Morpholine → 4-(1-(6-Fluoropyridin-3-yl)ethyl)morpholine

HRID 1621959Notes

Reaction equation

HRID 1621959 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH3:9])=[CH:4][CH:3]=1

Participants

8

Reactant 3

HCID 8083MorpholineHCID 31297Methanesulfonyl chlorideHCID 666001661-(6-Fluoropyridin-3-yl)ethan-1-ol

Product 1

HCID 665999104-(1-(6-Fluoropyridin-3-yl)ethyl)morpholineYield 85.2%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 1-(6-fluoropyridin-3-yl)ethanol (2.30 g, 16.3 mmol) and Et3N (4.52 mL, 32.6 mmol) in DCM (50 mL) in 500 mL round-bottomed flask, methanesulfonyl chloride (Aldrich, 1.30 mL, 16.8 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 min. Water (50 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford cloudy viscous pale yellow oil. To this intermediate, DCM (40 mL), Et3N (9 mL) and morpholine (5.68 mL, 65.2 mmol) were added and the mixture was stirred at room temperature overnight. THF (5 mL) was added and the stirring was resumed. After overnight stirring, water (60 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 5%) to give 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.92 g, 85% yield) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.12 (s, 1H) 7.79 (td, J=8.12, 2.35 Hz, 1H) 6.90 (dd, J=8.41, 2.93 Hz, 1H) 3.68 (t, J=4.60 Hz, 4H) 3.36-3.44 (m, 1H) 2.44-2.56 (m, 2H) 2.30-2.40 (m, 2H) 1.35 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 211.1 (M+H)+.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous phase was extracted with DCM (2×30 mL)
  3. dry with materialThe combined organic phases were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto afford cloudy viscous pale yellow oil
  7. stirringthe mixture was stirred at room temperature overnight
  8. stirringAfter overnight stirring
  9. customthe layers were separated
  10. extractionThe aqueous phase was extracted with EtOAc (2×60 mL)
  11. dry with materialThe combined organic phases were dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 5%)

Sources & evidence

ORD record
ord-b845d8d4877c4ec0b9ab09003b5fa9d8
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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