SYNTHESIS AND BIOLOGICAL EVALUATION
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178.05, 177.11, 176.55, 176.30, 88.27, 74.44, 71.91, CDCl3): d 8.64 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H),
70.47, 67.36, 61.47, 38.91, 38.80, 38.77, 38.74, 27.12, 7.75–7.90 (m, 2H), 7.55 (d, J 5 7.5 Hz, 1H), 7.42 (t,
27.07, 27.02, 27.01.
J 5 8.0 Hz, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 5.95 (d,
2,3,4-Tri-O-acetyl-a-L-arabinopyranosyl
azide J 5 10.5 Hz, 1H), 5.54 (t, J 5 9.5 Hz, 1H), 5.45 (t,
(3d).
Prepared from 2d (636 mg, 2.0 mmol) to J 5 9.5 Hz, 1H), 5.28 (t, J 5 9.5 Hz, 1H), 4.34 (dd,
give 3d (499 mg, 83%) as a white solid. M. p. J 5 12.5, 5.0 Hz, 1H), 4.29 (t, J 5 5.0 Hz, 2H), 4.24
1
1048C–1068C; H NMR (500 MHz, CDCl3) d 5.32 (t, J 5 5.0 Hz, 2H). 4.16–4.18 (m, 1H) 4.03–4.05 (m,
(m, 1H), 5.18 (dd, J 5 9.6, 8.0 Hz,1H), 5.07 (dd, 1H), 3.83-3.85 (m, 5H), 3.46 (s, 3H, OCH3), 3.44 (s,
J 5 9.6 Hz, 3.4, 1H), 4.61 (d, J 5 8.0 Hz, 1H), 4.13 3H, OCH3), 2.09, 2.08, 2.04, 1.88 (4s, 12H,
(dd, J 5 13.2, 2.8 Hz, 1H), 3.76 (dd, J 5 13.2, 1.3 Hz, 4COCH3); 13C NMR (126 MHz, CDCl3) d 170.56,
1H), 2.18 (s, 3H, COCH3), 2.11 (s, 3H, COCH3), 169.96, 169.42, 169.06, 156.43, 154.55, 153.33,
2.05 (s, 3H, COCH3); 13C NMR (126 MHz, CDCl3) 148.91, 148.12, 139.41, 130.58, 129.60, 121.96,
d 170.19, 169.98, 169.35, 88.55, 70.18, 68.52, 67.59, 121.44, 118.92, 118.32, 109.15, 108.35, 102.47, 85.80,
65.65, 20.87, 20.68, 20.60.
General procedure for the synthesis of erlotinib 61.61, 59.29, 59.24, 20.70, 20.55, 20.52, 20.18.
derivatives. To a mixture of the corresponding N-(3-(1-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyra-
glucopyranosyl azide 3 (541 mg, 1.0 mmol) and erlo- nosyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-meth
tinib (393 mg, 1.0 mmol) in tert-butyl alcohol oxyethoxy)-4-quinazolinamine (5c). Prepared
75.15, 72.72, 70.88, 70.43, 70.27, 69.11, 68.32, 67.74,
(1 mL), 0.5 mL of an aqueous solution of CuSO4 Á from 3c (600 mg, 1.0 mmol) and 4 (393 mg, 1.0
5H2O (50 mg, 0.2 mmol), and 0.5 mL of an aqueous mmol) to give 5c (654 mg, 70%) as a white solid. M.
solution of sodium ascorbate (79.2 mg, 0.4 mmol) p. 1918C–1928C; HRMS (ESI): m/z(%) 935.4746
1
were added. The reaction mixture was stirred vigor- [M 1 H]1; H NMR (400 MHz, CDCl3): d 8.61 (s,
ously for 24 h and the suspended product filtered 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.95 (d, J 5 7.5 Hz,
and washed with water. The crude product was puri- 1H), 7.53 (d, J 5 7.5 Hz, 1H), 7.46 (t, J 5 8.0 Hz,
fied by column chromatography on silica gel, eluting 1H), 7.31 (s, 1H), 7.25 (d, J 5 2.5 Hz, 1H), 6.25 (d,
with hexane/ethyl acetate mixtures of increasing J 5 9.0 Hz,1H), 6.00 (d, J 5 9.0 Hz, 1H), 5.53–5.60
polarity to afford the triazole products.
(m, 2H), 5.36 (t, J 5 9.5 Hz, 1H), 4.30–4.31 (m, 2H),
N-(3-(1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyrano- 4.21-4.25 (m, 4H), 4.07–4.14 (m, 2H), 3.83–3.85 (m,
syl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methox- 4H), 3.47 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 1.21,
yethoxy)-4-quinazolinamine
(5a).
