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

HRID 917692Notes

Reaction equation

HRID 917692 reaction equation
Cl[C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.S(OC)(O[CH3:26])(=O)=O.C(N(CC)CC)C.C(O)(=O)C.[OH2:40]>C(Cl)(Cl)Cl.CCO>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]([CH3:26])[C:2](=[O:40])[CH:12]=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 72%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6212ChloroformSolvent

Procedure

Ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate (200 mg, 0.48 mmol) was dissolved in CHCl3 (5 mL) and the solution cooled (ice/water). Dimethyl sulfate (0.27 mL, 2.86 mmol) was added, the solution allowed to warm to R.T., then heated at reflux for 20 h. The reaction mixture was allowed to cool to R.T., then a mixture of triethylamine (1.41 mL), acetic acid (0.94 mL) and EtOH (0.94 mL) was added and the reaction heated at reflux for a further 2 h. After cooling, water (10 mL) was added and the mixture was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was washed with further water (50 mL) and brine (50 mL), then dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by chromatography on silica gel (50% EtOAc/hexanes as eluant), giving ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a white solid (143 mg, 72%), m.p. (EtOAc/n-hexane) 169-170° C. 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, 43.3; H, 3.4; N, 6.7. Found: C, 43.7; H, 3.1; N, 7.0.

Workup

  1. temperatureheated
  2. temperatureat reflux for 20 h
  3. temperatureto cool to R.T.
  4. additionwas added
  5. temperaturethe reaction heated
  6. temperatureat reflux for a further 2 h
  7. temperatureAfter cooling
  8. customthe mixture was partitioned between EtOAc (100 mL) and water (50 mL)
  9. washThe EtOAc layer was washed with further water (50 mL) and brine (50 mL)
  10. dry with materialdried (Na2SO4)
  11. customThe solvent was removed under reduced pressure
  12. customthe resulting residue purified by chromatography on silica gel (50% EtOAc/hexanes as eluant)

Sources & evidence

ORD record
ord-298685d3f3bf448fb3f6f7583dac4adc
Source dataset
uspto-grants-2007_09
Patent number
US07273877B2

Reaction notes

Loading…