4920 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20
Curtin et al.
OCH2), 5.51 (s, 4H, 2 × CH2Ar), 7.28 (m, 10H, 10 × Ar-H);
MS (EI) 518 (M+).
3.25 (s, 6H, 2 × OCH3). 3.38 (t, 4H, 2 × CH2OCH3), 3.87 (t,
4H, 2 × OCH2CH2OCH3), 5.28 (br s, 8H, 4 × CH2Ar), 7.28 (m,
20H, 20 × Ar-H); MS (EI) 669 (M+ - 1).
2,6-Di-(2′-h yd r oxyp r op oxy)-4,8-d i-(N-b en zyl-N-m et h -
yla m in o)p yr im id o[5,4-d ]p yr im id in e (82). Compound 82
was prepared from NaH (0.30 g, 12.5 mmol), 2-triisopropyl-
silyloxypropan-1-ol (2.64 g, 11.4 mmol), 18 (1.00 g, 2.28 mmol),
and TBAF (5.0 mL, 5.0 mmol) in accordance with method VI.
2,6-Di-(2′-m eth oxyeth oxy)-4,8-d i-(ben zyla m in o)p yr im -
id o[5,4-d ]p yr im id in e (90). Acetyl chloride (0.06 g, 0.75
mmol) was added to dry MeOH (8 mL), the solution was stirred
for 15 min, and 89 (0.15 g, 0.22 mmol) was added. To the
resulting solution was added 10% Pd on carbon (40 mg), and
the mixture was stirred vigorously under H2 for 5 h at 25 °C.
After filtration and removal of solvents in vacuo, the product
was purified by chromatography on silica to afford 90 as a
cream solid. IR 3450 cm-1; 1H NMR δ 3.39 (s, 6H, 2 × OCH3),
3.72 (t, 4H, 2 × CH3OCH2CH2), 4.46 (t, 4H, 2 × CH3OCH2),
4.77 (d, 4H, 2 × ArCH2N), 7.02 (br s, 2H, 2 × NH), 7.33 (m,
10H, 2 × Ph); MS (EI) 490 (M+).
IR 3426, 3029, 2973, 2930, 1530 cm-1 1H NMR δ 1.06 (dd,
;
6H, 2 × CH3, J ) 14.8, 3.9), 3.35 (br s, 6H, 2 × NCH3), 3.43 (s,
2H, 2 × CH3CHOHCH), 3.82 (m, 3H, OH and 2 × CH3-
CHOHCH), 4.85 (m, 3H, 2 × CH3CHOHCH2 and OH), 5.55
(br s, 4H, 2 × PhCH2), 7.41 (m, 10H, 10 × Ar-H); MS (EI) 518
(M+).
2,6-Di-(3′-h ydr oxypr opoxy)-4,8-di-(N-4′-m eth oxyben zyl-
N-m eth yla m in o)p yr im id o[5,4-d ]p yr im id in e (83). Reaction
of 19 (0.87 g, 1.8 mmol) with NaH (0.18 g, 7.7 mmol),
3-triisopropylsilyloxypropan-1-ol (3) (1.87 g, 7.0 mmol), and
TBAF (10.3 mL, 10.3 mmol), following method VI, yielded
compound 83. IR 3398, 3027, 2931, 1530 cm-1; 1H NMR δ 1.81
(m, 4H, 2 × OCH2CH2CH2), 3.35 (s, 6H, 2 × NCH3), 3.48 (m,
4H, 2 × OCH2CH2CH2OH), 3.81 (s, 6H, 2 × OCH3),4.13 (t, 4H,
2 × OCH2CH2CH2OH), 4.58 (t, 2H, 2 × OH, J ) 5.1), 5.50 (br
s, 4H, 2 × ArCH2), 6.98 (d, 4H, Ar-3-H, Ar-5-H, J ) 8.6), 7.29
(d, 4H, Ar-2-H, Ar-6-H, J ) 8.6); MS (EI) 578 (M+).
A sample of 83, identical (1H NMR, MS, and mp) to that
synthesized above, was also prepared in low yield directly from
NaH (0.1 g, 4 mmol), 1,3-propanediol (0.3 mL, 4 mmol), and
19 by method V.
2,6-Di-(2′-t r iisop r op ylsilyloxyet h oxy)-4,8-b is(d i-N,N-
(3′,4′-d im e t h oxyb e n zyla m in o)p yr im id o[5,4-d ]p yr im i-
d in e (91). The reaction of 23 (1.00 g, 0.84 mmol) with NaH
(0.07 g, 2.76 mmol) and 2-triisopropylsilyloxyethanol (0.55 g,
2.51 mmol), in accordance with method V, gave compound 91.
IR 2936, 2865, 1512, 1264, 1137 cm-1; 1H NMR δ 0.92 (m, 42H,
i
42 × Pr-H), 3.72 (m, 16H, 4 × OCH3 and 2 × SiOCH2CH2O),
3.80 (s, 12H, 4 × OCH3), 3.97 (t, 4H, 2 × SiOCH2CH2O, J )
5.4), 5.16 (br s, 8H, 4 × PhCH2), 6.76 (m, 12H, 12 × Ar-H);
MS (EI) 1194 (M+).
