1850 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7
McGuigan et al.
solution of 2′3′-dideoxyuridine (6) (640 mg, 3.02 mmol) in
methanol (40 mL), and the resulting solution was stirred at
room temperature for 10 min. The pH of the solution was made
∼7.00 by adding a solution of ammonium bicarbonate (1 N).
The solvent was removed under high vacuum, and the residue
obtained was purified by flash column chromatography eluting
with 13% methanol in dichloromethane to afford a pale brown
oil (780 mg, 70%) which on trituration with dichloromethane
3-[2′,3′-Did eoxy-r ib o-â-D-fu r a n osyl]-6-oct yl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9b). This was prepared
entirely as outlined for 9a above. The product was purified by
flash column chromatography, eluting with 5% methanol in
ethyl acetate to afford a pale yellow oil (140 mg, 42%) which
1
gave a white solid on trituration with ethyl acetate. H NMR
(d6-DMSO): δ 8.85 (1H, S, H-4), 6.43 (1H, S, H-5), 6.01 (1H,
m, H-1′), 5.22 (1H, t, J ) 5.1 Hz, 5′-OH), 4.18 (1H, m, H-4′),
3.84 (1H, m, H-5′) 3.66 (1H, m, H-5′), 2.64 (2H, t, J ) 7.2 Hz,
R-CH2), 2.48 (1H, m, H-2′), 1.97 (1H, m, H-2′), 1.78 (2H, m,
H-3′), 1.63-1.25 (12H, m, 6 × CH2), 0.85 (3H, t, J ) 6.9 Hz,
CH3). MS [ES+] m/e 372 (15%), 371 (100%, MNa+), 271 (20%,
[base Na]+). C19H28N2O4 Na requires 371.1947, observed
371.1957. Anal. (C19H28N2O4) C, H, N.
1
gave an off white solid. H NMR (d6-DMSO): δ 10.65 (1H,S,
3-NH), 5.78 (1H, t, H-1′), 5.05 (1H, d, H-6), 4.80 (1H, bS, 5′-
OH), 4.65 (1H, d, H-5), 3.85 (1H, S, H-4′), 3.54 (2H, m, H-5′),
3.30 (3H, S, OCH3), 2.10 (2H, m, H-2′), 1.80 (2H, m, H-3′). MS
[ES+] m/e 393 (100%, MNa+). Accurate mass C10H15N2O5 Na
requires 392.9923, observed 392.9912.
3-[2′,3′-Did eoxy-r ib o-â-D-fu r a n osyl]-6-n on yl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9c). This was prepared
