6438 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20
Boyer et al.
(dd, J ) 9.4, 3.9 Hz, 1H), 4.28-4.19 (m, 1H), 3.77 (dd, J ) 9.4,
Hz, 1H), 6.87 (d, J ) 8.8 Hz, 1H), 5.96 (s, 1H), 5.78 (d, J ) 5.8
Hz, 1H), 5.23 (dd, J ) 5.8, 3.0 Hz, 1H), 4.35-4.17 (m, 6H),
1.57 (s, 3H), 1.40 (s, 3H).
1.4 Hz, 1H). Anal. (C22H19BrN4O3) C, H, N.
4-N-(4-Ethoxyphenyl)amino-5-phenyl-7-(â-D-erythro-
furanosyl)pyrrolo[2,3-d]pyrimidine (19f). Compound 19f
(620 mg) was deprotected by the procedure described for the
synthesis of compound 19c. Recrystallization from EtOH
4-N-(2-Methoxyphenyl)amino-5-iodo-7-(2,3-O-isoprop-
ylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]pyrimidine
(20d). Coupling of 2-methoxyaniline (1.8 mL, 15.96 mmol) with
16b (4.95 g, 11.73 mmol) by the procedure described for the
synthesis of 20a provided nucleoside 20d (5.56 g, 93%): 1H
NMR (DMSO-d6) δ 8.86 (s, 1H, exchangeable with D2O), 8.8-
8.7 (m, 1H), 8.41 (s, 1H), 7.71 (s, 1H), 7.15-6.90 (m, 3H), 6.19
(s, 1H), 5.30 (d, J ) 6.1 Hz, 1H), 5.22 (dd, J ) 6.1, 3.8 Hz,
1H), 4.10 (dd, J ) 10.7, 3.8 Hz, 1H), 4.03 (d, J ) 10.7 Hz, 1H),
4.03 (d, J ) 10.7 Hz, 1H), 3.96 (s, 3H), 1.46 (s, 3H), 1.31 (s,
3H).
1
provided nucleoside 19f (370 mg, 65%): mp 164-165 °C; H
NMR (DMSO-d6) δ 8.33 (s, 1H), 7.77 (s, 1H), 7.65-7.48 (m,
4H), 7.48-7.36 (m, 1H), 7.42 (d, J ) 8.9 Hz, 2H), 7.30 (s, 1H,
exchangeable with D2O), 6.87 (d, J ) 8.9 Hz, 2H), 6.16 (d, J )
6.8 Hz, 1H), 5.40 (d, J ) 6.7 Hz, 1H, exchangeable with D2O),
5.19 (d, J ) 3.7 Hz, 1H, exchangeable with D2O), 4.77-4.64
(m, 1H), 4.33 (dd, J ) 9.2, 3.7 Hz, 1H), 4.30-4.20 (m, 1H),
3.98 (q, J ) 7 Hz, 2H), 3.80 (dd, J ) 9.2, 1.4 Hz, 1H), 1.31 (t,
J ) 7 Hz, 3H). Anal. (C24H24N4O4‚0.5H2O) C, H, N.
4-N-(4-Fluorophenyl)amino-5-(3-aminophenyl)-7-(2,3-
O-isopropylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (21a). A heterogeneous mixture of 20a (1.0 g, 2.01
mmol), 3-aminophenylboronic acid (375 mg, 2.41 mmol), and
Pd(PPh3)4 (116 mg, 0.1 mmol) in EtOH (5 mL), ethylene glycol
dimethyl ether (25 mL), and saturated aqueous Na2CO3 (5 mL)
was heated at reflux for 7 h. The cooled reaction mixture was
diluted with EtOAc and washed with H2O and brine, dried
(Na2SO4), and concentrated to dryness. The solid residue was
purified by flash chromatography to provide protected nucleo-
side 21a (876 mg, 94%): 1H NMR (CDCl3) δ 8.42 (s, 1H), 7.60-
7.45 (m, 2H), 7.31 (t, J ) 6.9 Hz, 1H), 7.18 (s, 1H), 7.10-6.93
(m, 3H), 6.88 (d, J ) 7.6 Hz, 1H), 6.84-6.70 (m, 2H), 6.07 (s,
1H), 5.58 (d, J ) 6.4 Hz, 1H), 5.31 (dd, J ) 6.4, 3.8 Hz, 1H),
4.35 (dd, J ) 10.2, 3.8 Hz, 1H), 4.22 (d, J ) 10.2 Hz, 1H), 3.75
(br s, 2H), 1.60 (s, 3H), 1.45 (s, 3H).
