Acetic Acid → Ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate

HRID 917693Notes

Reaction equation

HRID 917693 reaction equation
[CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].S(OC)(O[CH3:26])(=O)=O.C(N(CC)CC)C.C(O)(=O)C.[OH2:40]>C(Cl)(Cl)Cl.CCO>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[CH:6][N:7]([CH3:26])[C:8](=[O:40])[CH:9]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 962WaterHCID 6497Dimethyl SulfateHCID 8471TriethylamineHCID 23631002Ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate

Product 1

HCID 11362025Ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylateYield 70%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6212ChloroformSolvent

Procedure

6-Chloro-4-(2-fluoro-4-iodo-phenylamino)-nicotinic acid ethyl ester (15.0 g, 35.70 mmol) was dissolved in CHCl3 (100 mL) and the solution cooled (ice/water). Dimethyl sulfate (20.25 mL, 214.0 mmol) was added, the solution allowed to warm to room temperature then heated at reflux for 20 h. The reaction mixture was allowed to cool to room temperature, then a mixture of triethylamine (60.0 mL), acetic acid (20.0 mL) and EtOH (20.0 mL) added and the reaction heated at reflux for a further 2 h. After cooling, water (50 mL) was added and the mixture was partitioned between EtOAc (400 mL) and water (100 mL). The EtOAc layer was washed with further water (100 mL) and brine (100 mL), then dried (MgSO4). The solvent was removed under reduced pressure and the resulting residue purified by chromatography on silica gel (5% MeOH/CH2CCl2 as eluant), giving ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a white solid (10.48 g, 70%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.31 (s, 1H), 8.54 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (br dd, J=8.3, 1.0 Hz, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.46 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.43 (s, 3H), 1.32 (t, J=7.1 Hz, 3H). Anal. Calcd for C15H14FIN2O3: C, 43.29; H, 3.39; N, 6.73. Found: C, 43.69; H, 3.26; N, 6.69.

Workup

  1. temperaturethen heated
  2. temperatureat reflux for 20 h
  3. temperatureto cool to room temperature
  4. additionadded
  5. temperaturethe reaction heated
  6. temperatureat reflux for a further 2 h
  7. temperatureAfter cooling
  8. customthe mixture was partitioned between EtOAc (400 mL) and water (100 mL)
  9. washThe EtOAc layer was washed with further water (100 mL) and brine (100 mL)
  10. dry with materialdried (MgSO4)
  11. customThe solvent was removed under reduced pressure
  12. customthe resulting residue purified by chromatography on silica gel (5% MeOH/CH2CCl2 as eluant)

Sources & evidence

ORD record
ord-16e855a5a7f2451fafcd28374d7c7f7b
Source dataset
uspto-grants-2007_09
Patent number
US07273877B2

Reaction notes

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