Mar. Drugs 2019, 17, 226
8 of 11
Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by a silica gel
column (CH2Cl2: MeOH, V/V = 100:1) to afford (16) (1.65 g, 2.60 mmol, 89%) as white solid. Rf= 0.40
(CH2Cl2/EtOAc = 5:1, V/V); m.p. 183
DMSO-d6) : 11.55 (s, 1H), 8.65 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 7.7 Hz, 2H), 7.65 (t, J = 7.2 Hz,
2H), 7.57 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 6.40~6.29 (m, 1H), 6.20 (d, J = 3.1 Hz, 1H), 4.80 (t,
J = 6.4 Hz, 1H), 4.71 (dd, J = 12.3, 2.3 Hz, 1H), 4.56 4.45 (m, 1H), 4.44 4.34 (m, 1H), 3.46 (s, 3H),
2.13 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.2, 167.4, 165.8 152.9, 151.8, 151.4, 133.9, 133.1, 129.6
−
186 ◦C; [α]2D5
−
38.00 (c = 0.1, CH3OH); 1H NMR (400 MHz,
δ
−
−
(C
×
2), 129.4 (C
×
2), 129.1 (C
×
2), 129.0 (C
×
2), 128.9 (C
×
2), 127.2, 114.2, 111.7, 91.3, 89.7, 80.1, 78.0,
72.6, 63.2, 59.1, 21.0; HRESIMS m/z: [M + Na]+ calcd. for C29H24BrN5O7Na 656.0751, found 656.0758.
4.6. Synthesis of 5-cyano-6-bromo-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (17)
A solution of (16) (2.0 g, 3.15 mmol) in methanolic ammonia (saturated with NH3 at 0 ◦C for
◦
2h, 20 mL) was placed in an autoclave and stirred at 40 C for 12 h. Then the reaction mixture
was concentrated to dryness and the residue was purified by a silica gel column (CH2Cl2: MeOH,
V/V = 30:1) to afford (17) (1.05 g, 2.73 mmol, 87%) as white solid. Rf = 0.45 (CH2Cl2:CH3OH = 20:1,
V/V); m.p. 204
−
206 ◦C; [α]2D5
−
41.50 (c = 0.10, CH3OH); 1H NMR (400 MHz, DMSO-d6)
δ 8.21 (s, 1H),
7.11 (s, 2H), 5.91 (d, J = 6.9 Hz, 1H), 5.76 (s, 1H), 5.55 (d, J = 6.6 Hz, 1H), 5.39 (dd, J = 7.8, 4.2 Hz, 1H),
5.25 (d, J = 6.0 Hz, 1H), 4.07 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 3.0 Hz, 1H), 3.68 (dd, J = 10.2, 5.9 Hz, 1H),
3.63
−
3.50 (m, 1H), 3.44 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ: 156.1, 153.2, 150.0, 121.6, 114.1, 102.1,
90.9, 87.5, 84.1, 80.0, 70.7, 61.9, 57.7; HRESIMS m/z: [M + Na]+ calcd. for C13H14BrN5O4Na 406.0121,
found 406.0126.
4.7. 4-carbonyl-5-cyano-6-bromo-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (18)
To a solution of (17) (1.0 g, 2.6 mmol) in CH3CO2H (20 mL), an aqueous solution (NaNO2/H2O,
1.79 g/9.0 mL) was added slowly. After addition, the reaction mixture was heated to 60 ◦C for 8 h.
After the reaction was finished (by TLC monitoring), the reaction mixture was concentrated to dryness.
The residue was dissolved with CH2Cl2 (20 mL). After filtration, the resulting solution was evaporated
under reduced pressure and the residue was purified by silica gel column to afford a white solid of
(
18) (0.795 g, 2.06 mmol, 80%). Rf = 0.32 (CH2Cl2:CH3OH = 20:1, V/V); m.p. 219
(c = 0.08, CH3OH); 1H NMR (400 MHz, DMSO-d6)
: 12.76 (brs, 1H), 8.14 (d, J = 3.6 Hz, 1H), 5.92 (d,
J = 6.6 Hz, 1H), 5.58 (brs, 1H), 5.14 (s, 1H), 4.99 (brs, 1H), 4.02 3.99 (m, 1H), 3.91 (dd, J = 5.2, 3.3 Hz,
1H), 3.65 (dd, J = 11.7, 5.2 Hz, 1H), 3.54 (dd, J = 11.5, 5.0 Hz, 1H), 3.42 (s, 3H); 13C NMR (100 MHz,
−
220 ◦C; [α]2D5
−
67.50
δ
−
DMSO-d6) δ: 156.0, 148.6, 147.0, 119.4, 114.0, 109.5, 91.4, 91.2, 84.3, 80.1, 71.4, 62.1, 58.2; HRESIMS m/z:
[M + Na]+ calcd. for C13H13BrN4O5Na 406.9962, found 406.9967.
4.8. Synthesis of 4-carbonyl-5-cyano-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (19)
To a solution of (18) (1.0 g, 2.6 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% Pd/C
(100 mg) and Et3N (0.1 mL). After stirring at room temperature for 5 h under H2 atmosphere, the
mixture was filtered with celite and the filtrated was concentrated to dryness under reduced pressure
and purified by a silica gel column to afford a white solid of (19) (0.74 g, 2.42 mmol, 92%). Rf = 0.15
(CH2Cl2:CH3OH = 20:1, V/V); m.p. 94
DMSO-d6) 12.55 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 6.01 (d, J = 5.3 Hz, 1H), 5.60 (d, J = 6.2 Hz, 1H), 5.22
(t, J = 5.1 Hz, 1H), 4.47 (dd, J = 10.7, 5.4 Hz, 1H), 4.02 (d, J = 3.7 Hz, 1H), 3.83 (t, J = 4.3 Hz, 1H), 3.66 (m,
−
96 ◦C; [α]2D5
−
38.0 (c = 0.10, CH3OH); 1H NMR (400 MHz,
δ
1H), 3.56 (m, 1H), 3.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 156.9, 148.0, 146.6, 130.5, 114.8, 107.6,
88.1, 86.7, 83.2, 79.3, 73.8, 61.1, 57.7; HRESIMS m/z: [M + Na]+ calcd. for C13H14N4O5Na 329.0856,
found 329.0848.