Thionyl Chloride → 6-[(4-Fluorophenyl)oxy]-3-pyridinecarbonyl chloride

HRID 644708Notes

Reaction equation

HRID 644708 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 24386Thionyl ChlorideHCID 167905786-(4-fluorophenoxy)nicotinic acid

Product 1

HCID 231490426-[(4-Fluorophenyl)oxy]-3-pyridinecarbonyl chloride

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (20.1 g, 0.0862 mol) was dissolved in 1,4-dioxane (400 mL) and thionyl chloride (28.5 mL, 4.972 mmol) added cautiously. The mixture was heated slowly to reflux and stirred for 4.5 h. The reaction mixture was allowed to cool and concentrated. Dioxane (200 mL) was added and the solution was re-concentrated (×2) to give crude 6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride which was re-dissolved in DCM (250 mL). This was added dropwise to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (25 g, 0.0783 mol, prepared in three different batches according to method D3B and consolidated) and triethylamine (14 mL, 0.1004 mol) in DCM (250 mL) cooled in an ice/water bath over 30 mins. The reaction mixture was warmed to room temperature and stirred for ˜15 h. The reaction mixture was washed with 2M NaOH solution (2×200 mL) and brine, then dried over MgSO4 and concentrated in vacuo to give a brown foam/gum. The crude product was purified by chromatography to give the title compound as a colourless foam (32.39 g).

Workup

  1. temperatureThe mixture was heated slowly
  2. temperatureto reflux
  3. temperatureto cool
  4. concentrationconcentrated
  5. additionDioxane (200 mL) was added
  6. concentrationthe solution was re-concentrated (×2)

Sources & evidence

ORD record
ord-8f75dd02b9834906a9e5dc69ab0d2e55
Source dataset
uspto-grants-2010_04
Patent number
US07700599B2

Reaction notes

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