2-Fluoroaniline → 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

HRID 929046Notes

Reaction equation

HRID 929046 reaction equation
[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13](F)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]

Participants

5

Reactant 3

HCID 95842-FluoroanilineHCID 2733832Lithium HexamethyldisilazideHCID 111186375-Bromo-2,3,4-trifluorobenzoic acid

Product 1

HCID 595193885-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acidYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).

Workup

  1. customThe reaction was quenched with 10% HCl (aq., 100 mL)
  2. extractionextracted with ethyl acetate (200 mL×3)
  3. washThe combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4c4b321853a44aae9d1234b4333085be
Source dataset
uspto-grants-2016_03
Patent number
US09290468B2

Reaction notes

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