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With [bis(acetoxy)iodo]benzene; potassium hydroxide In methanol for 1.33333 h; Cooling with ice
7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide (45 g, 102 mmol) was dissolved in methanol (500 mL) and potassium hydroxide (7.47 g, 133 mmol) was added. The mixture was stirred in an ice bath, then iodobenzene diacetate (39.6 g, 123 mmol) was added in small portions over 20 min and the mixture stirred for a further 1 h. The solvent was evaporated in vacuo, the residue diluted with water (1 L), and the resulting gummy suspension extracted with DCM (2 x 300 mL). The solvent was dried (sodium sulphate) and loaded directly onto a silica column (750 g), which was then eluted with a 2M ammonia in methanol / DCM gradient (0-10percent). After evaporation of solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-(2-pyridinyl)ethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (32.7 g, 77percent yield) was obtained as a beige solid. 1H-NMR (600 MHz, DMSO-d6) d ppm 2.03 (d, J=6.5 Hz, 3 H), 2.04 (s, 3 H), 2.25 (s, 3 H), 3.46 (bs, 3 H), 6.26 (q, J=7.1 Hz, 1 H), 6.69 (bs, 1 H), 7.35 (dd, J=7.0, 5.1 Hz, 1 H), 7.41 (d, J=6.6 Hz, 1 H), 7.76-7.79 (m, 1 H), 7.79 (s, 1 H), 8.59-8.65 (m, 2 H), 11.77 (bs, 1H). 13C NMR (151 MHz, DMSO-d6) d ppm 10.3, 11.3, 17.6, 51.8, 55.5, 100.8, 112.0, 115.4, 120.2, 121.0, 122.7, 122.7, 128.1, 132.3, 132. 8, 137.6, 139.8, 149.3, 154.3, 154.5, 159.0, 159.2, 166.0. MS (Method HpH): MH+ 416, Rt 0.85 min. HRMS (m/z): [MH]+ calcd for C23H22N5O3 416.1723; found 416.1718.
33%
With [bis-(trifluoroacetoxy)iodo]benzene In acetonitrile at 20℃;
The carboxamide intermediate (6 g) was treated with an excess of [bis(trifluoroacetoxy)iodo]benzene (19.35 g, 45 mmol) in CH3CN (100 ml), the mixture was stirred at room temperature overnignt. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in DCM and washed with water. The crude product was purified by flash chromatography on silica gel (DCM/MeOH, 95:5), the resulting compound was dissolved in DCM and precipitated from diethylether to give the title compound as an off-white powder (2.5 g, 33percent) LC-HRMS ES+ exact mass calculated for C23H21N5O3: 416.1722 MH+. Found 416.1736, Rt=2.22 min. (APCI-MS) m/z 415.97 MH+, Rt 2.5 min.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2963 - 2967
[2] Patent: US2012/232074, 2012, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2011/54846, 2011, A1, . Location in patent: Page/Page column 84
Multi-step reaction with 9 steps
1: caesium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere
2: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h
3: 1 h / 130 °C
4: diphenylether / 0.75 h / 255 °C
5: sodium hydroxide / ethanol / Reflux
6: trichlorophosphate / 4 h / Heating
7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
8: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C
9: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / 1.33 h / Cooling with ice
Multi-step reaction with 8 steps
1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 20 h / 80 °C
2.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h
2.2: 20 h
3.1: 1 h / 130 °C
4.1: diphenylether / 0.75 h / 255 °C
5.1: sodium hydroxide; water / ethanol / Reflux
5.2: 0.17 h / pH 4
6.1: trichlorophosphate / 20 °C / Heating
6.2: 0.5 h / Cooling with ice
7.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C
8.1: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C
Multi-step reaction with 8 steps
1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 80 °C
2.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h
3.1: 1 h / 130 °C
4.1: diphenylether / 0.75 h / 255 °C
5.1: ethanol; sodium hydroxide / Reflux
5.2: pH 4
6.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux
6.2: 1 h / 0 - 5 °C
7.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C
8.1: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice
Multi-step reaction with 8 steps
1.1: tetrakis(triphenylphosphine) palladium(0); barium hydroxide octahydrate / water; 1,2-dimethoxyethane / 16 h / 80 °C
2.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C
3.1: 0.5 h / 130 °C
4.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation
5.1: sodium hydroxide; ethanol / 17 h / 80 °C
6.1: trichlorophosphate / 2 h / 100 °C
6.2: 0.5 h / 0 °C
7.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 150 °C
8.1: potassium hydroxide; [bis(acetoxy)iodo]benzene / methanol / 1 h / 0 °C
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