entirely as outlined for 9a above. The product was was purified
by flash column chromatography, eluting with 7% methanol
in ethyl acetate to afford a pale yellow oil (138 mg, 52%) which
2′,3′-Did eoxy-5-iod or id in e (7) (Meth od 1). Iodine mono-
chloride (3.75 g, 23.113 mmol, 1.4 equiv) was added to a
solution of 2′,3′-dideoxyuridine (6) (3.5 g, 16.509 mmol) in
methanol (120 mL), and the solution was stirred at room
temperature for 2 h. The solution was made neutral on
addition of 10% aqueous ammonia solution. The solvent was
removed under high vacuum, the dark brown residue obtained
was dissolved in ethyl acetate (300 mL), and the excess of
iodine from this solution was removed by extracting it with a
0.5 M aqueous solution of sodium thiosulfate. The organic layer
was washed with water (50 mL × 2) and dried over anhydrous
MgSO4 and filtered. The solvent from the organic layer was
removed under high vacuum to obtain a yellowish oil which
on addition of ethyl acetate afforded an off white solid (4.31 g,
1
gave a white solid on trituration with diethyl ether. H NMR
(CDCl3): δ 8.76 (1H, S, H-4), 6.25 (1H, m, H-1′), 6.18 (1H, S,
H-5) 4.34 (1H, m, H-4′), 4.18 (1H, m, H-5′), 3.94 (1H, m, H-5′),
2.68 (3H, m, R-CH2+H-2′), 2.22 (1H, m, H-2′), 1.99 (2H, m,
H-3′), 1.74-1.31 (14H, m, 7 × CH2), 0.93 (3H, t, J ) 6.9 Hz,
CH3). MS [ES+] m/e 386 (15%), 385 (100%, MNa+), 285 (40%,
[base Na]+). C20H30N2O4 Na requires 385.2103, observed
385.2104. Anal. (C20H30N2O4‚1.5H2O) C, H, N.
3-[2′,3′-Did eoxy-r ib o-â-D-fu r a n osyl]-6-d ecyl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9d ). This was prepared
entirely as outlined for 9a above. The product was purified by
flash column chromatography, eluting with 6% methanol in
ethyl acetate to afford a pale yellow oil (360 mg, 81%) which
1
70%). H NMR (d6-DMSO): δ 11.62 (1H, S, 3-NH), 8.59 (1H,
S, H-6), 5.89 (1H, m, H-1′), 5.23 (1H, t, J ) 4.6 Hz, 5′-OH),
4.06 (1H, m, H-4′), 3.77 (1H, m, H-5′), 3.55 (1H, m, H-5′), 2.25
(1H, m, H-2′), 2.04 (1H, m, H-2′), 1.83 (2H, m, H-3′).
1
gave a white solid on trituration with ethyl acetate. H NMR
2′,3′-Did eoxy-5-iod or id in e (7) (Meth od 2). 2′,3′-Dideoxy-
5-iodo-6-methoxyuridine (8) (100 mg, 0.27 mmol) was dissolved
in acetonitrile (5 mL), and to this solution was added triethyl-
amine (70 mg, 0.70 mmol, 2.6 equiv, 100 µL). The resulting
solution was heated under reflux for 2 h. The solvent was
removed in vacuo, and the oil obtained afforded an amorphous
(d6-DMSO): δ 8.85 (1H, S, H-4), 6.43 (1H, S, H-5), 6.01 (1H,
m, H-1′) 5.21 (1H, t, J ) 5.2 Hz, 5′-OH), 4.18 (1H, m, H-4′),
3.84 (1H, m, H-5′), 3.65 (1H, m, H-5′), 2.64 (2H, t, J ) 7.3 Hz,
R-CH2), 2.48 (1H, m, H-2′), 1.97 (1H, m, H-2′), 1.78 (2H, m,
H-3′), 1.63-1.18 (16H, m, 8 × CH2), 0.85 (3H, t, J ) 6.9 Hz,
CH3). MS [ES+] m/e 399 (100%, MNa+), 299 (50%, [base Na]+).
1
solid on trituration with diethyl ether (80 mg, 80%). H NMR
C
21H32N2O4 Na requires 399.2260, observed 399.2254. Anal.
(d6-DMSO): δ 11.62 (1H, S, 3N-H), 8.58 (1H, S, H-6), 5.89
(1H, m, H-1′), 5.23 (1H, t, J ) 4.9 Hz, 5′-OH), 4.06 (1H, m,
H-4′), 3.78 (1H, m, H-5′), 3.55 (1H, m, H-5′), 2.33-1.84 (4H,
m, H-3′ and H-2′).
(C21H32N2O4) C, H, N.
3-[2′,3′-Did eoxy-r ibo-â-D-fu r a n osyl]-6-u n d ecyl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9e). This was prepared
entirely as outlined for 9a above. The product was purified by
flash column chromatography, eluting with 6% methanol in
ethyl acetate to afford an off white solid (145 mg, 50%). 1H
NMR (CDCl3): δ 8.74 (1H, S, H-4), 6.25 (1H, m, H-1′), 6.17
(1H, S, H-5), 4.34 (1H, m, H-4′), 4.21 (1H, m, H-5′), 3.94 (1H,
m, H-5′), 2.68 (2H, t, J ) 7.5 Hz, R-CH2), 2.53 (1H, m, H-2′),
2.28 (1H, m, H-2′), 1.99 (2H, m, H-3′), 1.74-1.13 (18H, m, 9 ×
CH2), 0.93 (3H, t, J ) 6.9 Hz, CH3). MS [ES+] m/e 429 (5%,
MK+), 414 (15%), 413 (80%, MNa+), 313 (100%, [base Na]+),
291 (20%, [base + 1]+). Anal. (C22H34N2O4‚3H2O) C, H, N.
