Methyl iodide → HCID 58573371, compound

HRID 932253Notes

Reaction equation

HRID 932253 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:13]([CH:22]([CH3:24])[CH3:23])[C:12](=[O:25])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].IC.[Li+].[CH3:29][CH:30]([N-]C(C)C)[CH3:31].[CH2:36](Br)C=C>C1COCC1>[CH2:31]([C@@:11]1([CH3:36])[CH2:10][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:13]([CH:22]([CH3:23])[CH3:24])[C:12]1=[O:25])[CH:30]=[CH2:29]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 7841Allyl bromideHCID 2724682Lithium diisopropylamideHCID 58573620HCID 58573620, compound

Product 1

HCID 58573371HCID 58573371, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of (5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one (0.50 g, 1.32 mmol; Example 390, Step C) in anhydrous THF (3 mL) was degassed by bubbling argon through the solution for 15 minutes. LHMDS (1 M in THF that was degassed by bubbling argon through the solution for 15 minutes) (1.64 mL, 1.64 mmol) was added to the lactam solution at −15° C. dropwise while keeping the temperature below −8° C. After 15 minutes at −15° C. iodomethane (0.085 mL, 1.354 mmol) was added. Thirty five minutes later freshly prepared LDA (3.29 mmol) in THF (1 mL) was added to the reaction mixture. After 30 minutes the reaction mixture was cooled to −78° C. and allyl bromide (0.398 mL, 4.60 mmol) was added slowly while keeping the temperature at or below −68° C. The reaction mixture was allowed to warm as the cold bath warmed. After 16 hours the reaction mixture temperature was 18° C. The reaction was quenched with MeOH (0.5 mL), washed with 10 mL of 50% brine/water, brine, dried (Na2SO4), decanted and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography on silica gel (eluent: 5-15% EtOAc/hexanes, gradient elution) provided the title compound.

Workup

  1. customby bubbling argon through the solution for 15 minutes
  2. customLHMDS (1 M in THF that was degassed
  3. customby bubbling argon through the solution for 15 minutes) (1.64 mL, 1.64 mmol)
  4. additionwas added to the lactam solution at −15° C. dropwise
  5. customthe temperature below −8° C
  6. custombelow −68° C
  7. temperatureto warm as the cold bath
  8. temperaturewarmed
  9. customThe reaction was quenched with MeOH (0.5 mL)
  10. washwashed with 10 mL of 50% brine/water, brine
  11. dry with materialdried (Na2SO4)
  12. customdecanted
  13. concentrationconcentrated in vacuo
  14. customto provide a yellow oil
  15. customPurification by flash chromatography on silica gel (eluent: 5-15% EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-2b4996b5c6f64f74819407ec643b9f3a
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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