4-N-(4-Cyanophenyl)amino-5-(4-ethoxyphenyl)-7-(2,3-
O-isopropylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (21b). Suzuki coupling of 20b (553 mg, 1.06
mmol) with 4-ethoxyphenylboronic acid (888 mg, 5.35 mmol)
by the procedure described for the synthesis of 21a provided
protected nucleoside 21b which was carried into the depro-
tection step without purification: 1H NMR (DMSO-d6) δ 8.49
(s, 1H), 8.15 (s, 1H, exchangeable with D2O), 7.80-7.75 (m,
5H), 7.48 (d, J ) 8.4 Hz, 2H), 7.04 (d, J ) 8.4 Hz, 2H), 6.30 (s,
1H), 5.38 (d, J ) 5.9 Hz, 1H), 5.27 (dd, J ) 5.9, 3.7 Hz, 1H),
4.18 (dd, J ) 10.2, 3.7 Hz, 1H), 4.08 (q, J ) 7 Hz, 2H), 4.05 (d,
J ) 10.2 Hz, 1H), 1.49 (s, 3H), 1.36 (t, J ) 7 Hz, 3H), 1.33 (s,
3H).
4-N-(4-Cyanophenyl)amino-5-(4-chlorophenyl)-7-(2,3-
O-isopropylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (21c). Suzuki coupling of 20b (528 mg) with
4-chlorophenylboronic acid by the procedure described for the
synthesis of 21a provided protected nucleoside 21c (404 mg,
79%): 1H NMR (DMSO-d6) δ 8.54 (s, 1H, exchangeable with
D2O), 8.51 (s, 1H), 7.8-7.65 (m, 5H), 7.60-7.4 (m, 4H), 6.32
(s, 1H), 5.39 (d, J ) 5.9 Hz, 1H), 5.28 (dd, J ) 5.9, 3.7 Hz,
1H), 4.19 (dd, J ) 10.2, 3.7 Hz, 1H), 4.05 (d, J ) 10.2 Hz, 1H),
1.49 (s, 3H), 1.39 (t, J ) 7 Hz, 3H), 1.34 (s, 3H).
4-N-(3,4-Ethylenedioxyphenyl)amino-5-(2-methyl-
phenyl)-7-(2,3-O-isopropylidene-â-D-erythro-furanosyl)-
pyrrolo[2,3-d]pyrimidine (21d). Suzuki coupling of 20c (525
mg) with 2-methylphenylboronic acid by the procedure de-
scribed for the synthesis of 21a provided protected nucleoside
21d (446 mg, 91%): 1H NMR (DMSO-d6) δ 8.36 (s, 1H), 7.50-
7.25 (m, 7H), 7.10 (d, J ) 2.2 Hz, 1H), 6.73 (d, J ) 8.4 Hz,
1H), 6.57 (dd, J ) 8.4, 2.2 Hz, 1H), 6.27 (s, 1H), 5.38 (d, J )
5.9 Hz, 1H), 5.31-5.22 (m, 1H), 4.25-3.92 (m, 6H), 2.21 (s,
3H), 1.49 (s, 3H), 1.33 (s, 3H).
4-N-(3-Ethoxyphenyl)amino-5-phenyl-7-(â-D-erythro-
furanosyl)pyrrolo[2,3-d]pyrimidine (19g). Compound 18g
(490 mg) was deprotected by the procedure described for the
synthesis of compound 19c. Recrystallization from ethanol
1
provided nucleoside 19g (365 mg, 84%): mp 183-184 °C; H
NMR (DMSO-d6) δ 8.42 (s, 1H), 7.75 (s, 1H), 7.65-7.48 (m,
6H, 1H exchangeable with D2O), 7.35 (t, J ) 1.8 Hz, 1H), 7.17
(t, J ) 8.2 Hz, 1H), 6.93 (dd, J ) 7.9, 1.8 Hz, 1H), 6.57 (dd, J
) 7.9, 2.5 Hz, 1H), 6.17 (d, J ) 6.7 Hz, 1H), 5.40 (d, J ) 6.7
Hz, 1H, exchangeable with D2O), 5.19 (d, J ) 4 Hz, 1H,
exchangeable with D2O), 4.77-4.64 (m, 1H), 4.35 (dd, J ) 9.2,
3.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.98 (q, J ) 7 Hz, 2H), 3.78
(dd, J ) 9.2, 1.4 Hz, 1H), 1.31 (t, J ) 7 Hz, 3H). Anal.
(C24H24N4O4) C, H, N.
