418
Z. Zhang et al. / European Journal of Medicinal Chemistry 60 (2013) 410e420
desired compound. Yield: 120 mg, 45%, 1H NMR (400 MHz, CDCl3):
5.1.12. General procedure for the preparation of 11aed
d
: 7.99 (s, 1H, AreH), 7.56 (s, 1H, AreH), 7.33e7.35 (d, J ¼ 8.4 Hz, 2H,
Acetic acid (20 mL) was added to corresponding 2-
chloronicotinamide (9aed) (2 mmol), the temperature raised to
125 ꢂC until the reaction had reached completion, as monitored by
TLC. The corresponding desired crude intermediates (10aed) were
obtained and the mixture was used in the next step without further
disposal. The resulting mixture was colded to room temperature.
Bromine (0.5 mL, 9.5 mmol) was slowly dropped to acetic acid
solution of (10aed) at room temperature within 0.5 h, kept stirring
for 3 h. Then the solution of sodium pyrosulfite (20%, 10 mL) was
added. The mixed was extracted with CH2Cl2 (3 ꢅ 20 mL).
The organic layer was washed with brine and dried with MgSO4.
Concentration of the organic layer afforded the desired
crude product. Purification by silica gel flash column chromatog-
raphy (dichloromethane/methanol, 20:1) afforded the desired
compound.
AreH), 7.21e7.23 (m, 3H, AreH), 7.14e7.16 (d, J ¼ 7.6 Hz, 2H, AreH),
6.87e6.89 (d, J ¼ 8.0 Hz, 2H, AreH), 4.98 (s, 2H, CH2), 1.26e1.27 (m,
1H, CH), 1.19 (s, 6H, CH(CH3)2). TOF MS (EIþ): C22H20N2OS, calcd for
360.1296, found 360.1290.
5.1.9. 2-chloronicotinic acid (7)
A solution of the 2-chloronicotinonitrile (4.14 g, 30 mmol) in
30 mL of 50% sulfuric acid was heated for at 100 ꢂC for 10 h and then
the reaction mixture was poured into the crushed ice. The resultant
precipitate was filtered, washed with water and dried. The solid
was recrystallized from 90% ethanol. Yield: 4.16 g, 88%.
5.1.10. 2-chloronicotinoylchloride (8)
A solution of 2-chloronicotinic acid (7) (1 g, 6.3 mmol), a cata-
lytic amount of anhydrous DMF (0.13 mmol, 10 mL), and thionyl
chloride (15 mL) was heated at reflux for 6 h. The reaction mixture
was cooled to room temperature and the excess of thionyl chloride
was removed under reduced pressure. The acid chloride thus
formed and the mixture was used in the next step without further
disposal.
5.1.12.1. N-isopropyl-5-bromo-2-hydroxynicotinamide
(11a). Yield:
275 mg, 53%. 1H NMR (400 MHz, CDCl3):
d
12.88 (s, 1H, AreOH), 9.56 (s,
1H, NeH), 8.27 (s,1H, AreH), 7.99 (s,1H, AreH), 3.99e4.04 (m,1H, CH),
1.15 (s, 6H, (CH3)2). TOF MS (ESI): C9H11BrN2O2, for [M þ H]þ, calcd for
259.0082, found 259.0078.
5.1.11. General procedure for the preparation of 9aed
5.1.12.2. N-butyl-5-bromo-2-hydroxynicotinamide
(11b). Yield:
The mixture of 2-chloronicotinoylchloride (8) in last step was
dissolved in anhydrous CH2Cl2 (10 mL) and then added dropwise to
a CH2Cl2 (10 mL) solution of the corresponding amine (15 mmol)
cooled at 0 ꢂC under stirring. The mixture was allowed to warm to
room temperature and stirring was continued for additional 4 h.
After treatment of the reaction mixture with a 5% solution of
sodium hydroxide (15 mL) and separation of the organic layer, the
aqueous phase was extracted with ethyl acetate (3 ꢅ 15 mL) to
recover further product. The combined organic extracts were dried
(Na2SO4) and evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel using dichloro-
methane/acetone (30:1).
251 mg, 46%. 1H NMR (400 MHz, CDCl3):
d
12.87 (s, 1H, AreOH),
9.64 (s, 1H, NeH), 8.27 (s, 1H, AreH), 7.99 (s, 1H, AreH), 3.27e
3.33 (t, 2H, CH2), 1.44e1.51 (m, 2H, CH2), 1.29e1.36 (m, 2H, CH2),
0.88e0.91 (t, 3H, CH3). TOF MS (ESI): C10H13BrN2O2, for [M þ H]þ,
calcd for 273.0239, found 273.0245.
5.1.12.3. N-benzyl-5-bromo-2-hydroxynicotinamide
(11c). Yield:
417 mg, 68%. 1H NMR (400 MHz, CDCl3):
d
12.53 (s, 1H, AreOH), 9.74
(s,1H, NeH), 8.71 (s,1H, AreH), 7.58 (s,1H, AreH), 7.34e7.36 (m, 2H,
AreH), 7.26e7.30 (m, 3H, AreH), 4.68 (s, 2H, CH2). TOF MS (ESI):
C
13H11BrN2O2, for [M þ H]þ, calcd for 307.0082, found 307.0086.
