Journal of Medicinal Chemistry
Article
tetramethylsilane (TMS) for 1H and 13C NMR. ESI mass spectra were
obtained by infusing samples into an LCQ Deca XP ion trap mass
instrument. HRMS were monitored on MicroMass Q-TOF instru-
ment. Purity (≥95%) was determined via HPLC analysis.
NMR: −107.45 (s). 13C NMR: 10.31 (s, CH3), 22.54 (s, CH2), 54.31
(d, J = 2 Hz, CH2), 110.47 (s, CH-5), 131.19 (d, J = 11 Hz, C-3),
134.02 (d, J = 4 Hz, CH-6), 149.88 (d, J = 264 Hz, C-2), 164.42 (d, J =
10 Hz, C-4). HRMS: calcd for C8H11NO2F (M + 1)+, 172.0774;
found, 172.0777.
3-Hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-
one (1a). To a solution of 1-(3,4-bis(benzyloxy)pyridin-2-yl)-2,2,2-
trifluoroethanol 3 (1 g) in methanol (15 mL) was added a catalytic
amount of Pd/C (5%, 0.1 g) and 1 mL of concentrated HCl. The
reaction was hydrogenated at room temperature and 2 atm for 3 h.
Then the catalyst was filtered off through Celite, and the residue was
concentrated under reduced pressure to afford the title compound as
an off-white solid. Recrystallization from EtOH/acetone gave a white
2-Fluoro-3-hydroxy-1-isopropylpyridin-4(1H)-one Hydrobromide
1
(1h). Yield: 60%. H NMR (DMSO-d6): δ 8.25 (dd, J = 5.1, 7.2 Hz,
1H, C-6H), 7.13 (d, J = 7.2 Hz, 1H, C-5H), 5.13−4.93 (m, 1H, CH),
4.70 (brs, OH), 1.53 (d, J = 6.7 Hz, 6H, 2CH3). 19F NMR: −105.59.
13C NMR: 21.32 (s, CH3), 55.77 (d, J = 5 Hz, CH), 110.64 (s, C-5H),
131.09 (d, J = 13 Hz, C-3), 143.76 (d, J = 22 Hz, CH-6), 149.90 (d, J =
272 Hz, C-2), 163.01 (d, J = 11 Hz, C-4). HRMS: calcd for
C8H11NO2F (M + 1)+, 172.0774; found, 172.0774.
1
solid. Yield 88%. H NMR (DMSO-d6): δ 8.16 (d, J = 6.5 Hz, 1H),
7.48 (d, J = 6.5 Hz, 1H), 5.77 (q, J = 6.6 Hz, 1H), 4.30 (br s, 3H). 19F
NMR: −72.24 (d, J = 6.6 Hz, 3F). 13C NMR: 63.58 (q, J = 32 Hz,
CHOH), 112.06 (CH-5), 123.90 (q, J = 282 Hz, CF3), 132.99 (C-2),
135.80 (CH-6), 143.38 (C-3), 161.63 (CO-4). HRMS: calcd for
C7H7NO3F3 (M + 1)+, 210.0378; found, 210.0382.
1-Butyl-2-fluoro-3-hydroxypyridin-4(1H)-one Hydrobromide (1i).
1
Yield: 64%. H NMR (DMSO-d6): δ 8.18 (d, J = 5.4, 7.0 Hz, 1H, C-
6H), 7.12 (d, J = 7.1 Hz, 1H, C-5H), 4.34 (t, J = 7.1 Hz, 2H, CH2),
1.80−1.72 (m, 2H, CH2), 1.35−1.26 (m, 2H, CH2), 0.91 (t, J = 7.4
Hz, 3H, CH3). 19F NMR: −107.11 (s). 13C NMR: 13.30 (s, CH3),
18.79 (s, CH2), 31.06 (s, CH2), 52.81 (d, J = 3 Hz, CH2), 110.46 (s,
CH-5), 131.20 (d, J = 11 Hz, C-3), 134.01 (d, J = 4 Hz, CH-6), 149.91
(d, J = 264 Hz, C-2), 164.25 (d, J = 10 Hz, C-4). HRMS: calcd for
C9H13NO2F (M + 1)+, 186.0930; found, 186.0925.
