Potassium Carbonate → 2-Chloro-3-(difluoromethoxy)pyridine

HRID 514315Notes

Reaction equation

HRID 514315 reaction equation
C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+]>CN(C)C=O>[Cl:7][C:8]1[C:13]([O:14][CH:16]([F:21])[F:20])=[CH:12][CH:11]=[CH:10][N:9]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 811362-Chloro-3-pyridinolHCID 2734985Sodium chlorodifluoroacetate

Product 1

HCID 533020352-Chloro-3-(difluoromethoxy)pyridine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
100 °C

Procedure

This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100° C. and slowly treated, in a drop-wise manner over 1 hour, with a solution of 2-chloropyridin-3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100° C. for 1 hour, then cooled to 25° C. and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4×2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6×2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40° C., 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.26-8.30 (m, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.28 (br dd, J=8.0, 4.8 Hz, 1H), 6.60 (t, JHF=72.5 Hz, 1H).

Workup

  1. additionAfter completion of the addition
  2. temperaturecooled to 25° C.
  3. custompartitioned between water (10 L) and tert-butyl methyl ether (5 L)
  4. extractionThe aqueous layer was extracted with ethyl acetate (4×2.5 L)
  5. washthe combined organic layers were washed with saturated aqueous sodium chloride solution (6×2.5 L)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. distillationwere purified via distillation at reduced pressure (30-40° C., 1-5 mm Hg)

Sources & evidence

ORD record
ord-2bc256457c95410582f16409fc207ba6
Source dataset
uspto-grants-2015_08
Patent number
US09107923B2

Reaction notes

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