Journal of Medicinal Chemistry
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at room temperature for 1 h. Amberlite IR-120B was added to the
solution until the solution became neutral. After filteration of a residual
precipitate, the filtrate was evaporated in vacuo. The residue was
purified by silica gel column chromatography (n-hexane:ethyl acetate/
1:1−1:3) to give the product as colorless crystals (25.4 g, 51% yield);
colorless crystals (919 mg, 56% yield); mp 242−244 °C. H NMR
(DMSO-d6) δ 3.91 (s, 3H), 4.52 (d, J = 5.8 Hz, 2H), 7.12−7.19 (m,
2H), 7.34−7.40 (m, 2H), 8.19−8.22 (m, 1H), 10.12 (brs, 1H), 10.20
(d, J = 5.8 Hz, 1H), 12.43 (brs, 1H). Anal. Calcd for C15H13FN2O5: C,
56.25; H, 4.09; F, 5.93; N, 8.75. Found: C, 56.00; H, 4.03; F, 5.58; N,
8.69.
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mp 242−244 °C. H NMR (CDCl3) δ 3.42 (brs, 1H), 3.89 (s, 3H),
4.41 (d, J = 5.7 Hz, 2H), 4.83 (s, 2H), 5.23 (s, 2H), 6.92−6.99 (m,
2H), 7.09−7.14 (m, 2H), 7.19−7.23 (m, 2H), 7.28−7.37 (m, 3H),
7.85 (brs, 1H), 9.03 (s, 1H). Anal. Calcd for C22H21FN2O4(H2O)0.3:
C, 65.76; H, 5.42; F, 4.73; N, 6.97. Found: C, 65.89; H, 5.32; F, 4.59;
N, 7.10.
5-(4-Fluorobenzylcarbamoyl)-3-hydroxy-4-oxo-1,4-dihydropyri-
dine-2-carboxylic Acid (12). To a solution of the compound 11 (100
mg, 0.31 mmol) in methanol (3 mL), 1 M aq LiOH (1 mL) was added
at room temperature. The reaction mixture was steirred for 2 h at 60
°C. After being cooled down by ice−water, 2 M aq HCl (1 mL) was
added. Precipitated crystals were collected and washed with water to
give the product as colorless crystals (91 mg, 96% yield); mp 221−222
4-Benzyloxy-N-(4-fluorobenzyl)-6-formyl-5-methoxynicotinea-
mide (8). To a solution of the compound 7 (25.0 g, 63.1 mmol),
DMSO (44.8 mL, 631 mmol), and Et3N (44.3 mL, 378 mmol) in
chloroform (250 mL), SO3−pyridine complex (50.2 g, 315 mmol) was
added under ice-cooling. The reaction mixture was stirred at room
temperature for 20 min. Water was added to the reaction mixture, and
chloroform was evaporated in vacuo. The residual aqueous solution
was extracted with ethyl acetate, and the extract was washed with
water. The organic layer was dried with anhydrous Na2SO4. The
solvent was evaporated in vacuo, and residual crystals (17.7 g) were
collected by filtration and washed by Et2O. The filtrate was evaporated
in vacuo, and precipitate was purified by silica gel column
chromatography to give another portion of crystals (3.16 g). Two
portions were combined to give the product as colorless crystals (20.9
g, 84% yield); mp 99−100 °C. 1H NMR (CDCl3) δ 4.02 (s, 3H), 4.41
(d, J = 5.7 Hz, 2H), 5.30 (s, 2H), 6.93−6.70 (m, 2H), 7.09−7.15 (m,
2H), 7.20−7.27 (m, 2H), 7.31−7.40 (m, 3H), 7.83 (brs, 1H), 9.20 (s,
1H), 10.26 (s, 1H). Anal. Calcd for C22H19FN2O4: C, 67.00; H, 4.86;
F, 4.82; N, 7.10. Found: C, 66.85; H, 4.86; F, 4.63; N, 7.06.