General Procedure for the Preparation of 1b−q and 1v−1z.
Methyl or ethyl protecting 3,4-dihydroxypyridine or 3-hydroxy-1-alkyl-
pyridin-4-one was dissolved into CH2Cl2 (20 mL) and flushed with
nitrogen at −5 °C. Boron trichloride or boron tribromide (1 M in
CH2Cl2, 8 mL) was slowly added, and the reaction mixture was stirred
at room temperature for 20 h. The excess BCl3/BBr3 was eliminated at
the end of the reaction by the addition of methanol (10 mL) and left
to stir for another half an hour. After removal of the solvents under
reduced pressure, the residues were purified by recrystallization to
afford white solids.
2-Fluoro-3-hydroxy-6-methyl-pyridin-4(1H)-one Hydrobromide
1
(1j). Yield: 78%. H NMR (DMSO-d6): δ 6.61 (s, 1H, C-5H), 5.99
(brs, OH and NH), 2.21 (s, 3H, CH3). 19F NMR (DMSO-d6): −90.71
(s). 13C NMR (DMSO-d6): 22.23 (s, CH3), 109.50 (d, J = 3 Hz, C-5),
125.04 (d, J = 29 Hz, C-3), 144.52 (d, J = 13 Hz, C-6), 152.92 (d, J =
227 Hz, C-2), 156.26 (d, J = 8 Hz, C-4). HRMS: calcd for C6H7NO2F
(M + 1)+, 144.0461; found, 144.0463.
3-Hydroxy-2-(2,2,2-trifluoroacetyl)pyridin-4(1H)-one Hydrochlor-
1
2-Fluoro-3-hydroxy-5-methyl-pyridin-4(1H)-one Hydrobromide
ide (1b). Yield: 70%. H NMR (DMSO-d6): δ 8.17 (d, J = 6.4 Hz,
1
1H), 7.46 (d, J = 6.4 Hz, 1H), 4.08 (br s, 2H). 19F NMR: −78.54 (s,
3F). 13C NMR: 113.37 (CH-5), 121.70 (q, J = 155 Hz, CF3), 131.37
(C-2), 134.53 (CH-6), 145.45 (C-3), 163.31 (CO-4), 168.68
(COCF3). HRMS: calcd for C7H5NO3F3 (M + 1)+, 208.0222;
found, 208.0219.
(1k). Yield: 74%. H NMR (DMSO-d6): δ 7.59 (brs, OH and NH),
7.36 (s, 1H, C-6H), 2.07 (s, 3H, CH3). 19F NMR (DMSO-d6): −91.60
(s). 13C NMR (DMSO-d6): 12.53 (s, CH3), 119.84 (d, J = 3 Hz, C-5),
126.56 (d, J = 29 Hz, C-3), 135.54 (d, J = 16 Hz, C-6), 152.69 (d, J =
224 Hz, C-2), 154.12 (C-4). HRMS: calcd for C6H7NO2F (M + 1)+,
144.0461; found, 144.0478.
2-(2,2,2-Trifluoroacetyl)-3-hydroxy-1,6-dimethylpyridin-4(1H)-
1
2-Fluoro-3-hydroxy-5,6-dimethyl-pyridin-4(1H)-one Hydrobro-
one Hydrochloride (1c). Yield: 65%. H NMR (DMSO-d6) δ 8.73
1
mide (1l). Yield: 75%. H NMR (DMSO-d6): δ 6.23 (brs, OH and
(brs, 1H, OH), 7.28 (s, 1H, C-5H), 4.18 (s, 3H, NCH3), 2.62 (CH3).
