N-Methoxy-N-methylacetamide → HCID 9856131, compound

HRID 1168192Notes

Reaction equation

HRID 1168192 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1.CCCCCC>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25]

Participants

6

Reactant 3

HCID 537505N-Methoxy-N-methylacetamideHCID 782859HCID 782859, compoundHCID 178418339Butyllithium

Product 1

HCID 9856131HCID 9856131, compoundYield 64.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-75 °C

Procedure

4-(3-Bromo-4-fluorobenzyl)morpholine (Preparation 7, 35.5 g) is dissolved in THF (400 mL) and cooled to −75° C. A solution of n-butyllithium in hexane (2.5 M, 57.0 mL) is added via addition funnel, maintaining the temperature below −68° C. A solution of N-methoxy-N-methylacetamide (16.0 g) in THF (50 mL) is added via addition funnel, maintaining the temperature below −65° C. The reaction is stirred at −75° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with 1 N HCl (150 mL) and poured into ethyl acetate (400 mL). The aqueous layer is separated, basified with sat. aq. NaHCO3, and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is distilled (135° C., 0.3 Torr) to afford 19.7 g (64%) of the title compound as a clear, colorless oil. Physical characteristics: Bp 135° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ7.72, 7.61-7.56, 7.31, 3.56, 3.48, 2.58, 2.34; IR (liq.) 1996, 1979, 1919, 1688, 1612, 1492, 1417, 1361, 1291, 1281, 1212, 1118, 865 cm−1; MS (ESI+) m/z 238 (M+H)+. Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.43; H, 6.75; N, 5.84.

Workup

  1. temperaturemaintaining the temperature below −68° C
  2. temperaturemaintaining the temperature below −65° C
  3. temperatureto warm to rt overnight
  4. customThe reaction is quenched with 1 N HCl (150 mL)
  5. additionpoured into ethyl acetate (400 mL)
  6. customThe aqueous layer is separated
  7. extractionextracted with ethyl acetate (2×100 mL)
  8. washThe combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL)
  9. extractionThe combined aqueous washes are back-extracted with ethyl acetate (100 mL)
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated in vacuo to a yellow oil
  12. distillationThe crude product is distilled (135° C., 0.3 Torr)

Sources & evidence

ORD record
ord-cea844b92ca74001bd1241808138fd2c
Source dataset
uspto-grants-2003_09
Patent number
US06624160B2

Reaction notes

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