Methyl 4-Benzyloxy-5-(4-fluorobenzylcarbamoyl)-3-methyoxy-
pyridine-2-carboxylate (9). To a solution of the compound 8 (300
mg, 0.761 mmol) in methanol (1 mL), a solution of KOH (111 mg,
1.99 mmol) in methanol (1 mL) was added under ice-cooling, and
then a solution of iodine (251 mg, 1.00 mmol) in methanol (4 mL)
was added. The mixture was stirred under ice-cooling for 1 h. A 5%
(w/v) solution of aq NaHSO3 and water were added to the reaction
mixture. Precipitate was collected by filtration to give the product as
colorless crystals (275 mg, 85% yield); mp 75−78 °C. 1H NMR
(CDCl3) δ 3.99 (s, 3H), 4.02 (s, 3H), 7.40 (d, J = 5.7 Hz, 2H), 5.26 (s,
2H), 6.92−6.99 (m, 2H), 7.10−7.15 (m, 2H), 7.19−7.23 (m, 2H),
7.25−7.39 (m, 3H), 7.81 (brs, 1H), 9.09 (s, 1H). Anal. Calcd for
C23H21FN2O5(H2O)0.4: C, 64.00; H, 5.09; F, 4.40; N, 6.49. Found: C,
63.95; H, 4.89; F, 4.37; N, 6.69.
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°C. H NMR (DMSO-d6) δ 4.51 (d, J = 5.7 Hz, 2H), 7.12−7.19 (m,
2H), 7.33−7.39 (m, 2H), 8.17 (s, 1H). Anal. Calcd for
C14H11FN2O5(H2O)1.0: C, 51.86; H, 4.04; F, 5.86; N, 8.64. Found:
C, 51.78; H, 3.98; F, 5.78; N, 8.64.
3-Hydroxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic Acid 5-(4-
Fluorobenzylamide) 2-(2-methoxyethyl)amide (13). To a solution of
the compound 11 (96 mg, 0.3 mmol) in methanol (3 mL), 2-
methoxyethanamine (113 mg, 1.5 mmol) was added. The reaction was
performed with a microwave reaction apparatus at 140 °C for 15 min.
After being cooled to room temperature, 2 M aq HCl (3 mL) was
added. Precipitate was collected by filtration and washed by water to
give the product as colorless crystals (101 mg, 93% yield); mp 295−
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299 °C. H NMR (DMSO-d6) δ 3.28 (s, 3H), 3.39−3.62 (m, 4H),
4.52 (d, J = 5.9 Hz, 2H), 7.14−7.20 (m, 2H), 7.35−7.39 (m, 2H), 8.24
(d, J = 7.2 Hz, 1H), 8.46 (t, J = 5.2 Hz, 1H), 10.32 (t, J = 5.8 Hz, 1H),
12.23 (d, J = 5.8 Hz, 1H). Anal. Calcd for C17H18FN3O5: C, 56.20; H,
4.99; F, 5.23; N, 11.56. Found: C, 55.86; H, 4.87; F, 5.10; N, 11.39.
3-Hydroxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic Acid 5-(4-
Fluorobenzylamide) 2-[(2-hydroxyethyl)amide] (14). This com-
pound was prepared in a similar manner to that described for 13
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(colorless crystals, 96 mg, 89% yield); mp 285−287 °C. H NMR
(DMSO-d6) δ 3.44−3.61 (m, 4H), 4.53 (d, J = 6.0 Hz, 2H), 4.91 (s,
1H), 7.13−7.21 (m, 2H), 7.35−7.40 (m, 2H), 8.24 (s, 1H), 8.53 (s,
1H), 10.34 (t, J = 5.7 Hz, 1H), 12.23 (brs, 1H). Anal. Calcd for
C16H16FN3O5: C, 55.01; H, 4.62; F, 5.44; N, 12.03. Found: C, 54.71;
H, 4.58; F, 5.28; N, 11.96.
