Hydrochloric Acid → Rofecoxib

HRID 2295096Notes

Reaction equation

HRID 2295096 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 (WO 9500501, Ex. 9 Step 1, hereby incorporated by reference) (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 changes from dark brown to yellow). Then 2.4 L of ice and water were added, stirred for a few minutes, then the precipitate was filtered and rinsed with water (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. The solvent was evaporated to near dryness (silica gel a bit sticky) and the residue was applied on top of a silica gel plug (sintered glass funnel) and eluted with 10% EtOAc/CH2Cl2, giving after evaporation of the solvent and a swish in EtOAc, 36.6 g (58%) of the title compound.

Workup

  1. temperaturecooled in an ice bath
  2. stirringstirred for a few minutes
  3. filtrationthe precipitate was filtered
  4. washrinsed with water (
  5. customgiving 64 g of crude wet product)
  6. addition300 g of silica gel was added
  7. customThe solvent was evaporated to near dryness (silica gel a bit sticky) and the residue
  8. washeluted with 10% EtOAc/CH2Cl2
  9. customgiving
  10. customafter evaporation of the solvent

Sources & evidence

ORD record
ord-d13a9c4464d442a89bbcf08a9973648e
Source dataset
uspto-grants-1997_11
Patent number
US05691374

Reaction notes

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