2′-Deoxy-2′-fluoro-2′-C-methylcytidine
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17 5507
N4-Benzoyl-2′-C-methyl-3′,5′-di-O-benzoylcytidine
(300 g) and chromatographed as before to give an off-white
solid (46.4 g, 61%). Crystallization from aqueous acetone
afforded an analytical sample: mp 197-200 °C; [R]22D +132.0°
(c 1, MeOH); 1H NMR (DMSO-d6) δ 1.20 (s, 3H), 3.62-3.69
(m, 2H), 3.73-3.78 (m, 2H), 5.19 (t, 1H, J ) 5.4 Hz), 5.25 (s,
1H), 5.52 (d, 1H, J ) 5.0 Hz), 5.99 (s, 1H), 7.32 (d, 1H, J ) 5.8
Hz), 7.50 (Ψt, 2H, J ) 7.7 Hz), 7.62 (Ψt, 1H, J ) 7.3 Hz), 8.00
(7c): mp 176.7-179.1 °C (EtOH); [R]22 +46.2° (c 1, CHCl3);
D
1H NMR (CDCl3) δ 1.29 (s, 3H), 4.67-4.80 (m, 3H), 4.82-4.87
(m, 1H), 5.30 (d, 1H, J ) 5.8 Hz), 6.09 (s, 1H), 7.47-7.56 (m,
4H), 7.89 (d, 2H, J ) 7.3 Hz), 8.07-8.14 (m, 4H), 8.68 (s, 1H);
13C NMR (CDCl3) δ 21.4, 62.7, 75.8, 78.5, 79.0, 93.4, 97.3, 127.8,
128.5, 128.7, 128.9, 129.0, 129.4, 129.6, 130.0, 132.9, 133.2,
133.6, 144.3, 156.0, 162.8, 165.8 166.2, 166.8. Anal. Calcd
(C31H27N3O8‚0.4H2O): C, 64.56; H, 4.86; N, 7.29. Found: C,
64.54; H, 4.81; N, 7.32.
(d, 2H, J ) 7.3 Hz), 8.14 (d, 1H, J ) 6.9 Hz), 11.22 (s, 1H); 13
C
NMR (DMSO-d6) δ 19.6, 61.3, 77.5, 78.5, 85.2, 88.9, 95.2, 128.5,
132.8, 133.3, 147.3, 154.9, 162.9, 167.4. Anal. Calcd (C17H19N3O6‚
0.5H2O): C, 55.14; H, 5.41; N, 11.35. Found: C, 55.21; H, 5.47;
N, 11.33.
3′,5′-Di-O-benzoyl-2′-deoxy-2′-fluoro-2′-methyluri-
dine (8). Compound 7a (0.225 g, 0.394 mmol) was suspended
in 80% aqueous HOAc (15 mL) and heated under reflux with
stirring for 12 h. The clear solution was cooled, concentrated
to dryness in vacuo, and coevaporated with 50% MeOH-water
(3 × 5 mL) to remove the residual HOAc. Purification by silica
gel chromatography, eluting with 2% EtOH-CH2Cl2, gave
0.160 g of 8 (87%) as a white solid. Crystallization from
N4-Benzoyl-1-(2-C-methyl-3,5-di-O-benzoyl-â-D-arabino-
furanosyl]cytosine (6). Compound 5 (46.0 g, 0.127 mol) was
dissolved in anhydrous pyridine (200 mL) and the solvent was
removed in vacuo. The resulting syrup was dissolved in
anhydrous pyridine, cooled to 0 °C under argon with stirring,
and treated with BzCl (30.0 mL, 0.250 mol) dropwise over 10
min. After the addition was complete, the ice bath was
removed and stirring was continued for 1.5 h. Water (5 mL)
was added and the mixture was concentrated to dryness in
vacuo. The residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3 (1 × 500 mL) and water (1 × 500 mL).
The organic layer was dried (Na2SO4), filtered, and concen-
trated to dryness to afford a syrup that was purified by silica
gel chromatography eluting with 1:1 EtOAc-hexanes. Com-
2-propanol afforded an analytical sample: mp 256.4-257.6 °C;
1
[R]22 +71.7° (c 1, CHCl3); H NMR (CDCl3 + CD3OD) δ 1.39
D
(d, 3H, J ) 22.3 Hz), 4.49 (dd, 1H, J ) 3.9, 12.7 Hz), 4.57 (m,
1H,), 4.79 (dd, 1H, J ) 2.7, 12.5 Hz), 5.42 (d, 1H, J ) 8.1 Hz),
5.49 (dd, 1H, J ) 9.20, 21.2 Hz), 6.17 (d, 1H, J ) 19.3), 7.37-
7.50 (m, 4H), 7.51-7.57 (m, 3H, H-6) 7.93-8.01 (m, 4H); 13C
NMR (CDCl3 + CD3OD) δ 17.3 (d, J ) 25.1 Hz), 62.1, 72.7 (d,
J ) 16.1 Hz), 90.7 (d, J ) 44.2 Hz), 99.9 (d, J ) 186.2 Hz),
103.1, 128.5, 128.6, 128.7, 129.4, 129.5, 130.1, 133.6, 134.0,
139.3, 150.4, 163.2, 165.7, 166.1; 19F NMR (CDCl3 + CD3OD)
