2-Fluoro-4-iodoaniline → 6-Fluoro-2-[(2-fluoro-4-iodophenyl)amino]nicotinic acid

HRID 2404227Notes

Reaction equation

HRID 2404227 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[N:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[F:30][C:28]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])[N:29]=1

Participants

5

Reactant 3

HCID 1856942-Fluoro-4-iodoanilineHCID 2733832Lithium HexamethyldisilazideHCID 105830702,6-Difluoropyridine-3-carboxylic acid

Product 1

HCID 248220326-Fluoro-2-[(2-fluoro-4-iodophenyl)amino]nicotinic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To solution of 2-fluoro-4-iodoaniline (0.82 g, 3.46 mmol) in THF (10 mL) at −78° C. LiHMDS (6.00 mL, 6.60 mmol) was added. After stirring for 15 min, 2,6-difluoronicotinic acid (0.50 g, 3.14 mmol) was added to the mixture. The mixture was allowed to warm to room temperature until completion. The mixture was washed with NaOH (1 N) and extracted with ether. The aqueous layer was acidified with concentrated HCl and back-extracted with ethyl acetate. The organic layer was concentrated to afford product. Second crop of product was obtained by purifying the THF/ether layer with silica gel chromatography. LC/MS [Method B: rt. 9.09 min, m/z 377 (M+1)].

Workup

  1. customat −78° C
  2. washThe mixture was washed with NaOH (1 N)
  3. extractionextracted with ether
  4. extractionback-extracted with ethyl acetate
  5. concentrationThe organic layer was concentrated
  6. customto afford product
  7. customSecond crop of product was obtained
  8. customby purifying the THF/ether layer with silica gel chromatography
  9. customLC/MS [Method B: rt. 9.09 min, m/z 377 (M+1)]

Sources & evidence

ORD record
ord-7f9257495d974fa19bfb0570e71ba64e
Source dataset
uspto-grants-2014_08
Patent number
US08802703B2

Reaction notes

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