Ethyl Acetate → Fasiglifam

HRID 1848782Notes

Reaction equation

HRID 1848782 reaction equation
[OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 62657Potassium Phosphate, TribasicHCID 53393313(S)-Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetateHCID 862228633'-(Chloromethyl)-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl

Product 1

HCID 24857286FasiglifamYield 99.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (85.00 g) and 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (149.91 g) in N,N-dimethylformamide (255 mL) was added tripotassium phosphate (130.00 g), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, ethyl acetate (1020 mL) and water (1020 mL) were added, and the mixture was partitioned. The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated under reduced pressure. To the concentrated residue were added dimethyl sulfoxide (510 mL) and 2M aqueous sodium hydroxide solution, and the mixture was stirred at 60° C. for 1 hr. The mixture was allowed to cool to room temperature, and washed with ethyl acetate (1020 mL). The organic layer was washed with water (1223 mL). 6M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate (1020 mL). The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (212.60 g). 100% ee. (high performance liquid chromatography conditions)

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customthe mixture was partitioned
  3. washThe organic layer was washed with water (1020 mL) and 10% brine (1020 mL)
  4. concentrationconcentrated under reduced pressure
  5. additionTo the concentrated residue were added dimethyl sulfoxide (510 mL) and 2M aqueous sodium hydroxide solution
  6. stirringthe mixture was stirred at 60° C. for 1 hr
  7. temperatureto cool to room temperature
  8. washwashed with ethyl acetate (1020 mL)
  9. washThe organic layer was washed with water (1223 mL)
  10. addition6M Hydrochloric acid was added
  11. extractionthe mixture was extracted with ethyl acetate (1020 mL)
  12. washThe organic layer was washed with water (1020 mL) and 10% brine (1020 mL)
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-c732c364108244d09576361b9130ba8c
Source dataset
uspto-grants-2015_02
Patent number
US08952185B2

Reaction notes

Loading…