Trifluoroacetic acid → 2-(5-Chloro-2,4-difluorophenyl)pyridin-4-amine

HRID 1522548Notes

Reaction equation

HRID 1522548 reaction equation
Br[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[C:18]([F:27])=[CH:19][C:20]([F:26])=[C:21](B(O)O)[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:16][C:17]1[C:18]([F:27])=[CH:19][C:20]([F:26])=[C:21]([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:22]=1

Participants

9

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 3769192(5-Chloro-2,4-difluorophenyl)boronic acidHCID 70155224-(Boc-amino)-2-bromopyridine

Product 1

HCID 674696122-(5-Chloro-2,4-difluorophenyl)pyridin-4-amineYield 21.5%

Reagents, catalysts & solvents 4

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

tert-Butyl 2-bromopyridin-4-ylcarbamate (258 mg, 0.945 mmol), 5-chloro-2,4-difluorophenylboronic acid (236 mg, 1.228 mmol) and bis(triphenylphosphine) palladium chloride (133 mg, 0.189 mmol) were combined in dioxane (5 mL) and saturated Na2CO3 (0.472 ml, 0.945 mmol). The reaction mixture was heated at 90° C. in an oil bath. After 12 hours, the reaction mixture was cooled, water (10 mL) was added and the reaction mixture was extracted with EtOAc (100 mL, 2×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid was added (4 mL). The reaction was stirred at room temperature for 20 minutes then the solvent was removed on a rotavap and the residue was further dried under high vacuum overnight. This residue was purified by NH column chromatography, eluted with EtOAc in Hexanes (0-100%) to give the title compound (49 mg) as white solid. ESI-MS: m/z 242.0 (M+H).

Workup

  1. temperaturethe reaction mixture was cooled
  2. extractionthe reaction mixture was extracted with EtOAc (100 mL, 2×)
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a residue
  8. customthe solvent was removed on a rotavap
  9. customthe residue was further dried under high vacuum overnight
  10. customThis residue was purified by NH column chromatography
  11. washeluted with EtOAc in Hexanes (0-100%)

Sources & evidence

ORD record
ord-ccee064e0c5e42d7b99cb1181d9941db
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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