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

HRID 1662213Notes

Reaction equation

HRID 1662213 reaction equation
C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[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]4[CH2:15][CH2:14]4)[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 457878654-Bromo-2-cyclopropylpyridineHCID 76821597N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamideHCID 178418306HCID 178418306, compound

Product 1

HCID 585794871-(2-Bromopyridin-4-yl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amineYield 45.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-100 °C

Procedure

Under an atmosphere of argon, tert-butyllithium (1.7 M in pentane) (0.576 mL, 0.98 mmol) was added dropwise to anhydrous tetrahydrofuran (4.00 mL) at −100° C. 4-Bromo-2-cyclopropylpyridine (0.097 g, 0.49 mmol) in anhydrous THF (2.00 mL) was added dropwise to the mixture. The solution was stirred for 2 minutes before dropwise addition of a solution of N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.200 g, 0.49 mmol) in anhydrous THF (2.00 mL). The reaction was stirred at −100° C. for 20 minutes, then the temperature was raised to −78° C. over a period of 10 minutes. The reaction was stirred at −78° C. for another 60 minutes. MeOH (2.0 mL) was added dropwise at −78° C. followed by hydrogen chloride (1.25 M in methanol) (1.176 mL, 1.47 mmol). The cooling bath was removed and the reaction was left to stir at ambient temperature for 60 minutes. The solvents were evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (×2), the organics were combined, dried (Na2SO4), filtered and evaporated. Purification by silica chromatography using 0 to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (0.094 g, 45%).

Workup

  1. temperaturethe temperature was raised to −78° C. over a period of 10 minutes
  2. stirringThe reaction was stirred at −78° C. for another 60 minutes
  3. customThe cooling bath was removed
  4. waitthe reaction was left
  5. stirringto stir at ambient temperature for 60 minutes
  6. customThe solvents were evaporated
  7. customthe residue was partitioned between EtOAc and saturated aqueous NaHCO3
  8. extractionThe aqueous layer was extracted with EtOAc (×2)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated
  12. customPurification by silica chromatography

Sources & evidence

ORD record
ord-1364d301fcab4396b1f9e25e005db769
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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