Hydrochloric Acid → 2-Chloro-6-(2,4-difluorophenyl)isonicotinic acid

HRID 1909130Notes

Reaction equation

HRID 1909130 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.C(NC(C)C)(C)C.Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=2[F:19])[N:10]=1)[C:5]([OH:7])=[O:6]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 7912DiisopropylamineHCID 948302,6-Dichloroisonicotinic acidHCID 27343342,4-Difluorophenylboronic acidHCID 86657030Tri(m-sulfophenyl)phosphine sodium salt

Product 1

HCID 823057102-Chloro-6-(2,4-difluorophenyl)isonicotinic acidYield 36.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 2,6-dichloroisonicotinic acid (2.43 g, 12.67 mmol) in DMF (38 mL) and water (12.7 mL) were added (2,4-difluorophenyl)boronic acid (2.0 g, 12.67 mmol), tri(m-sulfophenyl)phosphine sodium salt (0.54 g, 0.95 mmol), palladium(II) acetate (71.0 mg, 0.32 mmol) and diisopropylamine (6.3 mL, 44.3 mmol). The mixture was heated 50° C. After 2.5 h, the mixture was cooled to ambient temperature and stirred for 18 h. HCl (1.0 M in water) was added and the mixture was was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (1.24 g). MS 270.0 (M+1).

Workup

  1. temperaturethe mixture was cooled to ambient temperature
  2. extractionthe mixture was was extracted with ethyl acetate (3×)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-d14bf500784748c383ab7a142485f4c2
Source dataset
uspto-grants-2013_12
Patent number
US08598209B2

Reaction notes

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