反応 #635921

反応方程式

Cesium carbonate

3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

6-bromo-3,4-dihydro-2H-isoquinolin-1-one

2,2,6,6 tetramethyl-3,5-heptanedione

→

desired compound

N-(5-Methylpyrazin-2-yl)-3-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

溶媒

NMP

反応条件

後処理

1. 1
   ろ過The reaction mixture was filtered through diatomaceous earth
2. 2
   洗浄the filter pad washed thoroughly with DCM and methanol
3. 3
   濃縮The filtrate was concentrated in vacuo, water (20 mL)
4. 4
   workup.ADDITIONwas added to the residue
5. 5
   抽出the mixture extracted with ethyl acetate (3×50 mL)
6. 6
   洗浄The combined organic phases were washed with water (2×10 mL), brine (20 mL)
7. 7
   乾燥dried (MgSO4)
8. 8
   その他evaporated in vacuo
9. 9
   その他The crude product was chromatographed on silica
10. 10
    洗浄eluting with a gradient of 0-5% methanol in DCM

実験手順

Cesium carbonate (812 mg, 2.50 mmol) was added to a solution of 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (262 mg, 0.83 mmol), 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (226 mg, 1.0 mmol), copper (I) iodide (158 mg, 0.83 mmol) and 2,2,6,6 tetramethyl-3,5-heptanedione (0.7 mL, 3.3 mmol) in NMP (9 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The reaction mixture was filtered through diatomaceous earth and the filter pad washed thoroughly with DCM and methanol. The filtrate was concentrated in vacuo, water (20 mL) was added to the residue and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (2×10 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound a white solid (190 mg). 1H NMR δ (CDCl3): 2.17 (1H, m), 2.22-2.29 (1H, m), 2.56 (3H, s), 2.94-3.02 (2H, m), 3.49-3.59 (2H, m), 3.90-4.01 (4H, m), 5.00 (1H, s), 6.01 (1H, s), 6.77-6.80 (1H, m), 6.83 (1H, s), 6.96 (1H, d), 7.16 (1H, s), 7.26 (1H, d), 8.06 (1H, d), 8.15 (1H, s), 8.49 (1H, s), 9.54 (1H, s); m/z 461 (M+H)+, 459 (M−H)−

出典