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A. Kamal et al. / Bioorg. Med. Chem. 21 (2013) 6414–6426
5.15. 4b-[5-(3-(4-Fluorophenyl)-3,4-dihydro-2-methyl-4-
oxoquinazolin-6-yloxy)pentanamide]-4-desoxy-
podophyllotoxin (10af)
5.18. 4b-[6-(3,4-Dihydro-3-(4-methoxyphenyl)-2-methyl-4-
oxoquinazolin-6-yloxy)hexanamide ]-4-desoxy-
podophyllotoxin (10bc)
The compound 14f was prepared following the method de-
scribed for the preparation of the compound 14a, employing
14f (140.4 mg, 0.52 mmol) and 16a (362 mg, 0.63 mmol), and
the crude product was purified by column chromatography
(46% ethyl acetate–hexane) to afford the compound 14f as a
The compound 10bc was prepared following the method de-
scribed for the preparation of the compound 10aa, employing
14c (146.6 mg, 0.52 mmol) and 16b (371 mg, 0.63 mmol), and
the crude product was purified by column chromatography (48%
ethyl acetate–hexane) to afford the compound 10bc as a white so-
white solid (320 mg, 80%); mp 119–120 °C; ½a D25
ꢁ
ꢂ28.4 (c 1.0
lid (330 mg, 80%); mp 129–130 °C; ½a D25
ꢁ
ꢂ89.0 (c 1.0 in CHCl3), 1H
in CHCl3), 1H NMR (300 MHz, CDCl3): d 1.76–1.89 (m, 4H), 2.15
(s, 3H), 2.20–2.26 (m, 2H), 3.21 (dd, 1H, J = 1.7, 10.2 Hz), 3.36
(t, 1H, J = 6.8 Hz), 3.77 (s, 9H), 4.00–4.12 (m, 4H), 4.30–4.32
(m, 1H), 5.35 (dd, 1H, J = 5.1, 7.6 Hz), 5.88 (d, 2H, J = 12.2 Hz),
6.26 (s, 2H), 6.33 (d, 1H, J = 8.5 Hz), 6.49 (s, 1H), 6.65 (s, 1H),
7.19–7.24 (m, 3H), 7.27–7.31 (m, 1H), 7.37 (d, 1H, J = 1.7 Hz),
7.46 (d, 1H, J = 8.5 Hz); 13C NMR (300 MHz, CDCl3): d 22.1, 24,
28.2, 35.7, 37.9, 44.9, 45.2, 47.5, 56.1, 60.7, 67.7, 68.6, 101.2,
104.6, 106.3, 106.9, 109.8, 116.8, 117.1, 121, 125, 128.3, 129.6,
129.8, 129.9, 130.2, 133.6, 137.7, 141.8, 147.2, 147.4, 151.5,
153.4,157.7, 162.1,173, 178.7; MS (ESI): 766 [M+H]+; HRMS
(ESI) calcd for C42H41O10N3F [M+H]+ 766.2746.; found: 766.2757.
NMR (300 MHz, CDCl3): d 1.45–1.60 (m, 2H), 1.70–1.90 (m, 4H),
2.19 (s, 3H), 2.22–2.36 (m, 2H), 3.05–3.16 (m, 1H), 3.27 (dd, 1H,
J = 1.8, 10.7 Hz), 3.78 (s, 9H), 3.80 (s, 3H), 3.97–4.17 (m, 4H), 4.36
(s, 1H), 5.36 (dd, 1H, J = 5.4, 8.4 Hz), 5.94 (d, 2H, J = 13 Hz), 6.26
(s, 2H), 6.59 (d, 2H, J = 6.7 Hz), 6.83–6.97 (m, 2H), 7.0–7.12 (m,
2H), 7.29 (dd, 1H, J = 2.6, 8.8 Hz), 7.49–7.60 (m, 2H); 13C NMR
(300 MHz, CDCl3): d 24, 25, 25.3, 27.9, 36.2, 37.8, 45.2, 45.3, 47.3,
55.4, 56.1, 60.7, 67.8, 68.6, 101.2, 104.6, 106..2, 106.8, 109.7,
114.9, 115.2, 121.1, 125.1, 128.3, 128.5, 128.7, 128.8, 129.9,
130.1, 136.7, 137.6, 141.8, 147.2, 147.4, 152.3, 153.3, 157.4,
159.8, 173.4, 178.7; MS (ESI): 792 [M+H]+; HRMS (ESI) calcd for
C
44H46O11N3 [M+H]+ 792.3126; found: 792.3108.