5.1.12.4. N-phenylpropyl-5-bromo-2-hydroxynicotinamide
(11d).
5.1.11.1. N-isopropyl-2-chloronicotinamide (9a). Yield: 898 mg,
Yield: 382 mg, 57%. 1H NMR (400 MHz, CDCl3):
d
12.87 (s, 1H, Are
72%. 1H NMR (400 MHz, CDCl3):
d
8.44e8.46 (d, J ¼ 8.4 Hz,
OH), 9.68 (s, 1H, AreH), 8.26 (s, 1H, AreH), 7.99 (s, 1H, NeH), 7.44e
7.47 (m, 2H, AreH), 7.17e7.20 (m, 3H, AreH), 3.26e3.33 (t, 2H, CH2),
2.57e2.61 (m, 2H, CH2), 1.77e1.80 (t, 2H, CH2). TOF MS (ESI):
1H, AreH), 8.10e8.12 (d, J ¼ 9.2 Hz, 1H, AreH), 7.34 (m,
1H, AreH), 6.47 (s, 1H, NH), 2.84 (m, 1H, CH), 1.24 (s, 6H,
(CH3)2). TOF MS (EIþ): C9H11ClN2O, calcd for 198.0560, found
198.0562.
C
15H15BrN2O2, for [M þ H]þ, calcd for 335.0395, found 335.0391.
5.1.13. General procedure for the preparation of 12aed
5.1.11.2. N-butyl-2-chloronicotinamide (9b). Yield: 935 mg, 70%. 1H
Corresponding 5-bromo-2-hydroxynicotinonitrile (11aed)
(1 mmol), Potassium tert-butoxide (3 eq) and tetrakis(-
triphenylphosphine)palladium(0) (0.05 eq), CuI (20 mg) was added
to a flask. Then the flask was evacuated and backfilled with N2. 4-
isopropyl thiophenol (3 eq) and DMF (10 mL) were added under
argon atmosphere. The reaction mixture was refluxed overnight.
The solvent was removed under reduced pressure and the water
(20 mL) was added. The solution was extracted with dichloro-
methane (3 ꢅ 20 mL). The organic layer was collected and dried
with anhydrous MgSO4, and concentrated in vacuo to give the
crude product. Purification by silica gel flash column chromatog-
raphy (dichloromethane/methanol, 30:1) afforded the desired
compound.
NMR (400 MHz, CDCl3):
d
8.40e8.42 (d, J ¼ 8.0 Hz, 1H, AreH), 7.98e
8.01 (d, J ¼ 9.2 Hz, 1H, AreH), 7.33e7.36 (m, 1H, AreH), 6.42 (s, 1H,
NH), 3.47e3.52 (t, 2H, CH2), 1.60e1.67 (m, 2H, CH2), 1.42e1.47 (m,
2H, CH2), 0.96e0.99 (t, 3H, CH3). TOF MS (EIþ): C10H13ClN2O, calcd
for 212.0716, found 212.0720.
5.1.11.3. N-benzyl-2-chloronicotinamide (9c). Yield: 1224 mg, 79%.
1H NMR (400 MHz, CDCl3):
d
9.74e9.75 (d, J ¼ 6.4 Hz, 1H, AreH),
8.61e8.62 (d, J ¼ 8.4 Hz, 1H, AreH), 8.26e8.29 (m, 1H, AreH),
7.49 (s, 1H, NH), 7.34e7.35 (m, 2H, AreH), 7.26e7.29 (m, 3H, Are
H), 4.66e4.67 (s, 2H, CH2). TOF MS (EIþ): C13H11ClN2O, calcd for
246.0560, found 246.0563.
5.1.11.4. N-phenylpropyl-2-chloronicotinamide (9d). Yield: 1191 mg,
5.1.13.1. N-isopropyl-5-(4-isopropylthiophenol)-2-hydroxynicotina-
69%. 1H NMR (400 MHz, CDCl3):
d
9.48e9.49 (d, J ¼ 6.4 Hz, 1H, Are
mide (12a). Yield: 116 mg, 35%. 1H NMR (400 MHz, CDCl3):
d 12.68
H), 8.26e8.27 (d, J ¼ 4.8 Hz, 1H, AreH), 7.94e7.99 (m, 1H, AreH),
7.72 (s, 1H, NH), 7.44e7.45 (m, 2H, AreH), 7.36e7.38 (m, 3H, Are
H), 3.24e3.27 (t, 2H, CH2), 2.59e2.62 (m, 2H, CH2), 1.73e1.77 (t,
2H, CH2). TOF MS (EIþ): C15H15ClN2O, calcd for 274.0873, found
274.0869.
(s,1H, AreOH), 9.23 (s, 1H, NeH), 8.69 (s, 1H, AreH), 7.67 (s,1H, Are
H), 7.19e7.21 (d, J ¼ 8.0 Hz, 2H, AreH), 7.14e7.16 (d, J ¼ 8.0 Hz, 2H,
AreH), 4.21e4.25 (m, 1H, CH), 2.83e2.90 (m, 1H, CH), 1.23e1.25 (d,
6H, CH(CH3)2), 1.20e1.21 (d, 6H, (CH3)2). TOF MS (ESI):
C
18H22N2O2S, for [M þ H]þ, calcd for 331.1480, found 331.1481.