Réaction #635921

Équation de réaction

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

Solvants

NMP

Conditions de réaction

Traitement

1. 1
   FiltrationThe reaction mixture was filtered through diatomaceous earth
2. 2
   Lavagethe filter pad washed thoroughly with DCM and methanol
3. 3
   ConcentrationThe filtrate was concentrated in vacuo, water (20 mL)
4. 4
   workup.ADDITIONwas added to the residue
5. 5
   Extractionthe mixture extracted with ethyl acetate (3×50 mL)
6. 6
   LavageThe combined organic phases were washed with water (2×10 mL), brine (20 mL)
7. 7
   Séchagedried (MgSO4)
8. 8
   Autreevaporated in vacuo
9. 9
   AutreThe crude product was chromatographed on silica
10. 10
    Lavageeluting with a gradient of 0-5% methanol in DCM

Mode opératoire

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)−

Source