5296 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 21
Eldrup et al.
with dichloromethane/methanol (1:1, 50 mL). The combined
filtrate was evaporated in vacuo, and the residue was purified
on silica gel using dichloromethane and dichloromethane/
methanol (40:1 through 30:1) as the eluent to furnish the
desired compound (0.22 g, 78%) as colorless foam. 1H NMR
(DMSO-d6): δ 0.62 (s, 3H), 2.36 (s, 3H), 3.58-3.94 (m, 4H),
5.04-5.14 (m, 3H), 6.18 (s, 1H, H-1′), 7.77 (s, 1H), 8.54 (s, 1H).
HRMS: calcd for C13H16ClN3O4 + H+ 314.0908, found 314.0905.
4-Am in o-5-m et h yl-7-(2-C-m et h yl-â-D-r ib ofu r a n osyl)-
7H-p yr r olo[2,3-d ]p yr im id in e (31). To 4-chloro-5-methyl-7-
(2-C-methyl-â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (30)
(0.2 g, 0.64 mmol) was added methanolic ammonia (saturated
at 0 °C) (40 mL). The mixture was heated in a stainless steel
autoclave at 100 °C for 14 h and then cooled and evaporated
in vacuo. The crude mixture was purified on silica gel with
dichloromethane/methanol (30:1, 20:1) gradient as the eluent
to give the title compound (0.13 g, 69%) as a colorless solid.
1H NMR (DMSO-d6): δ 0.60 (s, 3H), 2.26 (s, 3H), 3.52-3.61
(m, 1H), 3.70-3.88 (m, 3H), 5.00 (s, 1H), 4.91-4.99 (m, 3H),
6.04 (s, 1H), 6.48 (br s, 2H), 7.12 (s, 1H), 7.94 (s, 1H). HRMS:
calcd for C13H18N4O4 + H+ 295.1406, found 295.1407.
gel using methanol/dichloromethane (1:9) as the eluent. Frac-
tions containing the product were pooled and evaporated in
vacuo. This product was dissolved in 2 N aqueous NaOH (2
mL) and heated at reflux for 2 h. The suspension was cooled
and neutralized with 2 N aqueous HCl. The suspension was
absorbed on silica gel and was purified on a silica gel column
using methanol/dichloromethane (1:9 through 1:5) as the
eluent. Fractions containing the product were pooled and
evaporated in vacuo to give the desired compound (14 mg, 42%)
as a colorless solid. 1H NMR (methanol-d4): δ 0.85 (s, 3H),
3.77 (m, 1H), 3.90-4.07 (overlapping m, 2H), 6.05 (s, 1H), 7.13
(s, 1H). HRMS calcd for C12H15ClN4O5 + H+ 331.0809, found
331.0815.
Ack n ow led gm en t. We thank Dr. Charles R. Aller-
son of Isis Pharmaceuticals for valuable comments
about the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Tables of experi-
mental details for compound 9, atomic parameters, and
interatomic distances and angles. This material is available
4-Am in o-7-(2-C-m eth yl-â-D-r ibofu r a n osyl)-7H-p yr r olo-
[2,3-d ]p yr im id in e-5-ca r boxylic a cid (34). 4-Amino-5-meth-
yl-7-(2-C-methyl-â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine (34) (0.035 g, 0.11 mmol) was dissolved in a mixture of
aqueous ammonia (4 mL, 30 wt %) and saturated methanolic
ammonia (2 mL), and a solution of H2O2 in water (2 mL, 35
wt %) was added. The reaction mixture was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure, and the residue was purified by HPLC on a reverse-
phase column (Altech Altima C-18, 10 mm × 299 mm, A )
water, B ) acetonitrile, 10 to 60% B in 50 min, flow 2 mL/
min) to yield the title compound (0.015 g, 41%) as a white solid.
1H NMR (methanol-d4): δ 0.85 (s, 3H), 3.61 (m, 1H), 3.82 (m,
1H) 3.99-4.86 (m, 2H), 6.26 (s, 1H), 8.10 (s, 2H) 8.22 (s, 1H).
HRMS (FAB): calcd for C13H16N4O6 + H+ 325.1148, found
325.1143.
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through 5:1) as the eluent to give the title compound (11 mg,
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1
56%) as a colorless solid. H NMR (DMSO-d6): δ 0.68 (s, 3H),
3.48-3.58 (m, 1H), 3.68-3.73 (m, 2H), 3.84 (m, 1H), 4.72 (s,
1H), 4.97-5.03 (m, 2H), 5.45 (s br, 2H), 6.00 (s, 1H), 6.28 (d,
J ) 3.7 Hz, 1H), 6.44 (br s, 2H), 6.92 (d, J ) 3.7 Hz, 1H).
HRMS: calcd for C12H17N5O4 + H+ 296.1359, found 296.1358.
4-Am in o-2-flu or o-7-(2-C-m eth yl-â-D-r ibofu r a n osyl)-7H-
p yr r olo[2,3-d ]p yr im id in e (36). To a solution of HF/pyridine
(70%, 2 mL) and pyridine (0.5 mL) at -25 °C was added 2,4-
diamino-7-(2-C-methyl-â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]py-
rimidine (35) (60 mg, 0.20 mmol) in pyridine (0.5 mL) followed
by tert-butyl nitrite (0.036 mL). Stirring was continued for 5
min at -25 °C, and the solution was then poured into ice water
(5 mL), neutralized with 2 N aqueous NaOH, and evaporated
in vacuo. The residue was purified on silica gel using dichlo-
romethane/methanol (20:1 to 10:1) as the eluent to give the
desired compound (18 mg, 30%) as a colorless powder. 1H NMR
(acetonitrile-d3): δ 0.80 (s, 3H), 3.46 (t, 1H), 3.52 (d, 1H), 3.58
(s, 1H), 3.72-3.82 (m, 1H), 3.85-4.01 (m, 2H), 4.13 (dd, 1H),
6.04 (s, 1H), 6.09 (br s, 2H), 6.55 (d, 1H), 7.37 (d, H). HRMS:
calcd for C12H15FN4O4 + H+ 299.1156, found 299.1157.
2-Am in o-5-ch lor o-7-(2-C-m eth yl-â-D-r ibofu r a n osyl)-7H-
p yr r olo[2,3-d ]p yr im id in -4(3H)-on e (37). To a precooled
solution (0 °C) of 2-amino-4-chloro-7-(2-C-methyl-â-D-ribofura-
nosyl)-7H-pyrrolo[2,3-d]pyrimidine (19) (31 mg, 0.10 mmol) in
dimethylformamide (0.5 mL) was added N-chlorosuccinimide
(14.3 g, 0.11 mmol) in dimethylformamide (0.5 mL) dropwise.
The solution was stirred at room temperature for 2 h, and the
reaction was quenched by addition of methanol (5 mL) and
evaporated in vacuo. The crude product was purified on silica
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