Hydrochloric Acid → Rofecoxib

HRID 1107879Notes

Reaction equation

HRID 1107879 reaction equation
[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=O.CCN(CC)CC.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.C(Cl)Cl.O>[C:1]1([C:7]2[C:8](=[O:10])[O:9][CH2:12][C:13]=2[C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 999Phenylacetic AcidHCID 8471TriethylamineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 7358232-Bromo-4'-(methylsulfonyl)acetophenone

Product 1

HCID 5090Rofecoxib

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of phenylacetic acid (27.4 g, 201 mmol) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Step 1) (60 g, 216 mmol, 1.075 eq.) in acetonitrile (630 mL) at 25° C. was added slowly Et3N (30.8 mL, 1.1 eq.). The mixture was stirred for 20 min. at r.t. and then cooled in an ice bath. DBU (60.1 mL, 3 eq.) was slowly added. After stirring for 20 min. in the ice bath, the reaction was complete and the mixture was acidified with 1N HCl (color changed from dark brown to yellow). Then 2.4 L of ice and H2O were added, the mixture was stirred for a few minutes, and the precipitate was filtered and rinsed with H2O, giving 64 g of crude wet product. The solid was dissolved in 750 mL of CH2Cl2, dried over MgSO4, filtered and 300 g of silica gel was added to the filtrate. The solvent was evaporated to near dryness (silica gel a bit sticky), the residue was applied on top of a silica gel plug in a sintered glass funnel and eluted with 10% EtOAc/CH2Cl2, giving after evaporation of the solvent and swishing in EtOAc, 36.6 g (58%) of the title compound.

Workup

  1. temperaturecooled in an ice bath
  2. stirringthe mixture was stirred for a few minutes
  3. filtrationthe precipitate was filtered
  4. washrinsed with H2O
  5. customgiving 64 g of crude wet product
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. addition300 g of silica gel was added to the filtrate
  9. customThe solvent was evaporated to near dryness (silica gel a bit sticky), the residue
  10. customwas applied on top of a silica gel plug in a sintered glass funnel
  11. washeluted with 10% EtOAc/CH2Cl2
  12. customgiving
  13. customafter evaporation of the solvent and swishing in EtOAc

Sources & evidence

ORD record
ord-ca13f7681f2f48a3981c722654f2a074
Source dataset
uspto-grants-2000_05
Patent number
US06063811

Reaction notes

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