4-Fluoroaniline → 1,1-Dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)amino]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

HRID 534739Notes

Reaction equation

HRID 534739 reaction equation
C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1.Cl[C:62]1[N:67]=[CH:66][C:65]([C:68]([N:70]([CH3:92])[C:71]2[CH:76]=[CH:75][C:74]([CH2:77][N:78]3[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@@H:80]([CH3:91])[CH2:79]3)=[CH:73][CH:72]=2)=[O:69])=[CH:64][CH:63]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:62]2[N:67]=[CH:66][C:65]([C:68]([N:70]([CH3:92])[C:71]3[CH:76]=[CH:75][C:74]([CH2:77][N:78]4[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[C@@H:80]([CH3:91])[CH2:79]4)=[CH:73][CH:72]=3)=[O:69])=[CH:64][CH:63]=2)=[CH:56][CH:55]=1

Participants

7

Reactant 4

HCID 97314-FluoroanilineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 592622291,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Product 1

HCID 592622221,1-Dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)amino]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylateYield 47.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

BINAP (0.041 g, 0.0654 mmol), cesium carbonate (0.213 g, 0.654 mmol) and palladium acetate (0.009 g, 0.0436 mmol) were combined in dioxane (1 mL) and sonicated for 1 h under an argon atmosphere. To the red mixture was added 4-fluoroaniline (0.053 g, 0.479 mmol) and 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.2 g, 0.436 mmol). The mixture was stirred at 60° C. for 1 h, the solvent was removed under vacuum and the residues partitioned between EtOAc and water. The EtOAc layer was dried and concentrated. The crude product was purified by chromatography. Elution with a 0-70% EtOAc/petroleum ether gradient yielded the title compound as a pale yellow oil (0.110 g). δH (CDCl3, 400 MHz) 8.10 (1H, m), 7.40 (1H, dd), 7.25 (3H, m), 7.02 (4H, m), 6.92 (1H, s), 6.43 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.48 (1H, d), 3.36 (1H, d), 3.10 (1H, td), 2.70 (1H, d), 2.52 (1H, d), 2.10 (1H, m), 1.98 (1H, m), 1.85 (1H, br.s), 1.45 (9H, s), 1.20 (3H, d). MS (ES): MH+ 534.3.

Workup

  1. customsonicated for 1 h under an argon atmosphere
  2. customthe solvent was removed under vacuum
  3. customthe residues partitioned between EtOAc and water
  4. dry with materialThe EtOAc layer was dried
  5. concentrationconcentrated
  6. customThe crude product was purified by chromatography
  7. washElution with a 0-70% EtOAc/petroleum ether gradient

Sources & evidence

ORD record
ord-34ce6fe18c204da2a6829249ef5a6e25
Source dataset
uspto-grants-2014_10
Patent number
US08853218B2

Reaction notes

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