Prepared 1.19, 1.13, 0.93 (4s, 36H, 4COC(CH3)3); 13C NMR
from 3a (373 mg, 1.0 mmol) and 4 (393 mg, 1.0 (126 MHz, CDCl3) d 177.97, 176.98, 176.60, 176.38,
mmol) to give 5a (637 mg, 83%) as a white solid. M. 156.43, 154.62, 153.04, 148.97, 148.11, 139.35,
p. 1978C–1998C; HRMS (ESI): m/z(%) 767.2820 130.62, 129.66, 121.95, 121.54, 118.92, 118.04,
1
[M 1 H]1; H NMR (500 MHz, DMSO) d 10.94 (s, 109.02, 102.32, 86.13, 75.69, 72.10, 70.87, 70.42,
1H), 9.03 (s, 1H), 8.79 (s, 1H), 8.23 (d, J 5 5.1 Hz, 70.15, 69.06, 68.33, 67.15, 61.36, 60.43, 59.31, 59.24,
2H), 7.79 (d, J 5 8.0 Hz, 1H), 7.71 (d, J 5 7.7 Hz, 38.91, 38.84, 38.79, 38.76, 27.12, 27.09, 27.04, 26.72.
1H), 7.58 (t, J 5 7.9 Hz, 1H), 7.36 (s, 1H), 6.43 (d,
J 5 9.0 Hz, 1H), 5.70 (t, J 5 9.3 Hz, 1H), 5.63 (t, 1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxye-
J 5 9.5 Hz, 1H), 5.20 (t, J 5 9.7 Hz, 1H), 4.43 (d, thoxy)-4-quinazolinamine (5d).
Prepared from
N-(3-(1-(2, 3, 4-tri-O-acetyl-a-L-arabinopyranosyl)-
J 5 22.0 Hz, 5H), 4.11–4.19 (m, 2H), 3.78–3.81 (m, 3d (301mg, 1.0 mmol) and 4 (393 mg, 1.0 mmol) to
4H), 3.37 (2s, 6H, 2OCH3), 2.05, 2.02, 1.99 (3s, 9H, give 5d (451 mg, 65%) as a white solid. M. p.
3COCH3), 1.83 (s, 3H, COCH3); 13C NMR (126 1618C–1628C; HRMS (ESI): m/z(%) 695.2666
MHz, DMSO) d 170.53, 170.05, 169.89, 169.12, [M 1 H]1;1H NMR (500 MHz, DMSO) d 9.56 (s,
158.13, 155.52, 149.53, 147.02, 138.76, 131.00, 1H), 8.86 (s, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 7.92 (d,
129.89, 124.50, 122.84, 121.20, 104.96, 84.46, 73.72, J 5 11.9 Hz, 2H), 7.64 (d, J 5 7.7 Hz, 1H), 7.48 (t,
72.50, 70.78, 70.41, 70.32, 69.26, 69.03, 68.01, 62.26, J 5 11.0 Hz, 1H), 7.24 (s, 1H), 6.20 (d, J 5 9.1 Hz,
58.87, 21.01, 20.88, 20.74, 20.41.
1H), 5.66 (t, J 5 9.6 Hz, 1H), 5.47 (d, J 5 6.5 Hz,
N-(3-(1-(3,4,6-tri-O-acetyl-2-N-acetyl-2-deoxy-b- 1H), 5.36 (s, 1H), 4.32 (s, 4H), 4.24 (s, 1H), 4.14–
D-glucopyranosyl)-1H-1,2,3-triazol-4-yl)phenyl)- 4.06 (m, 1H), 3.79 (dd, J 5 21.3, 6.8 Hz, 4H), 3.37,
6,7-bis(2-methoxyethoxy)-4-quinazolinamine
(5b).
3.39 (2s, 6H, 2OCH3), 2.21 (s, 3H, COCH3), 1.98 (s,
Prepared from 3b (372 mg, 1.0 mmol) and 3H, COCH3), 1.86 (s, 3H, COCH3); 13C NMR (126
4 (393 mg, 1.0 mmol) to give 5b (597 mg, 78%) as a MHz, DMSO) d 170.38, 170.00, 169.13, 148.62,
white solid. M. p. 1838C–1858C; HRMS (ESI): m/ 147.27, 140.54, 130.90, 129.51, 122.71, 121.14, 121.02,
z(%) 766.3058 [M 1 H]1; 1H NMR (500 MHz, 119.57, 103.88, 85.57, 70.79, 70.63, 70.56, 68.89,
Drug Dev. Res.