o-Methylvalerolactim → Methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate

HRID 29084

Reaction equation

HRID 29084 reaction equation
[CH3:1][O:2][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.C(NC(C)C)(C)C.[Li].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:4]2[CH2:5][CH2:6][CH2:7][N:8]=[C:3]2[O:2][CH3:1])[CH:25]([C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=1

Participants

5

Reactant 3

HCID 138567o-MethylvalerolactimHCID 45051747Lithium diisopropylamineHCID 54501938Methyl 2-[(4-fluorophenyl)methylidene]-4-methyl-3-oxopentanoate

Product 1

HCID 69310350Methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoateYield 106.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-60 °C

Procedure

6-Methoxy-2,3,4,5-tetrahydropyridine (102.7 g, 0.91 mole) was added over 25 min to a solution of lithium diisopropylamine (1.8 M, 505 mL, 0.91 mole) in THF (1.2 L) stirring at −60° C. under nitrogen. After stirring at −60° C. for 1 h, methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (175 g, 0.70 mole) was added over 75 min keeping the temperature below −50° C. The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min. After the reaction mixture had warmed to room temperature, ethyl acetate was added and the mixture transferred to a separatory funnel. The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine; dried over magnesium sulfate; and concentrated in vacuo to afford methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate (271 g).

Workup

  1. stirringAfter stirring at −60° C. for 1 h
  2. customthe temperature below −50° C
  3. customThe reaction was quenched with saturated ammonium chloride (750 mL) after the reaction
  4. stirringhad stirred at −60° C. for 35 min
  5. temperatureAfter the reaction mixture had warmed to room temperature
  6. additionethyl acetate was added
  7. customthe mixture transferred to a separatory funnel
  8. extractionThe mixture was extracted with ethyl acetate (2×1 L)
  9. washThe combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine
  10. dry with materialdried over magnesium sulfate
  11. concentrationand concentrated in vacuo

Sources & evidence

ORD record
ord-1509ee9d47b9491fa2051edd8cada5c5
Source dataset
uspto-grants-2008_09
Patent number
US07420059B2

Linked notes

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