Iodoethanol → Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate

HRID 917719Notes

Reaction equation

HRID 917719 reaction equation
ICCO.O1CCC[CH2:7][CH:6]1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[CH:37]=[C:36]([I:38])[CH:35]=[CH:34][C:20]=1[NH:21][C:22]1[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][NH:25][C:26](=[O:28])[CH:27]=1.[H-].[Na+].[I-]>CN(C=O)C.O>[F:18][C:19]1[CH:37]=[C:36]([I:38])[CH:35]=[CH:34][C:20]=1[NH:21][C:22]1[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][N:25]([CH2:7][CH2:6][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:26](=[O:28])[CH:27]=1

Participants

8

Reactant 5

HCID 12225IodoethanolHCID 24758Sodium hydrideHCID 30165Iodide IonHCID 263182Tetrahydropyranyl etherHCID 23630800Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate

Product 1

HCID 23630801Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

2-Iodoethanol was protected as the tetrahydropyranyl ether according to a literature method [J. Org. Chem., 54(10), 2407 (1989)]. Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (383 mg, 0.95 mmol) was dissolved/suspended in dry DMF (15 mL) and the solution cooled (ice/water). NaH (42 mg, 1.05 mmol) was added, the flask placed under nitrogen, and the resulting mixture allowed to warm and stirred at R.T. for 2 h. A solution of the protected iodide (1.22 g, 4.77 mmol) in dry DMF (5 mL) was added as a single portion and the entire mixture stirred at R.T. for 15 h. Water (100 mL) was added and the resulting aqueous suspension extracted with EtOAc (3×50 mL). The combined EtOAc fractions were then washed with water (2×50 mL) and brine (50 mL), then dried (Na2SO4). The solvent was removed under reduced pressure to afford an oil which was purified by chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxylate was isolated as a transparent oil which gave a waxy solid over time (249 mg, 49%), this material was used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 9.31 (s, 1H), 8.49 (s, 1H), 7.78 (dd, J=10.2, 1.9 Hz, 1H), 7.61 (br d, J=8.6 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 5.45 (s, 1H), 4.59 (br s, 1H), 4.30 (q, J=7.0 Hz, 2H), 4.11 (t, J=5.0 Hz, 2H), 3.75 (pentet, J=5.5 Hz, 1H), 3.61-3.49 (m, 2H), 3.40-3.32 (m, 1H), 1.74-1.33 (m, 6H), 1.30 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C21H24FIN2O5 (M+) 530.0714, found 530.0704.

Workup

  1. temperatureto warm
  2. stirringthe entire mixture stirred at R.T. for 15 h
  3. extractionthe resulting aqueous suspension extracted with EtOAc (3×50 mL)
  4. washThe combined EtOAc fractions were then washed with water (2×50 mL) and brine (50 mL)
  5. dry with materialdried (Na2SO4)
  6. customThe solvent was removed under reduced pressure
  7. customto afford an oil which
  8. customwas purified by chromatography on silica gel (50% EtOAc/hexanes as eluant)

Sources & evidence

ORD record
ord-b6ee0d3f28de471294aa790c6f495f1a
Source dataset
uspto-grants-2007_09
Patent number
US07273877B2

Reaction notes

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