4-Hydroxybenzaldehyde → 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one

HRID 1846276Notes

Reaction equation

[NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.II.[OH-].[K+]>CN(C)C=O>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:26]2[C:25]2[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]

Participants

Conditions

Temperature: 110 °C

Procedure

To a solution of 2-amino-N-(4-sec-butylphenyl)-benzamide (0.500 g, 1.86 mmol) in N,N-dimethylformamide (9 mL) under nitrogen atmosphere was added 4-hydroxy-benzaldehyde (0.450 g, 3.73 mmol) followed by iodine (0.560 g, 2.23 mmol) and potassium hydroxide (0.120 g, 2.23 mmol). The resulting mixture was heated at 110° C. overnight, then the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over sodium sulfate. The crude oil (0.97 g) was purified by column chromatography (silica gel 230-400 mesh; 1/1 hexanes/EtOAc as eluent) to give pure 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one as a yellow solid. Yield: 0.33 g (47.8%). To a mixture of 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one (0.11 g, 0.31 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in N,N-dimethylformamide (3.5 mL) under nitrogen atmosphere was added 2-chloroethanol (0.032 mL, 46 mmol). The reaction mixture was heated at reflux for 14 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 5% aqueous solution of sodium hydroxide, brine, and dried over sodium sulfate. The crude solid (0.13 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 1/1 hexanes/EtOAc, then 10/0 to 9.4/0.6 methylene chloride/MeOH as eluent) and triturated with Et2O to give the pure title compound as a light brown solid. Yield: 60 mg, (46.3%). MP 172.8-174.9° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.80 (d, 2H), 7.50 (m, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 7.05 (d, 2H), 6.72 (d, 2H), 4.00 (m, 2H), 3.95 (m, 2H), 2.58 (m, 1H), 1.95 (s, OH), 1.65-1.48 (m, 2H), 1.20 (d, 3H), 0.75 (t, 3H). MS (ES+) m/z: 415.09 (M+1).

Workup

customthe solvent was removed under reduced pressure
additionthe residue was diluted with ethyl acetate
washwashed with water
dry with materialdried over sodium sulfate
customThe crude oil (0.97 g) was purified by column chromatography (silica gel 230-400 mesh; 1/1 hexanes/EtOAc as eluent)

Sources & evidence

ORD record: ord-f9a62c2bdeef4caf804acc5649610994
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08952021B2

Reaction notes

Loading…