Sodium hydride → 6-Chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile

HRID 1471566Notes

Reaction equation

HRID 1471566 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16]([Cl:22])[CH:15]=1>CN(C=O)C>[Cl:22][C:16]1[CH:15]=[C:14]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:19]([C:20]#[N:21])=[CH:18][N:17]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 41668332-(Oxan-2-yloxy)ethan-1-olHCID 455880804,6-Dichloropyridine-3-carbonitrile

Product 1

HCID 866364476-Chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrileYield 60%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (6.32 g, 43.30 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 1.09 g, 43.30 mmol) portion-wise. After 1 h at room temperature, this mixture was slowly added to a solution of 4,6-dichloro-nicotinonitrile (5.0 g, 28.90 mmol) in DMF (25 mL) at 0° C. After overnight, DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (4.9 g, 60%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (s, 1 H), 7.10 (s, 1 H), 4.70 (t, J=3.3 Hz, 1 H), 4.32-4.45 (m, 2 H), 4.19-4.08 (m, 1 H), 3.91-3.80 (m, 2 H), 3.59-3.50 (m, 1 H), 1.83-1.68 (m, 2 H), 1.65-1.50 (m, 4 H).

Workup

  1. waitAfter overnight
  2. customDMF was removed under reduced pressure
  3. additionthe resulting mixture was diluted with EtOAc (50 mL)
  4. washThe organic layer was washed with water (20 mL) and brine (3×20 mL) solution
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification
  9. washwas accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution

Sources & evidence

ORD record
ord-ea03718fc7f64b7c9750b5dc1a63a38f
Source dataset
uspto-grants-2015_04
Patent number
US09012431B2

Reaction notes

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