Dimethylformamide → Tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

HRID 1676201Notes

Reaction equation

HRID 1676201 reaction equation
[O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.CN(C=O)C.[H-].[Na+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>CCOC(C)=O.O>[C:33]([C:32]1[CH:35]=[CH:36][C:37]([N:3]2[CH:4]=[CH:5][C:6]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:7][C:2]2=[O:1])=[C:30]([F:29])[CH:31]=1)#[N:34]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 5872033,4-DifluorobenzonitrileHCID 67366878Tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

Product 1

HCID 57468410Tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylateYield 58.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (730 mg, 2.480 mmol, Step A of Example 132) and DMF (12 mL) at room temperature was added sodium hydride (114 mg, 2.85 mmol). After stirring at room temperature for 1 hr, 3,4-difluorobenzonitrile (345 mg, 2.480 mmol, Aldrich) was added and the reaction mixture was heated at 100° C. for 1.5 hrs and cooled to room temperature. The resulting mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound (602.4 mg, 58.7%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.47-7.64 (m, 3H), 7.10 (d, J=7.70 Hz, 1H), 6.04 (dd, J=7.70, 2.20 Hz, 1H), 5.96 (d, J=2.20 Hz, 1H), 4.41-4.55 (m, 1H), 3.65-3.80 (m, 2H), 3.27-3.39 (m, 2H), 1.91-2.04 (m, 2H), 1.71-1.84 (m, 2H), 1.48 (s, 9H). MS (ESI) 358 (M+H−C4H8).

Workup

  1. temperaturethe reaction mixture was heated at 100° C. for 1.5 hrs
  2. temperaturecooled to room temperature
  3. extractionthe aqueous layer was extracted further with EtOAc (3×)
  4. washThe combined organic extracts were washed with water and brine
  5. dry with materialdried (MgSO4)
  6. customevaporated under reduced pressure
  7. customThe residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-25f079cf14444c93b7310af087ecf5d6
Source dataset
uspto-grants-2011_08
Patent number
US08003796B2

Reaction notes

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