Sodium hydride → HCID 57619655, compound

HRID 2239321Notes

Reaction equation

HRID 2239321 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C.OS([O-])(=O)=O.[K+]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:4][CH2:3]1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 660484-Piperidinol, 1-methyl-HCID 678803-Fluorobenzonitrile

Product 1

HCID 57619655HCID 57619655, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 516920Potassium bisulfateSolvent

Conditions

Temperature
0 °C

Procedure

1-Methyl-piperidin-4-ol (7.17 g, 62.25 mmol) was dissolved in DMF (40 ml) and cooled to 0° C. NaH (4.48 g, 93.4 mmol) was added in small portions and the reaction stirred for 30 min. 3-Fluoro-benzonitrile (8.0 ml, 74.7 mmol) was added and the reaction allowed to reach r.t. over 1 h and stirred for a further 16 h. The resulting brown solution was cooled to 0° C. and quenched by addition of water. The reaction mixture was separated between DCM (500×2 ml) and water (750 ml). The combined organics were washed with water (500 ml), dried through a phase separator and evaporated in vacuo. Flash silica gel chromatography using a 100 g Biotage column with a gradient of 20-100% EtOAc/MeOH/TEA 100:10:1 in heptane failed to give a pure product. The oil was dissolved in 0.1 M KHSO4 (aq) and washed with ether (×4), the aqueous layer basified (2 M NaOH (aq)) and extracted twice with ether. The organic phase was dried over a phase separator and evaporated in vacuo. To the red brown oil was added 4M HCl in dioxane and the resulting precipitate was filtered. To the salt was added 10% NaHCO3 (aq), extracted with DCM, dried through a phase separator and evaporated in vacuo to give a light orange oil. Yield: 4.73 g (29%). 1H NMR (400 MHz, CDCl3) δ 7.35 (t, 1H, JHH=7.84 Hz), 7.21 (dt, 1H, J=7.39 Hz, J=1.06 Hz), 7.15-7.10 (m, 2H), 4.32 (m, 1H, J=3.74 Hz), 2.68 (m, 2H), 2.33-2.24 (m, 5H), 2.04-1.95 (m, 2H), 1.88-1.78 (m, 2H). MS (ESI+) 217.07 (M+1H+).

Workup

  1. waitto reach r.t. over 1 h
  2. stirringstirred for a further 16 h
  3. temperatureThe resulting brown solution was cooled to 0° C.
  4. customquenched by addition of water
  5. customThe reaction mixture was separated between DCM (500×2 ml) and water (750 ml)
  6. washThe combined organics were washed with water (500 ml)
  7. customdried through a phase separator
  8. customevaporated in vacuo
  9. customto give a pure product
  10. washwashed with ether (×4)
  11. extractionextracted twice with ether
  12. customThe organic phase was dried over a phase separator
  13. customevaporated in vacuo
  14. additionTo the red brown oil was added 4M HCl in dioxane
  15. filtrationthe resulting precipitate was filtered
  16. additionTo the salt was added 10% NaHCO3 (aq)
  17. extractionextracted with DCM
  18. customdried through a phase separator
  19. customevaporated in vacuo
  20. customto give a light orange oil

Sources & evidence

ORD record
ord-11d045a84cd84cc0a598b98d79ca22ba
Source dataset
uspto-grants-2010_05
Patent number
US07723331B2

Reaction notes

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