 (1H, br d, J = 5.2 Hz, ArH(1)),
8.40 (1H, d, J = 8.4 Hz, ArH(3)), 8.11 (1H, d, J = 8.4 Hz, ArH(8)), 8.01 (1H, d,
J = 8.4 Hz, ArH(5)), 7.71–7.67 (1H, m, ArH(6)), 7.42–7.35 (2H, m, ArH(7+2)),
4.58 (1H, br s, NHBoc), 3.82 (2H, t, J = 7.0 Hz, NHCH2), 3.76 (2H, q, J = 6.4 Hz,
CONHCH2), 3.09 (2H, q, J = 6.4 Hz, CH2NHBoc), 2.71 (2H, t, J = 6.4 Hz,
CH2N(CH3)2), 2.42 (6H, s, N(CH3)2), 1.82–1.74 (2H, m, NHCH2CH2), 1.49–1.30
(15H, m, 3CH2, C(CH3)3). HRMS calcd for C29H42N5O3 (M+H) 508.3282; found
508.3275. 9-(6-Aminohexylamino)-N-(2-dimethylamino)ethyl)acridine-4-carboxamide
hydrochloride (1a) tert-butyl 6-(4-(2-(dimethylamino)ethylcarbamoyl)acridin-9-
ylamino)hexylcarbamate (5a) (100 mg, 0.20 mmol) was stirred in a mixture of
HCl/EtOAc (1 M, 5 mL) at room temperature overnight. The solvent was
removed in vacuo to yield to bright yellow hygroscopic oil (84 mg, 96%). IR mmax
(neat)/cmÀ1 3245 (NH), 2943 (CH2/CH3), 1622 (C@O). 1H NMR (MeOD,
400 MHz) dH ppm: 8.75 (1H, d, J = 8.0 Hz, ArH(1)), 8.59–8.54 (2H, m,
2ArH(3+8)), 8.03–8.00 (1H, m, ArH(6)), 7.93 (1H, dd, J1 = 0.8 Hz, J2 = 8.4 Hz,
ArH(5)), 7.68–7.60 (2H, m, 2ArH(2+7)), 4.18 (2H, t, J = 7.6 Hz, CH2NH2), 3.91
(2H, t, J = 5.8 Hz, CONHCH2), 3.52 (2H, t, J = 5.8 Hz, CH2N(CH3)2), 3.05 (6H, s,
N(CH3)2), 2.94 (2H, t, J = 7.6 Hz, NHCH2), 2.08–2.01 (2H, m, CH2CH2NH2), 1.74–
1.67 (2H, m, NHCH2CH2), 1.57–1.47 (4H, m, 2CH2). HRMS (ES+) calcd for
C24H34N5O (M+H) 408.2758; found 408.2759.
Synthesis of 1b: tert-butyl 6-(3-(2-(dimethylamino)ethylcarbamoyl)acridin-9-
ylamino)hexylcarbamate (5b) 9-chloro-N-(2-(dimethylamino)ethyl)acridine-3-
carboxamide (4b) (100 mg, 0.31 mmol) and excess dry phenol (1 g) were
heated and stirred at 110 °C for 15 min. On cooling to 55 °C tert-butyl 6-
aminohexylcarbamate (3) (99 mg, 0.46 mmol) was added and the reaction
stirred at 55 °C overnight. TLC confirmed the formation of the product. On
cooling to rt, 2 M NaOH (10 mL) was added to the flask. A small amount of
CH2Cl2 (5 mL) was added to a separating funnel and the reaction mixture
poured on top. After separation of the organic phase, the aqueous phase was
extracted successively with CH2Cl2 (3 Â 10 mL). The organic extracts were
combined, dried over MgSO4 and filtered. The solvent was removed under
vacuum to yield a dark yellow oil. Column chromatography (10% MeOH in
EtOAc + 1% Et3N) yielded the desired compound as a bright yellow oil (120 mg,
78%). IR mmax (neat)/cmÀ1 3310 (NH), 2925 (CH2/CH3), 2854 (CH2/CH3), 1684
(C@O). 1H NMR (CDCl3, 400 MHz) dH ppm: 8.35 (1H, d, J = 1.6 Hz, ArH(4)), 8.16
(1H, d, J = 9.2 Hz, ArH(1)), 8.12 (1H, d, J = 8.8 Hz, ArH(8)), 7.99 (1H, d, J = 8.4 Hz,
ArH(5)), 7.78 (1H, dd, J1 = 1.6 Hz, J2 = 8.8 Hz, ArH(2)), 7.66 (1H, m, ArH(6)), 7.42
(1H, br s, CONH), 7.39–7.35 (1H, m, ArH(7)), 4.58 (1H, br s, NHBoc), 3.87 (2H, t,
J = 7.2 Hz, NHCH2), 3.57 (2H, q, J = 5.6 Hz, CONHCH2), 3.13–3.09 (2H, m,
CH2NHBoc), 2.56 (2H, t, J = 5.6 Hz, CH2N(CH3)2), 2.30 (6H, s, N(CH3)2), 1.87–
1.80 (2H, m, NHCH2CH2), 1.50–1.35 (15H, m, C(CH3)3, 3CH2). HRMS (ES+) calcd
for C29H42N5O3 (M+H) 508.3282; found 508.3283. 9-(6-Aminohexylamino)-N-
(2-dimethylamino)ethyl)acridine-3-carboxamide hydrochloride (1b) tert-butyl 6-
(3-(2-(dimethylamino)ethylcarbamoyl)acridin-9-ylamino)hexylcarbamate
(5b) (2 g, 3.9 mmol) was stirred in a mixture of HCl/EtOAc (1 M, 30 mL)at room
temperature overnight. The solvent was removed in vacuo to yield to bright
yellow hygroscopic oil (1.7 g, 97%). IR m
max (neat)/cmÀ1 3238 (NH), 2927 (CH2/
CH3), 1636 (C@O). 1H NMR (MeOD, 400 MHz) dH ppm: 8.65 (1H, d, J = 8.4 Hz,
ArH(1)), 8.55 (1H, d, J = 8.4 Hz, ArH(8)), 8.36 (1H, s, ArH(4)), 8.03–7.99 (2H, m,
2ArH(2+6)), 7.87 (1H, d, J = 8.4 Hz, ArH(5)), 7.63–7.59 (1H, m, ArH(7)), 4.20 (2H,
t, J = 7.2 Hz, CH2NH2), 3.87 (2H, t, J = 5.2 Hz, CONHCH2), 3.49 (2H, t, J = 5.6 Hz,
CH2N(CH3)2), 3.03 (6H, s, N(CH3)2), 2.94 (2H, t, J = 7.6 Hz, NHCH2), 2.07–2.04
(2H, m, CH2CH2NH2), 1.75–1.68 (2H, m, NHCH2CH2), 1.59–1.52 (4H, m, 2CH2).
HRMS (ES+) calcd for C24H34N5O (M+H) 408.2758; found 408.2761.
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