Quinoline → 3,4-Difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid

HRID 2181434Notes

Reaction equation

HRID 2181434 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[C:5]([F:21])[CH:4]=1)#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:19][C:18]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][C:5]=2[F:21])=[C:11]([CH:15]=[CH:16][C:17]=1[F:20])[C:12]([OH:14])=[O:13]

Participants

5

Reactant 2

HCID 7047QuinolineHCID 220256332-(4-Ethynyl-2-fluoroanilino)-3,4-difluorobenzoic acid

Product 1

HCID 220256413,4-Difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acidYield 72%

Reagents, catalysts & solvents 2

HCID 131709914Lindlars catalystCatalystHCID 8028TetrahydrofuranSolvent

Procedure

The product of Example 1, Step C, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (540 mg, 1.86 mmol) and quinoline (220 mg) were dissolved in THF (50 mL), then Lindlar catalyst (11 mg) added. This mixture was stirred under an atmosphere of hydrogen (60 psi) for 3 periods of 15 minutes and monitored carefully by TLC (50% EtOAc/hexanes as eluant). The reaction mixture was filtered through Celite® which was washed well with EtOAc and the resulting filtrate concentrated (to 100 mL) under reduced pressure. This organic solution was then washed with 1 M HCl (2×100 mL), water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting crude solid was purified by flash chromatography on silica (10% EtOAc/hexanes as eluant) to afford 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid as a crystalline yellow solid (390 mg, 72%); m.p. (EtOAc/hexanes) 162-166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.20 (br s, 1 H), 9.30 (br s, 1 H), 7.52 (ddd, J=8.3, 6.1, 1.8 Hz, 1 H), 7.41 (dd, J=12.8, 1.7 Hz, 1 H), 7.19 (dd, J=8.3, 1.7 Hz, 1 H), 7.08 (dd, J=16.6, 9.3 Hz, 1 H), 7.00 (td, J=8.7, 5.2 Hz, 1 H), 6.67 (dd, J=17.6, 10.9 Hz, 1 H), 5.78 (d, J=17.6 Hz, 1 H), 5.22 (d, J=11.0 Hz, 1 H). Anal. Calcd for C15H10F3NO2: C, 61.4; H, 3.3; N, 4.9. Found C, 61.4; H, 3.4; N, 4.8.

Workup

  1. filtrationThe reaction mixture was filtered through Celite® which
  2. washwas washed well with EtOAc
  3. concentrationthe resulting filtrate concentrated (to 100 mL) under reduced pressure
  4. washThis organic solution was then washed with 1 M HCl (2×100 mL), water (100 mL) and saturated NaCl solution (100 mL)
  5. dry with materialdried (Na2SO4)
  6. customthe solvent removed under reduced pressure
  7. customThe resulting crude solid was purified by flash chromatography on silica (10% EtOAc/hexanes as eluant)

Sources & evidence

ORD record
ord-b20faf3cbc784f81823d079fe848ed1f
Source dataset
uspto-grants-2005_05
Patent number
US06891066B2

Reaction notes

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