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A Novel Class of Phosphonate Nucleosides
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11 2867
concentrated in vacuo. The residue was purified by a silica
gel column chromatography using EtOAc/n-hexane (1/1) to
afford 7.1 g of the phosphonate 5 (70% yield) as a pale yellow
liquid. 1H NMR (300 MHz, CDCl3): δ 0.54 (dd, J ) 7.1, 4.2
Hz, 2H), 0.88 (dd, J ) 7.1, 4.3 Hz, 2H), 1.05 (s, 9H), 1.29 (d, J
) 6.6 Hz, 6H), 1.33 (d, J ) 6.6 Hz, 6H), 3.79 (s, 2H), 3.97 (d,
J ) 9.3 Hz, 2H), 4.71 (m, 2H), 7.43 (m, 6H), 7.67 (m, 4H). 13C
NMR (75 MHz, CDCl3): δ 10.8 (2C), 19.1, 23.8 (d, J ) 4.6 Hz,
2C), 24.0 (d, J ) 3.8 Hz, 2C), 26.7 (3C), 63.6 (d, J ) 168 Hz),
64.4 (d, J ) 15.0 Hz), 67.1, 70.6 (d, J ) 7.5 Hz, 2C), 127.6
(4C), 129.6 (2C), 133.1 (2C), 135.5 (4C).
({1-[(2-Am in o-6-ch lor o-9H -p u r in -9-yl)m e t h yl]cyclo-
p r op yl}oxy)m eth ylp h osp h on ic Acid (15). To a solution of
the phosphonate 7 (765 mg, 1.8 mmol) in 85 mL of MDC was
added trimethylsilyl bromide (5.6 g, 36.6 mmol). The mixture
was heated under reflux for 18 h and then concentrated in
vacuo. The residue was partitioned between MDC and water.
The aqueous layer was freeze-dried to afford 600 mg of the
phosphonic acid 15 (100% yield) as pale yellowish solids. 1H
NMR (500 MHz, MeOH-d4): δ 0.99 (br s, 2H), 1.03 (br s, 2H),
3.92 (d, J ) 10.0 Hz, 2H), 4.50 (s, 2H), 9.29 (s, 1H). Purity:
HPLC analysis.
Diisop r op yl {[1-(H yd r oxym et h yl)cyclop r op yl]oxy}-
m eth ylp h osp h on a te (6). To a solution of the phosphonate 5
(8.3 g, 16.5 mmol) in 100 mL of MeOH was added ammonium
fluoride (3.1 g, 83.4 mmol). The mixture was heated under
reflux for 4 h. After removal of MeOH, the residue was directly
purified by a silica gel column chromatography using MeOH/
MDC (1/20) to afford 3.6 g of the phosphonate 6 (82% yield)
({1-[(2-Am i n o -6-h y d r o x y -9H -p u r i n -9-y l)m e t h y l]-
cyclop r op yl}oxy)m eth yl p h osp h on ic Acid (P MCG, 1). A
solution of the phosphonic acid 15 (820 mg, 2.4 mmol) in 20.0
mL of 2 N HCl was heated under reflux for 6 h and then was
freeze-dried. The residue was recrystallized from MeOH to
afford 740 mg of PMCG-monohydrogen bromide as white
1
solids. H NMR (400 MHz, DMSO-d6): δ 0.92 (br q, 4H), 3.74
1
as a colorless liquid. H NMR (400 MHz, CDCl3): δ 0.62 (t, J
(d, J ) 10.0 Hz, 2H), 4.30 (s, 2H), 6.98 (br s, 2H), 7.0-8.5 (br,
2H), 8.98 (s, 1H), 11.33 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 11.2 (2C), 46.7, 62.70 (d, J ) 6.0 Hz), 63.0 (d, J ) 159.0
Hz), 109.4, 137.7, 150.2, 154.2, 155.0. HRMS (M+): 316.0811
) 5.6 Hz, 2H), 0.89 (d, J ) 5.6 Hz, 2H), 1.35 (d, J ) 6.4 Hz,
12H), 3.66 (s, 2H), 3.86 (d, J ) 8.0 Hz, 2H), 4.78 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ 11.2 (2C), 23.8 (d, J ) 4.5 Hz, 2C),
23.9 (d, J ) 3.8 Hz, 2C), 62.3 (d, J ) 172 Hz), 65.9, 71.3 (d, J
) 6.8, 2C). HRMS (M+): 267.1361 calcd for C11H23O5P, found
267.1368. Anal. (C11H23O5P) C, H.
calcd for
C10H14N5O5P, found 316.0810. Anal. Calcd for
(C10H14N5O5P‚HBr): C, 30.32; H, 3.82; N, 17.68. found: C,
30.20; H, 4.13; N, 17.16.