δ 6.02 (m). Anal. Calcd (C24H21FN2O7): C, 61.54; H, 4.52; N,
5.98. Found: C, 61.42; H, 4.51; N, 5.96.
pound 6 was isolated as an off-white solid (48.5 g, 67%): [R]22
D
1
+9.6° (c 1, CHCl3); H NMR (CDCl3) δ 1.64 (s, 3H), 4.50 (m,
1H), 4.78-4.85 (m, 2H), 5.50 (d, 1H, J ) 3.4 Hz), 6.42 (s, 1H),
7.44-7.54 (m, 7H), 7.57-7.66 (m, 3H), 7.94 (d, 2H, J ) 7.8
Hz), 8.05-8.09 (m, 4H), 8.21 (d, 1H, J ) 7.3 Hz); 13C NMR
(CDCl3) δ 19.9, 64.4, 79.2, 80.6, 81.6, 90.3, 96.7, 128.1, 128.6,
128.8, 128.9, 129.5, 129.9, 130.0, 133.2, 133.5, 134.0, 147.5,
156.0, 162.7, 165.9, 166.6. Anal. Calcd (C31H27N3O8): C, 65.37;
H, 4.78; N, 7.38. Found: C, 65.59; H, 4.79; N, 7.16.
General Procedure for Deprotection. The free nucleo-
sides were prepared by treating compounds 7a-c and 8 with
NH3/MeOH (ca. 7 N, ∼12 mL/mmol) followed by stirring at
room temperature overnight (8-12 h). The solvent was
removed in vacuo, and the compounds were isolated as
indicated.
Reaction of 6 with DAST. To a stirred solution of 6 (2.96
g, 5.20 mmol) in anhydrous toluene (50 mL) was added DAST
(1.0 mL, 7.8 mmol) at -20 °C under argon. After the addition
was complete, the cooling bath was removed and stirring was
continued for 1 h. The reaction mixture was poured into
saturated NaHCO3 (50 mL) and washed until gas evolution
ceased. The organic phase was dried (Na2SO4), concentrated
to dryness, and purified by silica gel chromatography eluting
with 1:1:1 EtOAc-CHCl3-hexanes to afford compound 7a
(0.55 g, 19%) as a white solid, followed by compound 7b (0.39
g, 14%) as an off-white solid. Elution was continued with 1:1:1
EtOH-EtOAc-CHCl3-hexanes to afford compound 7c (0.451
g, 15%) as an off-white solid. Analytical samples were obtained
by recrystallization from the indicated solvents.
2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1). Compound
7a (6.30 g, 0.011 mol) was deprotected to give 1 (2.18 g, 76%)
as a white powder after column chromatography eluting with
9% EtOH in CHCl3 and then 17% EtOH and finally 25% EtOH
in CHCl3: mp 216.4-218.0 °C (EtOH); [R]22 +125.6° (c 1,
D
1
H2O); H NMR (DMSO-d6) δ 1.17 (d, 3H, J ) 22.3 Hz), 3.63
(dd, 1H, J ) 2.7, 13.7 Hz), 3.70-3.84 (m, 3H), 5.24 (app s,
1H), 5.60 (d, 1H, J ) 5.4 Hz), 5.74 (d, 1H, J ) 7.71 Hz), 6.07
(d, 1H, J ) 18.9 Hz), 7.31 (s, 1H, NH2), 7.42 (s, 1H, NH2), 7.90
(d, 1H, J ) 7.3 Hz); 13C NMR (DMSO-d6) δ 16.6 (d, J ) 25.9
Hz), 58.5, 70.5 (d, J ) 18.3 Hz), 81.4, 88.6 (d, J ) 37.4 Hz),
94.4, 101.2 (d, J ) 180.1 Hz), 140.5, 154.8, 165.2; 19F NMR
(DMSO-d6) δ 2.60 (m). Anal. Calcd (C10H14FN3O4‚1.5H2O): C,
41.96; H, 5.94; N, 14.69. Found: C, 42.24; H, 5.63; N, 14.54.
