4-Fluoroaniline → HCID 46208775, compound

HRID 2060729Notes

Reaction equation

HRID 2060729 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=O)[CH2:27][CH2:26]1)=[O:24].[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:68][C:67]2[CH:69]=[CH:70][C:64]([F:63])=[CH:65][CH:66]=2)=[O:30])[CH2:27][CH2:26]1)=[O:24]

Participants

6

Reactant 4

HCID 97314-FluoroanilineHCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate3×HCID 59322767HCID 59322767, compound

Product 1

HCID 46208775HCID 46208775, compoundYield 60.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of Example B5 (9.91 g, 23.58 mmol) in DMF (80 mL), under an atmosphere of argon, were added TBTU (11.36 g, 35.4 mmol), DIPEA (20.59 ml, 118 mmol) and 4-fluoroaniline (3.93 g, 35.4 mmol). The reaction mixture was stirred at RT overnight. An additional portion of TBTU (7.5 g, 17.8 mmol) was added and stirring was continued. After 2 h, an additional portion of TBTU (3.5 g, 8.33 mmol) was added and stirring was continued for 2 h. The solvent was removed under high vacuum and the residue was dissolved in EtOAc (700 mL) and washed with sat. aq. NaHCO3 (2×200 mL) and brine (50 mL), dried (MgSO4), concentrated to dryness and purified by silica gel chromatography (MeOH-DCM) to provide N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7.2 g, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.76 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J=12.1, 7.1 Hz, 1H), 7.99 (s, 1H), 7.62-7.53 (m, 3H), 7.27 (d, J=2.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.71 (dd, J=5.6, 2.4 Hz, 1H), 3.86 (s, 3H), 1.69-1.56 (m, 4H); MS (ESI): m/z 508.1 [M+1]+.

Workup

  1. stirringstirring
  2. waitAfter 2 h
  3. stirringstirring
  4. waitwas continued for 2 h
  5. customThe solvent was removed under high vacuum
  6. dissolutionthe residue was dissolved in EtOAc (700 mL)
  7. washwashed with sat. aq. NaHCO3 (2×200 mL) and brine (50 mL)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated to dryness
  10. custompurified by silica gel chromatography (MeOH-DCM)

Sources & evidence

ORD record
ord-8fcbc814afdc4ab4b011dafdee94af24
Source dataset
uspto-grants-2012_10
Patent number
US08278331B2

Reaction notes

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