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L. Tak-Tak et al. / European Journal of Medicinal Chemistry 46 (2011) 1254e1262
5.1.9. 1-Amino-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-N-(6-(3,4-
dimethoxyphenylethylamino)-9H-purin-2-yl)- -glucitol (12b)
The title compound was prepared as a brown solid (24 mg, 54%),
according to the procedure for 12a, starting from 11b (30 mg,
71 mmol, 1 equiv), sodium tetrafluoroborate (8 mg, 71 mmol, 1 equiv)
and 10 (60 mg, 178 mmol, 2.5 equiv). Rf 0.3 (CH2Cl2/MeOH, 95:5).
for 4 h at ꢁ40 ꢀC. Rf 0.34 (CH2Cl2/MeOH, 85:15). Mp ¼ 116 ꢀC.
D
[a
]D ¼ þ6 (c 1.0, DMF). 1H NMR (500 MHz, DMF-d6, 340 K):
d 11.76
(br s, 1H, HeN9), 7.70 (s, 1H, H-80), 7.00 (d, 1H, J ¼ 2 Hz, H-200), 6.93
(d, 1H, J ¼ 8 Hz, H-500), 6.88 (dd, 1H, J ¼ 8, 2 Hz, H-600), 6.76 (br s, 1H,
NH-6), 5.91 (t, 1H, J ¼ 6 Hz, NH-2), 4.15 (ddd, 1H, J ¼ 3, 5, 8 Hz, H-2),
4.08 (dd, 1H J ¼ 1, 2 Hz, H-4), 3.97 (dd, 1H, J ¼ 1, 3 Hz, H-3),
3.90e3.84 (m, 2H, H-a), 3.84 (s, 3H, CH3eO), 3.82 (s, 3H, CH3eO),
3.64e3.80 (m, 4H, H-6, H-5, H-1), 3.57 (ddd, 1H, J ¼ 13, 11, 5 Hz, H-
1), 2.97 (t, 2H, J ¼ 7 Hz, H-b). 13C NMR (125 MHz, DMF-d6, 340 K):
Mp ¼ 72 ꢀC. [
a
]D ¼ þ8 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3):
d
7.56 (s, 1H, H-80), 7.19e7.38 (m, 10H, HPh), 6.77 (d, 1H, J ¼ 8 Hz, H-
600), 6.76 (s, 1H, H-200), 6.73 (d, 1H, J ¼ 8 Hz, H-500), 6.17 (br s, 1H, NH),
5.31 (br s, 1H, NH), 4.66, 4.53, 4.51, 4.48 (AB, 4H, JAB ¼ 12 Hz,
CH2ePh), 4.31e4.24 (m, 1H, H-2), 4.09e4.02 (m, 3H, H-3, H-4, H-5),
3.88e3.82 (m, 2H, H-a), 3.80 (s, 3H, CH3eO), 3.79 (s, 3H, CH3eO),
3.77e3.71 (m, 2H, H-6), 3.70e3.60 (m, 1H, H-1), 3.58e3.50 (m, 1H,
d
160.6 (C-80), 155.4, 150.2, 148.7, 136.0, 133.4 (Cq), 121.4 (C-600),
114.3 (C-200), 113.6 (C-500), 87.3 (C-5), 81.4 (C-2), 79.6 (C-4), 77.8 (C-
3), 63.5 (C-6), 56.3 (CH3eO), 56.2 (CH3eO), 42.6 (C-a), 41.0 (C-1),
35.9 (C-b). MS: m/z ¼ 461.0 [M þ H]þ. HRMS: m/z ¼ 461.2157
[M þ H]þ (calcd for C21H29N6O6, 461.2149).
H-1), 2.91 (t, 2H, J ¼ 7 Hz, H-b). 13C NMR (125 MHz, CDCl3):
d 159.4,
154.9 (CqPurine), 149.1, 147.7 (C-300, C-400), 137.7, 137.3 (CqPh), 135.5 (C-
80), 132.0 (C-100), 128.7, 128.2, 128.1, 127.7 (CHPh), 120.7 (C-600), 113.8
(CqPurine),112.3,111.6 (C-200, C-500), 84.6, 83.0, 82.6 (C-3, C-4, C-5), 79.8
(C-2), 72.1, 71.8 (CH2ePh), 62.6 (C-6), 56.0 (CH3eO), 42.3 (C-1), 42.1
(C-a), 35.6 (C-b). MS: m/z ¼ 641.3 [M þ H]þ. HRMS: m/z ¼ 641.3061
[M þ H]þ (calcd for C35H41N6O6, 641.3088).