4-Benzyloxy-5-(4-fluorobenzylcarbamoyl)-3-methoxypyridine-2-
carboxylic Acid (15). To a solution of the compound 9 (900 mg, 2.12
mmol) in methanol (8 mL), a 2 M aq NaOH (4 mL) was added. The
reaction solution was stirred at room temperature for 2 h, and 2 M aq
HCl (3 mL) was added. Precipitate was collected by filteration to give
the product was obtained as colorless crystals (474 mg, 54% yield); mp
Methyl 5-(4-Fluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihy-
dropyridine-2-carboxylate (10). To a suspension of sodium iodide
(5.51 g, 36.8 mmol) in acetonitrile (50 mL), chlorotrimethylsilane
(4.66 mL, 36.8 mmol) was added. The reaction mixture was stirred at
room temperature for 10 min. To this solution the compound 9 (2.60
g, 6.13 mmol) was added under ice-cooling, and the mixture was
stirred at the same temperature for 20 min. To the reaction solution a
5% (w/v) solution of aq NaHSO3 was added and then extracted with
ethyl acetate. The extract was washed with a saturated aq Na2CO3 and
a saturated aq NaCl and dried with anhydrous Na2SO4. The solvent
was evaporated in vacuo, and the precipitate was recrystallized
(acetone−diisopropyl ether) to give the product as colorless crystals
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138−139 °C. H NMR (CDCl3) δ 4.05 (s, 3H), 4.40 (d, J = 5.6 Hz,
2H), 5.36 (s, 2H), 6.94−7.01 (m, 2H), 7.08−7.12 (m, 2H), 7.21−7.24
(m, 2H), 7.29−7.41 (m, 3H), 7.87 (brs, 1H), 9.03 (s, 1H). Anal. Calcd
for C22H19FN2O5: C, 64.39; H, 4.67; F, 4.63; N, 6.83. Found: C,
64.35; H, 4.62; F, 4.41; N, 6.87.
3-Hydroxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic Acid 2-
Amide 5-(4-fluorobenzyl)amide (19). The compound 15 (155 mg,
0.378 mmol), 2-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (87 mg, 0.453 mmol), and 1-hydroxybenzotriazole (61 mg,
0.453 mmol) were dissolved in DMF (2 mL), and the solution was
stirred at room temperature for 30 min. Thereafter, ammonium
chloride (40 mg, 0.756 mmol) and diisopropylethylamine (198 μL,
1.13 mmol) were added. The reaction solution was stirred at room
temperature for 1 h. Water was added to the solution, and precipitate
was collected by filtration and washed with Et2O to give crude product
16 of 127 mg. Directly to 16 pyridine−HCl (1.27 g) was added and
then heated at 180 °C for 5 min. After cooling the reaction mixture to
room temperature, water was added. Precipitate was collected by
filtration and washed with Et2O to give the product as skin-colored
crystals (88 mg, 76% yield for two steps); mp higher than 300 °C. 1H
NMR (DMSO-d6) δ 4.53 (d, J = 5.6 Hz, 2H), 7.14−7.20 (m, 2H),
7.35−7.40 (m, 2H), 7.79 (s, 1H), 8.24 (d, J = 7.0 Hz, 1H), 8.33 (s,
1H), 10.33 (t, J = 5.6 Hz, 1H), 12.23 (d, J = 7.0 Hz, 1H). Anal. Calcd
for C14H12FN3O4(H2O)0.2: C, 54.44; H, 4.05; F, 6.15; N, 13.60.
Found: C, 54.82; H, 3.96; F, 5.75; N, 13.53
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(1.73 g, 84% yield); mp 183−184 °C. H NMR (CDCl3) δ 4.04 (s,
6H), 4.60 (d, J = 6.0 Hz, 2H), 6.96−7.03 (m, 2H), 7.29−7.35 (m,
2H), 8.63 (s, 1H), 9.68 (s, 1H), 10.34 (brs, 1H). Anal. Calcd for
C16H15FN2O5: C, 57.48; H, 4.52; F, 5.68; N, 8.38. Found: C, 57.34; H,
4.50; F, 5.46; N, 8.39.
Methyl 5-(4-Fluorobenzylcarbamoyl)-3-hydroxy-4-oxo-1,4-dihy-
dropyridine-2-carboxylate (11). To a solution of the compound 10
(1.73 g, 5.17 mmol) in dichloromethane (150 mL) was added
aluminum chloride (6.97 g, 51.7 mmol), and the mixture was stirred at
room temperature for 2 h. The reaction mixture was poured into 2 M
aq HCl containing an ice, followed by extraction with ethyl acetate.
The extract was washed with 2 M aq HCl and water and then dried
with anhydrous Na2SO4. The solvent was removed in vacuo, and the
precipitate was recrystallized (THF−methanol) to give the product as
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dx.doi.org/10.1021/jm3010459 | J. Med. Chem. 2012, 55, 8735−8744