2,6-Di-(3′-tr iisop r op ylsilyloxyp r op oxy)-4,8-bis[d i-N,N-
(3′,4′-d im et h oxyb en zyl)a m in o]p yr im id o[5,4-d ]p yr im i-
d in e (92). Compound 92 was prepared from NaH (0.07 g, 2.8
mmol), 3-triisopropylsilyloxypropan-1-ol (0.74 g, 2.5 mmol),
and 23 (1.00 g, 0.84 mmol) following method V. IR 2943, 2866,
2,6-Di-(3′-h yd r oxyp r op oxy)-4,8-bis[(N-3′,4′-d im eth oxy-
ben zyl)-N-m eth yla m in o]p yr im id o[5,4-d ]p yr im id in e (84).
Compound 84 was prepared by method V from NaH (0.08 g,
3.2 mmol), 1,3-propanediol (0.24 mL, 3.2 mmol), and 20 (0.22
2836, 1514 cm-1
;
1H NMR δ 1.73 (m, 4H, 2 × SiOCH2CH2-
CH2O), 3.57 (t, 4H, 2 × SiOCH2CH2CH2O, J ) 6.2), 3.74 (s,
12H, 4 × OCH3), 3.80 (s, 12H, 4 × OCH3), 3.99 (t, 4H, 2 ×
SiOCH2CH2CH2O, J ) 6.4), 5.16 (br s, 8H, 4 × ArCH2), 6.78
(m, 12H, 12 × Ar-H); MS (EI) 1222 (M+).
g, 0.4 mmol). IR 1650 cm-1
;
1H NMR δ 1.87 (p, 4H, 2 ×
OCH2CH2CH2OH), 2.08 (t, 2H, 2 × OH), 3.30 (s, 6H, 2 ×
NCH3), 3.66 (t, 4H, 2 × OCH2), 5.38 (s, 4H, 2 × CH2Ar), 6.82
(s, 4H, 4 × Ar-H), 6.90 (s, 2H, 2 × Ar-H); MS (EI) 638 (M+).
2,6-Di-(2′-m et h oxyet h oxy)-4,8-d i-[N-b en zyl-N-m et h -
yla m in o]p yr im id o[5,4-d ]p yr im id in e (85). Treatment of 18
(0.22 g, 0.50 mmol) with NaH (0.12 g, 5.0 mmol) and 2-meth-
oxyethanol (0.38 g, 5.0 mmol), according to method V, fur-
2,6-Di-(2′-h yd r oxyeth oxy)-4,8-bis[d i-N,N-(3′,4′-d im eth -
oxyben zyl)a m in o]p yr im id o[5,4-d ]p yr im id in e (93). To a
solution of 91 (0.40 g, 0.34 mmol) in THF (15 mL) was added
TBAF (1.36 mL, 1.36 mmol), and the mixture was stirred at
25 °C for 12 h. Solvents were removed in vacuo, the residue
was triturated with H2O (30 mL), and the solid was collected
1
nished compound 85. H NMR δ 3.29 (s, 6H, 2 × NCH3), 3.29
to afford compound 93. IR 3435, 2997, 2954, 2937 cm-1 1H
;
(br s, 6H, 2 × OCH3), 3.48 (t, 4H, 2 × CH2OCH3), 4.04 (t, 4H,
2 × OCH2), 5.49 (br s, 4H, 2 × NCH2Ar), 7.24 (m, 10H, 10 ×
Ar-H); MS (EI) 518 (M+).
NMR δ 3.54 (m, 4H, 2 × HOCH2CH2O), 3.76 (s, 12H, 4 ×
OCH3), 3.81 (s, 12H, 4 × OCH3), 3.94 (t, 4H, 2 × HOCH2CH2O),
4.84 (t, 2H, 2 × OH), 5.30 (br s, 8H, 4 × ArCH2), 6.96 (m, 12H,
12 × Ar-H); MS (EI) 882 (M+).
2,6-Di-(2′-h ydr oxyeth oxy)-4,8-di-(4′-m eth oxyben zylam i-
n o)p yr im id o[5,4-d ]p yr im id in e (86). Compound 86 was
prepared from 15 (0.24 g, 0.50 mmol), sodium (0.24 g, 10
mmol), and ethane-1,2-diol (0.62 g, 10 mmol) in accordance
2,6-Di-(3′-h ydr oxypr opoxy)-4,8-bis[di-N,N-(3′,4′-dim eth -
oxyben zyl)a m in o]p yr im id o[5,4-d ]p yr im id in e (94). TBAF
(2.12 mL, 2.12 mmol) was added to a solution of 92 (0.65 g,
0.53 mmol) in dry THF (15 mL) under nitrogen, and the
mixture was stirred for 12 h at 25 °C. Evaporation of solvents
in vacuo gave a yellow oil, which was triturated with H2O (25
mL) to yield compound 94 as a white solid. IR 3555, 2936, 2838
cm-1; 1H NMR δ 1.73 (m, 4H, HOCH2CH2CH2O), 3.45 (m, 4H,
HOCH2CH2CH2O), 3.79 (s, 12H, 4 × OCH3), 3.83 (s, 12H, 4 ×
OCH3), 4.00 (t, 4H, HOCH2CH2CH2O), 4.57 (br s, 2H, 2 × OH),
5.20 (br s, 8H, 4 × ArCH2), 6.98 (m, 12H, 12 × Ar-H); MS (EI)
911 (M+).
