Hydrochloric Acid → 1-(3-Bromophenyl)-1-(2-(difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine

HRID 1662187Notes

Reaction equation

HRID 1662187 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 58579486HCID 58579486, compoundHCID 593275464-Bromo-2-(difluoromethyl)-6-methylpyridineHCID 178418339Butyllithium

Product 1

HCID 585795231-(3-Bromophenyl)-1-(2-(difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amineYield 12%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

n-Butyllithium (0.359 mL, 0.90 mmol) was added to 4-bromo-2-(difluoromethyl)-6-methylpyridine (166 mg, 0.75 mmol) in THF (5 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 30 min before (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (335 mg, 0.82 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. The reaction was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine and concentrated in vacuo. The residue was dissolved in methanol (2.0 mL) and then hydrochloric acid (2.0 M in diethyl ether, 0.393 mL, 0.79 mmol) was added at room temperature. The mixture was stirred over night and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (saturated) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane gave the title compound 40 mg (12%). MS (ES+) m/z 446, 448 [M+1]+.

Workup

  1. additionwas added
  2. customto reach room temperature
  3. customThe reaction was quenched with water
  4. extractionextracted with ethyl acetate (×3)
  5. washThe combined organic layers were washed with brine
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in methanol (2.0 mL)
  8. concentrationconcentrated in vacuo
  9. customThe residue was partitioned between aqueous sodium bicarbonate (saturated) and ethyl acetate (×3)
  10. dry with materialThe combined organic layers were dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-9c87812d0ed543ffa6d16842797e503e
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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