5.16. 4b-[6-(3,4-Dihydro-3-(3,4,5-trimethoxyphenyl)-2-methyl-
4-oxoquinazolin-6-yloxy)hexana mide]-4-desoxy-
podophyllotoxin (10ba)
5.19. 4b-[6-(3,4-Dichlorophenyl)3,4-dihydro-2-methyl-4-
oxoquinazolin-6-yloxy)hexanamide]-4-desoxy-
podophyllotoxin (10bd)
The compound 10ba was prepared following the method de-
scribed for the preparation of the compound 10aa, employing
14a (180 mg, 0.52 mmol) and 16b (371 mg, 0.63 mmol), and the
crude product was purified by column chromatography (50% ethyl
acetate–hexane) to afford the compound 10ba as a white solid
The compound 10bd was prepared following the method de-
scribed for the preparation of the compound 10aa, employing
14d (167 mg, 0.52 mmol) and 16b (371 mg, 0.63 mmol), and the
crude product was purified by column chromatography (43% ethyl
acetate–hexane) to afford the compound 10bd as a white solid
(330 mg, 74%); mp 139–140 °C; ½a D25
ꢁ
ꢂ43.4 (c 1.0 in CHCl3), 1H
(335 mg, 77%); mp 123–124 °C; ½a D25
ꢁ
ꢂ17.4 (c 1.0 in CHCl3), 1H
NMR (300 MHz, CDCl3): d 1.52–1.60 (m, 2H), 1.62–1.70 (m, 4H),
2.20–2.28 (m, 2H), 2.30 (s, 3H), 3.14–3.26 (m, 1H), 3.28–3.35 (m,
1H), 3.81 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 3.85 (s, 9H), 4.08 (t,
2H, J = 6.0 Hz), 4.22–4.43 (m, 3H), 5.39–5.48 (m, 1H), 5.94–5.98
(m, 2H), 6.37 (t, 2H, J = 2.2 Hz), 6.48 (d, 1H, J = 2.2 Hz), 6.51-6.57
(m, 1H), 6.75 (d, 1H, J = 2.2 Hz), 6.81 (s, 1H), 7.16 (s, 1H), 7.35
(dd, 1H, J = 3.0, 9.0 Hz), 7.59–7.63 (m, 1H); MS (ESI): 852 [M+H]+;
HRMS (ESI) calcd for C46H50O13N3 [M+H]+ 852.3338.; found:
852.3325.
NMR (300 MHz, CDCl3): d 1.43–1.58 (m, 2H), 1.66–1.78 (m, 2H),
1.79–1.89 (m, 2H), 2.21 (s, 3H), 2.22–2.29 (m, 2H), 2.98–3.15 (m,
1H), 3.16–3.26 (m, 1H), 3.79 (s, 9H), 4.01–4.22 (m, 4H), 4.33 (s,
1H), 5.33–5.42 (m, 1H), 5.90 (d, 2H, J = 6.9 Hz), 6.29 (d, 2H,
J = 2.8 Hz), 6.52 (s, 1H), 6.67 (s, 1H), 7.06–7.19 (m, 1H), 7.30 (dd,
1H, J = 2.6, 8.8 Hz), 7.40 (t, 1H, J = 2.4 Hz), 7.47 (t, 1H, J = 3.3 Hz),
7.51–7.63 (m, 2H); 13C NMR (300 MHz, CDCl3): d 24, 25.2, 25.6,
28.4, 36.4, 38, 44.8, 45.3, 45.9, 47.7, 47.8, 56.2, 60.8, 68.1, 68.7,
95.9, 101.3, 104.8, 106.4, 107, 109.9, 114.8, 125.3, 127.6, 127.7,
128.4, 128.5, 130.2, 130.3, 131.6, 137, 138.2, 138.7, 141.7, 147.3,
150.7, 157.8, 162.6, 173.3, 178.3; MS (ESI): 830 [M+H]+; HRMS
(ESI) calcd for C43H42O10N3Cl2 [M+H]+ 830.2241; found: 830.2244.
