Hydrochloric Acid → 2-(4-Chloro-2-{[2-fluoro-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)propanoic acid

HRID 2390374Notes

Reaction equation

HRID 2390374 reaction equation
Br[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].[C:16]([C:18]1[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:30])#[CH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CCOC(C)=O.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[F:30])[CH:14]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11776TriphenylphosphineHCID 20526233Methyl 2-(2-bromo-4-chlorophenoxy)propanoate2×HCID 585219352-Ethynyl-1-fluoro-4-(propylsulfonyl)benzene2×

Product 1

HCID 565955692-(4-Chloro-2-{[2-fluoro-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)propanoic acid

Reagents, catalysts & solvents 4

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of methyl 2-(2-bromo-4-chlorophenoxy)propanoate (Intermediate 263 ; 130 mg; 0.44 mmol), 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109 ; 110 mg; 0.49 mmol), bis(triphenylphosphine)palladium (II) chloride (9.3 mg; 0.01 mmol), triphenylphosphine (23.2 mg; 0.09 mmol) and cuprous iodide (2.5 mg; 0.01 mmol) in TEA (985 μl) was degassed with nitrogen. The reaction mixture was heated overnight at 80° C., diluted with EtOAc and washed with sat. ammonium chloride solution and brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a dark brown sticky solid, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The intermediate thus obtained was dissolved in a mixture of dioxane (2.6 ml) and water (2.6 ml) and treated with a 4 N solution of HCl in dioxane (1.33 ml). After heating at 100° C. for 16 hours, water was added and the reaction mixture was extracted 3 times with EtOAC. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a yellow sticky solid, which was triturated in diethylether/pentane to afford the title compound as a white solid.

Workup

  1. washwashed with sat. ammonium chloride solution and brine
  2. dry with materialThe organic phase was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated to dryness
  5. customaffording a dark brown sticky solid, which
  6. customwas purified by flash column chromatography (silica)
  7. washeluting with cyclohexane containing
  8. temperatureincreasing amounts of EtOAc
  9. customThe intermediate thus obtained
  10. temperatureAfter heating at 100° C. for 16 hours
  11. extractionthe reaction mixture was extracted 3 times with EtOAC
  12. dry with materialThe organic phase was dried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated to dryness
  15. customaffording a yellow sticky solid, which
  16. customwas triturated in diethylether/pentane

Sources & evidence

ORD record
ord-d9997fc46c6f4769962887670a5fe5d8
Source dataset
uspto-grants-2012_09
Patent number
US08273769B2

Reaction notes

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