1
with method IV. H NMR δ 2.61 (br s, 2H, 2 × OH), 3.73 (s,
6H, 2 × ArOCH3), 3.89 (t, 4H, 2 × CH2OH), 4.40 (t, 4H, 2 ×
OCH2), 4.62 (d, 4H, 2 × CH2Ar), 6.79 (d, 4H, 4 × Ar-H), 6.97
(br s, 2H, 2 × NH), 7.21 (d, 4H, 4 × Ar-H); MS (EI) 522 (M+).
2,6-Di-(3′-h yd r oxyp r op oxy)-4,8-d i-(4′-m e t h oxyb e n z-
yla m in o)p yr im id o[5,4-d ]p yr im id in e (87). Reaction of 15
(0.35 g, 0.75 mmol) with NaH (0.36 g, 15 mmol) and propane-
1,3-diol (1.14 g, 15 mmol) according to method V gave
1
compound 87. H NMR δ 1.97 (t, 4H, 2 × OCH2CH2CH2OH),
2.30 (br s, 2H, 2 × OH), 3.74 (s, 6H, 2 × ArOCH3), 3.78 (t, 4H,
2 × CH2OH), 4.41 (t, 4H, 2 × OCH2), 4.63 (d, 4H, 2 × CH2Ar),
6.81 (d, 4H, 4 × Ar-H), 7.01 (t, 2H, 2 × NH), 7.26 (d, 4H, 4 ×
Ar-H); MS (EI) 550 (M+).
2,6-Di-(2′-h yd r oxyeth oxy)-4,8,-bis(3′,4′-d im eth oxyben z-
yla m in o)p yr im id o[5,4-d ]p yr im id in e (95). A solution of 93
(0.13 g, 0.15 mmol) in TFA (2.5 mL) was stirred at 25 °C for
3 h. Excess TFA was removed in vacuo to leave a yellow
residue, which was triturated with saturated aqueous NaHCO3
solution (20 mL). The yellow solid that was deposited was
collected and purified by chromatography on silica to give 95
as a pale-yellow solid. IR 3538, 3290, 2955, 2932, 2836, 1570
2,6-Di-(2′-(S)-h yd r oxyp r op oxy)-4,8-d i-(4′-m eth oxyben z-
yla m in o)p yr im id o[5,4-d ]p yr im id in e (88). Reaction of 15
(0.47 g, 1.0 mmol) with NaH (0.48 g, 20 mmol) and (S)-
propane-1,2-diol (1.46 mL, 20 mmol) according to method V
1
gave 88. H NMR δ 1.18 (d, 6H, 2 × CH3), 2.84 (br s, 2H, 2 ×
cm-1
;
1H NMR δ 3.80 (m, 6H, 2 × OCH3), 3.82 (s, 6H, 2 ×
OH), 3.76 (s, 6H, 2 × ArOCH3), 4.16 (m, 4H, 2 × OCH2), 4.16
(m, 2H, 2 × CHOH), 4.62 (d, 4H, 2 × CH2Ar), 6.80 (d, 4H, 4 ×
Ar-H), 6.96 (t, 2H, 2 × NH), 7.21 (d, 4H, 4 × Ar-H); MS (EI)
550 (M+).
OCH3), 4.41 (m, 4H, 2 × HOCH2CH2O), 4.69 (m, 8H, 2 ×
HOCH2CH2O and 2 × ArCH2), 4.92 (t, 2H, 2 × OH, J ) 5.3),
7.05 (m, 6H, 6 × Ar-H), 8.51 (t, 2H, 2 × NH); MS (EI) 610
(M+).
2,6-Di-(2′-m et h oxyet h oxy)-4,8-b is(d ib en zyla m in o)p y-
r im id o[5,4-d ]p yr im id in e (89). Compound 89 was prepared
from 21 (0.35 g, 0.60 mmol), NaH (0.14 g, 6 mmol), and
2-methoxyethanol (0.47 mL, 6 mmol) by method V. 1H NMR δ
2,6-Di-(3′-h ydr oxypr opoxy)-4,8-bis(3′,4′-dim eth oxyben z-
yla m in o)p yr im id o[5,4-d ]p yr im id in e (96). A solution of 94
(0.40 g, 0.44 mmol) in TFA (7 mL) was stirred at 25 °C for 2