Sodium Hydroxide → Fasiglifam

HRID 1848781Notes

Reaction equation

HRID 1848781 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+].[OH-].[Na+]>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 14798Sodium HydroxideHCID 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 96.6%

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 (10.0 g) and 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (17.6 g) in N,N-dimethylformamide (30.0 mL) was added tripotassium phosphate (16.8 g), and the mixture was stirred at 60° C. for 3 hr. 2.4M Aqueous sodium hydroxide solution (32.9 g) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled, water (100 mL) was added, and the mixture was extracted with toluene (50 mL). To the aqueous layer was added toluene (50 mL), and the mixture was extracted. To the obtained aqueous layer were added acetone (10 mL) and concentrated hydrochloric acid (17.6 mL), and the mixture was stirred at 30° C. for 1 hr, at 50° C. for 30 min, and at 25° C. for 2 hr. The precipitated crystals were collected by filtration, and washed with a mixed solution (50 mL) of acetone.water (3:7) and then water (50 mL). The obtained crystals were dried at 60° C. under reduced pressure to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (24.3 g). 100% ee. (high performance liquid chromatography conditions)

Workup

  1. stirringthe mixture was stirred at 80° C. for 2 hr
  2. temperatureThe reaction mixture was cooled
  3. extractionthe mixture was extracted with toluene (50 mL)
  4. additionTo the aqueous layer was added toluene (50 mL)
  5. extractionthe mixture was extracted
  6. additionTo the obtained aqueous layer were added acetone (10 mL) and concentrated hydrochloric acid (17.6 mL)
  7. stirringthe mixture was stirred at 30° C. for 1 hr, at 50° C. for 30 min
  8. waitat 25° C. for 2 hr
  9. filtrationThe precipitated crystals were collected by filtration
  10. washwashed with a mixed solution (50 mL) of acetone
  11. customThe obtained crystals were dried at 60° C. under reduced pressure

Sources & evidence

ORD record
ord-4fc9d8617121456aba8bd5e2c99ea9ff
Source dataset
uspto-grants-2015_02
Patent number
US08952185B2

Reaction notes

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