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

HRID 1068045Notes

Reaction equation

HRID 1068045 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.CN(OC)[C:23](=[O:25])[CH3:24]>C1COCC1>[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:23](=[O:25])[CH3:24]

Participants

5

Reactant 3

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

Product 1

HCID 9856131HCID 9856131, compoundYield 64.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-75 °C

Procedure

A solution of 4-(3-bromo-4-fluorobenzyl)morpholine (35.5 g) of Preparation No. 53 in THF (400 mL) is cooled to −75° C., and n-butyllithium is added via addition funnel maintaining the temperature below −65° C. A solution of N-methyl-N-methoxyacetamide (16.0 g, prepared as described in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) is added via addition funnel, again maintaining temperature below −65° C. The reaction is stirred at −75° C. for 1 hour and then is allowed to warm to room temperature overnight. The reaction mixture is quenched with 1 N HCl (150 mL) and diluted with ethyl acetate (400 mL). The layers are separated, and the aqueous layer is basified with sat. sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. sodium bicarbonate (2×100 mL) and brine (50 mL). The aqueous layers are back-extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to a yellow oil. The oil is purified by fractional distillation at 135-140° C./0.3 torr to afford 19.7 g (64%) of the title compound as a clear, colorless oil.

Workup

  1. temperaturemaintaining the temperature below −65° C
  2. temperatureagain maintaining temperature below −65° C
  3. temperatureto warm to room temperature overnight
  4. customThe reaction mixture is quenched with 1 N HCl (150 mL)
  5. additiondiluted with ethyl acetate (400 mL)
  6. customThe layers are separated
  7. extractionThe aqueous layer is extracted with ethyl acetate (2×100 mL)
  8. washThe combined organic layers are washed with sat. sodium bicarbonate (2×100 mL) and brine (50 mL)
  9. extractionThe aqueous layers are back-extracted with ethyl acetate (100 mL)
  10. dry with materialThe combined organic layers are dried (Na2SO4)
  11. concentrationconcentrated in vacuo to a yellow oil
  12. distillationThe oil is purified by fractional distillation at 135-140° C./0.3 torr

Sources & evidence

ORD record
ord-dd03aab5b94446a6b6ab6cd8c9451e9b
Source dataset
uspto-grants-2001_06
Patent number
US06248739B1

Reaction notes

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