N4-Benzoyl-3′,5′-di-O-benzoyl-2′-fluoro-2′-C-methyl-
cytidine (7a): mp 241 °C (CH2Cl2-hexanes); [R]22D +82.0° (c
Compound 1 was converted to the HCl salt and crystallized
from aqueous ethanol: mp 243 °C (dec); [R]22 +108.4° (c 1,
1
1, CHCl3); H NMR (CDCl3) δ 1.49 (d, 3H, J ) 22.4 Hz), 4.64
D
1
H2O); H NMR (DMSO-d6) δ 1.29 (d, 3H, J ) 22.6 Hz), 3.65
(dd, 1H, J ) 3.44, 12.9 Hz), 4.73 (d, 1H, J ) 9.5 Hz), 4.90 (dd,
1H, J ) 2.4, 12.7 Hz), 5.56 (dd, 1H, J ) 8.6, 20.7 Hz), 6.52 (d,
1H, J ) 18.0 Hz), 7.47-7.57 (m, 7H), 7.62-7.71 (m, 3H), 7.89
(d, 2H, J ) 6.9 Hz), 8.07-8.11 (m, 5H), 8.67 (bs, 1H); 13C NMR
(CDCl3) δ 17.4 (d, J ) 25.2 Hz), 62.1, 72.4 (d, J ) 16.0 Hz),
77.7, 91.2 (d, J ) 42.0 Hz), 97.5, 100.2 (d, J ) 187.7 Hz), 127.8,
128.6, 128.8, 128.9, 129.2, 129.6, 129.7, 130.3, 133.2, 133.4,
133.8, 134.1, 143.8, 154.6, 162.6, 165.6, 166.1; 19F NMR (CDCl3)
δ 3.9 (m). Anal. Calcd (C31H26FN3O7‚0.7H2O): C, 63.74; H, 4.73;
N, 7.19. Found: C, 63.71; H, 4.54; N, 7.20.
(dd, 1H, J ) 2.3, 12.7 Hz), 3.76-3.90 (m, 3H), 5.96 (d, 1H, J
) 17.3 Hz), 6.15 (d, 1H, J ) 7.9 Hz), 8.33 (d, 1H, J ) 7.9 Hz),
8.69 (s, 1.5H), 9.78 (s, 1.5H); 13C NMR (DMSO-d6) δ 16.2 (d, J
) 24.4 Hz), 58.2, 69.9 (d, J ) 16.8 Hz), 82.1, 88.8 (d, J ) 32.0
Hz), 94.6, 101.1 (d, J ) 181.5 Hz), 143.2, 147.6, 159.6; 19F NMR
(DMSO-d6) δ 1.69 (m). Anal. Calcd (C10H15ClFN3O4): C, 40.62;
H, 5.11; N, 14.21. Found: C, 40.80; H, 5.09; N, 14.23.
2′-Deoxy-2′-fluoro-2′-C-methyluridine (9). Deprotection
of 8 (0.120 g, 0.209 mmol) followed by column chromatography
eluting with 5-10% acetone in diethyl ether provided 9 (0.054
N4-Benzoyl-1-[2-deoxy-2-methylidene-3,5-di-O-benzoyl-
g, 100%) as a white solid: mp 237.3-238.0 °C; [R]25 +83.2°
D
â-D-glycero-pentofuranosyl]cytosine (7b): mp 173.4-174.4
1
1
(EtOH); [R]22 -40.4° (c 1, CHCl3); H NMR (CDCl3): δ 4.58
(c 1, MeOH); H NMR (CD3OD) δ 1.35 (d, 3H, J ) 22.3 Hz),
D
3.79 (dd, 1H, J ) 2.1, 12.5 Hz), 3.94-4.02 (m, 3H, 5.70 (d, 1H,
J ) 8.1 Hz), 6.13 (d, 1H, J ) 18.9 Hz), 8.09 (d, 1H); 13C NMR
(CD3OD) δ 16.9 (d, J ) 25.2 Hz), 60.1, 72.5 (d, J ) 17.6 Hz),
83.5, 90.6 (d, J ) 44.0 Hz), 102.1 (d, J ) 180.1 Hz), 103.0,
142.0, 152.4, 166.0; 19F NMR (CD3OD) δ 4.07 (bs). Anal. Calcd
(C10H13FN2O5): C, 46.16; H, 5.04; N, 10.77. Found: C, 45.96;
H, 4.93; N, 10.49.
(dd, 1H, J ) 3.7, 5.0 Hz), 4.70-4.81 (m, 2H), 5.55 (s, 1H), 6.09-
6.11 (m, 1H), 7.03 (d, 1H, J ) 1.3 Hz), 7.40-7.66 (m, 10H),
7.85 (d, 1H, J ) 7.3 Hz), 7.91 (d, 2H, J ) 7.7 Hz), 8.03 (dd,
2H, J ) 0.9, 8.3 Hz), 8.03 (dd, 2H), 8.86 (bs, 1H); 13C NMR
(CDCl3) δ 63.9, 73.3, 80.7, 85.9, 97.8, 117.3, 127.8, 128.0, 128.7,
128.9, 129.1, 129.4, 129.6, 129.9, 130.2, 133.0, 133.6, 133.8,
144.1, 144.9, 155.1, 162.5, 165.9, 166.1. Anal. Calcd (C31H25-
N3O7): C, 67.51; H, 4.57; N, 7.62. Found: C, 67.21; H, 4.51;
N, 7.66
Isolation of 2′-C-methylcytidine. Compound 7c (0.1 g,
0.176 mmol) upon deprotection and crystallization from MeOH