3-[2′,3-Did eoxy-r ib o-â-D-fu r a n osyl]-6-h exyl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9a ). Diisopropylethylamine
(267 mg, 2.07 mmol, 2 equiv, 0.36 mL), 1-octyne (342 mg, 3.106
mmol, 3 equiv, 0.45 mL), tetrakis(triphenylphosphine)pal-
ladium(0) (120 mg, 0.104 mmol, 0.1 equiv), and copper(II)
iodide (39 mg, 0.206 mmol, 0.2 equiv) were added to a solution
of 2′3′-dideoxy-5-iodoridine (7) (350 mg, 1.035 mmol) in dry
N,N-dimethylformamide (25 mL) at room temperature under
N2 atmosphere, and the mixture was stirred at room temper-
ature for 16 h under N2. To the resulting solution were added
copper(I) iodide (39 mg, 0.206 mmol, 0.2 equiv) and triethyl-
amine (10 mL), and the solution was heated to 70-80 °C for
6 h. Solvent was removed under high vacuum. Dichloro-
methane and methanol (1:1 50 mL mixture) were added to the
above residue, to this solution was added an excess of Amber-
3-[2′,3′-Did eoxy-r ibo-â-D-fu r a n osyl]-6-d od ecyl-2,3-d ih y-
d r ofu r o[2,3-d ]p yr im id in -2-on e (9f). This was prepared
entirely as outlined for 9a above. The product was purified by
flash column chromatography eluting with 6% methanol in
ethyl acetate to afford a pale yellow oil (230 mg, 55%) which
1
gave a white solid on trituration with diethyl ether. H NMR
-
lite IRA-400 (HCO3 form), and the resulting mixture was
(d6-DMSO): δ 8.82 (1H, S, H-4), 6.41 (1H, S, H-5), 6.03 (1H,
m, H-1′), 5.09 (1H, bS, 5′-OH), 4.17 (1H, m, H-4′), 3.80 (1H,
m, H-5′), 3.67 (1H, m, H-5′), 2.64 (2H, t, J ) 7.3 Hz, R-CH2),
2.45 (1H, m, H-2′), 1.97 (1H, m, H-2′), 1.78 (2H, m, H-3′), 1.63-
1.25 (20H, m, 10 × CH2), 0.87 (3H, t, J ) 6.9 Hz, CH3). MS
[ES+] m/e 443 (5%, MK+), 428 (20%), 427 (100%, MNa+), 327
(30%, [base Na]+). C23H36N2O4 Na requires 427.2573, observed
427.2575. Anal. (C23H36N2O4) C, H, N.
stirred at room temperature for 1 h. The resin was filtered
and washed with methanol, and the combined filtrate was
evaporated to dryness to afford a dark brown residue. This
was purified by flash column chromatography, eluting with
6% methanol in ethyl acetate to afford a pale yellow oil (150
mg, 45%) which gave a white solid on trituration with ethyl
acetate. 1H NMR (d6-DMSO): δ 8.82 (1H, S, H-4), 6.40 (1H,
S, H-5), 5.98 (1H, m, H-1′), 5.19 (1H, t, J ) 5.3 Hz, 5′-OH),
4.15 (1H, m, H-4′), 3.82 (1H, m, H-5′) 3.63(1H, m, H-5′), 2.62
(2H, t, J ) 7.3 Hz, R-CH2), 2.48 (1H, m, H-2′), 1.99 (1H, m,
H-2′), 1.78 (2H, m, H-3′), 1.60-1.22 (8H, m, 4 × CH2), 0.83
(3H, t, J ) 6.9 Hz, CH3). MS [ES+] m/e 344 (10%), 343 (100%,
MNa+), 243 (15%, [base Na]+). C17H24N2O4 Na requires
343.1634, observed 343.1633. Anal. (C17H24N2O4) C, H, N.
3-[2′,3′-Did eoxy-r ibo-â-D-fu r a n osyl]-6-tetr a d ecyl-2,3-d i-
h yd r ofu r o[2,3-d ]p yr im id in -2-on e (9g). This was prepared
entirely as outlined for 9a above. The product was purified by
flash column chromatography, eluting with 5% methanol in
1
ethyl acetate to afford a white solid (250 mg, 56%). H NMR
(CDCl3): δ 8.74 (1H, S, H-4), 6.25 (1H, m, H-1′), 6.17 (1H, S,
H-5), 4.34 (1H, m, H-4′), 4.21 (1H, m, H-5′) 3.94 (1H, m, H-5′),