{1-[(Diisop r op ylp h osp h or yl)m et h oxy]cyclop r op yl}-
m eth yl Meth a n esu lfon a te (17). To a solution of the phos-
phonate 6 (1.5 g, 5.6 mmol) in 50 mL of MDC were added
methansulfonyl chloride (0.84 g, 7.3 mmol) and triethylamine
(0.85 g, 8.4 mmol) at 0 °C. The mixture was stirred for 30 min
at 25 °C and then quenched with saturated NH4Cl. The organic
layer was washed with brine (20 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by a flash
silica gel column chromatography using EtOAc/n-hexane (1/
Diisop r op yl ({1-[(2-Am in o-9H-p u r in -9-yl)m eth yl]cyclo-
p r op yl}oxy)m eth ylp h osp h on a te (18). To a solution of the
phosphonate 7 (150 mg, 0.36 mmol) in 15.0 mL of THF was
added 5 wt % palladium on carbon (15 mg). The mixture was
hydrogenated under H2 atmosphere for 18 h. The Pd on C was
filtered out through a Celite, and the filtrate was concentrated
in vacuo, which was purified by a silica gel column chroma-
tography to afford 130 mg of 18 (94% yield) as white solids.
1H NMR (500 MHz, CDCl3): δ 0.86 (t, J ) 6.5 Hz, 2H), 1.03
(t, J ) 6.5 Hz, 2H), 1.23 (d, J ) 6.5 Hz, 6H), 1.30 (d, J ) 6.5
Hz, 6H), 3.83 (d, J ) 8.0 Hz, 2H), 4.23 (s, 2H), 4.71 (m, 2H),
5.20 (s, 2H), 8.17 (s, 1H).
({1-[(2-Am in o-9H-p u r in -9-yl)m eth yl]cyclop r op yl}oxy)-
m eth ylp h osp h on ic Acid (P MCDG, 8). To a solution of the
phosphonate 18 (130 mg, 0.34 mmol) in 10 mL of MDC was
added trimethylsilyl bromide (560 mg, 3.7 mmol). The mixture
was heated under reflux for 18 h and then concentrated in
vacuo. The residue was partitioned between MDC and water.
The aqueous layer was freeze-dried to afford 91 mg of 8 (89.5%
yield) as yellowish solids. The compound was recrystallized
from water for X-ray crystallography. 1H NMR (400 MHz,
DMSO-d6): δ 0.92 (br q, 4H), 3.76 (d, J ) 12.0 Hz, 2H), 4.33
(s, 2H), 8.0 (br s, 2H), 8.74 (s, 1H), 9.00 (s, 1H). 13C NMR (100
MHz, DMSO-d6): δ 11.6 (2C), 45.9, 62.9 (d, J ) 15.0 Hz), 63.0
(d, J ) 161 Hz), 125.6, 139.1, 149.8, 154.2, 157.1. HRMS
(MH+): 300.0862 calcd for C10H14N5O4P, found 300.0872. Anal.
(C10H14N5O4P‚H2O) C, H, N.
({1-[(2-Am in o-9H-p u r in -9-yl)m eth yl]cyclop r op yl}oxy)-
m eth ylp h osp h on ic Acid Dip ivoxyl (P MCDG Dip ivoxyl,
2). To a solution of 8 (42.8 g, 143 mmol) in 257 mL of 1-methyl-
2-pyrrolidinone was added TEA (43.4 g, 430 mmol) at 60 °C
and stirred for 30 min at the same temperature. Chloromethyl
pivaloate (64.6 g, 429 mmol) was added the above mixture for
20 min and stirred for 48 h at 25 °C. The reaction mixture
was diluted with EtOAc (640 mL) and water (1000 mL). After
separation of the organic layer, the aqueous layer was back
extracted with EtOAc (640 mL). The combined organic layers
were washed water (3 × 600 mL) and brine, dried over MgSO4,
and concentrated in vacuo. The residue was diluted with
diethyl ether (210 mL) and stored for 12 h at -4 °C to afford
29 g of 2 (38.5% yield) as white solids. mp: 92 °C. 1H NMR
(400 MHz, CDCl3): δ 0.89 (br t, 2H), 1.06 (br t, 2H), 1.21 (s,
18H), 3.97 (d, J ) 10.0 Hz, 2H), 4.23 (s, 2H), 5.0 (br s, 2H),
5.62 (m, 2H), 8.01 (s, 1H), 8.68 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 12.3 (2C), 26.7 (6C), 38.6 (2C), 46.0, 62.1 (d, J )
170 Hz), 64.1 (d, J ) 15.0 Hz), 81.6 (d, J ) 6.0 Hz, 2C), 127.6,
143.0, 149.4, 153.4, 158.9, 176.6 (2C). HRMS (MH+): 528.2223
calcd for C10H14N5O4P, found 528.2233. Anal. (C22H34N5O8P)
C, H, N.
