840
H. Cai et al. / Journal of Fluorine Chemistry 127 (2006) 837–841
solvents and reagents were commercially available and used as
received unless otherwise specified.
3.2.3. N2-( p-Anisyldiphenylmethyl)-9-[(4-fluoro)-3-p-
anisyldiphenylmethoxy-methylbutyl] guanine (6)
Analytical thin-layer chromatography (TLC) was carried out
on precoated plate (silica gel 60 F254), and spots were visualized
with ultraviolet light. Normal phase flash column chromato-
graphy was carried out on silica gel (200–300 mesh) with
common flow of the indicated solvent system in the proportions
described below.
Compound 5 (67 mg, 0.07 mmol), TBAF (315.2 mg,
1.0 mmol) were dissolved in mixed solution of acetonitrile
(2 mL) and DMF (1 mL). The reaction was heated to 110 8C for
40 min while stirring. Solvent was removed by evaporation, and
the residue was transferred to the top of a silica gel column with
the aid of CH2Cl2. The column was eluted with 3.5% MeOH/
CH2Cl2. 40.6 mg of the desired product yellowish solid was
obtained in 72.4% yield. UV (EtOH): l 216, 231 and 262 nm;
IR (KBr): n 3440, 2930, 1680, 1610, 1250, 1030, 825,
3.2. Synthetic procedures
3.2.1. N2-( p-Anisyldiphenylmethyl)-9-[(4-hydroxy)-3-p-
anisyldiphenyl-methoxymethylbutyl] guanine (4)
700 cmꢀ1; H NMR (CDCl3): d 7.41–7.10 (m, 25H, aromatic
1
and C8–H), 6.83 (d, 2H, aromatic, J = 8.85 Hz), 6.75 (d, 2H,
aromatic, J = 8.6 Hz), 4.50–4.25 (dm, 2H, 40H, JFH = 47 Hz),
3.77 (s, 3H, CH3O), 3.68 (s, 3H, CH3O), 3.60–3.40 (m, 2H,
10H), 3.10–3.00 (m, 2H, 50H), 2.0–1.5 (m, 1H, 30H), 1.40–0.8
(m, 2H, 20H).
Penciclovir (200 mg, 0.79 mmol), monomethoxytrityl
chloride (600 mg, 1.94 mmol), DMAP (12 mg, cat. amount),
and triethylamine (0.8 mL) were placed in a dry flask under
nitrogen atmosphere. Dimethyformamide (DMF, 12 mL) was
added, and the reaction mixture was stirred at room temperature
overnight. TLC analysis of the product showed no starting
material remained. The reaction mixture was diluted with ethyl
acetate (25 mL), and washed with water (25 mL). The aqueous
phase was extracted with ethyl acetate (25 mL). The combined
organic phase was dried over MgSO4 and evaporated to remove
the solvents. After chromatography on a silica gel column using
5% MeOH in CH2Cl2, 340 mg of the desired product as white
solid was obtained in 54.4% yield. mp 140.1–142.8 8C; UV
(EtOH): l 214, 232 and 262 nm; IR (KBr): n 3720, 3410, 2980,
2920, 1610, 1530, 1510 cmꢀ1; 1H NMR (DMSO-d6): d 10.40 (s,
1N, NH), 7.56 (s, 1N, NH), 7.45 (s, 1H, C8H), 7.36–7.20 (m,
24H, aromatic), 6.85 (d, 2H, aromatic, J = 9 Hz), 6.75 (d, 2H,
aromatic, J = 9 Hz), 4.35 (t, 1H, J = 5 Hz), 3.74 (s, 3H, CH3O),
3.64 (s, 3H, CH3O), 3.40 (t, 2H, J = 7 Hz, 10H), 3.38–3.10 (m,
2H, CH2OH), 2.80–2.60 (m, 2H, 50H), 1.43 (m, 1H, 30H), 1.23
(m, 2H, 20H).
