Dichloromethane → HCID 67696368, compound

HRID 343183Notes

Reaction equation

HRID 343183 reaction equation
[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.ClCCl>CN(C=O)C>[F:41][C:37]1[CH:36]=[C:35]([N:5]2[C:4](=[O:28])[CH2:3][C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]2=3)[CH:40]=[CH:39][CH:38]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 140821-Bromo-3-fluorobenzene2×HCID 517044Potassium AcetateHCID 54046412HCID 54046412, compound

Product 1

HCID 67696368HCID 67696368, compoundYield 80.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirring solution of 500 mg (1.3 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 5 mL DMF is added 248 mg (3.9 mmol, 3 equiv) of Cu powder, 255 mg (2.6 mmol, 2 equiv) of potassium acetate, and 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene. The reaction is heated to 100° C., and after 3 h an additional 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene and 248 mg (3.9 mmol, 3 equiv) of Cu powder were added. The reaction is heated at 100° C. for 20 h then is poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 2:1-1:1 hexanes:ethyl acetate) to afford 497 mg of 2-[5-(3-Fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ7.45-7.25 (m, 4H), 7.18-6.93 (m, 8H), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.17 (d, 1H, J=16.1), 3.88 (s, 3H), 3.56 (dd, 2H, J=12.0, 29.8), 1.12 (d, 6H, J=6.8); low resolution MS (FAB)m/e 476 (MH+).

Workup

  1. temperatureThe reaction is heated at 100° C. for 20 h
  2. additionthen is poured onto ice
  3. filtrationthe mixture is filtered through celite
  4. additionThe filtrate is poured into a separatory funnel
  5. customthe layers separated
  6. addition2 mL of a 30% solution of NH4OH were added to the aqueous layer
  7. extractionthe resulting blue solution is extracted with dichloromethane
  8. dry with materialThe combined organics were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue is purified by silica gel flash column chromatography (gradient 2:1-1:1 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-8f1a1033a1d744e38c361c396d11ce13
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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