1
1) to afford 1.64 g of the methansulfonate 17 (85% yield). H
NMR (500 MHz, CDCl3): δ 0.77 (t, J ) 6.0 Hz, 2H), 1.10 (d, J
) 6.0 Hz, 2H), 1.31 (t, J ) 5.0 Hz, 12H), 3.10 (s, 3H), 3.86 (d,
J ) 10.0 Hz, 2H), 4.33 (s, 2H), 4.70 (m, 2H). MS (ESI): 421
(MH)+.
Diisopr opyl ({1-[(2-Am in o-6-ch lor o-9H-pu r in -9-yl)m eth -
yl]cyclop r op yl}oxy)m eth ylp h osp h on a te (7). To a suspen-
sion of 2-amino-6-chloro-9H-purine (773 mg, 4.6 mmol) in 10
mL of DMF was added NaH (219 mg, 5.47 mmol) at 25 °C
and stirred for 30 min. A solution of the methansulfonate 17
(1.63 g, 4.7 mmol) in 10 mL of DMF at 25 °C was added to the
above mixture and stirred at 80 °C for 4 h. The reaction
mixture was quenched with saturated NH4Cl at 25 °C. After
removal of DMF in vacuo, the aqueous layer was extracted
with EtOAc (3 × 50 mL). The combined extracts were washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by a flash silica gel column chromatog-
raphy using MeOH/MDC (1/20) to afford 765 mg of 7 (39%
yield), 130 mg of 9 (7.0%), and 20 mg of 10 (1.0%). 1H NMR
(400 MHz, CDCl3): δ 0.86 (t, J ) 6.8 Hz, 2H), 1.03 (t, J ) 6.8
Hz, 2H), 1.26 (d, J ) 6.0 Hz, 6H), 1.31 (d, J ) 6.0 Hz, 6H),
3.84 (d, J ) 8.0 Hz, 2H), 4.23 (s, 2H), 4.71 (m, 2H), 5.20 (s,
2H), 8.17 (s, 1H). 13C NMR (100 MHz, CDCl3): δ11.2 (2C), 23.8
(d, J ) 4.5 Hz, 2C), 23.9 (d, J ) 3.8 Hz, 2C), 62.3 (d, J ) 172
Hz), 65.9, 71.3 (d, J ) 6.8 Hz, 2C). HRMS (M+): 418.1411 calcd
for C11H23O5P, found 418.1412. Anal.(C16H25N5O4P) C, H, N.
Diisopr opyl ({1-[(2-Am in o-6-ch lor o-7H-pu r in -7-yl)m eth -
yl]cyclop r op yl}oxy)m eth ylp h osp h on a te (9). 1H NMR (400
MHz, CDCl3): δ 0.85 (br t, 2H), 1.11 (br t, 2H), 1.29 (d, J )
8.0 Hz, 6H), 1.32 (d, J ) 8.0 Hz, 6H), 3.76 (d, J ) 12.0 Hz,
2H), 4.55 (s, 2H), 4.73 (m, 2H), 5.01 (s, 2H), 8.50 (s, 1H). MS
m/e (M+): 418.
Diisopr opyl {[1-(2-Am in o-6-ch lor o-9H-pu r in -9-yl)cyclo-
bu tyl]oxy}m eth ylp h osp h on a te (10). 1H NMR (300 MHz,
CDCl3): δ 1.27 (d, J ) 5.7 Hz, 6H), 1.30 (d, J ) 5.7 Hz, 6H),
1.95 (m, 1H), 2.10 (m, 1H), 2.78 (m, 2H), 2.95 (m, 2H), 3.52 (d,
J ) 11.1 Hz, 2H), 4.55 (s, 2H), 4.73 (m, 2H), 5.01 (s, 2H), 8.50
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.8, 23.8 (4C), 32.8 (2C),
58.7 (d, J ) 200 Hz), 71.4 (2C), 90.0, 125.8, 140.5, 151.6, 154.0,
159.0. MS m/e (M+): 418.