Dimethylformamide → 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

HRID 575094Notes

Reaction equation

HRID 575094 reaction equation
Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.CN(C=O)C.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C@:35]([OH:39])([C:37]#[CH:38])[CH3:36])[CH:31]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[F:23][C:3]1[C:2]([C:38]#[C:37][C@@:35]([OH:39])([C:32]2[CH:31]=[C:30]([CH3:29])[O:34][N:33]=2)[CH3:36])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 58221468(R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-olHCID 8669312610-Bromo-9-fluoro-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

Product 1

HCID 866931259-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
90 °C

Procedure

The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (73 mg, 0.12 mmol) in a mixture of anhydrous DMF (0.5 mL) and acetonitrile (0.7 mL) were introduced (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (168 mg, 1.10 mmol), copper(I) iodide (4 mg, 0.02 mmol) and triethylamine (700 mg, 6.92 mmol). The solution was de-oxygenated by bubbling with nitrogen for 5 min, then bis(triphenylphosphine)palladium(II) chloride was added and bubbling continued for a further 5 min. The reaction mixture was warmed to 90° C. for 48 hr under an atmosphere of nitrogen, then allowed to stand at room temperature for a further 24 hr. Following evaporation of the reaction mixture in vacuo, the residue was re-dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo. Purification by silica gel flash column chromatography (heptane/ethyl acetate gradient) furnished a tan solid which was suspended in acetonitrile (0.3 mL), sonicated for 30 seconds, and the solid isolated by suction filtration. Drying on the filter gave the title compound as an off-white solid: 1H NMR (500 MHz, DMSO) δ 1.81 (3H, s), 2.41 (3H, s), 4.50-4.55 (2H, m), 4.58-4.63 (2H, m), 6.35 (1H, d, J=0.63 Hz), 6.60 (1H, s), 7.10 (1H, d, J=10.40 Hz), 7.53 (1H, br. s.), 7.99 (1H, s), 8.63 (1H, d, J=8.20 Hz); 19F NMR (235 MHz, DMSO) δ −54.3, −108.0; LC-MS: m/z 465.05 (M+H)+.

Workup

  1. customThe title compound was prepared similarly
  2. customby bubbling with nitrogen for 5 min
  3. additionbis(triphenylphosphine)palladium(II) chloride was added
  4. custombubbling
  5. waitto stand at room temperature for a further 24 hr
  6. customevaporation of the reaction mixture in vacuo
  7. dissolutionthe residue was re-dissolved in ethyl acetate (20 mL)
  8. washwashed with saturated aqueous sodium bicarbonate solution (15 mL)
  9. extractionThe organic extract
  10. dry with materialwas dried over sodium sulfate
  11. filtrationfiltered
  12. customevaporated in vacuo
  13. customPurification by silica gel flash column chromatography (heptane/ethyl acetate gradient)
  14. customfurnished a tan solid which
  15. customsonicated for 30 seconds
  16. customthe solid isolated by suction filtration
  17. customDrying on the filter

Sources & evidence

ORD record
ord-9e4dc9d3a3664218ad5c028ee20bd144
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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