Hydrochloric Acid → 6-(2,2-difluoroethoxy)nicotinic acid

HRID 341551Notes

Reaction equation

HRID 341551 reaction equation
[OH-].[K+].Cl[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].Cl>CS(C)=O.O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:4]1[N:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14797Potassium Hydroxide2×HCID 792226-Chloronicotinic acidHCID 1361872,2-Difluoroethan-1-ol2×

Product 1

HCID 251162916-(2,2-difluoroethoxy)nicotinic acidYield 96.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

Powdered potassium hydroxide (712 mg, 12.7 mmol) was added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol) and 2,2-difluoroethanol (520 mg, 6.35 mmol) in DMSO (15 mL) and the mixture was stirred at 120 C for 14 h. An additional two equivalents of 2,2-difluoroethanol and potassium hydroxide were added and the mixture was heated for 24 h. The mixture was cooled to room temperature, diluted with water (5 mL), acidified with 1N aq. HCl (to pH 1) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×25 mL) then brine (50 mL) and concentrated under reduced pressure to provide title compound as a beige solid (620 mg, 96%). Method B HPLC-MS: MH+ requires m/z=204. Found: m/z=204, Rt=1.54 min (90%).

Workup

  1. temperaturethe mixture was heated for 24 h
  2. extractionextracted with EtOAc (3×50 mL)
  3. washThe combined organic layers were washed with water (2×25 mL)
  4. concentrationbrine (50 mL) and concentrated under reduced pressure

Sources & evidence

ORD record
ord-2b7768f1002f4dd59f20f18a65f7dd7b
Source dataset
uspto-grants-2014_11
Patent number
US08895733B2

Reaction notes

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