4-Amino-5-oxopyrido[2,3-d]pyrimidine Nucleosides
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3711
3.85 (m, 1 H), 3.99 (m, 1 H), 4.81 (s, 1 H, OH), 5.23 (t, J ) 4.2
Hz, 1 H, OH), 5.34 (d, J ) 6.6 Hz, 1 H, OH), 6.25 (d, J ) 8.1
Hz, 1 H), 6.79 (d, J ) 7.8 Hz, 1 H), 8.20 and 9.60 (2 br d, J )
4.8 Hz, 2 H, NH2), 8.29 (s, 1 H), 8.44 (d, J ) 8.1 Hz, 1 H); MS
307 (M - H), 161 (base - H). Anal. (C13H16N4O5) C, H, N.
were prepared as a mixture from 1-O-acetyl-5(R,S)-C-methyl-
2,3,5-tri-O-benzoyl-D-ribofuranoses19 (R/S ratio, 2:3 or 3:2; 0.65
g, 1.3 mmol) and 25 (0.24 g, 1.5 mmol) as described in the
general procedure: total yield 150 mg (25%, 2 steps) as a
colorless solid (5′(R/S)-isomers, 2:3); 1H NMR (DMSO-d6) δ 1.11
and 1.17 (2 d, J ) 6.6 and 6.3 Hz, 3 H, Me), 3.70-3.78 (m, 1
H), 3.86 (m, 1 H), 3.98-4.15 (m, 2 H), 5.08-5.20 (m, 2 H, OH),
5.33 and 5.37 (2 d, J ) 5.1 and 5.4 Hz, 1 H, OH), 6.21-6.24
(m, 1 H), 6.60 and 6.67 (2 d, J ) 4.5 and 5.4 Hz, 1 H), 8.21
and 9.58 (2 br m, 2 H, NH2), 8.27-8.47 (m, 2 H). Anal.
(C13H16N4O5‚0.25H2O) C, H, N.
4-Am in o-5-oxo-8-(3-d eoxy-3-C-m eth ylen e-â-D-r ibofu r a -
n osyl)p yr id o[2,3-d ]p yr im id in e (2e) was prepared from 13
(0.54 g, 1.6 mmol) and 25 (0.34 g, 2.1 mmol) as described in
the general procedure: total yield 0.12 g (28%, 2 steps).
Recrystallization from water gave 2e as a colorless solid: mp
1
137-138 °C; H NMR (DMSO-d6) δ 3.68-3.74 (m, 2 H), 4.62
(m, 2 H), 5.14 (t, J ) 5.1 Hz, 1 H, OH), 5.20 (d, J ) 9.9 Hz, 2
H), 5.87 (d, J ) 4.8 Hz, 1 H, OH), 6.26 (d, J ) 7.8 Hz, 1 H),
6.58 (d, J ) 6.6 Hz, 1 H), 8.23 and 9.58 (2 br d, J ) 4.8 Hz, 2
H, NH2), 8.27 (d, J ) 8.1 Hz, 1 H), 8.30 (s, 1 H). Anal.
(C13H14N4O4‚0.5H2O) C, H, N.
4-Am in o-5-oxo-8-(5(R)-C-eth yl-â-D-r ibofu r an osyl)pyr ido-
[2,3-d]pyr im idin e (3b) an d 4-Am in o-5-oxo-8-(5(S)-C-eth yl-
â-D-r ibofu r a n osyl)p yr id o[2,3-d ]p yr im id in e (4b). A sus-
pension of a mixture of 3f and 4d (R/S ratio, 1:3 or 3:1; 0.14 g,
0.45 mmol) and 10% Pd/C (200 mg) in methanol (50 mL) was
shaken in a hydrogenation apparatus (3 psi hydrogen) at room
temperature for 2 h, and the catalyst was filtered and washed
with methanol. The solvents were evaporated, and the residue
was subjected to chromatography (10% methanol in dichlo-
romethane) to give a mixture of 3b+4b (R/S ratio, 1:3 or 3:1;
0.12 g, 79%) as a colorless solid (two isomers, 1:3): 1H NMR
(DMSO-d6) δ 0.88-0.94 (m, 3 H, CH3CH2), 1.46-1.56 (m, 2
H, CH3CH2), 3.54 (m, 1 H), 3.80 and 3.86 (2 m, 1 H), 4.00-
4.12 (m, 2 H), 5.09 (m, 1 H, OH), 5.15 and 5.24 (2 d, J ) 6.0
and 5.4 Hz, 1 H, OH), 5.32 and 5.38 (2 d, J ) 5.1 and 5.4 Hz,
1 H, OH), 6.22 (d, J ) 7.8 Hz, 1 H), 6.59 and 6.65 (2 d, J ) 4.5
and 5.7 Hz, 1 H), 8.20 and 9.59 (2 br d, J ) 4.5 Hz, 2 H, NH2),
8.29-8.47 (m, 2 H). Anal. (C14H18N4O5) C, H, N.
