3-Bromopyridine → 2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide

HRID 343155Notes

Reaction equation

HRID 343155 reaction equation
[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[N:10]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:4]=2[CH:3]=1

Participants

6

Reactant 3

HCID 122863-Bromopyridine2×HCID 517044Potassium AcetateHCID 540958782-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide

Product 1

HCID 540873952-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamideYield 67.2%

Reagents, catalysts & solvents 2

HCID 23978CopperCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 0.880 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part D, (2.20 mmol), 420 mg of copper powder (6.61 mmol, 3 equiv), 476 mg of potassium acetate (4.85 mmol, 2.2 equiv), and 0.290 mL of 3-bromopyridine (4.85 mmol, 2.2 equiv) in 10 mL of dimethylformamide is heated at 100° C. under nitrogen for 3 hrs. An additional 0.132 mL of 3-bromopyridine (2.43 mmol, 1.1 equiv) is added and the reaction is maintained for an additional 2 hrs. The reaction mixture is cooled to ambient temperature, filtered through a sintered glass funnel and then evaporated in vacuo to a residue. The residue is partitioned between ethyl acetate and aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL). After separating the layers, the organic layer is washed with aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL), and then saturated aqueous brine. The organic phase is then extracted three times with aqueous HCl (1N). The acid layers were combined and neutralized with aqueous sodium hydroxide (1N). The neutralized mixture is extracted twice with methylene chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue is triturated with hexane and then concentrated in vacuo to provide 0.705 g of 2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a tan solid: H NMR (300 MHz, CDCl3) δ8.60 (m, 2H), 8.08 (s, br, 1H), 7.54 (s, 1H), 7.39 (m, 1H), 7.15 (m, 2H), 7.00 (m, 3H), 6.57 (dd, 1H, J=2.7, 9.2), 4.95 (m, 1H), 4.32 (d, 1H, J=17.9), 4.14 (d, 1H, J=17.8), 3.85 (s, 3H), 3.61 (d, 1H, J=12.1), 3.52 (d, 1H, J=12.1), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 477 (MH+).

Workup

  1. temperaturethe reaction is maintained for an additional 2 hrs
  2. temperatureThe reaction mixture is cooled to ambient temperature
  3. filtrationfiltered through a sintered glass funnel
  4. customevaporated in vacuo to a residue
  5. customThe residue is partitioned between ethyl acetate and aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL)
  6. customAfter separating the layers
  7. washthe organic layer is washed with aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL)
  8. extractionThe organic phase is then extracted three times with aqueous HCl (1N)
  9. extractionThe neutralized mixture is extracted twice with methylene chloride
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. customevaporated in vacuo to a residue
  13. customThe residue is triturated with hexane
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cc25c33752dc4c378517bd7bf5ab9b69
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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