5.1.13. 1-Amino-2,5-anhydro-1-deoxy-N-(6-(2-morpholinoethyl-
amino)-9H-purin-2-yl)-
The title compound was prepared as a yellow solid (16 mg, 73%),
according to the procedure for 2a, starting from 12c (31 mg, 55 mol,
D-glucitol (2c)
m
1 equiv) and boron trichloride (500 mL, 500 m
mol, 9 equiv) at 0 ꢀC. Rf
0.3 (CH2Cl2/MeOH, 85:15). Mp ¼ 191 ꢀC. [
a
]D ¼ ꢁ7 (c 1.0, MeOH). 1H
5.1.10. 1-Amino-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-N-(6-(2-
NMR (500 MHz, CD3OD): d
7.71 (s, 1H, H-80), 4.17e4.12 (m, 1H, H-2),
morpholinoethylamino)-9H-purin-2-yl)-
The title compound was prepared as a beige solid (103 mg, 65%),
according to the procedure for 12a, starting from 11c (100 g,
D
-glucitol (12c)
4.02e3.99 (m, 1H, H-4), 3.94e3.91 (m, 1H, H-3), 3.80 (dd, 1H, J ¼ 5,
7 Hz, H-5), 3.77e3.64 (m, 9H, H-200, H-a, H-6, H-1), 3.53 (dd, 1H,
J ¼ 14, 5 Hz, H-1), 2.73 (t, 2H, J ¼ 6 Hz, H-b), 2.67e2.60 (m, 4H, H-300).
270
m
mol, 1 equiv), sodium tetrafluoroborate (30 mg, 270
m
mol,
13C NMR (125 MHz, CD3OD): 161.2, 155.9 (Cq), 137.2 (C-80), 87.6 (C-
d
1 equiv) and 10 (235 mg, 680
m
mol, 2.5 equiv). Rf 0.3 (CH2Cl2/
5), 82.1 (C-2), 79.9 (C-4), 78.3 (C-3), 67.5 (C-200), 63.8 (C-6), 58.8 (C-b),
54.7 (C-300), 41.4 (C-1), 37.9 (C-a). MS: m/z ¼ 410.2 [M þ H]þ. HRMS:
m/z ¼ 410.2164 [M þ H]þ (calcd for C17H28N7O5, 410.2152).
MeOH, 92:8). Mp ¼ 90 ꢀC. [
a
]D ¼ þ3 (c 1.0, CH2Cl2). 1H NMR
(500 MHz, CDCl3): d
7.81 (s, 1H, H-80), 7.41e7.09 (m, 10H, HPh), 6.79
(br s, 1H, NH), 6.19 (br s, 1H, NH), 4.76e4.45 (m, 4H, CH2ePh),
4.44e4.38 (m, 1H, H-2), 4.22e4.14 (m, 1H, H-5), 4.00e3.95 (m, 1H,
H-4), 3.95e3.89 (m,1H, H-3), 3.89e3.81 (m,1H, H-a), 3.75e3.64 (m,
8H, H-200, H-1, H-6), 3.52e3.40 (m, 1H, H-a), 2.72e2.61 (m, 2H, H-
300), 2.61e2.55 (m, 2H, H-b), 2.55e2.43 (m, 2H, H-300). 13C NMR
5.1.14. 1-Amino-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-N-(2-iodo-
9H-purin-6-yl)- -glucitol (13)
D
The title compound was prepared as a yellow solid (890 mg,
85%), according to the procedure for 11a, starting from 7 (500 mg,
1.78 mmol, 1 equiv), 10 (612 mg, 1.78 mmol, 1 equiv) and triethyl-
amine (1.25 mL, 8.95 mmol, 5 equiv) except that purification step
requires column chromatography instead of filtration. Rf 0.27
(125 MHz, CDCl3): d 158.9,154.6,150.6,137.7,137.0 (Cq),128.7,128.7,
128.3, 128.1, 127.7 (CHPh), 86.6 (C-5), 83.0 (C-3), 82.1 (C-4), 79.9 (C-
2), 71.7, 71.4 (CH2ePh), 66.7 (C-200), 62.7 (C-6), 58.2 (C-b), 53.7 (C-
300,C-1), 45.3 (C-2), 37.1 (C-a). MS: m/z ¼ 590.3 [M þ H]þ. HRMS: m/
z ¼ 590.3101 [M þ H]þ (calcd for C31H40N7O5, 590.3091).
(CH2Cl2/MeOH, 95:5). Mp ¼ 186 ꢀC. [
a]
¼ ꢁ39 (c 1.0, CH2Cl2). 1H
D
NMR (250 MHz, CDCl3):
d
13.56 (br s, 1H, H-N9), 7.85 (s, 1H, H-80),
7.51e7.19 (m, 10H, HPh), 5.29 (br s, 1H, NH-6), 4.74e4.54 (m, 5H,
CH2ePh, H-2), 4.33e4.09 (m, 4H, H-1, H-3, H-4, H-5), 3.93e3.72 (m,
2H, H-6), 3.63 (d, 1H, J ¼ 12 Hz, H-1). 13C NMR (63 MHz, CDCl3):
5.1.11. 1-Amino-2,5-anhydro-1-deoxy-N-(6-phenethylamino-9H-
purin-2-yl)-
To a solution of 12a (40 mg, 69
methane (4 mL) previously cooled to 0 ꢀC was added dropwise
a 1 M solution of boron trichloride in dichloromethane (620 L,
620
mol, 9 equiv). After 2 h at 0 ꢀC the reaction was quenched by
D
-glucitol (2a)
mmol, 1 equiv) in dry dichloro-
d
153.8, 148.7 (CqPurine), 138.0 (C-80), 137.8, 137.4 (CqPh), 128.5, 128.5,
127.9, 127.8, 127.5 (CHPh), 118.6,118.1 (CqPurine), 84.1 (C-5), 82.9, 82.0
(C-3, C-4), 77.8 (C-2), 72.2, 72.0 (CH2ePh), 62.3 (C-6), 42.0 (C-1).