4-N-(3,4-Ethylenedioxyphenyl)amino-5-phenyl-7-(â-D-
erythro-furanosyl)pyrrolo[2,3-d]pyrimidine (19h). Com-
pound 18h (460 mg) was deprotected by the procedure
described for the synthesis of compound 19c. Recrystallization
from EtOH provided nucleoside 19h (331 mg, 78%): mp 196-
197 °C; 1H NMR (DMSO-d6) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.65-
7.36 (m, 5H), 7.30 (s, 1H, exchangeable with D2O), 7.24 (d, J
) 2.1 Hz, 1H), 6.82 (dd, J ) 8.3, 2.1 Hz, 1H), 6.74 (d, J ) 8.3
Hz, 1H), 6.15 (d, J ) 6.7 Hz, 1H), 5.39 (d, J ) 6.7 Hz, 1H,
exchangeable with D2O), 5.19 (d, J ) 4 Hz, 1H, exchangeable
with D2O), 4.75-4.62 (m, 1H), 4.33 (dd, J ) 9.2, 3.7 Hz, 1H),
4.28-4.14 (m, 5H), 3.77 (d, J ) 9.2 Hz, 1H). Anal. (C24H22N4O5)
C, H, N.
4-N-(4-Fluorophenyl)amino-5-iodo-7-(2,3-O-iso-
propylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (20a). A solution of t-BuOK (18.3 mL, 1 M in
THF, 18.3 mmol) was added to a solution of 16b (5.14 g, 12.2
mmol) and 4-fluoroaniline (1.62 g, 14.6 mmol) in THF (24 mL)
at -20 °C. After stirring at -20 °C for 30 min, the reaction
mixture was quenched with saturated aqueous NH4Cl and the
resulting solution was extracted with EtOAc (3 × 25 mL). The
combined organic extracts were dried (MgSO4) and concen-
trated under reduced pressure, and the residue was purified
by flash chromatography (CH2Cl2/hexane 3/1) to provide
nucleoside 20a (5.44 g, 90%): 1H NMR (CDCl3) δ 8.38 (s, 1H),
7.85 (s, 1H), 7.75-7.60 (m, 2H), 7.15 (s, 1H), 7.10 (t, J ) 8.9
Hz, 2H), 5.99 (s, 1H), 5.50 (d, J ) 6.1 Hz, 1H), 5.24 (dd, J )
6.1, 3.8 Hz, 1H), 4.35-4.15 (m, 2H), 1.58 (s, 3H), 1.41 (s, 3H).
4-N-(4-Cyanophenyl)amino-5-iodo-7-(2,3-O-iso-
propylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (20b). Coupling of 4-cyanoaniline (1.79 g, 15.19
mmol) with 16b (5.07 g, 12.03 mmol) by the procedure
described for the synthesis of 20a provided nucleoside 20b
(4.99 g, 82%): 1H NMR (DMSO-d6) δ 8.87 (s, 1H, exchangeable
with D2O), 8.73 (s, 1H), 7.93 (d, J ) 8.8 Hz, 2H), 7.8 (d, J )
8.8 Hz, 2H), 7.79 (s, 1H), 6.22 (s, 1H), 5.32 (d, J ) 5.9 Hz,
1H), 5.23 (dd, J ) 5.9, 2.9 Hz, 1H), 4.13 (dd, J ) 10.3, 2.9 Hz,
1H), 4.04 (d, J ) 10.3 Hz, 1H), 1.47 (s, 3H), 1.32 (s, 3H).
4-N-(2-Methoxyphenyl)amino-5-(4-ethoxyphenyl)-7-
(2,3-O-isopropylidene-â-D-erythro-furanosyl)pyrrolo[2,3-
d]pyrimidine (21e). Suzuki coupling of 20d (521 mg, 1.03
mmol) with 4-ethoxyphenylboronic acid (856 mg, 5.16 mmol)
by the procedure described for the synthesis of 21a provided
protected nucleoside 21e (392 mg, 76%): 1H NMR (DMSO-d6)
δ 8.82-8.75 (m, 1H), 8.44 (s, 1H), 7.68 (s, 1H, exchangeable
with D2O), 7.45 (d, J ) 8.4 Hz, 2H), 7.44 (s, 1H), 7.11 (d, J )
8.4 Hz, 2H), 7.00-6.98 (m, 3H), 6.28 (s, 1H), 5.38 (d, J ) 5.9
Hz, 1H), 5.27 (dd, J ) 5.9, 3.7 Hz, 1H), 4.20 (dd, J ) 10.2, 3.7
4-N-(3,4-Ethylenedioxyphenyl)amino-5-iodo-7-(2,3-O-
isopropylidene-â-D-erythro-furanosyl)pyrrolo[2,3-d]-
pyrimidine (20c). Coupling of 3,4-ethylenedioxyaniline (2.2
mL, 18.3 mmol) with 16b (5.1 g, 12.3 mmol) by the procedure
described for the synthesis of 20a provided nucleoside 20c
(5.93 g, 90%): 1H NMR (CDCl3) δ 8.35 (s, 1H), 7.84 (s, 1H),
7.38 (d, J ) 2.6 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J ) 8.8, 2.6