1594
A. Ghosh et al.
(m, 2H). IR (KBr, cm−1): 3415, 3028, 2876, 1605, 1472, 1446, and 1219.
HRMS calcd for C49H46N5O5P (M+H)+ 816.3315. Found 816.3331.
( )-9-[(1-Trityloxyethyl)(3-di-tert -butylcarbonyloxymethylphosphono-
methoxy)propyl]-N6-trityladenine (14). To a solution of 13 (0.14 g, 0.17
mmol) in DMF (6 mL) were added Et3N (6.2 mL, 42.89 mmol) and
chloromethyl pivalate (3.1 mL, 21.45 mmol) under N2 atmosphere and the
reaction mixture stirred at room temperature for 4 days. The mixture was
diluted with water (40 mL) and then extracted with chloroform (3
30
mL). Combined chloroform extracts were dried over MgSO4, filtered, and
the filtrate concentrated. The residue was purified on a silica gel column
using ethyl acetate:hexanes:methanol (90:10:0 to 50:49:1) to provide 0.093 g
(52%) of 14 as a light yellow solid, mp 73–75◦C: 1HNMR (DMSO-d6): 8.16
(s, 1H), 7.82 (s, 1H), 7.12–7.33 (m, 31H), 5.60 (s, 2H), 5.56 (s, 2H), 4.72–
4.87 (m, 1H), 3.79 (d, J = 7.9 Hz, 2H), 3.15–3.48 (m, 4H), 1.95–3.0 (m,
4H), and 1.11 (bs, 18H). IR (KBr, cm−1): 3419, 3028, 2973, 1753, 1605,
1473, 1448, and 1280. HRMS calcd for C61H66N5O9P (M+H)+ 1044.4676.
Found 1044.4629. Anal. calcd for C61H66N5O9P 0.25 EtOAc: C, 69.84; H,
6.42; N, 6.56. Found: C, 69.61; H, 6.32; N, 6.47.
( )-9-[(1-Hydroxyethyl)(3-di-tert -butylcarbonyloxymethylphosphono-
methoxy)propyl]adenine (15). A mixture of 14 (0.16 g, 0.15 mmol), HCl
(2.0 N, 15 mL), and MeCN (15 mL) was stirred at room temperature for
15 h. The reaction mixture was neutralized with Et3N, and then diluted
with water (40 mL). After evaporating the organic volatiles, the residue
was extracted with chloroform (3
70 mL), dried (MgSO4), filtered,
and the filtrate evaporated to dryness. The residue was purified over a
silica gel column eluting with chloroform:methanol (100:0 to 96:4). First, a
compound (60 mg) (49%) with one trityl group still attached was obtained.
Further elution of the column gave 24 mg (28%) of the desired 15 as a gum:
1HNMR (CDCl3): 8.27 (s, 1H, aromatic), 7.89 (s, 1H, aromatic), 6.17 (brs,
2H, NH2), 5.58–5.79 (m, 4H, 2 OCH2O), 4.92 (m, 1H, NCH), 3.75 (d,
J = 7.9 Hz, 2H, OCH2P), 3.52–3.64 (m, 2H, CH2CH2O), 3.1–3.42 (m, 2H,
CH2OH), 2.11–2.56 (m, 4H, NCH(CH2)2), 1.22 (s, 18H, t-butyl). IR (KBr,
cm−1): 3341, 2974, 2876, 1752, 1646, 1611, 1479. MS (ES+) 582.43 (M+Na).
Anal. calcd for C23H38N5O9P 0.75 H2O: C, 48.20; H, 6.94; N, 12.22. Found:
C, 48.26; H, 7.04; N, 11.94.
REFERENCES
1. Holy, A. Phosphonylmethyl analogs of nucleotides and their derivatives: Chemistry and biology.
Nucleosides Nucleotides 1987, 6(1&2), 147–155.
2. Kim, C.U.; Luh, B.Y.; Misco, P.F.; Bronson, J.J.; Hitchcock, M.J.M.; Ghazzouli, I.; Martin, J.C. Acyclic
purine phosphonate analogues as antiviral agents. Synthesis and structure-activity relationships.
J. Med. Chem. 1990, 33, 1207–1213.