2-(R)-(1-(3,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl morpholine → Aprepitant Impurity 40

HRID 582109Notes

Reaction equation

HRID 582109 reaction equation
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[C@H:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH2:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].C(O)(C)C.C(OCC)(=O)C>[F:36][C:2]([F:1])([F:35])[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:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1.[F:36][C:2]([F:1])([F:35])[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:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1

Participants

5

Reactant 1

HCID 106492802-(R)-(1-(3,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl morpholine

Product 2

HCID 10598151Aprepitant Impurity 40HCID 106457422-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl morpholine

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 22055037Isopropanol ethyl acetateSolvent

Procedure

A mixture of 1.50 g (2.9 mmol) of 2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl morpholine (from Example 68) and 750 mg 10% palladium on carbon catatlyst in 25 mL of 3:2 v/v isopropanol/ethyl acetate was stirred under an atmosphere of hydrogen for 48 hours. The catalyst was filtered onto a pad of Celite; the reaction flask and filter pad were rinsed with 500 mL of ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography on 60 g of silica gel using 2:1 v/v hexanes/ether, then 2:1 v/v hexanes/ether afforded 106 mg of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl morpholine and 899 mg of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl morpholine, both as oils (84% total yield).

Workup

  1. filtrationThe catalyst was filtered onto a pad of Celite
  2. filtrationthe reaction flask and filter pad
  3. washwere rinsed with 500 mL of ethyl acetate
  4. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-7037c7e65ef646fda58243f8503ae06b
Source dataset
uspto-grants-1999_07
Patent number
US05922706

Reaction notes

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