Triethylamine → Ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate

HRID 1047170Notes

Reaction equation

HRID 1047170 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:16][N:17]([CH3:25])[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([C:19](=[CH:18][N:17]([CH3:25])[CH3:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 121015Ethyl 3-(N,N-dimethylamino)acrylateHCID 467392772-Bromo-5-fluoroisonicotinic acid

Product 1

HCID 86665047Ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylateYield 73%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 2-bromo-5-fluoroisonicotinic acid (25 g, 113.64 mmol, 1 equiv.) in toluene (251 mL) was added thionyl chloride (41.5 mL, 568.19 mmol, 5 equiv.). The reaction was stirred at 110° C. for 4 h. The reaction was cooled to room temperature and concentrated. The residue was re-suspended in THF (100 mL) and added drop-wise to a solution of ethyl 3-(dimethylamino)acrylate (16.3 mL, 113.64 mmol, 1 equiv.) and triethylamine (23.8 mL, 170.46 mmol, 1.5 equiv.) in THF (151 mL). The reaction was stirred at 70° C. for 5 h. The reaction was cooled to room temperature and diluted with water. The reaction was partitioned between water (300 mL) and ethyl acetate (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL), and the organics were washed with 1 N HCl (300 mL) and saturated brine (300 mL), dried over sodium sulfate, and concentrated. The compound was purified (silica gel chromatography) and concentrated to provide ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate as a solid (28.6 g, 73%). Calcd for C13H14BrFN2O3 [M+H]+: 346.90.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated
  3. stirringThe reaction was stirred at 70° C. for 5 h
  4. temperatureThe reaction was cooled to room temperature
  5. customThe reaction was partitioned between water (300 mL) and ethyl acetate (300 mL)
  6. extractionThe aqueous layer was extracted with ethyl acetate (2×300 mL)
  7. washthe organics were washed with 1 N HCl (300 mL) and saturated brine (300 mL)
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated
  10. customThe compound was purified (silica gel chromatography)
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-a5aad6e151cd43459a60f4f006eaeec9
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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