2-Fluoro-4-iodoaniline → 4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

HRID 508147Notes

Reaction equation

HRID 508147 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]([CH3:27])[C:23](=[O:26])[C:24]=1[CH3:25]

Participants

5

Reactant 3

HCID 1856942-Fluoro-4-iodoanilineHCID 2724682Lithium diisopropylamide2×HCID 115429654-Chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Product 1

HCID 574581874-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidYield 52%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To the stirred solution of 2-fluoro-4-iodoaniline (470 mg, 1.94 mmol) in dry THF (4 mL) cooled to −78° C., was added LDA (2M in THF) (1.35 mL, 2.70 mmol). After vigorous stirring for 10 minutes at this temperature, a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (160 mg, 0.792 mmol) dissolved in dry THF (8 mL) was added dropwise through a syringe. The dry-ice bath was removed after 1 hour, and the reaction was stirred for 16 hours at room temperature At this time, LC/MS indicated 23% of the title product and 33% of unreacted chloride in the reaction mixture. The same reaction mixture was continued to stir at room temperature for additional 24 hours. The mixture was then re-cooled to −78° C. under a dry-ice/acetone bath. Additional LDA (1.35 mL, 2.70 mmol) (2M in THF) was added to the reaction mixture and slowly warmed to room temperature in 16 hours until LC/MS showed the consumption of chloride material. The mixture was cooled to −5° C., and aqueous HCl (1N) (15 mL) was added. The solution was extracted with EtOAc (15 mL×3). The combined organic layers was dried (MgSO4) and concentrated to give a residue which was triturated with DCM to give a solid. The title compound was used for the next reaction without further purification. (165 mg, 52% yield). MW m/z: 403.13 (MW+1), 401.18 (MW−1). 1H NMR (DMSO-d6, 300 Hz): δ ppm 13.26 (s, br, 1H), 9.08 (s, 1H), 8.48 (s, 1H), 7.62 (d, J=10.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 6.49 (t, J=8.7 Hz, 1H), 3.48 (s, 3H), 1.58 (s, 3H)

Workup

  1. additionwas added dropwise through a syringe
  2. customThe dry-ice bath was removed after 1 hour
  3. stirringthe reaction was stirred for 16 hours at room temperature At this time, LC/MS
  4. stirringto stir at room temperature for additional 24 hours
  5. temperatureslowly warmed to room temperature in 16 hours until LC/MS
  6. customthe consumption of chloride material
  7. temperatureThe mixture was cooled to −5° C.
  8. additionaqueous HCl (1N) (15 mL) was added
  9. extractionThe solution was extracted with EtOAc (15 mL×3)
  10. dry with materialThe combined organic layers was dried (MgSO4)
  11. concentrationconcentrated
  12. customto give a residue which
  13. customwas triturated with DCM
  14. customto give a solid

Sources & evidence

ORD record
ord-96087d6fae7b4f2e8a3ccdf087ca200d
Source dataset
uspto-grants-2015_08
Patent number
US09095581B2

Reaction notes

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