19F NMR: −81.77 (d, J = 7.4 Hz). 13C NMR: 21.13 (s, CH3), 41.48 (s,
J = 20 Hz, NCH3), 113.58 (s, CH-5), 122.20 (d, J = 306 Hz, CF3),
134.54 (s, C-2), 145.17 (s, C-3), 150.91 (s, C-6), 160.93 (s, C-4),
214.00 (s, COCF3). HRMS: calcd for C9H9NO3F3 (M + 1)+,
236.0535; found, 236.0539.
2-Fluoro-3-hydroxypyridin-4(1H)-one Hydrobromide (1d). Yield:
60%. 1H NMR (CD3OD): δ 7.41 (d, J = 5.5 Hz, 1H, C-6H), 6.72 (d, J
= 5.5 Hz, 1H, C-5H)), 4.94 (brs, 2H, OH and NH). 19F NMR
(CD3OD): −85.48 (s). 13C NMR (CD3OD): 111.67 (d, J = 3 Hz, C-
5), 129.35 (d, J = 29 Hz, C-3), 137.17 (d, J = 16 Hz, C-6), 155.75 (d, J
= 228 Hz, C-2), 157.58 (d, J = 9 Hz, C-4). HRMS: calcd for
C5H5NO2F (M + 1)+, 130.0304; found, 130.0314.
NH), 2.23 (s, 3H, 6-CH3), 2.02 (s, 3H, 5-CH3). 19F NMR (DMSO-
d6): −94.63 (s). 13C NMR (DMSO-d6): 11.03 (s, 5-CH3), 20.43 (s, 6-
CH3), 117.10 (d, J = 4 Hz, C-5), 124.59 (d, J = 29 Hz, C-3), 142.63
(d, J = 13 Hz, C-6), 150.60 (d, J = 227 Hz, C-2), 155.10 (d, J = 8 Hz,
C-4). HRMS: calcd for C7H9NO2F (M + 1)+, 158.0617; found,
158.0609.
2-Fluoro-3-hydroxy-1,5-dimethyl-pyridin-4(1H)-one Hydrobro-
1
mide (1m). Yield: 79%. H NMR (DMSO-d6): δ 8.19 (d, J = 5.4
Hz, 1H, C-6H), 6.15 (brs, 1H, OH), 3.95 (d, J = 3.7 Hz, 3H, 1-CH3),
2.14 (s, 3H, 5-CH3). 19F NMR (DMSO-d6): −105.50 (s). 13C NMR
(DMSO-d6): 12.60 (s, 5-CH3), 39.48 (d, J = 5 Hz, 1-CH3), 120.41 (s,
C-5), 129.51 (d, J = 13 Hz, C-3), 133.68 (d, J = 5 Hz, C-6), 149.57 (d,
J = 263 Hz, C-2), 162.73 (d, J = 9 Hz, C-4). HRMS: calcd for
C7H9NO2F (M + 1)+, 158.0617; found, 158.0627.
2-Fluoro-3-hydroxy-1-methylpyridin-4(1H)-one Hydrobromide
1
(1e). Yield: 66%. H NMR (CD3OD): δ 8.06 (dd, J = 5.1, 7.1 Hz,
5-Fluoro-3-hydroxy-2-methylpyridin-4(1H)-one Hydrobromide
1
1H, C-6H), 7.13 (dd, J = 0.8 7.1 Hz, 1H, C-5H), 4.96 (brs, 1H, OH),
(1n). Yield: 69%. H NMR (DMSO-d6): δ 8.55 (d, J = 5.0 Hz, 1H,
4.09 (d, J = 3.8 Hz, 3H, CH3). 19F NMR (CD3OD): −102.49 (s). 13
C
C-6H), 4.54 (brs, OH and NH), 2.54 (s, 3H, CH3). 19F NMR
(DMSO-d6): −148.82 (s). 13C NMR (DMSO-d6): 14.04 (s, CH3),
121.88 (d, J = 32 Hz, C-6), 137.31 (s, C-2), 144.11 (d, J = 7 Hz, C-3),
148.73 (d, J = 238 Hz, C-5), 150.48 (d, J = 12 Hz, C-4). HRMS: calcd
for C6H7NO2F (M + 1)+, 144.0461; found, 144.0468.
