Hydrochloride methanol → 1-(3-Bromophenyl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine

HRID 1662186Notes

Reaction equation

HRID 1662186 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:18]=[C:19]([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:21][CH:22]=1.Cl.CO>O1CCCC1.CO>[Br:16][C:17]1[CH:18]=[C:19]([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:21][CH:22]=1

Participants

7

Reactant 4

HCID 21893726Hydrochloride methanolHCID 457878654-Bromo-2-cyclopropylpyridineHCID 76821598N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamideHCID 178418306HCID 178418306, compound

Product 1

HCID 593275531-(3-Bromophenyl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amineYield 38.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-112.5 °C

Procedure

Under an atmosphere of argon, tert-butyllithium (0.731 mL, 1.24 mmol) was added drop wise over 3 minutes to tetrahydrofuran (5 mL) in a flask cooled in a liquid nitrogen-pentane bath at an external temperature between −105 to −120° C. To the solution was added drop wise over a period of 6 minutes 4-bromo-2-cyclopropylpyridine (123 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL). The solution was stirred for 4 minutes before drop wise addition of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (253 mg, 0.62 mmol) dissolved in anhydrous tetrahydrofuran (2 mL) over a period of 10 minutes. The reaction mixture was stirred at a temperature below −100° C. for 45 minutes. MeOH (5.0 mL) was added at −100° C. and then hydrogen chloride-methanol solution (0.745 mL, 0.93 mmol) was added at −90° C. The reaction was left to stir overnight (17 h) and was allowed to reach ambient temperature. The solvents were evaporated and the residue was partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The organics were combined, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography on silica gel and gave 100 mg (38%) of the title compound. MS (ES+) m/z 422, 424 [M+H]+

Workup

  1. waitThe reaction was left
  2. stirringto stir overnight (17 h)
  3. customto reach ambient temperature
  4. customThe solvents were evaporated
  5. customthe residue was partitioned between EtOAc (25 mL) and saturated aqueous NaHCO3 (25 mL)
  6. extractionThe aqueous layer was extracted with EtOAc (25 mL)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-8105b864aa3a4007a172ec1d37234a25
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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