4-Am in o-5-oxo-8-(3-C-eth yn yl-â-D-xylofu r an osyl)pyr ido-
[2,3-d ]p yr im id in e (2d ). Hydrazine hydrate (0.99 mL, 20
mmol) was added to a solution of 31, the major coupling
product from the condensation of 25 and 1,2-di-O-acetyl-3,5-
di-O-benzoyl-D-xylofuranose26 (3.7 g, 6.8 mmol), in a mixture
of pyridine (48 mL) and acetic acid (12 mL). The reaction
mixture was stirred at room temperature for 20 h, then acetone
(20 mL) was added. The solvent was evaporated and the crude
32 was dissolved in pyridine (55 mL). DMT-Cl (5.6 g, 16 mmol)
was added and the reaction mixture was stirred at 60 °C for
4 days, then cooled to 0 °C, quenched with methanol (5 mL).
After the usual workup, the residue was subjected to chroma-
tography (0-6% methanol in dichloromethane) to give 3.2 g
of the fully protected nucleoside, which was added to metha-
nolic ammonia (73 mL). The reaction mixture was sealed and
stirred at room temperature for 20 h. The solvent was
evaporated and the residue (33) was dissolved in pyridine (28
mL). DMT-Cl (1.0 g, 3.1 mmol) was added at 0 °C and the
mixture was stirred at the same temperature for 2 h. Methanol
(5 mL) was added and the solvent was evaporated. After the
usual workup, the residue was dissolved with DCC (1.2 g, 5.6
mmol) in a mixture of toluene (4 mL) and DMSO (17 mL).
Dichloroacetic acid (0.12 mL, 1.4 mmol) was added at 0 °C and
the reaction mixture was stirred at room temperature for 20
h. After the usual workup, the residue was subjected to
chromatography (0-5% ethyl acetate in dichloromethane) to
give 1.5 g (18%, 5 steps) of the keto nucleoside 34.
4-Am in o-5-oxo-8-(5(R)-C-p r op yl-â-D-r ibofu r a n osyl)p y-
r id o[2,3-d ]p yr im id in e (3c) was prepared from 3d (85 mg,
0.25 mmol) by a similar procedure as described for 3b: yield
55 mg (65%). Recrystallization from water/methanol gave 3c
1
as a colorless solid: mp 218-220 °C; H NMR (DMSO-d6) δ
0.88 (t, J ) 6.6 Hz, 3 H, CH3CH2), 1.30-1.50 (m, 4 H,
CH3CH2CH2), 3.67 (m, 1 H), 3.78 (m, 1 H), 4.10 (m, 2 H), 5.10
(d, 1 H, J ) 4.5 Hz, OH), 5.14 (d, J ) 5.7 Hz, 1 H, OH), 5.32
(d, J ) 5.4 Hz, 1 H, OH), 6.22 (d, J ) 8.4 Hz, 1 H), 6.66 (d, J
) 5.4 Hz, 1 H), 8.21 and 9.59 (2 br d, J ) 4.5 Hz, 2 H, NH2),
8.30 (m, 2 H). Anal. (C15H20N4O5) C, H, N.
4-Am in o-5-oxo-8-(5(R)-C-allyl-â-D-r ibofu r an osyl)pyr ido-
[2,3-d ]p yr im id in e (3d ) was prepared from 1-O-acetyl-2,3,5-
tri-O-benzoyl-5(R)-C-allyl-D-ribofuranose19 (0.65 g, 1.2 mmol)
and 25 (0.23 g, 1.4 mmol) as described in the general
procedure: total yield 0.15 g (39%, 2 steps). Recrystallization
Compound 34 (0.85 g, 0.7 mmol) in THF (18 mL) was added
to a solution of ethynylmagnesium bromide (0.5 M in THF, 5
mL) in ether (18 mL), and the reaction mixture was stirred at
0 °C for 8 h, quenched with water, diluted with ethyl acetate
and 2 mL of acetic acid. After the usual workup and chroma-
tography (0-5% ethyl acetate in dichloromethane), the residue
was dissolved in 80% acetic acid (8.2 mL). The reaction mixture
was stirred at room temperature for 5 h and then at 50 °C for
1 h. The solvent was evaporated and the residue was subjected
to chromatography (15% methanol in dichloromethane) to give
0.11 g of 2d (49%, 2 steps) as a white foam. Recrystallization
1
from water gave 3d as a colorless solid: mp 208-209 °C; H
NMR (DMSO-d6) δ 2.14-2.30 (m, 2 H), 3.71-3.82 (m, 2 H),
4.08-4.15 (m, 2 H), 5.03-5.14 (m, 3 H, incl. 1 OH), 5.31 (d, J
) 5.4 Hz, 1 H, OH), 5.36 (d, J ) 5.7 Hz, 1 H, OH), 5.80-5.93
(m, 1 H), 6.22 (d, J ) 8.1 Hz, 1 H), 6.65 (d, J ) 5.7 Hz, 1 H),
8.22 and 9.58 (2 br d, J ) 4.8 Hz, 2 H, NH2), 8.29 (d, J ) 9.0
Hz, 1 H), 8.30 (s, 1 H). Anal. (C15H18N4O5) C, H, N.