5.17. 4b-[6-(3,4-Dihydro-3-(3,5-dimethoxyphenyl)-2-methyl-4-
oxoquinazolin-6-yloxy)hexana mide]-4-desoxy-
podophyllotoxin (10bb)
5.20. 4b-[6-(3,4-Dihydro-2-methyl-3-(4-nitrophenyl)-4-
oxoquinazolin-6-yloxy)hexanamide]-4-desoxy-
podophyllotoxin (10be)
The compound 10bb was prepared following the method de-
scribed for the preparation of the compound 10aa, employing
14b (162 mg, 0.52 mmol) and 16b (371 mg, 0.63 mmol), and
the crude product was purified by column chromatography
(47% ethyl acetate–hexane) to afford the compound 10bb as a
The compound 10be was prepared following the method de-
scribed for the preparation of the compound 10aa, employing
14e (154.5 mg, 0.52 mmol) and 16b (371 mg, 0.63 mmol), and
the crude product was purified by column chromatography (48%
ethyl acetate–hexane) to afford the compound 10be as a white so-
white solid (325 mg, 76%); mp 141–142 °C; ½a D25
ꢂ22.4 (c 1.0
ꢁ
in CHCl3), 1H NMR (300 MHz, CDCl3): d 1.45–1.57 (m, 4H),
1.69–1.88 (m, 4H), 2.18 (s, 3H), 3.19–3.31(m, 2H), 3.70 (s, 3H),
3.73 (s, 3H), 3.78 (s, 3H), 3.79 (s, 6H), 4.01–4.16 (m, 4H), 4.35
(br s, 1H), 5.31–5.40 (m, 1H), 5.91 (d, 2H, J = 9.0 Hz), 6.29 (s,
2H), 6.57 (d, 1H, J = 8.3 Hz), 6.65–6.70 (m, 2H), 6.86 (dd, 1H,
J = 3.0, 9.0 Hz), 6.91–6.95 (m, 1H), 7.27–7.32 (m, 1H), 7.50–7.60
(m, 2H); 13C NMR (300 MHz, CDCl3): d 23, 25.1, 25.4, 28, 36.1,
37.7, 45.2, 45.3, 47.5, 55.6, 55.7, 56.1, 60.7, 67.9, 68.6, 101.2,
104.6, 106.2, 106.9, 107, 109.7, 109.8, 112.9, 115.5, 121.2,
124.9, 126.5, 128.1, 128.4, 128.5, 130, 136.6, 137.6, 141.9,
147.2, 147.4, 152.4, 153.3, 157.3, 161.8, 173.4, 178.8; MS (ESI):
822 [M+H]+; HRMS (ESI) calcd for C45H48O12N3 [M+H]+
822.3205.; found: 822.3208.
lid (345 mg, 82%); mp 132–133 °C; ½a D25
ꢁ
ꢂ12.9 (c 1.0 in CHCl3), 1H
NMR (300 MHz, CDCl3): d 1.49–1.59 (m, 2H), 1.68–1.78 (m, 2H),
1.79-1.89 (m, 2H), 2.17 (s, 3H), 2.25 (t, 2H, J = 7.5 Hz), 3.04–3.16
(m, 1H), 3.21(dd, 1H, J = 3.0, 9.8 Hz), 3.78 (s, 9H), 4.0–4.17 (m,
5H), 5.37 (dd, 1H, J = 6.0, 9.0 Hz), 5.91 (d, 2H, J = 6.7 Hz), 6.28 (s,
2H), 6.52 (s, 1H), 6.64 (s, 1H), 7.33 (dd, 1H, J = 3.0, 9.0 Hz), 7.39–
7.60 (m, 4H), 8.34-8.43 (m, 2H); 13C NMR (300 MHz, CDCl3): d
24, 25.1, 25.4, 28.2, 36.4, 37.9, 44.8, 45.2, 47.6, 56.2, 60.7, 68.1,
68.6, 101.3, 104.8, 106.3, 107, 109.9, 125.1, 125.2, 125.4, 128.4,
128.6, 129.5, 129.6, 130.3, 136.9, 138, 141.7, 143.4, 147.2, 147.6,
148, 149.9, 153.5, 157.9, 161.8, 173.1, 178.4; MS (ESI): 807