Triphenylphosphine → methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate

HRID 1700Notes

Reaction equation

HRID 1700 reaction equation
C[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:34]1[CH:39]=[CH:38][C:37]([C@@H:40](O)[CH3:41])=[CH:36][CH:35]=1>C1COCC1>[F:12][C:9]1[C:10]([O:11][C@H:40]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)[CH3:41])=[CH:2][C:3]([O:13][CH3:14])=[C:4]([CH:8]=1)[C:5]([O:7][CH3:15])=[O:6]

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 10920507(S)-(-)-alpha-Methyl-4-pyridinemethanolHCID 19691011Methyl 5-fluoro-2-methoxy-4-hydroxybenzoic acid

Product 1

HCID 22883081methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A stirred solution of methyl 5-fluoro-2-methoxy-4-hydroxybenzoic acid (250 mg, 1.25 mmol, see Scheme II) in THF (15 mL) was treated with triphenylphosphine (494 mg, 1.88 mmol) and cooled to 0° C. under Argon. To this was added, dropwise over a period of 1 h, a solution of (S)-(-)-1-(4-pyridyl)-ethanol (232 mg, 1.88 mmol) and N,N'-diethylazodicarboxylate (300 μL, 1.88 mmol) in THF (5 mL). The reaction was allowed to warm to ambient temperature overnight with stirring. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 1:1 CH2Cl2 :EtOAc and elated with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford an impure mixture of 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxylbenzoate. The residue was rechromatographed on a preparative HPLC using a gradient of 95:5 to 5:95 water:acetonitrile (0.1% TFA added). The appropriate fractions were combined and the solvent removed under reduced pressure to afford the methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate.

Workup

  1. additionTo this was added, dropwise over a period of 1 h
  2. temperatureto warm to ambient temperature overnight
  3. filtrationThe reaction was filtered
  4. customthe solvent was removed under reduced pressure
  5. customThe residue was chromatographed on a silica gel column
  6. customthe solvent removed under reduced pressure
  7. customto afford
  8. customThe residue was rechromatographed on a preparative HPLC
  9. customthe solvent removed under reduced pressure

Sources & evidence

ORD record
ord-69fd522121284a219b8d7faaa6a44613
Source dataset
uspto-grants-1998_03
Patent number
US05726172

Reaction notes

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