4-Am in o-5-oxo-8-(5(R,S)-C-vin yl-â-D-r ibofu r a n osyl)p y-
r id o[2,3-d ]p yr im id in e (3e) a n d 4-a m in o-5-oxo-8-(5(R,S)-
C-vin yl-â-D-r ibofu r a n osyl)p yr id o[2,3-d ]p yr im id in e (4c)
were prepared as a mixture from 1-O-acetyl-2,3,5-tri-O-ben-
zoyl-5(R,S)-C-vinyl-D-ribofuranoses19 (R/S ratio, 1:1; 0.41 g,
0.77 mmol) and 25 (0.15 g, 0.93 mmol) as described in the
general procedure: total yield 0.095 g (39%, 2 steps) as a
colorless solid (5′(R/S)-isomers, 1:1); 1H NMR (DMSO-d6) δ
3.85-3.92 (m, 1 H), 4.00-4.19 (m, 2 H), 4.25 (m, 1 H), 5.10-
5.19 (m, 2 H, including 1 OH), 5.27-5.41 (m, 2 H, include. 1
OH), 5.59 (m, 1 H, OH), 6.23 (m, 1 H), 6.58 and 6.72 (2 d, J )
5.1 and 7.2 Hz, 1 H), 8.21 and 9.58 (2 br m, 2 H, NH2), 8.29-
8.44 (m, 2 H). Anal. (C14H16N4O5‚0.2H2O) C, H, N.
1
from water gave a colorless solid: mp 240-242 °C; H NMR
(DMSO-d6) δ 3.56 (s, 1 H), 3.81 (m, 2 H), 3.98 (d, J ) 6.0 Hz,
1 H), 4.14 (m, 1 H), 5.96 (t, J ) 5.7 Hz, 1 H, OH), 6.09 (s, 1 H,
OH), 6.20 (d, J ) 8.4 Hz, 1 H), 6.33 (d, J ) 6.3 Hz, 1 H, OH),
6.36 (s, 1 H), 8.12 (d, J ) 8.4 Hz, 1 H), 8.20 and 9.59 (2 br d,
J ) 5.1 Hz, 2 H, NH2), 8.32 (s, 1 H). Anal. (C14H14N4O5‚
0.25H2O) C, H, N.
4-Am in o-5-oxo-8-(3-C-eth yn yl-â-D-r ibofu r an osyl)pyr ido-
[2,3-d ]p yr im id in e (2f) was prepared from 1-O-acetyl-2,3,5-
tri-O-benzoyl-3-C-ethynyl-D-ribofuranose28 and 25 according to
the general procedure: total yield 38% (2 steps) as a colorless
solid; 1H NMR (DMSO-d6) δ 3.56 (s, 1 H), 3.68-3.82 (m, 2 H),
3.97 (m, 1 H), 4.29 (t, J ) 6.6 Hz, 1 H), 5.21 (t, J ) 4.4 Hz, 1
H, OH), 5.86 (d, J ) 6.6 Hz, 1 H, OH), 5.99 (s, 1 H, OH), 6.25
(d, J ) 7.8 Hz, 1 H), 6.72 (d, J ) 6.9 Hz, 1 H), 8.21 and 9.57
(2 d, J ) 5.1 Hz, 2 H, NH2), 8.30 (s, 1 H), 8.37 (d, J ) 8.1 Hz,
1 H). Anal. (C14H14N4O5‚0.25H2O) C, H, N.
4-Am in o-5-oxo-8-(5(R,S)-C-eth yn yl-â-D-r ibofu r a n osyl)-
pyr ido[2,3-d]pyr im idin e (3f) an d 4-am in o-5-oxo-8-(5(R,S)-
C-eth yn yl-â-D-r ibofu r an osyl)pyr ido[2,3-d]pyr im idin e (4d)
were prepared as a mixture from 1-O-acetyl-2,3,5-tri-O-ben-
zoyl-5(R,S)-C-ethynyl-D-ribofuranoses19 (R/S ratio, 1:1; 1.5 g,
2.8 mmol) and 25 (0.50 g, 3.1 mmol) as described in the general
procedure: total yield 0.43 g (51%, 2 steps) as a colorless solid
4-Am in o-5-oxo-8-(5(R)-C-m eth yl-â-D-r ibofu r a n osyl)p y-
r id o[2,3-d ]p yr im id in e (3a ) a n d 4-a m in o-5-oxo-8-(5(S)-C-
m eth yl-â-D-r ibofu r a n osyl)p yr id o[2,3-d ]p yr im id in e (4a )
1
(5′(R/S)-isomers, 1:1); H NMR (DMSO-d6) δ 3.42 and 3.50 (2
d, J ) 1.8 Hz, 1 H), 3.92 (m, 1 H), 4.02-4.20 (m, 2 H), 4.44-