NMR (CD3OD): 40.70 (d, J = 6 Hz, CH3), 111.39 (s, C-5), 133.03 (d,
J = 12 Hz, C-3), 136.10 (d, J = 5 Hz, C-6), 152.32 (d, J = 265 Hz, C-
2), 165.05 (d, J = 10 Hz, C-4). HRMS: calcd for C6H7NO2F (M + 1)+,
144.0461; found, 144.0460.
1-Ethyl-2-fluoro-3-hydroxypyridin-4(1H)-one Hydrobromide (1f).
Yield: 59%. 1H NMR (DMSO-d6): δ 8.17 (dd, J = 5.3, 7.1 Hz, 1H, C-
6H), 7.11 (d, J = 7.1 Hz, 1H, C-5H), 4.37 (dq, J = 2.5, 7.2 Hz, 2H,
CH2), 1.41 (t, J = 7.2 Hz, 3H, CH3). 19F NMR (DMSO-d6): −106.84
(s). 13C NMR (DMSO-d6): 14.81 (s, CH3), 48.69 (d, J = 4 Hz, CH2),
110.50 (s, C-5), 131.15 (d, J = 12 Hz, C-3), 133.60 (d, J = 5 Hz, C-6),
149.98 (d, J = 264 Hz, C-2), 163.89 (d, J = 11 Hz, C-4). HRMS: calcd
for C7H9NO2F (M + 1)+, 158.0617; found, 158.0622.
5-Fluoro-3-hydroxy-1,2-dimethyl-pyridin-4(1H)-one Hydrobro-
1
mide (1o). Yield: 62%. H NMR (DMSO-d6): δ 8.72 (d, J = 6.1
Hz, 1H, C-6H), 4.89 (brs, OH), 3.99 (s, 3H, 1-CH3), 2.47 (s, 3H, 2-
CH3). 19F NMR (DMSO-d6): −149.61 (d, J = 6.1 Hz). 13C NMR
(DMSO-d6): 12.70 (s, 2-CH3), 43.91 (s, 1-CH3), 127.24 (d, J = 35 Hz,
C-6), 139.28 (s, C-2), 144.58 (d, J = 7 Hz, C-3), 147.60 (d, J = 237
Hz, C-5), 149.80 (d, J = 13 Hz, C-4). HRMS: calcd for C7H9NO2F (M
+ 1)+, 158.0617; found, 158.0617.
2-Fluoro-3-hydroxy-1-propylpyridin-4(1H)-one Hydrobromide
3-Fluoro-5-hydroxy-2-methylpyridin-4(1H)-one Hydrobromide
1
1
(1g). Yield: 70%. H NMR (DMSO-d6): δ 8.14 (dd, J = 5.3, 7.1 Hz,
(1p). Yield: 72%. H NMR (DMSO-d6): δ 8.04 (d, J = 0.5 Hz, 1H,
1H, C-6H), 7.09 (d, J = 7.1 Hz, 1H, C-5H), 4.30 (t, J = 7.1 Hz, 2H,
C-6H), 4.30 (brs, OH and NH), 2.64 (d, J = 2.8 Hz, 3H, CH3). 19F
NMR (DMSO-d6): −146.32 (s). 13C NMR (DMSO-d6): 12.67 (s,
CH2), 1.85−1.78 (m, 2H, CH2), 0.89 (t, J = 7.3 Hz, 3H, CH3). 19F
2193
dx.doi.org/10.1021/jm201475u | J. Med. Chem. 2012, 55, 2185−2195