Ammonium Chloride → HCID 66599441, compound

HRID 2410712Notes

Reaction equation

HRID 2410712 reaction equation
CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33](F)=[C:34]([CH:37]=1)[C:35]#[N:36].[NH4+].[Cl-]>CS(C)=O.ClCCl>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:27][CH:28]=2)=[C:34]([C:35]#[N:36])[CH:37]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 27249005-Bromo-2-fluorobenzonitrileHCID 2763355Tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylateHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 66599441HCID 66599441, compoundYield 57.5%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent3×HCID 6344DichloromethaneSolvent

Procedure

KOtBu (2.81 g, 25.08 mmol) was dissolved into 20 ml DMSO in a round bottom flask. tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (7 g, 22.92 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at room temperature, then cooled in an iced bath for 5 minutes. 5-bromo-2-fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. LCMS showed product and unreacted starting materials. Additional KOtBu (2 g, 17.82 mmol) was added and the reaction stirred at room temperature overnight. The mixture was transferred into a separating funnel that was loaded with dichloromethane and dilute aq. NH4Cl solution. The layers were separated, the organic layer washed one more time with water, then brine, dried over Mg504, filtered and concentrated in vacuum. The crude was dissolved in dichloromethane, and refluxed while adding ethyl acetate until the solution becomes cloudy, then allowed to stand and cool to room temperature. The product precipitated and was collected by filtration. 6.40 g tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)-benzoyl)piperazine-1-carboxylate were isolated as a white solid. The mother liquor was concentrated in vacuum and purified by column chromatography on silica, gradient from 100% dichloromethane to 50% ethyl acetate in dichloromethane. Product containing fractions were combined and evaporate to give additional 0.90 g product as a pale yellow solid. MS (ESI) m/z 485/487 (1 Br isotope pattern) (M+H), 429/431 (1 Br isotope pattern) (M+H—C4H8). 1H NMR (CDCl3) δ ppm 7.64 (s, 1H), 7.50 (d, 1H, J=9.2), 7.42 (d, 2H, J=8.3), 7.19-7.15 (m, 3H), 6.39 (s, 1H), 3.80-3.40 (b, 8H), 1.47 (s, 9H).

Workup

  1. temperaturecooled in an iced bath for 5 minutes
  2. customThe ice bath was removed
  3. stirringthe mixture stirred for 5 hours
  4. temperaturewhile warming to room temperature
  5. stirringthe reaction stirred at room temperature overnight
  6. customThe mixture was transferred into a separating funnel
  7. customThe layers were separated
  8. washthe organic layer washed one more time with water
  9. dry with materialbrine, dried over Mg504
  10. filtrationfiltered
  11. concentrationconcentrated in vacuum
  12. dissolutionThe crude was dissolved in dichloromethane
  13. temperaturerefluxed
  14. additionwhile adding ethyl acetate until the solution
  15. temperaturecool to room temperature
  16. customThe product precipitated
  17. filtrationwas collected by filtration

Sources & evidence

ORD record
ord-1bedd4368e8b499d96106ae09293afd3
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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