3.2.4. 9-[(4-Fluoro)-3-hydroxy-methylbutyl] guanine (2)
Compound 6 (77.6 mg, 0.10 mmol) was dissolved in
methanol (4 mL), acidified with 1.0 mol/L HCl (0.90 mL),
and heated at 110 8C for 30 min when TLC analysis showed no
starting material remained. The crude mixture was neutralized
with NaOH. Solvent was removed by evaporation, and
transferred to the top of a silica gel column. The column
was eluted with 15% MeOH/CH2Cl2 to afford FHBG as a white
solid (21.0 mg, 85%). UV (EtOH): l 210, 255 nm; IR (KBr): n
3390, 3160, 2920, 1680, 1500, 1380, 1050, 783, 687 cmꢀ1; 1H
NMR (DMSO-d6): d 7.70 (s, 1H, C8H), 4.45–4.35 (dd, 2H, 40H–
CH2, JFH = 47 Hz, JHH = 4.7 Hz), 3.95 (t, 2H, 10H,
J
FH = 7.1 Hz), 3.40–3.35 (d, 2H, 50H), 1.80–1.50 (m, 3H, 20
& 30H); 19F NMR (DMSO-d6): d ꢀ227.96 (dt, JFH = 47 Hz,
J
FH = 23.5 Hz); MS m/z (%): 255 (M+, 46), 204 (40), 165 (100).
3.2.5. 2-Amino-6-chloro-9-(4-hydroxy-3-
hydroxymethylbutyl) purine (8)
3.2.2. N2-( p-Anisyldiphenylmethyl)-9-[(4-tosyl)-3-p-
anisyldiphenylmethoxy-methylbutyl] guanine (5)
Intermediate
2-amino-6-chloro-9-(4-acetoxy-3-acetoxy-
Compound 4 (570 mg, 0.714 mmol) was dissolved in dry
pyridine (10 mL) and kept at 0 8C for 10 min. p-Tosyl chloride
(1.20 g, 6.32 mmol) dissolving in CH2Cl2 was added to the
above solution and stirred at 0 8C overnight. TLC analysis of
the product showed no significant amount of starting material
remained. To the reaction mixture, ethyl acetate (25 mL) was
added, and washed with water (25 mL). The aqueous phasewas
extracted with ethyl acetate (25 mL). The combined organic
phase was dried over MgSO4 and evaporated to yield the crude
product. After chromatography on silica gel column using 5%
MeOH in CH2Cl2, 479 mg of the desired product was obtained
in 70.5% yield. mp 200.2–203.8 8C; UV (EtOH): l 209, 225
and 265 nm; IR (KBr): n 3380, 3050, 1680, 1180, 1030,
methylbutyl) purine (358 mg, 1.0 mmol) dissolving in THF
(12 mL) was added a mixed solution of water (5 mL) and
methanol (5 mL) containing potassium carbonate at 0 8C and
the reaction was stirred for overnight at the same condition.
When TLC analysis showed no starting material remained,
solvent was removed by rotary evaporation, and the residue was
transferred to the top of a silica gel column with the aid of THF
and methanol. The column was eluted with 10% MeOH/
CH2Cl2 to afford compound 8 as a white solid (212 mg, 78.4%).
mp 141.6–142.0 8C; UV (EtOH): l 223, 248 and 310 nm; IR
(KBr): n 3320, 3200, 2930, 1610, 1570, 1380, 1060 cmꢀ1; 1H
NMR (DMSO-d6): d 8.15 (s, 1H, C8H), 4.05–4.15 (t, 2H,
NCH2, J = 7.3 Hz), 3.30–3.50 (m, 4H, OCH2), 1.70–1.80 (m,
2H, CH2CH), 1.40–1.50 (m, 1H, CH2CH); MS m/z (%): 271
(M+, 72), 240 (57), 170 (100).
702 cmꢀ1 1H NMR (CDCl3): d 7.74 (d, 2H, aromatic,
;
J = 8 Hz), 7.35–7.05 (m, 27H, aromatic and C8–H), 6.80 (d,
2H, aromatic, J = 8.76 Hz), 6.71 (d, 2H, aromatic,
J = 8.46 Hz), 4.10–3.80 (m, 2H, 40-CH2OTs), 3.77 (s, 3H,
CH3O), 3.68 (s, 3H, CH3O), 3.50–3.20 (m, 2H, 10H), 3.10–2.80
(m, 2H, 50H), 2.42 (s, 3H, CH3), 1.58 (m, 1H, 30H), 1.50–1.30
(m, 2H, 20H).
3.2.6. 2-Amino-9-(4-hydroxy-3-hydroxymethylbutyl)-
N,N,N-trimethyl-9H-purin-6-aminium chloride (9)
Ethanolic trimethylamine solution (9 mL) was cooled at
0 8C and added dropwise to a cooled solution of Compound