Reacción #635921

Ecuación de reacción

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

Disolventes

NMP

Condiciones de reacción

Tratamiento posterior

1. 1
   FiltraciónThe reaction mixture was filtered through diatomaceous earth
2. 2
   Lavadothe filter pad washed thoroughly with DCM and methanol
3. 3
   ConcentraciónThe filtrate was concentrated in vacuo, water (20 mL)
4. 4
   workup.ADDITIONwas added to the residue
5. 5
   Extracciónthe mixture extracted with ethyl acetate (3×50 mL)
6. 6
   LavadoThe combined organic phases were washed with water (2×10 mL), brine (20 mL)
7. 7
   Secadodried (MgSO4)
8. 8
   Otroevaporated in vacuo
9. 9
   OtroThe crude product was chromatographed on silica
10. 10
    Lavadoeluting with a gradient of 0-5% methanol in DCM

Procedimiento

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)−

Fuente