Dimethylamine → (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-prop-2-ynylmorpholine

HRID 1004780Notes

Reaction equation

HRID 1004780 reaction equation
[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][C:32]1C=CC(S(O)(=O)=O)=C[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C#C.CNC>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:37][C:32]#[CH:31])[C@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1

Participants

6

Reactant 4

HCID 674DimethylamineHCID 7842Propargyl bromideHCID 11430Potassium CarbonateHCID 115924984-Methylbenzene-1-sulfonic acid--(2R,3S)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)morpholine (1/1)

Product 1

HCID 11751868(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-prop-2-ynylmorpholine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine TsOH salt (1.83 assay Kg, 3.00 mol) was suspended in 10 L of DMF and potassium carbonate (1.04 Kg, 7.5 mol) was added in one portion to give a white slurry. Propargyl bromide (80 wt % in toluene, 535 g, 3.6 mol) was added dropwise over 30 minutes, the reaction was sligtly exothermic <30° C. (without cooling). The reaction mixture was stirred at room temperature for ~3 hours (~99.9% conversion) and then 40% aqueous dimethylamine was added, and aged for 30 minutes (to destroy excess propargyl bromide), then the reaction solution was partitioned between 20 L of toluene and 20 L of water. The organic layer was washed with water twice (2×18 L). The resulting organic layer was concentrated to 6 L with KF<250 μg/mL (additional toluene may need to be used to achieve this KF specifcation).

Workup

  1. customto give a white slurry
  2. customwas sligtly exothermic <30° C.
  3. temperature(without cooling)
  4. custom(to destroy excess propargyl bromide)
  5. customthe reaction solution was partitioned between 20 L of toluene and 20 L of water
  6. washThe organic layer was washed with water twice (2×18 L)
  7. concentrationThe resulting organic layer was concentrated to 6 L with KF<250 μg/mL (additional toluene

Sources & evidence

ORD record
ord-7b06791028194fa08ec315d0296cfb7f
Source dataset
uspto-grants-2000_04
Patent number
US06051707

Reaction notes

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