Hydrochloric Acid → 1-(2-Bromopyridin-4-yl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amine

HRID 1662194Notes

Reaction equation

HRID 1662194 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 585795394-Bromo-2-(difluoromethyl)pyridineHCID 76821597N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamideHCID 178418339Butyllithium

Product 1

HCID 585795001-(2-Bromopyridin-4-yl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amineYield 20.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

n-Butyllithium (2.5 M in hexane) (0.353 mL, 0.88 mmol) was added to 4-bromo-2-(difluoromethyl)pyridine (183 mg, 0.88 mmol) in THF (7 mL) at −78° C. under argon atmosphere. The reaction was stirred for 30 min before N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. Methanol (5 mL) was added followed by hydrochloric acid (1 M in diethylether) (2.204 mL, 2.20 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 20%).

Workup

  1. additionwas added
  2. customto reach room temperature
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. customthe residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate
  5. extractionThe aqueous phase was extracted with EtOAc (×3)
  6. dry with materialThe combined organic phases were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by prep

Sources & evidence

ORD record
ord-62a026e36e4b4dc0a49b6e6a247f0550
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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