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

HRID 548739Notes

Reaction equation

HRID 548739 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]2.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.[Cu]I>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=[C:8]([O:7][C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]4)[CH:9]=2)=[N:15][CH:16]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 218654506-Bromo-3,4-dihydro-2H-isoquinolin-1-oneHCID 576632213-Hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Product 1

HCID 57663170N-(5-Methylpyrazin-2-yl)-3-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

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)−

Workup

  1. filtrationThe reaction mixture was filtered through diatomaceous earth
  2. washthe filter pad washed thoroughly with DCM and methanol
  3. concentrationThe filtrate was concentrated in vacuo, water (20 mL)
  4. additionwas added to the residue
  5. extractionthe mixture extracted with ethyl acetate (3×50 mL)
  6. washThe combined organic phases were washed with water (2×10 mL), brine (20 mL)
  7. dry with materialdried (MgSO4)
  8. customevaporated in vacuo
  9. customThe crude product was chromatographed on silica
  10. washeluting with a gradient of 0-5% methanol in DCM

Sources & evidence

ORD record
ord-26d2bf25f3ab4257ab861126a18dd2e9
Source dataset
uspto-grants-2011_05
Patent number
US07943607B2

Reaction notes

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