Hydrochloric Acid → 3-(2-Chloro-pyridin-4-yl)-3-(5-difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3H-isoindol-1-ylamine

HRID 1662217Notes

Reaction equation

HRID 1662217 reaction equation
C([Li])CCC.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH:15]([F:17])[F:16])=[C:9]([CH3:18])[CH:8]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[C:41]#[N:42])=[N:27]S(C(C)(C)C)=O)[CH:23]=[CH:22][N:21]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.CO.ClCCl>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]2([C:7]3[CH:8]=[C:9]([CH3:18])[C:10]([O:14][CH:15]([F:17])[F:16])=[C:11]([CH3:13])[N:12]=3)[C:34]3[C:35](=[C:36]([F:40])[CH:37]=[CH:38][CH:39]=3)[C:41]([NH2:42])=[N:27]2)[CH:23]=[CH:22][N:21]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 585795136-Bromo-3-difluoromethoxy-2,4-dimethyl-pyridineHCID 76821601N-[(2-Chloropyridin-4-yl)(2-cyano-3-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamideHCID 178418339Butyllithium

Product 1

HCID 585795123-(2-Chloro-pyridin-4-yl)-3-(5-difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3H-isoindol-1-ylamineYield 36%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

n-Butyllithium (2.5 M in hexane, 0.144 mL, 0.36 mmol) was added dropwise to a solution of 6-bromo-3-difluoromethoxy-2,4-dimethyl-pyridine (0.29 g, 1.15 mmol) in dry THF (1 mL) at −78° C. The reaction mixture was stirred for 5 minutes and a solution of N-[(2-chloro-4-pyridyl)-(2-cyano-3-fluoro-phenyl)methylene]-2-methyl-propane-2-sulfinamide (0.28 g, 0.77 mmol) in dry THF (1 mL) was added dropwise at −78° C. The stirring was continued for 1 hour, a solution of HCl in CH3OH (1.25M, 1.1 mL) was added dropwise at −78° C. and the mixture was allowed to warm slowly to room temperature and stirred overnight. Dichloromethane (20 mL) and saturated sodium bicarbonate solution (50 mL) were added and the phases separated. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 5% CH3OH in DCM to afford the title compound (120 mg, 36%).

Workup

  1. waitThe stirring was continued for 1 hour
  2. stirringstirred overnight
  3. customthe phases separated
  4. washThe organic layer was washed with H2O
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-cd31d931946f4422bf702b5f7f95a99e
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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