(4-Aminophenyl)(4-methylpiperazin-1-yl)methanone → HCID 66599439, compound

HRID 2410706Notes

Reaction equation

HRID 2410706 reaction equation
CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30]>CS(C)=O.ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:28]([CH:31]=1)[C:29]#[N:30]

Participants

6

Reactant 3

HCID 231408(4-Aminophenyl)(4-methylpiperazin-1-yl)methanoneHCID 27249005-Bromo-2-fluorobenzonitrileHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 66599439HCID 66599439, compoundYield 19.8%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent3×HCID 6344DichloromethaneSolvent

Procedure

KOtBu (2.81 g, 25.08 mmol) was dissolved in 20 ml DMSO in a round bottom flask. (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (5.0 g, 22.80 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at r.t. The mixture was 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. Additional KOtBu (2 g, 17.82 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, extracted twice with water, once with brine, then dried over MgSO4, filtered and concentrated. 8.8 g crude brown oil were isolated. The crude product was recrystallized from dichloromethane+ethyl acetate+hexanes. 5.012 g pale yellow crystals were collected by filtration. The mother liquor was concentrated and purified by chromatography on silica, using a gradient from 100% Solvent A to 50% Solvent A+50% Solvent B. Solvent A: 99% dichloromethane+1% Triethylamine, Solvent B: 99% Ethylacetate+1% Triethylamine. Evaporation of product containing fractions gave additional 1.8 g product of ˜70% purity. MS (ESI) m/z 399/401(M+H). 1H NMR (CDCl3) δ ppm 7.63 (s, 1H), 7.48 (d, 1H, J=9.2), 7.42 (d, 2H, J=7.9), 7.18-7.14 (m, 3H), 6.41 (s, 1H), 3.80-3.40 (bm, 4H), 2.42 (bs, 4H), 2.32 (s, 3H).

Workup

  1. temperatureThe mixture was cooled 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 mixture stirred at room temperature overnight
  6. extractionextracted twice with water, once with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custom8.8 g crude brown oil were isolated
  11. customThe crude product was recrystallized from dichloromethane+ethyl acetate+hexanes
  12. filtration5.012 g pale yellow crystals were collected by filtration
  13. concentrationThe mother liquor was concentrated
  14. custompurified by chromatography on silica
  15. customEvaporation of product
  16. additioncontaining fractions

Sources & evidence

ORD record
ord-06dfdd7f277243feb75982becc5cbf82
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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