MS: m/z ¼ 588.2 [M þ H]þ. HRMS: m/z ¼ 610.0933 [M þ Na]þ (calcd
for C25H26N5O4NaI, 610.0927).
m
m
addition of methanol (4 mL). The mixture was concentrated and the
resulting residue was purified by column chromatography to yield
2a (25 mg, 90%) as a yellow solid. Rf 0.35 (CH2Cl2/MeOH, 85:15).
5.1.15. 1-Amino-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-N-(2-
phenethylamino-9H-purin-6-yl)-D-glucitol (14a)
The title compound was prepared as a beige solid (74 mg, 75%),
according to the procedure for 12a, starting from 13 (100 mg,
Mp ¼ 186 ꢀC. [
a
]D ¼ ꢁ2 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD):
d
7.84 (s, 1H, H-80), 7.29e7.25 (m, 4H, H-200, H-300), 7.20e7.15 (m, 1H,
H-400), 4.24e4.20 (m, 1H, H-2), 4.05e4.02 (m, 1H, H-3), 4.01e3.98
(m, 1H, H-4), 3.86e3.77 (m, 4H, H-5, H-6, H-a), 3.73, 3.68 (AB, 2H,
J ¼ 12, 4, 5 Hz, H-1), 3.62 (dd, 1H, J ¼ 14, 6 Hz, H-a), 2.98 (t, 2H,
170
m
mol, 1 equiv), sodium tetrafluoroborate (19 mg, 170
m
mol,
mol, 2.5 equiv). Rf
¼ þ11 (c 0.25, CH2Cl2).
1 equiv) and phenyl-2-ethanamine (54 mL, 425 m
J ¼ 7 Hz, H-b). 13C NMR (125 MHz, CD3OD):
d
154.2 (Cq), 139.9 (C-
0.24 (CH2Cl2/MeOH, 95:5). Mp ¼ 72 ꢀC. [
a]
D
80), 129.9, 129.5 (C-200, C-300), 127.5 (C-400), 87.4 (C-5), 80.4 (C-2), 79.9
(C-3), 78.6 (C-4), 63.4 (C-6), 43.8 (C-a), 42.5 (C-1), 36.3 (C-b). MS: m/
z ¼ 401.3 [M þ H]þ. HRMS: m/z ¼ 401.1935 [M þ H]þ (calcd for
C19H25N6O4, 401.1937).
1H NMR (500 MHz, CDCl3): 7.48e7.15 (m, 16H, HPh, H-80), 6.31 (br
d
s, 1H, NH), 5.20 (br s, 1H, NH), 4.72e4.50 (m, 4H, CH2ePh),
4.44e4.33 (m, 1H, H-2), 4.27e4.21 (m, 1H, H-4), 4.21e4.15 (m, 1H,
H-3), 4.09e4.02 (m, 1H, H-5), 4.00e3.85 (m, 2H, H-1), 3.78 (dd, 1H,
J ¼ 3, 12 Hz, H-6), 3.74e3.58 (m, 3H, H-a, H-6), 2.95 (t, 2H, J ¼ 7 Hz,
5.1.12. 1-Amino-2,5-anhydro-1-deoxy-N-(6-(3,4-dimethoxyphenyl-
H-b). 13C NMR (125 MHz, CDCl3):
d 139.5, 137.7, 137.5 (Cq), 128.8,
ethylamino)-9H-purin-2-yl)-D-glucitol (2b)
128.6, 128.0, 127.8, 126.4 (CHAr), 84.3 (C-5), 83.6, 82.6 (C-3, C-4),
79.6 (C-2), 72.6, 72.4 (CH2ePh), 62.7 (C-6), 44.0 (C-a), 40.8 (C-1),
36.3 (C-b). MS: m/z ¼ 581.3 [M þ H]þ. HRMS: m/z ¼ 581.2870
[M þ H]þ (calcd for C33H37N6O4, 581.2876).
The title compound was prepared as a brown solid (16 mg, 57%),
according to the procedure for 2a, starting from 12b (40 mg,
62 mmol, 1 equiv) and boron trichloride (560 mL, 560 mmol, 9 equiv)