Sodium hydride → (R)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile

HRID 1483983Notes

Reaction equation

HRID 1483983 reaction equation
[OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 5226592-Amino-6-fluorobenzonitrileHCID 28345459(R)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one

Product 1

HCID 86714307(R)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrileYield 41.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 34c) (145 mg, 0.73 mmol) in THF (15 mL) was added NaH (44 mg, 1.09 mmol, 60% dispersion in mineral oil) at 0° C. The reaction was warmed to room temperature and stirred for 15 minutes, at which time 2-amino-6-fluorobenzonitrile (109 mg, 0.80 mmol) was added. The mixture was heated at 80° C. overnight, quenched with water, concentrated under reduced pressure to remove THF and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (EtOAc/hexanes). The residue was further purified by chiral HPLC (normal phase, ethanol/isopropanol/methanol/hexanes) to give the title compound as a white solid (96 mg, 41%). MS 316 (MH+).

Workup

  1. additionwas added
  2. temperatureThe mixture was heated at 80° C. overnight
  3. customquenched with water
  4. concentrationconcentrated under reduced pressure
  5. customto remove THF
  6. extractionextracted with EtOAc (3×)
  7. dry with materialThe combined extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. custompurified by flash chromatography on silica gel (EtOAc/hexanes)
  11. customThe residue was further purified by chiral HPLC (normal phase, ethanol/isopropanol/methanol/hexanes)

Sources & evidence

ORD record
ord-27118dd7e812499d9e416331fb59b140
Source dataset
uspto-grants-2016_08
Patent number
US09420814B2

Reaction notes

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